Ethnobotany

ETHNOBOTANY
Application of Medicinal Plants
Editors
José L. Martinez
Vice Rectory of Research
Development and Innovation
Universidad de Santiago de Chile
Santiago, Chile
Amner Muñoz-Acevedo
Chemistry and Biology Research Group
Department of Chemistry and Biology
Universidad del Norte
Barranquilla, Colombia
Mahendra Rai
Department of Biotechnology
SGB Amravati University
Amravati, Maharashtra, India
p,
p,
A SCIENCE PUBLISHERS BOOK
A SCIENCE PUBLISHERS BOOK
Cover credit: Reproduced by kind courtesy of Prof. Amner Muñoz-Acevedo (co-editor)
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Library of Congress Cataloging-in-Publication Data
Names: Martinez, José L. (José Luis), 1959- editor. | Muñoz-Acevedo,
Amner, editor. | Rai, Mahendra, editor.
Title: Ethnobotany : application of medicinal plants / editors, José L.
Martinez, Amner Muñoz-Acevedo, Mahendra Rai.
Other titles: Ethnobotany (Martinez)
Description: Boca Raton, FL : CRC Press/Taylor & Francis Group, [2018] | "A
Science Publishers book." | Includes bibliographical references and index.
Identifiers: LCCN 2018021988 | ISBN 9781138320666 (hardback : alk. paper)
Subjects: | MESH: Plants, Medicinal | Ethnobotany--methods
Classification: LCC QK99 | NLM QV 766 | DDC 581.6/3--dc23
LC record available at https://lccn.loc.gov/2018021988
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Preface
Ethnobotany is essentially an important branch of plant science, which deals with the study of the relationship
between plants and people. Since time immemorial, people are using plants for food, medicine, shelter and
agriculture. These plants are mostly used by rural and tribal people for their livelihood. Unfortunately, this
traditional knowledge is being lost because it is not being preserved.
The book discusses the current research on ethnobotany and includes the most important investigations
of Latin America, Africa, Asia, Egypt, Europe and other parts of the world, where plants are used as
medicines by people in general and tribes in particular. In fact, this book incorporates important studies
based on ethnobotany of different geographic zones.
More specifically, the book incorporates description about ethnomedicinal plants used in Latin America
since the Latin American ethnobotany is less known beyond South America. This book covers medicinal
and aromatic plants, ethnopharmacology, bioactive molecules, plants used in cancer, hypertension, disorders
of central nervous system, and also as antipsoriatic, antibacterial, antioxidant, antiurolithiatic, etc. Each
chapter has been written by one or more specialists in the concerned topic.
The book would be very useful for a diverse group of readers including plant scientists, pharmacologists,
clinicians, herbalists, natural therapy experts, chemists, microbiologists, NGOs and those who are interested
in traditional therapies. The students should find this book useful and reader friendly.
José L. Martinez
Amner Muñoz-Acevedo
Mahendra Rai
Contents
Preface iii
Section I: Applications of Ethnomedicinal Plants

1. Some Medicinal and Aromatic Plants Used for the Treatment of 3
Cancers/Tumors, with Special Reference to Its Scientific Validations
Amner Muñoz-Acevedo, María C. González, Sandra M. Rodríguez,
Martha Cervantes-Díaz and Carlos E. Díaz
2. Use of Ethnomedicinal Herbs to Treat and Manage Schistosomiasis in Zimbabwe: 35
Past Trends and Future Directions
Alfred Maroyi
3. Ethnobotany: Medicinal Plants Used in the Management of Hypertension 47
Patricia Landazuri, Nelsy Loango Chamorro and Beatriz Restrepo Cortes
4. Plants Used for Central Nervous System Disorders by Brazilian Indians 56
Priscila Yazbek, Thamara Sauini, Fernando Cassas, Giuseppina Negri and Eliana Rodrigues
5. Ethnobotanical Retrospective and Features of the Multipurpose Plant 69
Genipa americana L. (Rubiaceae)
Kyria Cilene de Andrade Bortoleti, Roberta Lane de Oliveira Silva, Silvany de Sousa Araújo,
Ana Christina Brasileiro-Vidal and Ana Maria Benko-Iseppon
6. Paramela (Adesmia boronioides Hook. f.): From Popular Uses to Commercialization 89
Silvia B. González, Ana H. Ladio, Bruno Gastaldi, Fresia M. Silva Sofrás,
Ariel Mazzoni and Gustavo Sánchez
7. The Genus Vismia: Geographical Distribution, Chemical Composition and 105
Recent Biological Studies
Janne Rojas and Alexis Buitrago
8. Curcuma longa L.: From Ethnomedicinal to Novel Biomedical Applications 136
Mahendra Rai, Avinash Ingle, Raksha Pandit, Priti Paralikar, Farkhanda Rehman,
Netravati Anasane, Pramod Ingle and Suneesh Buxy
9. Medicinal Plants of the Khyang Tribe of Bandarban District, Bangladesh 156
Md. Shahadat Hossan, Christophe Wiart, Emratul Jannat, Abu Hanif, Prozzal Roy,
Taufiq Rahman, Rownak Jahan, Tracey D. Bradshaw and Mohammed Rahmatullah
10. Management of Cardiovascular Diseases and Related Complications Using 177
Traditional Herbs and Spices
Kavisha Mooroteea and Fawzi Mahomoodally
11. Use of Ethnomedicinal Plants in Primary Health Care 189
Nélida Soria Rey
vi Ethnobotany: Application of Medicinal Plants
12. Secondary Metabolites of Some Ethno-medicinal Plants of Arunachal Pradesh, India 202
Pallabi Kalita Hui, Debmalya Das Gupta and Hui Tag
13. Characterization and Purification of Antiurolithiatic Metabolites from Medicinal 217
Plants
Ankit S. Kale, Anita S. Patil, Hariprasad Paikrao and Surendra R. Patil
Section II: Ethnopharmacology

14. In Vitro Experimental Design and Data Analysis in Ethnopharmacology 233
Raúl Vinet, Marcela Knox, Marcos Lorca-Morales, Claudio Laurido and José Luis Martínez
15. Insights into the Ethnopharmacological Uses of Rutaceae: A Golden Source for Many 240
Pharmaceutical Preparations
Dalia I. Hamdan, Fadia S.Youssef, Mohamed L. Ashour and Assem M. El-Shazly
16. Pharmacological Properties of Extracts and Compounds Isolated from 271
Platonia insignis Mart.—A Perspective for Developing Phytomedicines
Antonio do Nascimento Cavalcante, Chistiane Mendes Feitosa, Layana Karine Farias Lima,
Ronaldo dos Santos Sousa Júnior and Ana Gabriela Sousa Alencar
Index 285
Editors Biography 287
Section I
Applications of Ethnomedicinal
Plants
1
Some Medicinal and Aromatic Plants
Used for the Treatment of Cancers/
Tumors, with Special Reference to
Its Scientific Validations
Amner Muñoz-Acevedo,1,* María C. González,1 Sandra M. Rodríguez,2
Martha Cervantes-Díaz3 and Carlos E. Díaz 4
Introduction
Cancer is one of the main diseases causing morbidity/mortality (second cause of death) in the world and
the main factor considered for its development/progression/death is heredity, though other factors could
also contribute significantly (e.g., behavioral, labor and dietary risks, and viruses). For this reason, a timely
cancer diagnosis is required in order to receive the adequate treatment, e.g., radiotherapy, chemotherapy,
and surgery, or combination thereof, which are the most frequent therapeutical alternatives. If the cancer
is detected and treated early, it has a high cure rate. Based on the statistical data recorded up to 2014,
ca. 14 million of people were diagnosed, ca. 8 million of them died, and it is expected to increase ca. 19
million of people diagnosed for 2024. The cancers that produced the most deaths were lung cancer, liver
cancer, colorectal cancer, stomach cancer, and breast cancer; it is very important to emphasize that cancer
mortality is higher in men than in women (1.4 men/1 woman).
Since 1995 until 2017, the most prestigious multinational pharmaceutical companies (e.g., Novartis,
Bristol-Myers Squibb, Boehringer Ingelheim, Bayer HealthCare, etc.) have registered ca. 215 drugs for
treatment of cancer and palliative care in the U.S. FDA agency, which has approved them for marketing.
Despite this, the pharmaceutical industries are in a search of new drugs for the treatment of cancer,
with highest effectiveness, and lowest toxicity and side effects; some active pharmaceutical ingredients
1
Chemistry and Biology Research Group, Department of Chemistry and Biology, Universidad del Norte, Barranquilla,
Colombia.
2
Economic Analysis Group, Caribbean Economic Studies Institute - Department of Economy, Universidad del Norte, Colombia.
3
Environmental Research Group for Sustainable Development, Environmental Chemistry Faculty, Universidad Santo Tomás,
Bucaramanga, Colombia.
4
Photochemistry and Photobiology Research Group, Department of Chemistry, Universidad del Atlántico, Barranquilla,
Colombia.
* Corresponding author: amnerm@uninorte.edu.co
4 Ethnobotany: Application of Medicinal Plants
(f.i., afatinib, belinostat, cabozantinib, eribulin, nivolumab, etc.) obtained by means of chemical synthesis
have been effective for treatment of some types of cancers. Besides producing synthetic drugs, some
biologically active molecules (e.g., etoposide, teniposide, topotecan, irinotecan, paclitaxel, and vinblastine/
vincristine) against cancer have also been isolated from plants (e.g., Podophyllum peltatum, Camptotheca
acuminate, Taxus brevifolia, and Catharanthus roseus) and approved by FDA for use.
In the scientific literature, numerous articles have been published about plants that have presented
cytotoxicity/antiproliferative/antitumor properties on different cell lines, which have proved to be
promising. Nevertheless, some of them were not “medicinal plants”, or if they were medicinal plants
did not have ethnobotanical uses for treatment of cancer; thus, the anticancer activity was the result of
“serendipity”. In contrast, other medicinal plants that have been used in ethnomedicine for treatment of
cancer, when they were tested on cancer cell lines did not have any effectivity. Therefore, after a thorough
review of medicinal plants with anticancer/antitumor properties, evidenced in the traditional medicine and
scientifically validated, were selected ca. 49 plants, most of them from the ethnobotanical point of view,
were useful to treat cancer in general, whose 50% inhibition/lethal/effective concentration/dose values
were lower than 10 µg/mL or 10 mM.
Finally, the patent analysis related to the development of anticancer/antitumor drugs from the
plants selected allowed to establish that the highest number of patents by plant was for Solanum lyratum
(56 patents), followed by Curcuma longa (54 patents), Marsdenia tenacissima (54 patents), Sarcandra
glabra (44 patents), and Withania somnifera (14 patents). Most of these patents were related to the plant
fractions/extracts (e.g., Annona squamosa, C. longa, M. tenacissima, etc.) and only some patents with
isolated compounds (e.g., saponin mixture from M. tenacissima, etc.).
This chapter will discuss some medicinal/aromatic plants ethnobotanically recognized by their
efficacy for the treatment of cancers/tumors, whose biological properties (e.g., cytotoxicity, antineoplastic,
antiproliferative, and antitumor activities) have been scientifically validated.
Cancer: general aspects

As reported by International Agency for Research on Cancer of World Health Organization in its website
(WHO 2015) “cancer is related to a set of diseases” affecting some organs and tissues, in which cells
constituting them undergo an alteration/modification in the cell cycle causing them to be divided/replicated
without control. The abnormality in cell behavior (cycle altered) is a consequence of changes in genes,
e.g., proto-oncogenes (normal cell growth/division), tumor suppressor genes (control cell growth/division)
(Levine et al. 1983), and DNA repair genes (fixing damaged DNA), which govern the main cell functions.
Therefore, cancer could be the result of a “genetic disease”, and in this way, the modified genes could be
inherited from parents to children. Likewise, there are other factors (besides the genetic) involved with the
development and progression on cancer such as behavioral (tobacco/alcohol abuses, sedentary lifestyles)
and dietary (bad food habits) factors, and environmental (chemical substances/physical exposures) risks.
Cancer is one of the main diseases causing morbidity/mortality (second cause of death) in the world:
in 2015, ca. 9 million of people died, and the most common cancers that were related to death were lung
cancer (~ 1.7 million), liver cancer (788 thousand), colorectal cancer (774 thousand), stomach cancer
(754 thousand), and breast cancer (571 thousand) (MEDS/AHRQ 2014). According to the statistical data
recorded in 2008–2012, the prevalence of cancer by sickness (new cases) and deceases were ca. 455 new
cases/100000 men-women/year and 171 death/100000 men-women/year. In 2014, ca. 14 million of people
were diagnosed and it is expected to increase ca. 19 million for 2024. It is worth highlighting that mortality
by cancer is higher among men (208 death/100000 men) than women (145 death/100000 women).
Africa, Asia, and Central and South America are the most affected regions of the world by this chronic
disease; 70% of deaths occur in the low- and middle-income countries, attributable to that only one in
five countries have necessary data and public programs (advertising and prevention) against the cancer.
In 2010, the total annual cost of this sickness was estimated ca. USD $ 1.2 trillion, converting it into a
disease with a high economic impact for the countries and the world. It is very important to state that
the estimated costs did not include the indirect charges: that is, all the required expenditures (family and
labor budgets, etc.) for patients to participate in the treatment, which can sometimes equalize the direct
Some Medicinal Plants Useful for Cancers/Tumors Treatment 5
costs (Singleterry 2017). One of the reasons for high economic impact is due to the fact that most drugs
available on the market, used for treatment of cancer are very expensive, and these drugs are getting
increasingly costlier as they get more complex; also, the costs for patients are related to both the category
and the spread of treatment. According to the U.S. National Bureau of Economic Research, between 1995
and 2013 the prices of cancer drugs had an increase of 10% per year. Given the steady rise in prices, the
estimates show that payments for drug against cancer could rise from USD $ 100 billion in 2014 to USD
$ 150 billion in 2020 (Goldstein et al. 2016).
Figure 1.1 shows the distribution by the number of cancer deaths (2012) in agreement to gender, types
of cancer (most common), geographic location and the world, based on data of GLOBOCAN 2012 website
(WHO 2015). As can be observed in the figure, there were a significant difference among regions and gender
in the number of deaths by types of cancer, f.i., cancers of liver, stomach, and cervical were highly correlated
to the region-developing level; in the same sense, 19% of deaths of women due to stomach/liver cancers
were in more-developed regions; whilst, 73–81% were in less-developed regions. The highest number of
deaths was related to a higher occurrence of lung cancer, mainly in males; however, two specific cancers
(breast and cervix) for females were the second cause of mortality. It should be noted that colon-rectal and
prostate cancers were persistent (prevailed), regardless of the regions (less-developed/more-developed,
except the America-region), indicating the aggressiveness of these types of cancers. For the year 2016
(based on U.S.A. National Cancer Institute website) (NCI 2017) the most common cancers were projected
as: breast cancer, lung and bronchus cancer, prostate cancer, colon and rectum cancer, bladder cancer,
melanoma of the skin, kidney and pelvis cancer, leukemia, endometrial cancer, and pancreatic cancer.
1200
1099
1000
800
682
600 521 522 522

491
441
374
400 320 324 324 307
281 254 266
224 198 230
182 186 165
200 149
113
35 43
0
Men Women Men Women Men Women Men Women Women Women Men
Lung Liver Colorectal Stomach Breast Cervix Prostate
World More developed regions Less developed regions WHO Americas region (PAHO)
Fig. 1.1
Source: Data were taken of GLOBOCAN 2012 website (WHO 2015). Graph elaborated by authors.
Text mining about cancer, medicinal plants and scientific validation

Through a preliminary review of some medicinal plants/species, whose anticancer/antitumor properties
(evidenced in traditional medicine) have been scientifically validated, 157 species/plants were identified;
and based on these medicinal plants a search equation was structured into the Scopus database including
title-abs-key, doctype and pubyear > 1999. In correspondence, 2156 registers were found. Frequency of
publication monitored, in agreement to the numbers of articles/year concerning individual/specific medicinal
plants reported with ethnobotanical information and effectiveness for the treatment of cancers/tumors,
together with scientific validation, is shown in the Fig. 1.2. Based on the timeline selected (2000–2017),
since 2000 an exponential growth in the register numbers on this theme was observed, 2012–2015 being
250
30 00
Y = 610.96e0.1389x
25 00 R2 = 0.983
20 00
200
15 00
10 00
500
Number of records
150
0
0 2 4 6 8 10 12
100
50
0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Series 1 36 52 52 65 72 78 96 113 103 117 147 149 189 205 196 204 168 69
Fig. 1.2
Source: Bibliometry Unit – CRAI-Library, Universidad Santo Tomás (Bucaramanga). Calculations based on Scopus information
(Elsevier, B.V., 2017), processed with VantagePoint software (VP Student, Search Technology).
the years with the highest article production with 189–204 records. With the aid of De Solla Price’s Law1
(De Solla Price 1963) it was possible to estimate during this period, the growth rate (percentage value/
year) of the articles related to this subject, which was 14.9%/year.
Pursuant to the search equation preceding it was also found that the most studied plants related
to anticancer properties (against more than five types of cancers) have been C. longa (444 articles),
V. album (428 articles), A. vera (134 articles), C. roseus (96 articles), U. dioica (52 articles), and A. muricata
(51 articles). In the same way, the main types of cancers examined, in agreement to the numbers of
registers found (from highest to lowest), were: breast cancer, colon cancer, lung cancer, prostate cancer,
colorectal cancer, etc. with 272 records, 86 records, 76 records, 76 records, 75 records, etc., respectively.
A correlation matrix was constructed (Fig. 1.3), based on the previous search equation, to establish the
relationships between 157 medicinal plants and the different types of cancers. The figure shows that breast
cancer was mainly correlated with V. album (101 records), followed by C. longa (51 records), and A. vera
(27 records); similarly, C. longa (37 registers), along with V. album (13 registers), and A. vera (8 registers)
were correlated with colon cancer, predominantly.
Traditional drugs used as therapeutical agents against cancer

Since 1995 until 2017, the most recognized multinational pharmaceutical companies have registered ca.
215 drugs for treatment of cancer and palliative care in the U.S. Food and Drug Administration (FDA)
agency, who has approved them for use and marketing (FDA 2017). In spite of these achievements, the
pharmaceutical industries are in continuous search of new drugs for the treatment of cancer, with highest
effectiveness, and lowest toxicity and side effects. Besides producing synthetic and hemisynthetic drugs,
some biologically active molecules against cancer have also been isolated from plants and approved by
FDA, e.g., etoposide (1) and teniposide (2) (both compounds isolated from Podophyllum peltatum extract)
(Damayanthi and Lown 1998) are the active ingredients of two drugs with the trade names of Etopophos®,
1
De Solla Price’s Law results from the observation of the growth in the number of science papers published. As has been
observed—with reliable records since the 18th century-, scientific articles have an almost constant growth rate, taking into
account both the set of science publications in all disciplines considered as a whole, and the one of each discipline separately.
90
80
70
60
50
40
30
20
10
Curcuma longa L
0
r Viscum album
ce er r Aloe vera
c an anc ce cer er
n r Tripterygium wilfordii
st n c ca an nc ce er r
ea lo te l c ca an nc ce er r Urtica dioica
Br co sta cta ng s c ca an nc ce er er
o re lu ea ry h c ca an nc nc er r Jatropha curcas L.
Pr olo r a c ix c a c e r
c nc ov ma erv ver in c k ca can anc nce ain Taxus brevifolia
pa o c li sk ec er c a p er r
st ne n dd uth y c cer nc ce r Acorus calamus
e
ir
n d la o n e n l ca can nce ter er r
ut m kid ca ica a n
a b s c ce an
c ce er
ad v
er hag ria
u n
er ic c an anc
he C p a n c t c
s id c
o v a a u
es O c re er o
nc ut thyr
Pa
Fig. 1.3
Source: Bibliometry Unit – CRAI-Library, Universidad Santo Tomás (Bucaramanga). Calculations based on Scopus information
(Elsevier, B.V, 2017), processed with VantagePoint software (VP Student, Search Technology).
and Vumon®, respectively; the camptothecin derivatives, topotecan (3) and irinotecan (4), isolated from
Camptotheca acuminata (trade names Hycamptin® and Camptosar®).Two of the most important and
successful examples are paclitaxel (5) (taxol®) and vinblastine (6)/vincristine (7) alkaloids (velban®/
oncovin®) (Breza et al. 1975) isolated correspondingly, from Taxus brevifolia, and Catharanthus roseus.
These two drugs are used for treatment of several cancers: taxol® is applied to treat the cancers of breast,
lung, cervical, and pancreatic, and sarcoma, etc.; velban®/oncovin® is used for leukemia, neuroblastoma,
melanoma, lymphoma, and lung cancer, etc.
Scientific validation of medicinal plants ethnobotanically recognized by

their effectiveness for the treatment of cancers/tumors
In the scientific literature, numerous articles have been published about plants that have presented
cytotoxicity/antiproliferative/antitumor properties on different cell lines, which have proved to be
promising (Réthy et al. 2007, Cates et al. 2013, Ravipati et al. 2013). Nevertheless, some of them were
not “medicinal plants”, or if they were medicinal plants did not have ethnobotanical uses for treatment of
cancer (Mena-Rejón et al. 2009); thus, the anticancer activity was the result of a “serendipity”. In contrast,
other medicinal plants that have been used in ethnomedicine for treatment of cancer, when these plants
were tested on cancer cell lines did not have any effectivity (Alonso-Castro et al. 2011, Schmidt and Cheng
2017). This document dealt with some medicinal plants ethnobotanically recognized by their efficacy for
the treatment of cancers/tumors, whose biological properties have been scientifically validated. Table 1.1
contains a list of 49 medicinal plants used for the treatment of cancer/tumor along with forms evaluated of
plant preparations and cell lines tested. Additionally, the discussion about anticancer/antitumor properties
of plants listed was carried out principally based on type(s) of extract(s) or active compound(s) isolated,
cell line(s) tested, assay(s) used, and 50% inhibitory concentration (IC50), 50% lethal dose (LD50), 50%
effective dose (ED50), 50% lethal concentration (LC50) or 50% growth inhibition (GI50) values calculated,
lower than 10 µg/mL or 10 mM.
Ten diarylheptanoid compounds isolated from A. japonica bark were tested on four cell lines. The IC50
values obtained by MTT method applied on each cell line were between ~ 17–76 µM for B16, ~ 28–55 µM
for SNU1, ~ 48–102 µM for SNU354, and ~ 45–320 µM for SNUC4. In the case of B16 melanoma and
SNU1 carcinoma, the most active compounds were 8 (IC50 ~ 17 µM) and 9 (IC50 ~ 17 µM), respectively.
Platyphylloside (8) was the compound with lowest IC50 values on SNU354 (IC50 ~ 48 µM) and SNUC4
(IC50 ~ 45 µM) (Choi et al. 2008). One of the main antraquinones [aloe-emodin (10)] constituent of
A. vera was assessed on cell lines of neuroblastoma and Ewing’s sarcoma. The neuroectodermal tumor cells
were specifically inhibited in growth by 10 and ED50 (equivalent to IC50) values were ~ 1 µM, ~ 7 µM, and
~ 13 µM, respectively, for neuroblastoma, pPNET, and Ewing’s sarcoma (Pecere et al. 2000). The cytotoxic
effects of a solid residue obtained of hydroalcohol extract from A. scholaris stem bark were determined
on three cell lines. The IC50 values were ~ 6 μg/mL (HeLa cells), 10 μg/mL (KB line) and ~ 11 μg/mL
(HL60 cells) (Jagetia and Baliga 2016).
A plant studied in almost all continents is A. muricata, whose ethnobotany always has been related
to antitumoral/anticancer properties. According to a review by Coria-Téllez et al. (2017), six types of
acetogenins have been isolated from different parts of the plant; and, these molecules are responsible for
the extraordinary effectiveness against cancers. Wu et al. (1995) isolated annomuricins A (11) y B (12)
from plant leaves. These acetogenins showed remarkable antiproliferative capacities when tested on A549
and HT29 cell lines by means of MTT method. The ED50 value for 11 was 3.3 x 10–1 µg/mL on A549
cells; whilst, for 12, the ED50 values were 1.6 x 10–1 µg/mL (on A549 line) and 4.4 x 10–1 µg/mL (on HT29
cells). Zeng et al. (1996) isolated annopentocins A-C 13–15 and a mixture of cis- and trans-annomuricin-
D-ones (16–17) from plant leaves. The antineoplastic screening of these compounds was carried out on six
cancer lines, resulting in significant effects on all lines; thereby, for 13, ED50 values were between
~ 3.6 x 10–2 µg/mL – ~ 18 µg/mL, with PaCa2 line being the most sensitive; for 14 and 15, ED50 values
were between ~ 2.1 x 10–2 µg/mL – ~ 3.6 µg/mL, being A549 line the most susceptible for both compounds;
and for the mixture 16 and 17, ED50 values were between < 10–2 µg/mL – ~ 1.3 µg/mL, being the most
injured cell lines the A549, HT29 and PaCa2 (ED50 < 10–2 µg/mL).
To end with the Annona species, Li et al. (1990) studied the bark from A. squamosa. They isolated
three acetogenins (bullatacin 18, bullatacinone 19 and squamone 20), which resulted to be highly efficacious
against A549, MCF7 and HT29 cell lines (by MTT method). The effectivity order on: (1) HT29 was 18
(< 10–12 µg/mL) > 19 (< 10–3 µg/mL) > 20 (~ 2 µg/mL); (2) A549 was 18 (~ 9 x 10–12 µg/mL) > 19
(~ 1.4 x 10–4 µg/mL) > 20 (~ 1 µg/mL); and (3) MCF7 was 19 (< 10–7 µg/mL) > 20 (~ 2 µg/mL) > 18
(> 10 µg/mL). Chen et al. (2012) isolated some acetogenins (annosquacins A-D, and annosquatins A and
B) from fruit seeds, which were screened to estimate of cytotoxic potential against six cancer cells by MTT
method. The six acetogenins were able to powerfully inhibit the growth of all cancer cells, with IC50 values
between ~ 6 x 10–2 µg/mL – ~ 5 µg/mL. The most effective acetogenins with lower IC50 values ranged
Table 1.1. Medicinal plant list with ethnobotanical uses for treatment of cancers/tumors (without specificity on a kind of cancer/tumor) along with types of plant preparations evaluated and
cell lines tested.
Species Ethnobotanical Ref. Plant preparation form; Type of cell lines Ref.
use
Alnus japonica (Thunb.) Anticancer Choi et al. 2008 Isolated compounds (10 diarylheptanoids); B16, SNU1, SNU354 and Choi et al. 2008
Steud. SNUC4 cell lines.
Aloe vera (L.) Burm. f. De Melo et al. 2011 Commercial compound (aloe-emodin 10), IMR32, IMR5, AF8, SJNPK, Pecere et al. 2000
pPNET (TC32) and TC106 cell lines.
Alstonia scholaris (L.) R. Ahmed et al. 2001 Solid residue/hydroalcohol extract; HeLa, HL60, and KB cell lines. Jagetia and Baliga 2016
Br.
Annona muricata L. Gavamukulya et al. Isolated compounds (acetogenins); PC3, A549, MCF7, A498, HT29 and Wu et al. 1995, Zeng et al. 1996
2014, Coria-Téllez et MIA PaCa2 cell lines.
al. 2017
Annona squamosa L. Antitumor Li et al. 1990 Isolated compounds (acetogenins); A549, MCF7, HeLa, HepG2, Li et al. 1990, Chen et al. 2012
SMMC7721, MKN45 and HT29 cell lines.
Aspidosperma polyneuron Anticancer Oliveira et al. 2009 Isolated compound (aspidospermine 21), HepG2 line cell. Coatti et al. 2016
Mull.
Boswellia carteri Birdw. Antitumor Zhao et al. 2003 Isolated compounds (boswellic acid acetates); KB, HCT8, B16F10, A2780 Zhao et al. 2003
and HT1080 cell lines.
Calendula officinalis L. Anticancer De Melo et al. 2011 Isolated compound [triterpene glycoside compounds (oleananes)]; human Ukiya et al. 2006, De Melo et al.
cancer cell line panel. 2011
Commiphora myrrha Nees Antitumor Su et al. 2011 Residual hydroalcohol extract/petroleum ether fraction/isolated compounds; Su et al. 2011
A2780, SKOV3 and Shikawa cell lines.
Cuphea aequipetala Cav. Anticancer Vega-Ávila et al. 2004 Acetone:water extract; HCT15 and DU145 cell lines. Vega-Ávila et al. 2004
Curcuma longa L. Antitumor Desai et al. 2008 Isolated curcumin (28); CHO and Dalton’s lymphoma cell lines. Kuttan et al. 1985, Naama et al.
Alcohol extract/isolated 28; hepatocellular carcinoma. 2010
Curcuma mangga Valeton Anticancer Malek et al. 2011 Hexane/ethyl acetate extracts/isolated compound (2 labdanes); MCF7, KB, Malek et al. 2011, Widowati et al.
& Zijp. A549, Ca Ski, HCT116 and HT29 cell lines. 2013
Davallia divaricata Blume Monteiro et al. 2014 Isolated compound (davallic acid 31); A549 cell line. Cheng et al. 2012
Dendropanax morbifera Kim and Song 2011 Isolated compound (32); MG63, T98G and Hep3B cell lines. Lee et al. 2013
Lev.
Echinops grijisii Hance Antitumor Lin and Lin 1993 Isolated tiophenes/bithiophenes; HL60 and K562 cell lines Zhang et al. 2009
Table 1.1 contd.…
…Table 1.1 contd.
Species Ethnobotanical Ref. Plant preparation form; Type of cell lines Ref.
use
Epipremnum pinnatum (L.) Anticancer Tan et al. 2005 Hexane/chloroform extracts; T47D cell line. Wong et al. 1996b, Tan et al. 2005,
Engl. Isolated compound (5,6-dihydroxyindole 35); P388 cell line. 2007
Erigeron annuus (L.) Pers. Kim and Song 2011 Hexane/chloroform/50% methanol/aqueous fractions; HeLa, MCF7 and Réthy et al. 2007
A431 cell lines.
Euonymus alatus (Thunb.) Antitumor Kim and Song 2011 Methanol extract; SKBR3 cell line Park et al. 2005
Fissistigma oldhamii Merr. Anticancer Wu et al. 1993 Isolated compounds (aporphine alkaloids); A549, HCT8, P388, KB, L1210, Tzeng et al. 1990, Wu et al. 1993
CCRFCEM and HL60 cell lines.
Glochidion zeylanicum Sultana et al. 2014 Aqueous extract; HepG2 and HT29 cell lines. Sharma et al. 2011
(Gaertn.)
Heterostemma brownii Antitumor Lin et al. 1997 Isolated compounds (heteromines A/B 39/40); HCE6, Molt4, HL60 and Lin et al. 1997
Hayata. K562 cell lines.
Himatanthus sucuuba Sp. Perdue and Blomster Isolated compounds (iridoid lactones); KB cell line and 3T3 cells. Castillo et al. 2007
(M.Arg.) 1978
Kigelia africana (L.) Arkhipov et al. 2014 Methanol/ethanol extracts; SKW3 and MCF7 cell lines, and LLC bearing Momekova et al. 2012
Benth. BDF1 mice.

Marsdenia tenacissima Luo et al. 1993 Extract/isolated compounds; NSCLC and HepG2/Dox cell lines. Hu et al. 2008, Han et al. 2012,
(Roxb.) Wight et. Arn. 2014, 2015
Maytenus blepharodes Anticancer Gupta et al. 1996 Isolated compounds (three phenolic triterpenes); HeLa cell line. Rodríguez et al. 2005
(Pitt.)
Maytenus emarginata Antitumor Sagwan et al. 2011 Ethanol extract/chloroform/chloroform:methanol/ethyl acetate:acetone Ling et al. 1981, Kuo et al. 1989,
(Willd.) Ding Hou fractions/isolated compounds (49–53); six cell lines. 1990, 1994a,b
Melia azadirachta L. Antitumor Jain and Tarafder 1970, Ethyl acetate fraction, ethanol extract/isolated compounds (limonoids); Cohen et al. 1996, Roy et al. 2007,
Paul et al. 2011 HL60, AZ521, A549, SKBR3 and B16 cell lines. Harish Kumar et al. 2009,
Supercritical extract/three fractions; LNCaP-luc2 and PC3 cell lines. Priyadarsini et al. 2010, Babykutty
Isolated compounds (mainly nimbolide 69); N1E115, 143B.TK–, et al. 2012, Elumalai et al. 2012,
RAW264.7, HeLa, BeWo, HCT116, HT29, CaCo2, U937, HL60, TPH1, Pan et al. 2014, Takagi et al. 2014,
MDAMB231, WiDr and B16 cell lines. Wu et al. 2014
Nandina domestica Thunb. Iwasa et al. 2008 Isolated compound (nandsterine 74); HL60 cell line. Peng et al. 2014
Panax ginseng C.A. Mey. Anticancer Wang et al. 2007, Isolated saponins; A549, H1299, H838, H358, LNCaP, PC3, MCF7, Wang et al. 2007
Sultana et al. 2014 MDAMB468, HPAC, Panc1, T98G and A172 cell lines.
Petiveria alliacea L. Mena-Rejón et al. 2009 Aqueous decoction; IM9, Daudi, Molt4 and K562 cell lines. Rossi et al. 1990, 1993, Jovicevic
et al. 1993
Pfaffia paniculata Kuntze Li et al. 2009 Isolated compound (pfaffic acid 78); B16, HeLa (S3) and LLC lines. Takemoto et al. 1983
Physalis peruviana L. Anticancer Arbiastutie et al. 2017 Ethanol extract; Saos2 and Hep3B cell lines. Yen et al. 2010, Demir et al. 2014
Isolated compound (4βHWE 79); H1299 cell line.
Rhaphidophora korthalsii Wong and Tan 1996a Petroleum ether extract; P388, Molt4, KB and SW620 cell lines. Wong and Tan 1996a
Schott
Rhus javanica L. Kim and Song 2011 Ethanol extract; Panc1, SW1990 and Capan1 cell lines. Lau et al. 2008
Rhus verniciflua Stokes Jung et al. 2007 Hexane fraction; A549, SW620, ACHN and Molt4F cell lines. Hong et al. 1999, Kim et al. 2002,
Isolated compounds (80–85); A549, SKOV3, SKOV3/PAX, SKMEL2 and Kim et al. 2015, Choi et al. 2016
HCT15 cell lines.
Isolated compounds (86–89); 29 cell lines.
Rollinia mucosa (Jacq.) Antitumor Gupta et al. 1996 Chloroform:methanol extract/methanol fraction/isolated compounds Shi et al. 1996, 1997, Gu et al. 1997,
Baill. (acetogenins 90–98); A549, MCF7, HT29, A498, PC3 and PaCa2 cell lines, Chávez et al. 1998, 1999, Mata et
and brine-shrimp lethality. al. 2001
Sarcandra glabra (Thunb.) Anticancer Tsui and Brown 1996 Isolated compounds (99–101); HL60 and BGC823 cell lines. Ni et al. 2013, Wu et al. 2015
Nakai
Scutellaria baicalensis Antitumor Scheck et al. 2006 DMSO extract; HL60, NB4, THP1, U937, Blin1, Nalm6, Daudi, Raji, Kumagai et al. 2007, Gao et al.
Georgi Ramos, NCEB1 and NCIH929 cell lines. 2008, Huang et al. 2010, Neves et
Isolated compounds (flavones); nine cell lines. al. 2011, Ji et al. 2015
Selaginella tamariscina Anticancer Kim and Song 2011 Ethyl acetate extract; HeLa, Bel7402 and HT29 cell lines. Li et al. 2014a
(Beauv.) Spring
Solanum torvum Swartz. Arbiastutie et al. 2017 Isolated compound (105); A375 and MCF7 cell lines. Li et al. 2014b, Balachandran et al.
2015
Stephania venosa (Blume) Ethanol extract; NCIH187 cells Niwat et al. 2001, Nantapap et al.
Spreng. CH2Cl2/butanol fractions/compounds 106–111; HeLa, MDAMB231, MCF7, 2010, Leewanich et al. 2011, Le et
K562, K562/Adr, GLC4 and GLC4/Adr cell lines. al. 2017
Tabebuia avellanedae Yamashita et al. 2007, Isolated compounds (112–117); PC3, A549, SiHa and MCF7 cell lines. Yamashita et al. 2007, 2009, Zhang
Lorentz ex Griseb. Sultana et al. 2014 et al. 2015
Tabebuia rosea (Bertol.) Hemamalini et al. 2012 Isolated compounds (112, 118–121); KB and HeLa cell lines. Sichaem et al. 2012
DC.
Tripterygium wilfordii Chen et al. 2008, Yang Isolated compounds (122–131); HepG2, Hep3B, Bcap37, U251, MCF7, Yang et al. 2011, Gao et al. 2016,
Hook. f. et al. 2011 HeLa, A549 and A549T cell lines. 2017, Fan et al. 2016
Viscum album L. Kim and Song 2011 Aqueous extract; SKBR3 cell line. Weissenstein et al. 2016
Withania somnifera L. Sultana et al. 2014 Hydroalcohol extract; A549, MCF7 and PA1 cell lines. Jayaprakasam et al. 2003, Nema et
Dunal. Methanol extract/isolated compounds (132–135); NCIH460, HCT116, al. 2013, Choudhary et al. 2015
SF268 and MCF7 cell lines.
among ~ 6 x 10–2 µg/mL – ~ 5 x 10–1 µg/mL, and ~ 9 x 10–2 µg/mL – ~ 3 x 10–1 µg/mL, were annosquatin
A and annosquacin C, in that order. In the same sense, annosquatin B and annosquacin B were secondary,
with IC50 values between ~ 8 x 10–2 µg/mL – ~ 2 µg/mL and ~ 1 x 10–1 µg/mL – ~ 3 µg/mL, respectively;
and lastly, annosquacins A and D had IC50 values among ~ 4 x 10–1 µg/mL – ~ 4 µg/mL and ~ 3 x 10–1
µg/mL – ~ 5 µg/mL, correspondingly. The most active compounds per each cell line were annosquatin
B (IC50: ~ 8 x 10–2 µg/mL) on A549 cells, annosquacin C (IC50: ~ 3 x 10–1 µg/mL, ~ 1 x 10–1 µg/mL) on
HeLa/HepG2, and SMMC7721 cancer lines; annosquatin A (IC50: ~ 6 x 10–2 µg/mL, ~ 1 x 10–1 µg/mL)
on MCF7 and MKN45 cell lines.
From A. polyneuron roots an indole alkaloid (aspidospermine 21) was isolated which was tested on
HepG2 cells. A concentration of 75 µM of 21 was able to decrease ca. 68% of cell population (Coatti et
al. 2016). Zhao et al. (2003) assayed an isoform mixture [α-(22) and β-(23)] of boswellic acid acetate
(isolated from B. carteri resin) on five cancer lines. According to the authors, the compound mixture
(22 and 23) showed a growth potential inhibition on KB, HCT8, and A2780 cells with IC50 values between
~ 11 µM – ~ 13 µM.
The other well-known plant is C. officinalis, where there are reports on its use for cancer treatment.
One of these reports was prepared by Ukiya et al. (2006), where they isolated two triterpene glycosides
(24 and 25), from the flowers. Compounds 24 and 25 were tested (by SRB method) on a panel of 60
human cancer cell lines (derived of seven types of cancer: lung, colon, melanoma, renal, ovarian, brain
and leukemia). The authors found that 24 showed GI50 values < 10 µM against almost of the cancer cells
tried except for leukemia (CCRF-CEM cells), renal (CAKI-1 and UO-31 lines) and breast (NCI/ADR-
RES cells) cancer lines. In addition, 24 showed the most potent cytotoxicity against leukemia (Molt4 and
RPMI8226 lines), colon (HCC2998 cells), and melanoma (LOX IMVI, SKMEL5 and UACC62 lines)
cells, with GI50 values of ~ 0.8 µM – ~ 1.0 µM. Compound 25 exhibited GI50 values < 20 µM against all
of the cancer cells tested, except for ovarian (IGROV1 cells) and renal (UO31 cells) lines.
A famous herb is Myrrh (C. myrrha, Burseraceae), whose multi-purpose fragrant resin has been used
millennially. Su et al. (2011) reported the evaluation of cytotoxicity effects (by MTT method) against
gynecologic cancer cell lines (A2780, SKOV3, SiHa and Shikawa) of residual hydroalcohol (85%)
extract (RHE), Petroleum Ether Fraction (PEF) and two isolated compounds (26 and 27) from C. myrrha
dried resin. 26 and 27 significantly inhibited the growth of three cell lines; the IC50 values were between
~ 47 µM – ~ 64 µM for 26 and ~ 27 µM – ~ 36 µM for PEF. The most susceptible lines were A2780
(~ 47 µM) for 26, and SKVO3 (~ 27 µM) for 27. A plant used in traditional Mexican medicine, as treatment
of different types of tumors since the prehispanic ages is C. aequipetala (Lythraceae). Vega-Ávila et al.
(2004) studied the cytotoxic potential (ED50) of different fractions from acetone:water (7:3) extract of the
whole plant, using the SRB assay and two cell lines. The ED50 values were ~ 8 µg/mL (DU145 cells) and
~ 19 µg/mL (HCT15 line) for total extract in each cell line. E (yellow powder, constituted by compounds
type flavonoids) and PB1 (solid with a metallic appearance, constituted by compounds type tannins)
fractions, from total extract, presented ED50 values of ~ 0.4 µg/mL and ~ 2.5 µg/mL, respectively.
The rhizome of C. longa (Zingiberaceae), popularly known as turmeric or Indian saffron, has been
applied for cancer prevention/treatment. Kuttan et al. (1985) evaluated in vitro (by using cell culture
of Chinese Hamster Ovary (CHO) line and normal lymphocytes) the anticancer activity of the isolated
curcumin (28) from turmeric rhizome; in a similar manner, 8 µg/mL of 28 showed an effective cytotoxicity
(100% cell death) for normal lymphocytes, and human leukemic cells; while 4 µg/mL of 28 produced the
100% death on Dalton’s lymphoma cells. The in vitro experiments indicated that curcumin was cytotoxic
at concentrations between l µg/mL – 4 µg/mL. Also, Naama et al. (2010) studied the rhizome extract and
isolated curcumin from C. longa of Iraqi origin. The cytotoxic effect of alcohol extract/curcumin from
C. longa was valued against the hepatocellular carcinoma by means of MTT assay. The IC50 values were
0.8 µg/mL and 0.6 µg/mL for total extract and isolated 28, respectively. Other authors have studied the
antineoplastic effect of 28 against different types of cancer/tumor, e.g., breast carcinoma cells, colorectal
cancer cells, gastric cancer, leukemic cell lines, lung squamous cell carcinoma, ovarian cancer cells (Shao
et al. 2002, Shi et al. 2006, Alaikov et al. 2007, Guo et al. 2013, Zhao et al. 2015, Zhou et al. 2017).
C. mangga from Indonesia is a species closely related to C. longa. Malek et al. (2011) investigated the
cytotoxic effects of the methanol extract and the hexane/ethyl acetate fractions from C. mangga rhizome
against six cell lines by using SRB assay. The authors found that methanol extract and the two fractions
showed good cytotoxic effects against the cell lines, whose IC50 values were between 8.1 ± 0.2 µg/mL
and 47.1 ± 0.5 µg/mL. The hexane fraction showed the best antineoplastic effects against the six cancer
lines, with IC50 values among 8.1 ± 0.1 µg/mL (MCF7 line) and 31.5 ± 0.1 µg/mL. Likewise, they isolated
to E-labda-8(17),12-dien-15,16-dial (29) and zerumin A (30), which displayed high cytotoxicity on six
cancer lines. 29 presented IC50 values between ~ 4 ± 1 µg/mL (MCF7 line) – 19.9 ± 0.4 µg/mL; whilst for
30, the IC50 values were among 8.7 ± 0.3 µg/mL (MCF7 line) – 16.2 ± 0.2 µg/mL (Widowati et al. 2013).
D. divaricata (Davalliaceae) is a species from Taiwan, which has been traditionally applied as a
treatment for lung cancer. Cheng et al. (2012) isolated the davallic acid (31) from plant dried rhizome and
evaluated the ability of 31 to inhibit the growth of A549 cells using MTT test. They found that 20 μM of
31 decreased A549 cell viability up to 73% (12 hours) and 57% (24 hours). D. morbifera (Araliaceae) is
an endemic species growing in South Korea and has been used in traditional medicine. Lee et al. (2013)
isolated dendropanoxide (32) from plant dried leaves and assessed the capability of compound 32 to
inhibit the growth of three types of cell lines using MTT assay. The results showed that 40 μM, 50 μM
and 60 μM of compound 32 inhibited the cell growth up to ~ 55% , ~ 60% and ~ 60% on Hep3B, T98G
and MG63 cell lines, respectively.
E. grijisii (Compositae) is a species broadly distributed in China, and it is listed in “Chinese
Pharmacopeia” by its different ethnobotanical uses. Zhang et al. (2009) investigated the cytotoxicity against
two human leukemia cell lines, by using modified SRB method, of seven compounds type “thiophenes/
bitiophenes” isolated from E. grijisii roots. The authors found that all compounds exhibited cytotoxic effects
against the cell lines examined, with IC50 values between ~ 0.2 µg/mL and ~ 17 µg/mL for HL60 cells
and ~ 0.4 µg/mL and ~ 31 µg/mL for K562 cells. The most cytotoxic compound were 33 (IC50~ 0.2 µg/
mL and ~ 0.5 µg/mL) and 34 (IC50~ 0.3 µg/mL and ~ 0.4 µg/mL) for the two cell lines (HL60 and K562).
E. pinnatum (Araceae, common name: Dragon tail plant) has been widely used in Malaysia and Singapore
as a traditional anticancer preparation. Anticancer properties of chloroform/hexane extracts from whole
plants were validated by Tan et al. (2005, 2007) against T47D line using MTS/PMS assay. Thus, the IG50
values were ~ 12 µg/mL (48 hours) and ~ 6 µg/mL (72 hours) for chloroform extract; the IG50 values were
~ 12 µg/mL (48 hours) and ~ 3 µg/mL (72 hours) for hexane extract. Also, Wong et al. (1996b) isolated
35 from R. korthalsii leaves, and determined its antineoplastic capacity against P388 cancer line by MTT
assay. The IC50 value calculated for 35 was of ~ 4 µg/mL.
Regarding E. annuus (Asteraceae), Réthy et al. (2007) screened the in vitro antiproliferative activity
of four types of fractions/extracts from this plant against three cell lines, using the MTT assay. Inhibition
percentage values, from plant root extracts on MCF7 line,were ~ 14 ± 3% – ~ 62 ± 2%, when 10 µg/mL
of each extracts/fractions were tested. The IC50 values calculated for hexane and chloroform fractions
against the three cell lines were ~ 12–13 µg/mL (HeLa line), ~ 6–9 µg/mL (MCF7 line) and ~ 13–20 µg/
mL (A431 line). A traditional Korean medicinal plant used for centuries to treat tumors in Korea and China
is E. alatus (Celastraceae). Park et al. (2005) evaluated the antiproliferative and apoptotic capacities of
methanol extract from plant on SKBR3 cell line by MTT method; the ED50 value was of 6.5 ± 0.3 µg/mL
and the methanol extract induced apoptosis on cancer cells.
F. oldhamii (Annonaceae) is a species used in folk medicine for treatment of tumors in Taiwan and
southern China. Wu et al. (1993) demonstrated the cytotoxicity of xylopine (36) and norannuradhapurine
(37) isolated from plant against four cell lines, by MTT assay. The ED50 values for 36 and 37 were among
~ 2 µg/mL and ~ 3 µg/mL for the four cell lines. Even so, the most sensitive cells were KB and HCT8
to compounds 36 and 37, whose ED50 values were ~ 2 µg/mL and ~ 3 µg/mL, independently. Tzeng et
al. (1990) evaluated the inhibitory effect on growth of three leukemic cell lines, using the MTT method,
of aporphine alkaloids (37 and fissoldine 38) isolated from the plant. The IC50 values of 37 and 38 were
ranged between ~ 3–15 µg/mL (~ 9–35 µM) for the three cell lines. Nonetheless, L1210 and CCRFCEM
lines were the most susceptible cells to alkaloid 37 with IC50 values of ~ 4 µg/mL (~ 9 µM) and ~ 6 µg/
mL (~ 14 µM), correspondingly; whilst the IC50 values of 38 was of 15 µg/mL (~ 35 µM) on HL60 cells.
In the traditional ayurdevic medicine from India, there is a plant called Neeru mamidi [G. zeylanicum
(Euphorbiaceae)], which has been used for the treatment of cancer. Sharma et al. (2011) evaluated the in
vitro cytotoxic activity of aqueous extract from plant roots against two cell lines, by using the XTT method.
The CC50 values were ~ 3 µg/mL and ~ 26 µg/mL, for the HepG2 and HT29 cell lines, respectively. Based
on the folk medicine of Taiwan about the use for treatment of tumors from H. brownii (Asclepiadaceae)
aerial parts, Lin et al. (1997) isolated heteromines A (39) and B (40), which were evaluated against four
cell lines by using the MTT assay. The IC50values for 39 and 40 respectively, on each cell line were
~ 4 µM, ~ 36 µM for HCE6 cells; ~ 14 µM, ~ 52 µM for Molt 4 cells; ~ 7 µM,~ 27 µM for HL60 line;
and, ~ 10 µM, ~ 63 µM for K562 cells. A tree from the Amazon rain forest of Peru, Colombia and Brazil
which has been used in the traditional medicine for treatment of tumors, is H. succuba (Apocynaceae,
common name: “bellaco-caspi”). The first report about scientific validation for the use of this plant to
treat the cancer was published by Perdue and Blomster 1978. The authors isolated to fulvoplumierin (41)
from the plant stem bark after testing a 50% ethanol extract against KB cell line. While Castillo et al.
(2007) studied the cytotoxicity on 3T3 line (using the SRB method) of plumericin (42) and isoplumericin
(43) isolated from the stem bark. The IC50 values determined for 42 and 43 correspondingly, were 2 µM
and 1 µM on cell line. An African plant is K. africana (syn. K. pinnata, Bignoniaceae), whose bark/fruit
have been traditionally used as treatment of neoplastic diseases. Momekova et al. (2012) assessed the
antineoplastic activity on two cell lines, and LLC bearing BDF1 mice from methanol extract of the plant
stem bark. The IC50 values were 10 ± 3 µg/mL (LLC bearing-mice), 12 ± 4 µg/mL (MCF7 cells) and 15
± 3 µg/mL (SKW3 line). Another important plant in the traditional Chinese medicine is M. tenacissima
(Asclepiadaceae), which has been widely used for the treatment of cancers; and, more than decade ago,
its application was approved to treat esophageal, gastric, and lung cancers, and hepatocell carcinoma by
China Food and Drug Administration Office. Some authors have carried out the scientific validations
against different cell lines. Hu et al. (2008) determined that 20 µg/mL of two compounds [tenacissimoside
A (44, eq. 25 µM) and 11α-O-benzoyl-12β-O-acetyltenacigenin B (45, eq. 39 µM)] isolated from the plant
increased the sensitivity of antitumor drugs, e.g., doxorubicin (18-fold and 16-fold), vinblastine (10-fold
and 53-fold), puromycin (11-fold and 16-fold) and paclitaxel (6-fold and 326-fold) by HepG2/Dox cells.
Additionally, other authors like Han et al. (2012, 2014, 2015) studied the synergistic effect between an
extract of plant stem with other drug (e.g., gefitinib) against four non-small cell lung cancer lines. They
found that the mixture (extract + gefitinib) as a therapeutical prepared resulted in a promising therapy to
improve the effectiveness of gefitinib in resistant NSCLC. A species from Panaman flora is M. blepharodes
(Celastraceae), which was studied for its ethnobotanical uses for the treatment of cancer by Rodriguez et
al. (2005). These authors isolated three phenolic triterpenes [7-oxo-blepharodol (46), blepharotriol (47),
and 6-deoxoblepharodol (48)] from the plant bark and assessed the cytotoxicity (by MTT assay) on HeLa
cell line. The IC50 values were ~ 12 µg/mL for 47, ~ 14 µg/mL for 48 and ~ 20 µg/mL for 46.
Ling et al. (1981) reported the potent cytotoxic effect of the ethanol extract from
M. emarginata (Celastraceae) against P388 cell line. Kuo et al. (1989) isolated to emarginatine A (49),
whose ED50 value was of 4 µg/mL on KB cells. Again, Kuo et al. (1990) established the ED50 values
on KB cell line for chloroform, chloroform:methanol and ethyl acetate:acetone fractions along with
emarginatine B (50) isolated from the plant stem, which were respectively, 0.4 µg/mL, 0.08 µg/mL, 0.04
µg/mL, and 0.4 µg/mL. While Kuo et al. (1994a) reported the isolation and the cytotoxicity against KB
cell line of emarginatine E (51) and emarginatinine (52); the ED50 values were 2.5 µg/mL and 2.1 µg/mL,
in that order. In the same year, Kuo et al. (1994b) isolated from the plant stem emarginatine F (53), which
was cytotoxic against six cell lines. The ED50 values for 53 were < 0.1 µg/mL for RPMI7951 cells, 0.2
µg/mL for TE671 line, 0.5 µg/mL for KB cells, 0.7 µg/mL for P388 line, ~ 1 µg/mL for HCT8 cells and
~ 6 µg/mL for A549 line.
A perennial tree (endemic of India, and broadly distributed in Asia, Africa and other continents)
important for the world is M. azadirachta (Meliaceae, syn. Azadirachta indica, common name: Neem), due
to its extraordinary benefits (e.g., for ethnomedicine, agriculture, and domestic uses), and by its proximity
with the cultures and civilization. In Ayurverdic medicine the leaves, bark, fruits, and seed-oil are widely
used for treatment of cancers (Paul et al. 2011). Pan et al. (2014) estimated the cytotoxic effects against
four cell lines of defatted more-polar fraction, and isolated compounds (type limonoids) from plant fruits
by means of the MTT assay. The authors found that the fraction was active on all cell lines with IC50
values of ~ 3 ± 2 µg/mL – 21.9 ± 0.6 µg/mL. From this fraction, they isolated 20 compounds [limonoids
and triterpenoid (e.g., some as 54–61)], which showed some activity against the cancer lines. Thus, 19
compounds were effective on HL60 cells; 14 compounds were active against AZ521 line; nine compounds
inhibited the SKBR3 cell growth; and, three compounds inhibited to A549 cell line. While two compounds
were able to inhibit the four types of cancer cells: 56 and 60 (IC50 5.0 ± 0.9 µg/mL – 82.3 ± 0.3 µg/mL);
whereas four compounds were effective on three cell lines, i.e., 54, 57 and 61 (IC50 4.6 ± 0.6 µg/mL –
~ 54 ± 4 µg/mL), which were inactive on A549 cells, and 55 (IC50 9.9 ± 0.6 µg/mL – ~ 94 ± 1 µg/mL), that
was ineffective on AZ521 line. One compound (58) only was active against HL60 cells, with IC50 value
of 4.9 ± 0.5 µg/mL. The remaining compounds (eight) inhibited two (HL60 and AZ521) of the four cell
lines; the IC50 values were ranged among 2.8 ± 0.6 µg/mL – ~ 83 ± 1 µg/mL. As endpoint, the most active
compounds against the cell lines were 59 (IC50 2.8 ± 0.6 µg/mL, on HL60 cells; IC50 3.2 ± 0.6 µg/mL,
on AZ521 line), 56 (IC50 ~ 15 ± 2 µg/mL, on SKBR3 cells) and 60 (IC50 ~ 26 ± 2 µg/mL, on A549 line).
Takagi et al. (2014) also evaluated the cytotoxicity on five cell lines, of some isolated compounds
(type limonoids) from the ethyl acetate fraction from neem leaves. The authors isolated 17 limonoid
compounds, of which 15 compounds were active against the cell lines under study. Thus, 15 compounds
were active on HL60 cells; 12 limonoids were effective against AZ521 line; 10 compounds inhibited
the SKBR3 cell growth; and, seven limonoids inhibited to A549 cell line. On the other hand, six limonoid
compounds inhibited the four types of cancer lines: 62–64, 66, 70 and 72 (IC50 1.7 ± 0.1 µg/mL –
~ 98 ± 8 µg/mL); whereas four compounds were effective on three cell lines, i.e., 65, 68, 71 and 73
(IC50 ~ 9 ± 1 µg/mL – ~ 92 ± 4 µg/mL), these same compounds were ineffective on A549 cells. Only two
compounds were effective on HL60 cells; and, two limonoids (67 and 69) were able to inhibit two (HL60
and AZ521) of the four cell lines; the IC50 values were ranged among 0.10 ± 0.01 µg/mL – ~ 76 ± 4 µg/
mL. The most active compounds against the cell lines were 69 (nimbolide, IC50 0.10 ± 0.01 µg/mL, on
HL60 cells; IC50 0.80 ± 0.01 µg/mL, on AZ521 line), 70 (IC50 ~ 1.7 ± 0.1 µg/mL, on SKBR3 cells) and
63 (IC50 ~ 8 ± 3 µg/mL, on A549 line).
Other researchers have also verified the anticancer efficacy of different extracts from neem parts. Wu
et al. (2014) evaluated the cytotoxicity on PC3 cell line of the methanol fractions (11) from the supercritical
extract of neem leaves. Fractions 2, 3 and 5 resulted highly effective against PC3 line with IC50 values
< ~ 2 µg/mL; whilst fractions 6–11 presented IC50 values between ~ 8 µg/mL and ~ 15 µg/mL. One of first
reports about the isolation of compounds with cytotoxic properties from neem was published by Cohen et
al. (1996). These authors measured the cytotoxic potential of six limonoids (included 69) isolated of the
seeds against N1E115, 143B.TK– and RAW264.7 cell lines. The IC50 values established were ~ 4 ± 1 µM
(143B.TK– cells) and ~ 5 ± 1 µM (N1E115 and RAW264 lines) for nimbolide. Priyadarsini et al. (2010)
studied the cytotoxic effect of nimbolide 69 on HeLa cancer line; 5 µM was the IC50 value. Other authors
estimated the anticancer/antiproliferative properties of 69 isolated from M. azadirachta. Harish Kumar et al.
(2009) found that IC50 value of 69 against BeWo cells was of ~ 1 µM (at 24 h). Roy et al. (2007) established
that nimbolide (0.5–5.0 µM), isolated from neem flowers, showed antiproliferative activity against four
cancer cell lines. The IC50 values were 1.1 μM (HL60 cells), 1.2 μM (U937 line), 1.4 μM (THP1 cells)
and 1.7 μM (B16 line). Meanwhile, Elumalai et al. (2012) proved the inhibitory effects of nimbolide (IC50:
~ 3 µM, at 48 h) on the invasive ability of MCF7 and MDAMB231 tumor cell lines. Babykutty et al. (2012)
demonstrated that 69 (IC50: ~ 2.6 µM, at 48 hours) inhibited the proliferation of the WiDr cancer cells by
delaying its migration, invasive capacity, and angiogenesis, and inducing them apoptosis.
N. domestica (Berberidaceae) is the only species of Nandina found in China, and there, different
parts of the plant (e.g., fruits, stems, roots and leaves) have been used in the indigenous medicine system
for the treatment of pharyngeal tumors and uterine bleeding. Peng et al. (2014) isolated 11 alkaloids from
the plant fruit and determined the cytotoxic activity by the MTT test of a new compound (nandsterine
74) against HL60 line. The IC50 value was ~ 52 µM. A millenary (ca. 5000 years) plant of Korean origin
is P. ginseng (Araliaceae, common name: Ginseng), which has been used as prophylactic/curative agent
for treatment different diseases, including cancer. The most used part is the root containing at least
28 active ginsenosides. Wang et al. (2007) determined the cytotoxicities (by MTT assay) on 12 cell lines of
11 saponins isolated from plant fruits. Three saponins (75–77) were the most active compounds against all
cell lines tested, with IC50 values ranged between ~ 12 µM – ~ 69 µM for 76, ~ 20 µM – ~ 72 µM for 75 and
~ 20 µM – ~ 78 µM for 77. An herbaceous plant of great importance in the Mexican and Latin American
traditional herbalist is P. alliacea (Phytolaccaceae, common name: anamú), which has been used to treat
cancer. Rossi et al. (1990, 1993) and Jovicevic et al. (1993) determined the antiproliferative activity by the
MTT test of an aqueous decoction from Anamú leaves against IM9 (human myeloma), Daudi (Burkitt’s
lymphoma) and Molt4 cell lines. They found that the decoction produced the cell growth inhibitions (%)
of 80–90% on IM9 cells, 50–60% on Daudi and Molt4 lines. The IC50 value was 10 µg/mL on IM9 line.
A Brazilian plant is P. paniculata (Amaranthaceae, called Brazilian ginseng) whose roots have been used
in folk medicine as cancer therapy. Takemoto et al. (1983) isolated to pfaffic acid (78) from plant roots
which showed high inhibitory effects against B16, HeLa (S3) and LLC cell lines at concentrations of
4–6 µg/mL. P. peruviana (Solanaceae) is native to western South America (Andes region, mainly Peru),
and its fruits, in particular have been used in ethnomedicine for treating diseases such as cancer. Demir
et al. (2014) evaluated the cytotoxic capacity of the ethanol extract from the plant fruit against Saos2 and
Hep3B cell lines using the MTT method. The IC50 values found were ~ 15 µg/mL on Saos2 cells, and
~ 25 µg/mL on Hep3B. Yen et al. (2010) isolated to 4β-hydroxywithanolide E (79) from plant leaves
and stem which showed anticancer property on H1299 cell line. The IC50 values were ~ 0.6 µg/mL and
~ 0.7 µg/mL at 24 hours and 48 hours, respectively.
R. korthalsii (Araceae) is a native species from Borneo. Wong and Tan (1996a) examined the
cytotoxicity (by the MTT assay) of petroleum ether extract from plant leaves against P388, Molt4, KB
and SW620 cell lines. The ED50 values calculated were 8 μg/mL on KB cells, 12 μg/mL on P388 line,
13 μg/mL on SW620 cells and 14 μg/mL on Molt4 line. R. javanica (syn: Brucea javanica, Simaroubaceae)
is a perennial shrub distributed mainly in Southeast Asia. In China, its fruits are used to treat cancer. Lau
et al. (2008) confirmed that the ethanol extract from Fructus Bruceae (dried ripe fruits of B. javanica)
presented cytotoxic activities against three cell lines. The IC50 values were 1.5 µg/mL, 2.5 µg/mL and
5.1 µg/mL for Capan1, Panc1 and SW1990 cancer cells, respectively. The tree R. verniciflua (Anacardiaceae,
syn: Toxicodendron vernicifluum, common name: lacquer tree) is widely distributed in China, Korea and the
Indian subcontinent. This plant has been used (although restricted) in traditional medicine to treat cancers
for centuries. Kim et al. (2002) determined the cytotoxicity on four cancer cells of the hexane fraction
(free of urushiols) from the plant bark. The GI50 values were ~ 13 µg/mL on Molt4F cells, ~ 16 µg/mL on
SW620 line, ~ 19 µg/mL on ACHN cells and ~ 20 µg/mL on A549 line. Kim et al. (2015) estimated the
cytotoxic potential of nine isolated compounds of two active fractions obtained from the ethanol extract
(free of urushiols) of the plant bark against A549, SKOV3, SKMEL2 and HCT15 cell lines using SRB
assay. Six compounds of nine resulted active against the four cell lines tested. The IC50 values for 80–85
on the four cell lines were between ~ 5 ± 1 µM – ~ 29 ± 1 µM. The most active compound with the lowest
IC50 values (~ 5 ± 1 µM – ~ 10 ± 1 µM) was butein (84). Choi et al. (2016) investigated the effect of 84
on cell death of SKOV3/PAX line. They found that 10 µg/mL of compound inhibited the SKOV3/PAX
cell growth (~ 50% population). Hong et al. (1999) isolated four urushiols (86–89) from the plant sap and
screened the cytotoxic potential against 29 cell lines [PC3; OVCAR4, SKOV3, Molt4F, K562, RPMI8226,
MDAMB235, MCF7/ADR, MCF7; SKMEL2, M14, LOXIMVI, UACC62, SNB75, SNB19, SF539;
SW620, KM12, HCT116, HCT15, and Colo205, UO31,CAKI1, ACHN, NCIH522, NCtH23, NCIH226
and A549]. The GI50 values for 86 were ranged among ~ 0.6–8.6 µg/mL on 29 cancer cells; for 87 were
between ~ 0.4–4.8 µg/mL on 28 cancer cells; for 88 were amongst ~ < 0.1–8.2 µg/mL on 28 cancer cells;
and, for 89 were between ~ 0.2–5.4 µg/mL on 27 cancer cells. The most susceptible cell lines to the
four urushiols were NCIH522, Molt4F and RPMI8226, with GI50 values < 1 µg/mL. Other cancer cells
also sensitive to one of the urushiols were SKMEL2 for 86 (GI50: 1 µg/mL), OVCAR4 for 87 (GI50:
0.8 µg/mL) and M14 and SKMEL2 for 88 (GI50: 0.2 µg/mL and 1 µg/mL).
Another interesting species is R. mucosa (Annonaceae, common name: anonillo or cherimoya),

which is a fruit tree distributed in Central America and West Indies, and in indigenous medicine its
different parts have been used for treatment of cancer. Cytotoxic screening on brine shrimp and six cancer
lines of the chloroform:methanol extract, methanol fraction and isolated jimenezin (90) from fruit seeds
were carried out by Chávez et al. (1998) and Mata et al. (2001). They found that the LC50 (A. salina)
values for the extract and fraction were ~ 4x10–1 µg/mL and 6 x 10–2 µg/mL, respectively. Similarly, the
LC50 values of extract were < 1 x 10–3 µg/mL on A498 and PC3 lines, ~ 1.7 µg/mL on HT29 cells and
~ 7.0 µg/mL on PaCa2 line. Again, Chávez et al. (1999) isolated to membranacin (91) and desacetyluvaricin
(92) from plant seeds, which were also highly active. The cytotoxic evaluation established that 90 was a
powerful cytotoxic agent on both brine shrimp and five cell lines (PaCa2, PC3, HT29, A549 and A498)
tested, with LC50 values of ~ 6 x 10–3 µg/mL on A. salina, and ~ 2 x 10–4 µg/mL – ~ 5 x 10–2 µg/mL for
the lines; whereas, 91 and 92 were strong cytotoxic agents against all systems tried: 92 and 91 obtained
LC50 values of ~ 2 x 10–2 µg/mL and ~ 5 x 10–2 µg/mL on A. salina, respectively; and ED50 values of
< 1 x 10–3 µg/mL – ~ 3 µg/mL. Shi et al. (1996, 1997) studied the cytotoxicity on six cell lines and brine
shrimp of rollitacin (93), rollinacin (94), and rollinecins A (95) and B (96) isolated from plant leaves. They
found that the four compounds were highly effective against the model systems evaluated; LC50 values
presented by 93–96 were between ~ 1 x 10–1 µg/mL – ~ 4 µg/mL on A. salina, and ED50 values were
among ~ 4 x 10–5 µg/mL – ~ 3 µg/mL on the cell lines. Gu et al. (1997) also determined the cytotoxicity
against six cell lines of rodillecins C (97) and D (98) isolated from plant leaves. The authors verified that
both compounds were effective on the six cell lines tested; 97 showed ED50 values of ~ 6 x 10–2 µg/mL
– ~ 1 µg/mL; whilst, 98 had ED50 values of ~ 1 µg/mL – ~ 6 µg/mL.
S. glabra (Chloranthaceae, common name: Caoshanhu) is an evergreen shrub used in traditional
Chinese medicine for treatment of cancers. Ni et al. (2013) screened the anticancer potential (on HL60 cell
line) of 22 sesquiterpenoids isolated from the whole plant. The authors established that two compounds
(99 and 100) of the eight new sesquiterpenoids were active, with IC50 values of 0.03 µM and 1.2 µM,
respectively. Also, Wu et al. (2015) isolated 3,3’-biisofraxidin (101) from the plant. The IC50 value of 101
was ~ 20 µM on BGC823 cells. S. baicalensis (Lamiaceae, common name: Huang-Qin, Chinese skullcap)
is a species native from East Asia and their roots have been used in traditional Chinese medicine for more
than 2000 years as treatment of tumors. Kumagai et al. (2007) investigated the antitumor activities on 11
types of cancer cells of DMSO extract from the plant powder. They found that the ED50 values for Daudi
and NCIH929 cancer cells were ~ 4.6 µg/mL and ~ 5 µg/mL, respectively. Gao et al. (2008) determined
the cytotoxic effect of wogonin (102) against two cell lines. The IC50 values were ~ 11 ± 3 µg/mL (A549
line) and ~ 22 ± 3 µg/mL (SKLU1 cells). Ji et al. (2015) isolated 30 constituents [including 102, baicalin
(103) and baicalein (104)] from dried slices of the plant root and assessed the cytotoxic capacity against
HepG2, SW480 and MCF7 cell lines by the MTS assay. They found that 10 µM 102–104 inhibited the
cancer cell growth. Neves et al. (2011) evaluated the cytotoxicity against three cancer lines of 104. The
GI50 values were 7.7 ± 0.5 µM on A375-C5 cells, ~ 27 ± 3 µM on NCIH460 line and ~ 33 ± 2 µM on
MCF7 cells. Huang et al. (2010) determined that 50 µM of 102 inhibited the HL60 cancer cell growth
~ 48%. S. tamariscina (Selaginellaceae) is another traditional Chinese herb used as therapy for some
kinds of cancers. Li et al. (2014a) determined the anticancer properties of the ethyl acetate extract from
the plant against three cell lines. The IC50 values were 3.2 ± 0.4 µg/mL on HT29 line, 3.2 ± 0.8 µg/mL
on HeLa cells and ~ 8 ± 2 µg/mL on Bel7402 cells. S. torvum (Solanaceae, common name: turkey berry)
is a shrub native to southern Mexico and Central America and is also distributed in Asia and Africa. In
herbal medicine from Indonesia, it is used as an anticancer agent. Balachandran et al. (2015) investigated
the anticancer activity of methyl caffeate (105) isolated from plant fruits against MCF7 cell line. The IC50
value was ~ 0.6 µM. Li et al. (2014b) isolated five new steroidal glycosides from plant fruits and evaluated
the cytotoxicity against A375 cancer cell. The authors found that four of them were moderately active,
with IC50 values ranged between ~ 40–260 µM.
S. venosa (Menispermaceae) is a shrub native to the eastern and southern Asia and in traditional
Thai medicine is used for treating cancer. Leewanich et al. (2011) investigated the antineoplastic effect
on NCIH187 cancer line of ethanol extract from the plant. The IC50 value was ~ 5 µg/mL. Le et al. (2017)
studied the anticancer properties against HeLa, MDAMB231 and MCF7 cell lines of dichloromethane/
butanol fractions, and five isolated alkaloids from plant tubers. The authors found that all fractions were
active on the three cell lines: the IC50 values were ~ 11 ± 3 µg/mL – 14.1 ± 0.6 µg/mL for dichloromethane
fraction, and ~ 18 ± 3 µg/mL – ~ 26 ± 2 µg/mL for butanol fraction. Besides, four compounds (106–109)
were efficacious against the cancer lines; the IC50 values were 3.3 ± 0.2 µM – 6.5 ± 0.4 µM for 107
(stephanine); ~ 11 ± 2 µM – ~ 19 ± 1 µM for 106; ~ 30 ± 5 µM – ~ 48 ± 2 µM for 108, and ~ 39 ± 6 µM
– ~ 70 ± 11 µM for 109. Nantapap et al. (2010) investigated the antiproliferative effects of four alkaloids
isolated from plant tubers on K562, K562/Adr, GLC4 and GLC4/Adr cancer lines. They found that
108–110 were effective on cancer cells; the IC50 values were ~ 7 ± 2 µg/mL – ~ 10 ± 4 µg/mL for 108
(crebanine); ~ 9 ± 1 µg/mL – ~ 14 ± 4 µg/mL for 109 (o-methylbulbocapnine); and ~ 20 ± 5 µg/mL – ~
61 ± 6 µg/mL for 110. Niwat et al. (2001) assessed the cytotoxic activities on MCF7 line of the ethanol
extract and two isolated alkaloids from plant tubers. The IC50 values were ~ 12 µg/mL (for extract) and ~
5–6 µg/mL (for 111 and 108).
T. avellanedae (Bignoniaceae) is a tree found in the northeast of Brazil. The purple bark (Taheebo) of
this plant has been used by the Callawaya tribe for treatment of skin cancer. Yamashita et al. (2007, 2009)
studied the cytotoxic effects of naphthoquinone (112), lapachol (113) and β-lapachone (114) against three
cell lines. The EC50 values of 112 were ~ 0.1 µM, ~ 0.8–1 µM and ~ 0.5–4 µM on PC3, A549 and MCF7
cancer cells, respectively; the EC50 values of 113 and 114 on the same cell lines were ~ 1–2 µM, ~ 4–5 µM
and ~ 10 µM. Zhang et al. (2015) isolated two furanonaphthoquinones from T. avellanedae inner bark,
which showed antiproliferative effects on A549, SiHa and MCF7 cancer lines. The IC50 values were 0.50
± 0.06 µM – 1.2 ± 0.3 µM for 112; 1.1 ± 0.1 µM – 2.0 ± 0.4 µM for 115; 2.0 ± 0.3 µM – 3.4 ± 0.6 µM for
116; and 10.2 ± 0.4 µM – > ~ 14 µM for 117. T. rosea (common name: pink trumpet tree) is a tree native
from Mexico to Venezuela and Ecuador, used in traditional medicine for treating tumors. Sichaem et al.
(2012) isolated 13 compounds from plant roots and studied the cytotoxic potential of the compounds against
KB and HeLa cell lines. They found that 13 compunds were active on the two cancer lines; nonetheless,
the most active were 112, 118–121. The IC50 values, respectively were ~ 0.5 µg/mL and ~ 0.8 µg/mL
for 118, ~ 1.8 µg/mL and ~ 0.7 µg/mL for 119, ~ 1.4 µg/mL and ~ 1.2 µg/mL for 112, ~ 2.0 µg/mL and
~ 4.2 µg/mL for 120, and ~ 16 µg/mL and ~ 14 µg/mL for 121.
T. wilfordii (Celastraceae, common name: thunder god vine) is a shrub native to Southeast Asia,
used in traditional Chinese medicine from ancient times for the treatment of different ailments including
cancer. Gao et al. (2017) isolated 13 compounds from plant dried roots and screened the cytotoxic effects
on four cell lines. The authors found that only five compounds were effective on the cancer cells with
IC50 values between ~ 11 ± 2 µM – ~ 88 ± 1 µM. The most active compounds were 122 and 123 on
HepG2 cells with IC50 values of ~ 11 ± 2 µM and ~ 18 ± 2 µM, along with 124 on A549 line with IC50
value of ~ 16 ± 2 µM. Gao et al. (2016) isolated 21 diterpenoids from plant dried roots and evaluated
the cytotoxic potential against six cancer lines. The results revealed that 125 and 126 (triptotin A) were
the most active compounds against all cells, with IC50 values between ~ 5 ± 2 µM – ~ 23 ± 2 µM. The
lowest IC50 values were ~ 5 ± 2 µM and ~ 6 ± 2 µM for 125 on HepG2 and MCF7 lines, ~ 8 ± 2 µM for
125 and 126 on Bcap37 cells, ~ 9 ± 2 µM for 125 on U251 line, ~ 11 ± 3 µM for 126 and 127 on A549
cells, and ~ 17 ± 3 µM for 128 on Hep3B line. Fan et al. (2016) isolated 17 compounds from plant dried
stems and determined the cytotoxicity on A549 and A549T cancer cells. The authors found that five of the
17 compounds were active on the A549T line with IC50 values among ~ 11 ± 2 µM – 54.4 ± 0.3 µM;
while, only triptofordin B (129) was effective against A549 cancer cells. The most active compound on
A549T and A549 cell lines was 129 with IC50 values of ~ 11 ± 2 µM and ~ 21 ± 2 µM, respectively. Yang
et al. (2011) isolated eight triterpenoids from plant roots and estimated the cytotoxic effect against HeLa
cancer cells. The most active compounds were tripterfrielanons A (130) and B (131) with IC50 values of
8.5 µg/mL and 25 µg/mL, individually.
V. album (Santalaceae, common name: mistletoe) is a perennial hemiparasite shrub native to Europe
and Asia, which has been used in folk medicine for both treatment and in complementary therapies against
cancer. Weissenstein et al. (2016) investigated the effect of a standardized preparation on the action
of Trastuzumab (drug used against breast cancer). The authors also determined the cytotoxic effect of
standardized extract on SKBR3 cancer cells. They found that 1 µg/mL or ≥ 10 µg/mL of extract produced
a cell growth inhibition > 60% or ~ 100%, respectively. Finally, W. somnifera (Solanaceae, common name:
Ashwagandha, Indian ginseng) is a perennial herb native from the dry regions of Asia and other continents
such as Africa. It is an important plant in Ayurvedic and traditional Chinese medicines due to its wide
uses for treatment of several diseases, including cancer (Rai et al. 2016). Nema et al. (2013) screened the
cytotoxicity of hydroalcohol extract from plant leaves against three cancer lines. The IC50 values were
~ 10 ± 1 µg/mL (MCF7 cells), ~ 11 ± 1 µg/mL (A459 line) and ~ 13 ± 1 µg/mL (PA1 cells). Jayaprakasam
et al. (2003) isolated 12 whitanolides from plant dried leaves and evaluated the cytotoxic potential on four
types of cancer cells. The results showed that 10 whitanolides exhibited cytotoxicity on all cancer lines
tested with IC50 values between 0.24 ± 0.01 µg/mL – ~ 24 ± 1 µg/mL. 132–134 (3-dihydrowithaferin A)
were the most active compounds with IC50 values among 0.24 ± 0.01 µg/mL – 0.9 ± 0.2 µg/mL. The lowest
IC50 values were 0.24 ± 0.01 µg/mL for 132 (whitaferin A) on NCIH460 line; 0.36 ± 0.04 µg/mL, and
0.5 ± 0.2 µg/mL for 132 and 133 (viscosalactone B) on HCT116 cells; 0.28 ± 0.04 µg/mL for 132 on SF268
line; and 0.27 ± 0.04 µg/mL for 132 on MCF7 cells. Choudhary et al. (2015) isolated two whitanolides
(included 132) from methanol extract of plant aerial parts and evaluated the cytotoxicity on NCIH460 line
for both the extract and whitanolides. The extract showed GI50 and LC50 values of 1.5 ± 0.2 µg/mL and
7.60 ± 0.05 µg/mL; whilst 132 presented GI50 and LC50 values of 0.18 ± 0.01 µg/mL and 0.45 ± 0.01 µg/
mL; and, 135 exhibited GI50 and LC50 values of 1.5 ± 0.1 µg/mL and 8.5 ± 0.2 µg/mL.
Development of anticancer/antitumor drugs from chemical constituents of

plants in accordance with patent analysis
In order to assess the innovation/inventive activities related to medicinal plants with anticancer/antitumor
properties along with development of anticancer/antitumor drugs, the Derwent Innovations Index (Clarivate
Analytics 2017) database was used. Five hundred and ten records of patents were obtained, which were
analyzed by means of VantagePoint software (VP student, Search Technology). Figure 1.4 contains the
inventive dynamic on 157 medicinal plants and antitumor/anticancer properties, in the last 20 years. An
irregular behavior of the patent numbers per year could be observed in the timeline 1997–2006. Since
2007 an increase on the number of patents was evidenced: 2015 and 2016 were the most active years with
99 patents and 89 patents, respectively. To date (2017), only 44 records have been found. Considering
the distribution of patents per offices (top five), it was found that China reported 338 patents, followed
by South Korea (66 patents), United States (47 patents), Switzerland (10 patents), and Japan (nine
patents). The plants with the highest number of patents related to anticancer/antitumor properties were:
S. lyratum (56 patents), C. longa (54 patents), M. tenacissima (54 patents), S. glabra (44 patents), C. roseus
(30 patents) and W. somnifera (14 patents). In agreement with the inventions correlated to applications on
a specific cancer of an isolated compound/extract of plants, the following assignments were found: patents
attendant to lung cancer (65 records), patents associated to gastric cancer (57 records), patents related to
breast cancer (49 records), patents correspondent to liver cancer (42 records), patents mentioning effects
on colorectal cancer (24 records), patents stating results on cervical cancer (22 records), etc. The patents
were found from academic institutions, private corporations and natural persons, mainly: e.g., Qingdao
Tumour Hospital (89 patents), Yinchuan Shanghetu New Technology Dev Co. (20 patents), Jinan Xinshidai
Medical Technology Co. (eight patents), Fenghua Kechuang Technology Service Co. (four patents), Lifeline
Nutraceuticals Corp. (four patents).
With the purpose of identifying what the plants validated on the different types of cancer and
protected by patents, a correlational matrix was elaborated (Fig. 1.5). The analysis of the figure showed
that S. lyratum and C. longa were the most protected plants, which had the greatest application/evaluation
on the different types of cancer (21); followed by M. tenacissima (20 types of cancer) and S. glabra
(18 types of cancer). Nonetheless, individual plants had a highest patent numbers depending on type of
cancer, f.i., S. lyratum related to gastric cancer (14 registers), and C. longa associated to breast cancer
(9 records). On the other hand, the main type of cancer on which the highest medicinal plant numbers (15)
have been protected, was lung cancer; followed by, breast cancer (13 plants), and liver cancer (10 plants).
100
90
80
70
Number of records
60
50
40
30
20
10
0 1997 1998 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Series 1 3 2 2 4 6 12 9 12 5 16 17 23 22 19 34 40 52 99 89 44
Fig. 1.4
Source: Bibliometry Unit – CRAI-Library, Universidad Santo Tomás (Bucaramanga). Calculations based on Derwent Innovations
Index (Clarivate, Analytics, 2017) database, processed with VantagePoint software (VP Student, Search Technology).
14
14
12
10 10
10
9 9 9 9
8 8 8
8
7 7
66 6
6
5 5 55
4 4 4 4 4
4
3 3 3 3 3 3
2 2 2 2 2 2 2 2 2 2
2
1 1 11 1 1 1 1 11 111 111 111
0
gastric lung liver cervical breast esophagus pancreatic prostate intestinal bladder rectal colorectal colon ovarian
cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer
Solanum lyratum Curcuma longa Marsdenia tenacissima Sarcandra glabra Catharanthus roseus
Fig. 1.5
Source: Bibliometry Unit – CRAI-Library, Universidad Santo Tomás (Bucaramanga). Calculations based on Derwent
Innovations Index (Clarivate Analytics, 2017), processed with VantagePoint software (VP Student, Search Technology).
Table 1.2 includes some patents conferred from the medicinal plants (isolated compounds/extracts)
with anticancer/antitumor properties scientific validated. This table contains the names of medicinal plant,
patent codes, patent titles, IPC classifications, assignees, and dates.
Table 1.2. Some patent applications from the medicinal plants (isolated compounds/extracts) with anticancer/antitumor properties scientifically validated.
Medicinal plant Patent code Title IPC classifications Asignees Date

Annona squamosa CN 101401806 A Use of A. squamosa bullatacin for preparing A61K-031/365, A61P-035/00 Univ. Nanjing Chinese Sep 17, 2008
CN 101342202 A drug used to treat lung, breast or liver Medicine & Pharmaco
cancers
CN 1593495 A Compound medicine for treating cancer, in A61K-035/78, A61K-009/08, A61P- Xing Lok Road Mar 16, 2005
CN 1269521 C which the medicament is prepared from total 035/00, A61K-036/13, A61K-036/22, Aug 16, 2006
A. squamosa, Polygoni multiflori, Curcuma A61K-036/53, A61K-036/704, A61K-
aromatica 036/75, A61K-036/9066
CN 1319424 A Anticancer medicine of A. squamose A61K-035/78, A61K-009/06, A61P- Univ. Nangjing Trad. Chinese Oct 31, 2001
extractum and preparation method thereof 035/00 Medici
Artemisiae argyi CN 101468184 B Medicament for treating digestive system A61K35/24, A61K36/9066, Haitang Liu Sep 7, 2011
cancer and preparation method thereof A61K9/20, A61K9/48, A61P35/00
Curcuma longa GB 2531850 B Phyto-active based anti-cancer formulation A61K36/324, A61K36/87, Omni Cure Ltd. Jun 28, 2017
A61K36/906, A61P35/00
CN 102302742 B Traditional Chinese medicine composition A61K35/36, A61K35/64, Hongkun Zhao Oct 24, 2012
for treating cardiac and esophageal cancers A61K36/9066, A61P35/00
Mahonia fortunei CN 102008685 B Chinese medicinal powder for treating liver, A61K36/9066, A61K9/14, A61P1/16, Xuezhe Gao Jul 4, 2012
lung and pancreatic cancers A61P11/00, A61P35/00
Marsdenia tenacissima CN 101215313 B M. tenacissima carbon-21 steroid saponin A61K31/7048, A61K36/185, Zhejiang Academy Medical Jun 9, 2010
mixture with antineoplastic effect A61P35/00, C07J71/00 Sci.
CN 101463065 B M. tenacissima extract A61K31/7048, A61K36/27, Jiangsu Simcere Pharm. Res. Jul 4, 2012
A61P35/00, C07J71/00 Co.
Petiveria alliacea WO 2011039629 A2 Bioactive fraction used for preparing drug A61K-000/00, A61K-036/185, Univ. Javeriana Pontificia Apr 07, 2011
CA 2776446 A1 for treating cancer, is obtained from A61P-035/00, A61K-031/7048, Nov 22, 2012
US 2012294897 A1 P. alliacea by bio-engineered, standardized A61K-038/17, A61K-039/39, A61K- May 27, 2014
BR 112012009362 A2 and analytical processes… 036/28 Jun 07, 2016
Sarcandra glabra CN 101919967 B Traditional Chinese drug for treating A61K35/50, A61K35/62, Yi Junyu Dec 7, 2011
esophagus cancer A61K35/646, A61K36/898
CN 101703726 B Medicament for treating lung cancer A61K35/57, A61K35/646, Yuwei He Sep 8, 2010
A61K36/9064, A61P35/00
CN 101972454 B Medicament for treating lymphoma A61K35/413, A61K35/57, Yuwei He Oct 5, 2011
A61K35/583, A61K36/9066
Table 1.2 contd. ...

...Table 1.2 contd.
Medicinal plant Patent code Title IPC classifications Asignees Date

Sarcandra glabra CN 102133378 B Medicament for treating breast cancer A61K35/57, A61K35/586, Yuwei He Feb 29, 2012
Solanum lyratum A61K35/618, A61P35/00
Solanum lyratum CN 101049449 B Composition of Chinese traditional medicine A61K35/32, A61K36/8994, Shi-Jie Li Feb 29, 2012
for malignant tumor A61P35/00
CN 101940708 B Traditional Chinese medicinal preparation A61K36/8966, A61P35/00, A61P7/10 Feng Cao Jun 6, 2012
for curing malignant pleural effusion
Viscum album GR 1008177 B Method for the treatment of fir-based extract A61K36/15 Polychronis Argyrios Apr 17, 2014
exhibiting biological action… Konstantinou
MD 743 F1 Remedy for immunity system and hormonal A61K35/64 Victor Babco; Petru Pihut; Jun 30, 1997
homeostasis normalization Vladislav Babco
GB 1152618 A Process for the preparation of a A23J1/10, A61K36/00, A61K36/185, Ciba Ltd. May 21, 1969
physiologically active protein material C07K14/415
Conclusion
The scientific validation of the ethnobotanical uses of medicinal plants for cancer treatment is a topic that
has been strengthening since the last 10 years, based on the scientific dynamics observed in the analysis of
text mining carried out; at present, there is a strong and persistent interest in the scientific community and
the pharmaceutical industries for finding/obtaining new drugs with the greatest effectiveness/selectivity,
least side effects and lowest cost, which can act by different mechanisms of action in order to: improve the
quality of life of people with cancer, or find a definitive cure for the disease. Some of the most effective
drugs commercially available for the treatment of cancer were isolated from nature (plants) and perhaps
from the plants themselves, the best molecules could be obtained with the benefits mentioned above. As a
final point, there are still medicinal plants used in ethnomedicine to treat cancer from which its extracts/
fractions/isolated compounds have not yet been scientifically validated by in vitro and in vivo methods,
or in other cell lines and animal models. In the same sense, preparations/isolated compounds from
the plants which were evaluated on in vivo assays (animal models), not all they have been submitted
to preclinical (phase 0) and clinical studies (phases I–IV), together with safety, efficacy, and quality
assessments that are necessary for the development of commercially available drugs. Therefore, scientists
who study medicinal plants (e.g., ethnobotanists, ethnopharmacologists, biologists, molecular biologists,
chemists, pharmacologists, toxicologists, pharmacists, etc.) could still take part to fill each knowledge
gap in this area and thus contribute to solving in part this problem/disease.
Acknowledgement
The authors would like to thank: Universidad del Norte, Division of Basic Sciences; and, Universidad
Santo Tomás de Aquino (Bucaramanga) by using of the Bibliometric Unit.
References
Ahmed, S., Rahman, A., Mathur, M., Athar, M. and Sultana, S. 2001. Anti-tumor promoting activity of Asteracantha longifolia
against experimental hepatocarcinogenesis in rats. Food Chem. Toxicol. 39: 19–28.
Alaikov, T., Konstantinov, S.M., Tzanova, T., Dinev, K., Topashka-Ancheva, M. and Berger, M.R. 2007. Antineoplastic and
anticlastogenic properties of curcumin. Ann. N.Y. Acad. Sci. 1095: 355–370.
Alonso-Castro, A.J., Villarreal, M.L., Salazar-Olivo, L.A., Gomez-Sanchez, M., Dominguez, F. and Garcia-Carranca, A. 2011.
Mexican medicinal plants used for cancer treatment: pharmacological, phytochemical and ethnobotanical studies. J.
Ethnopharmacol. 133: 945–972.
Arbiastutie, Y., Marsono, D., Hartati, M.S. and Purwanto, R. 2017. The potential of understorey plants from Gunung Gede
Pangrango National Park (West Java, Indonesia) as cervixs anticancer agents. Biodiversitas J. Biol. Divers 18: 109–115.
Arkhipov, A., Sirdaarta, J., Rayan, P., McDonnell, P.A. and Cock, I.E. 2014. An examination of the antibacterial, antifungal,
anti-Giardial and anticancer properties of Kigelia africana fruit extracts. Pharmacogn. Commun. Bangalore 4: 62–76.
Babykutty, S., Priya, P.S., Nandini, R.J., Suresh Kumar, M.A., Nair, M.S., Srinivas, P. and Gopala, S. 2012. Nimbolide retards
tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and
reducing DNA-binding activity of NF-κB in colon cancer cells. Mol. Carcinog. 51: 475–490.
Balachandran, C., Emi, N., Arun, Y., Yamamoto, Y., Ahilan, B., Sangeetha, B., Duraipandiyan, V., Inaguma, Y., Okamoto, A.,
Ignacimuthu, S., Al-Dhabi, N.A. and Perumal, P.T. 2015. In vitro anticancer activity of methyl caffeate isolated from
Solanum torvum Swartz. fruit. Chem. Biol. Interact. 242: 81–90.
Breza, T.S., Halprin, K.M. and Taylor, J.R. 1975. Photosensitivity reaction to vinblastine. Arch. Dermatol. 111: 1168–1170.
Castillo, D., Arevalo, J., Herrera, F., Ruiz, C., Rojas, R., Rengifo, E., Vaisberg, A., Lock, O., Lemesre, J.-L., Gornitzka, H. and
Sauvain, M. 2007. Spirolactone iridoids might be responsible for the antileishmanial activity of a Peruvian traditional
remedy made with Himatanthus sucuuba (Apocynaceae). J. Ethnopharmacol. 112: 410–414.
Cates, R.G., Prestwich, B., Innes, A., Rowe, M., Stanley, M., Williams, S., Thompson, R., McDonald, S., Cates, S.,
Shrestha, G., Soria, J.A.F., Espinoza, L.V., Ardon, C., Galvez, B., Diaz, M.R., Coronado, F.S., Garcia, J.R., Arbizu,
D.A. and Martinez, J.V. 2013. Evaluation of the activity of Guatemalan medicinal plants against cancer cell lines and
microbes. J. Med. Plants Res. 4: 2616–2627.
Chávez, D., Acevedo, L.A. and Mata, R. 1998. Jimenezin, a novel annonaceous acetogenin from the seeds of Rollinia mucosa
containing adjacent tetrahydrofuran-tetrahydropyran ring systems. J. Nat. Prod. 61: 419–421.
Chávez, D., Acevedo, L.A. and Mata, R. 1999. Tryptamine derived amides and acetogenins from the seeds of Rollinia mucosa.
J. Nat. Prod. 62: 1119–1122.
Chen, M., Ni, Y., Duan, H., Qiu, Y., Guo, C., Jiao, Y., Shi, H., Su, M. and Jia, W. 2008. Mass spectrometry-based metabolic
profiling of rat urine associated with general toxicity induced by the multiglycoside of Tripterygium wilfordii Hook. f.
Chem. Res. Toxicol. 21: 288–294.
Chen, Y., Chen, J.-W., Wang, Y., Xu, S.-S. and Li, X. 2012. Six cytotoxic annonaceous acetogenins from Annona squamosa
seeds. Food Chem. 135: 960–966.
Cheng, A.-S., Chang, W.-C., Cheng, Y.-H., Chen, K.-Y., Chen, K.-H. and Chang, T.-L. 2012. The effects of davallic acid from
Davallia divaricata Blume on apoptosis induction in A549 lung cancer cells. Molecules 17: 12938–12949.
Choi, H.S., Kim, M.K., Choi, Y.K., Shin, Y.C., Cho, S.-G. and Ko, S.-G. 2016. Rhus verniciflua Stokes (RVS) and butein
induce apoptosis of paclitaxel-resistant SKOV-3/PAX ovarian cancer cells through inhibition of AKT phosphorylation.
BMC Complement. Altern. Med. 16: 122 (7 p.).
Choi, S.E., Kim, K.H., Kwon, J.H., Kim, S.B., Kim, H.W. and Lee, M.W. 2008. Cytotoxic activities of diarylheptanoids from
Alnus japonica. Arch. Pharm. Res. 31: 1287–1289.
Choudhary, B., Shetty, A. and Langade, D.G. 2015. Efficacy of Ashwagandha (Withania somnifera [L.] Dunal) in improving
cardiorespiratory endurance in healthy athletic adults. Ayu 36: 63–68.
Coatti, G.C., Marcarini, J.C., Sartori, D., Fidelis, Q.C., Ferreira, D.T. and Mantovani, M.S. 2016. Cytotoxicity, genotoxicity
and mechanism of action (via gene expression analysis) of the indole alkaloid aspidospermine (antiparasitic) extracted
from Aspidosperma polyneuron in HepG2 cells. Cytotechnology 68: 1161–1170.
Cohen, E., Quistad, G.B., Jefferies, P.R. and Casida, J.E. 1996. Nimbolide is the principal cytotoxic component of neem-seed
insecticide preparations. Pestic. Sci. 48: 135–140.
Coria-Téllez, A.V., Montalvo-Gónzalez, E., Yahia, E.M. and Obledo-Vázquez, E.N. 2017. Annona muricata: a comprehensive
review on its traditional medicinal uses, phytochemicals, pharmacological activities, mechanisms of action and toxicity.
Arab. J. Chem. (in press).
Damayanthi, Y. and Lown, J.W. 1998. Podophyllotoxins: current status and recent developments. Curr. Med. Chem. 5: 205–252.
De Melo, J.G., Santos, A.G., de Amorim, E.L.C., do Nascimento, S.C. and de Albuquerque, U.P. 2011. Medicinal plants used
as antitumor agents in Brazil: an ethnobotanical approach. Evid. Based Complement. Alternat. Med. 2011: 365359.
De Solla Price, D.J. 1963. Little science, big science. Columbia Univ. Press, New York.
Demir, T., Ozen, M.O. and Hameş-Kocabaş, E.E. 2014. Antioxidant and cytotoxic activity of Physalis peruviana. Med. Plant
Res. 4: 30–34.
Desai, A.G., Qazi, G.N., Ganju, R.K., El-Tamer, M., Singh, J., Saxena, A.K., Bedi, Y.S., Taneja, S.C. and Bhat, H.K. 2008.
Medicinal plants and cancer chemoprevention. Curr. Drug Metab. 9: 581–591.
Elumalai, P., Gunadharini, D.N., Senthilkumar, K., Banudevi, S., Arunkumar, R., Benson, C.S., Sharmila, G. and Arunakaran,
J. 2012. Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway.
Toxicol. Lett. 215: 131–142.
Fan, D., Zhu, G.-Y., Chen, M., Xie, L.-M., Jiang, Z.-H., Xu, L. and Bai, L.-P. 2016. Dihydro-β-agarofuran sesquiterpene
polyesters isolated from the stems of Tripterygium regelii. Fitoterapia 112: 1–8.
FDA. 2017. FDA approved drugs in oncology. https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic-
area/12/oncology (accessed 8.11.17).
Gao, C., Wang, D., Zhang, Y., Huang, X.-X. and Song, S.-J. 2016. Kaurane and abietane diterpenoids from the roots of
Tripterygium wilfordii and their cytotoxic evaluation. Bioorg. Med. Chem. Lett. 26: 2942–2946.
Gao, C., Lou, L.-L., Wang, D., Zhang, Y., Huang, X.-X. and Song, S.-J. 2017. Chemical constituents from the roots of
Tripterygium wilfordii and their cytotoxic activity. J. Asian Nat. Prod. Res. 19: 725–731.
Gao, J., Sanchez-Medina, A., Pendry, B.A., Hughes, M.J., Webb, G.P. and Corcoran, O. 2008. Validation of a HPLC method
for flavonoid biomarkers in skullcap (Scutellaria) and its use to illustrate wide variability in the quality of commercial
tinctures. J. Pharm. Pharm. Sci. 11: 77–87.
Gavamukulya, Y., Abou-Elella, F., Wamunyokoli, F. and AEl-Shemy, H. 2014. Phytochemical screening, anti-oxidant activity
and in vitro anticancer potential of ethanolic and water leaves extracts of Annona muricata (Graviola). Asian Pac. J.
Trop. Med. 7: S355–S363.
Goldstein, D.A., Clark, J., Tu, Y., Zhang, J., Fang, F., Goldstein, R.M., Stemmer, S.M. and Rosenbaum, E. 2016. Global
differences in cancer drug prices: a comparative analysis. J. Clin. Oncol. 34: LBA6500-LBA6500.
Gu, Z.M., Zhou, D., Lewis, N.J., Wu, J., Shi, G. and McLaughlin, J.L. 1997. Isolation of new bioactive annonaceous acetogenins
from Rollinia mucosa guided by liquid chromatography/mass spectrometry. Bioorg. Med. Chem. 5: 1911–1916.
Guo, L., Chen, X., Hu, Y., Yu, Z., Wang, D. and Liu, J. 2013. Curcumin inhibits proliferation and induces apoptosis of human
colorectal cancer cells by activating the mitochondria apoptotic pathway. Phytother. Res. 27: 422–430.
Gupta, M.P., Monge, A., Karikas, G.A., Lopez de Cerain, A., Solis, P.N., de Leon, E., Trujillo, M., Suarez, O., Wilson, F.,
Montenegro, G., Noriega, Y., Santana, A.I., Correa, M. and Sanchez, C. 1996. Screening of Panamanian medicinal plants
for brine shrimp toxicity, crown gall tumor inhibition, cytotoxicity and DNA intercalation. Int. J. Pharmacogn. 34: 19–27.
Han, S.-Y., Zhao, M.-B., Zhuang, G.-B. and Li, P.-P. 2012. Marsdenia tenacissima extract restored gefitinib sensitivity in
resistant non-small cell lung cancer cells. Lung Cancer 75: 30–37.
Han, S.-Y., Ding, H.-R., Zhao, W., Teng, F. and Li, P.-P. 2014. Enhancement of gefitinib-induced growth inhibition by
Marsdenia tenacissima extract in non-small cell lung cancer cells expressing wild or mutant EGFR. BMC Complement.
Altern. Med. 14: 165.
Han, S.Y., Zhao, W., Sun, H., Zhou, N., Zhou, F., An, G. and Li, P.P. 2015. Marsdenia tenacissima extract enhances gefitinib
efficacy in non-small cell lung cancer xenografts. Phytomedicine Int. J. Phytother. Phytopharm. 22: 560–567.
Harish Kumar, G., Chandra Mohan, K.V., Jagannadha Rao, A. and Nagini, S. 2009. Nimbolide a limonoid from Azadirachta
indica inhibits proliferation and induces apoptosis of human choriocarcinoma (BeWo) cells. Invest. New Drugs 27:
246–252.
Hemamalini, K., Soujanya, G.L., Bhargav, A. and Vasireddy, U. 2012. In-vivo anticancer activity of Tabebuia rosea (Bertol)
Dc. leaves on Dalton’s ascetic lymphoma in mice. Int. J. Pharm. Sci. Res. 3: 4496–4502.
Hong, D.H., Bae Han, S., Lee, C., Hyung Park, S., Jin Jeon, Y., Kim, M.-J., Kwak, S.-S. and Kim, H. 1999. Cytotoxicity of
urushiols isolated from sap of Korean lacquer tree (Rhus vernicifera Stokes). Arch. Pharm. Res. 22: 638–641.
Hu, Y.-J., Shen, X.-L., Lu, H.-L., Zhang, Y.-H., Huang, X.-A., Fu, L.-C. and Fong, W.-F. 2008. Tenacigenin B derivatives
reverse P-glycoprotein-mediated multidrug resistance in HepG2/Dox cells. J. Nat. Prod. 71: 1049–1051.
Huang, S.-T., Wang, C.-Y., Yang, R.-C., Chu, C.-J., Wu, H.-T. and Pang, J.-H.S. 2010. Wogonin, an active compound in
Scutellaria baicalensis, induces apoptosis and reduces telomerase activity in the HL-60 leukemia cells. Phytomedicine
17: 47–54.
Iwasa, K., Takahashi, T., Nishiyama, Y., Moriyasu, M., Sugiura, M., Takeuchi, A., Tode, C., Tokuda, H. and Takeda, K. 2008.
Online structural elucidation of alkaloids and other constituents in crude extracts and cultured cells of Nandina domestica
by combination of LC-MS/MS, LC-NMR, and LC-CD analyses. J. Nat. Prod. 71: 1376–1385.
Jagetia, G.C. and Baliga, M.S. 2016. Preclinical evaluation of the anticancer activity of hydroalcoholic stem bark extract of
Alstonia scholaris in Ehrlich ascites carcinoma transplanted in the Swiss albino mice. J. Alt. Med. Res. 2: 115–126.
Jain, S.K. and Tarafder, C.R. 1970. Medicinal plant-lore of the santals (A revival of P. O. Bodding’s work). Econ. Bot.
24: 241–278.
Jayaprakasam, B., Zhang, Y., Seeram, N.P. and Nair, M.G. 2003. Growth inhibition of human tumor cell lines by withanolides
from Withania somnifera leaves. Life Sci. 74: 125–132.
Ji, S., Li, R., Wang, Q., Miao, W.-J., Li, Z.-W., Si, L., Qiao, X., Yu, S.-W., Zhou, D.-M. and Ye, M. 2015. Anti-H1N1 virus,
cytotoxic and Nrf2 activation activities of chemical constituents from Scutellaria baicalensis. J. Ethnopharmacol. 176:
475–484.
Jovicevic, L., Troiani, M.P., Capezzone de Joannon, A., Saso, L., Mezzanti, G. and Rossi, V. 1993. In vitro antiproliferative
activity of Petiveria alliacea L. on several tumor cell lines. Pharmacol. Res. 27: 105–106.
Jung, C.H., Kim, J.H., Hong, M.H., Seog, H.M., Oh, S.H., Lee, P.J., Kim, G.J., Kim, H.M., Um, J.Y. and Ko, S.-G. 2007.
Phenolic-rich fraction from Rhus verniciflua Stokes (RVS) suppress inflammatory response via NF-κB and JNK pathway
in lipopolysaccharide-induced RAW 264.7 macrophages. J. Ethnopharmacol. 110: 490–497.
Kim, H. and Song, M.-J. 2011. Analysis and recordings of orally transmitted knowledge about medicinal plants in the southern
mountainous region of Korea. J. Ethnopharmacol. 134: 676–696.
Kim, K.H., Moon, E., Choi, S.U., Pang, C., Kim, S.Y. and Lee, K.R. 2015. Identification of cytotoxic and anti-inflammatory
constituents from the bark of Toxicodendron vernicifluum (Stokes) F.A. Barkley. J. Ethnopharmacol. 162: 231–237.
Kim, M.-J., Choi, W.-C., Barshinikov, A.M. and Kobayashi, A. 2002. Anticancer and antioxidant activity of allergen-removed
extract in Rhus verniciflua Stokes. Korean J. Med. Crop Sci. 10: 288–293.
Kumagai, T., Müller, C.I., Desmond, J.C., Imai, Y., Heber, D. and Koeffler, H.P. 2007. Scutellaria baicalensis, a herbal
medicine: anti-proliferative and apoptotic activity against acute lymphocytic leukemia, lymphoma and myeloma cell
lines. Leuk. Res. 31: 523–530.
Kuo, Y.H., Chen, C.H., Kuo, L.M.Y., King, M.L., Wu, T.S., Lu, S.T., Chen, I.S., McPhail, D.R., McPhail, A.T. and Lee, K.H.
1989. Structure and stereochemistry of emarginatine-A, a novel cytotoxic sesquiterpene pyridine alkaloid from Maytenus
emarginata: X-ray crystal structure of emarginatine-A monohydrate. Heterocycles 29: 1465–1468.
Kuo, Y.-H., Chen, C.-H., Kuo, L.-M.Y., King, M.-L., Wu, T.-S., Haruna, M. and Lee, K.-H. 1990. Antitumor agents, 112.
Emarginatine B, a novel potent cytotoxic sesquiterpene pyridine alkaloid from Maytenus emarginata. J. Nat. Prod. 53:
422–428.
Kuo, Y.-H., Chen, C.-H., King, M.-L., Wu, T.-S. and Lee, K.-H. 1994a. Sesquiterpene pyridine alkaloids from Maytenus
emarginata: emarginatine-C and -D and cytotoxic emarginatine-E and emarginatinine. Phytochemistry 35: 803–807.
Kuo, Y.-H., King, M.-L., Chen, C.-F., Chen, H.-Y., Chen, C.-H., Chen, K. and Lee, K.-H. 1994b. Two new macrolide
sesquiterpene pyridine alkaloids from Maytenus emarginata: emarginatine G and the cytotoxic emarginatine F. J. Nat.
Prod. 57: 263–269.
Kuttan, R., Bhanumathy, P., Nirmala, K. and George, M.C. 1985. Potential anticancer activity of turmeric (Curcuma longa).
Cancer Lett. 29: 197–202.
Lau, S.T., Lin, Z.-X., Zhao, M. and Leung, P.S. 2008. Brucea javanica fruit induces cytotoxicity and apoptosis in pancreatic
adenocarcinoma cell lines. Phytother. Res. 22: 477–486.
Le, P.M., Srivastava, V., Nguyen, T.T., Pradines, B., Madamet, M., Mosnier, J., Trinh, T.T. and Lee, H. 2017. Stephanine
from Stephania venosa (Blume) Spreng showed effective antiplasmodial and anticancer activities, the latter by inducing
apoptosis through the reverse of mitotic exit. Phytother. Res. 31: 1357–1368.
Lee, J.-W., Kim, K.-S., An, H.-K., Kim, C.-H., Moon, H.-I. and Lee, Y.-C. 2013. Dendropanoxide induces autophagy through
ERK1/2 activation in MG-63 human osteosarcoma cells and autophagy inhibition enhances dendropanoxide-induced
apoptosis. PLoS ONE 8: e83611.
Leewanich, P., Worachartcheewan, A., Prachayasittikul, S. and Prachayasittikul, V. 2011. Anticancer and antioxidative activities
of Stephania venosa. Eur. J. Sci. Res. 51: 150–156.
Levine, A.J., Reich, N. and Thomas, R. 1983. The regulation of a cellular protein, p53, in normal and transformed cells. Prog.
Clin. Biol. Res. 119: 159–169.
Li, J., Jadhav, A.N., Rumalla, C.S. and Khan, I.A. 2009. New terpenoids from Pfaffia paniculata Kuntze. Planta Med. 75: 37.
Li, J., Lei, X. and Chen, K. 2014a. Comparison of cytotoxic activities of extracts from Selaginella species. Pharmacogn.
Mag. 10: 529–535.
Li, J., Zhang, L., Huang, C., Guo, F. and Li, Y. 2014b. Five new cyotoxic steroidal glycosides from the fruits of Solanum
torvum. Fitoterapia 93: 209–215.
Li, X.-H., Hui, Y.-H., Rupprecht, J.K., Liu, Y.-M., Wood, K.V., Smith, D.L., Chang, C.-J. and McLaughlin, J.L. 1990. Bullatacin,
bullatacinone, and squamone, a new bioactive acetogenin, from the bark of Annona squamosa. J. Nat. Prod. 53: 81–86.
Lin, C.-C. and Lin, C.-H. 1993. Pharmacological and pathological studies on Taiwan folk medicine (IX): the hepatoprotective
effect of the methanolic extract from Echinops grijisii. Am. J. Chin. Med. 21: 33–44.
Lin, Y.-L., Huang, R.-L., Chang, C.-M. and Kuo, Y.-H. 1997. Two new puriniums and three new pyrimidines from Heterostemma
brownii. J. Nat. Prod. 60: 982–985.
Ling, H.-C., King, M.-L., Su, M.-H., Chen, G.-L. and Wang, C.-T. 1981. Study on antitumor plant Gymnosporia trilocularis.
J. Chin. Chem. Soc. 28: 95–101.
Luo, S.-Q., Lin, L.-Z., Cordell, G.A., Xue, L. and Johnson, M.E. 1993. Polyoxypregnanes from Marsdenia tenacissima.
Phytochemistry 34: 1615–1620.
Malek, S.N.A., Lee, G.S., Hong, S.L., Yaacob, H., Wahab, N.A., Faizal Weber, J.-F. and Shah, S.A.A. 2011. Phytochemical
and cytotoxic investigations of Curcuma mangga rhizomes. Molecules 16: 4539–4548.
Mata, R., Rivero-Cruz, J.F. and Chávez, D. 2001. Bioactive secondary metabolites from selected Mexican medicinal plants:
recent progress. In: Bioactive compounds from natural sources: isolation, characterization and biological properties.
Taylor and Francis Group, New York.
MEDS - Medical Expenditure Panel Survey from AHRQ - Agency for Healthcare Research and Quality. Summary Data Tables
Search Results. 2014. https://meps.ahrq.gov/data_stats/quick_tables_results.jsp?component=1&subcomponent=0&tabl
eSeries=2&year=-1&SearchMethod=1&Action=Search (accessed 8.11.17).
Mena-Rejón, G., Caamal-Fuentes, E., Cantillo-Ciau, Z., Cedillo-Rivera, R., Flores-Guido, J. and Moo-Puc, R. 2009. In vitro
cytotoxic activity of nine plants used in Mayan traditional medicine. J. Ethnopharmacol. 121: 462–465.
Momekova, D., Momekov, G., Pencheva, I. and Konstantinov, S. 2012. Antineoplastic activity of a methanolic extract from
Kigelia pinnata DC stem bark. J. Cancer Ther. Res. 1: 17 (8 p.).
Monteiro, L.S., Bastos, K.X., Barbosa-Filho, J.M., de Athayde-Filho, P.F., Diniz, M.F.F.M. and Sobral, M.V. 2014. Medicinal
plants and other living organisms with antitumor potential against lung cancer. Evid. Based Complement. Alternat. Med.
2014: 604152 (15 p.).
Naama, J.H., Al-Temimi, A.A. and Hussain Al-Amiery, A.A. 2010. Study the anticancer activities of ethanolic curcumin
extract. Afr. J. Pure Appl. Chem. 4: 68–73.
Nantapap, S., Loetchutinat, C., Meepowpan, P., Nuntasaen, N. and Pompimon, W. 2010. Antiproliferative effects of alkaloids
isolated from the tuber of Stephania venosa via the induction of cell cycle arrest in mammalian cancer cell lines. Am.
J. Appl. Sci. 7: 1057–1065.
NCI - National Cancer Institute. 2017. Cancer statistics. https://www.cancer.gov/about-cancer/understanding/statistics
(accessed 8.11.17).
Nema, R., Khare, S., Jain, P. and Pradhan, A. 2013. Anticancer activity of Withania somnifera (leaves) flavonoids compound.
Int. J. Pharm. Sci. Rev. Res. 19: 103–106.
Neves, M.P., Cidade, H., Pinto, M., Silva, A.M., Gales, L., Damas, A.M., Lima, R.T., Vasconcelos, M.H. and de São José
Nascimento, M. 2011. Prenylated derivatives of baicalein and 3,7-dihydroxyflavone: synthesis and study of their effects
on tumor cell lines growth, cell cycle and apoptosis. Eur. J. Med. Chem. 46: 2562–2574.
Ni, G., Zhang, H., Liu, H.-C., Yang, S.-P., Geng, M.-Y. and Yue, J.-M. 2013. Cytotoxic sesquiterpenoids from Sarcandra
glabra. Tetrahedron 69: 564–569.
Niwat, K., Itharat, A., Aranya, T., Suttipong, R. and Preecha, I. 2001. Cytotoxic alkaloids from the tuber of Stephania venosa.
J. Sci. Technol. 23: 225–234.
Nopsiri, W., Chansakaow, S., Putiyanan, S., Natakankitkul, S. and Santiarworn, D. 2014. Antioxidant and anticancer activities
from leaf extracts of four Combretum species from Northern Thailand. CMU J. Nat. Sci. 13: 195–205.
Oliveira, V.B., Freitas, M.S.M., Mathias, L., Braz-Filho, R. and Vieira, I.J.C. 2009. Biological activity and indole alkaloids
of the genus Aspidosperma (Apocynaceae): a review. Rev. Bras. Plantas Med. 11: 92–99.
Pan, X., Matsumoto, M., Nakamura, Y., Kikuchi, T., Zhang, J., Ukiya, M., Suzuki, T., Koike, K., Akihisa, R. and Akihisa, T.
2014. Three new and other limonoids from the hexane extract of Melia azedarach fruits and their cytotoxic activities.
Chem. Biodivers 11: 987–1000.
Park, Y., Han, J., Lee, T. and Kim, D. 2005. Growth inhibitory and antioxidative effects of crude methanolic extract from
Euonymus alatus (Thunb.) Sieb on SKBR3 human breast cancer cell line. J. Orient. Obstet. Gynecol. 18: 45–54.
Paul, R., Prasad, M. and Sah, N.K. 2011. Anticancer biology of Azadirachta indica L. (neem): a mini review. Cancer Biol.
Ther. 12: 467–476.
Pecere, T., Gazzola, M.V., Mucignat, C., Parolin, C., Vecchia, F.D., Cavaggioni, A., Basso, G., Diaspro, A., Salvato, B., Carli,
M. and Palù, G. 2000. Aloe-emodin is a new type of anticancer agent with selective activity against neuroectodermal
tumors. Cancer Res. 60: 2800–2804.
Peng, C.-Y., Liu, J.-Q., Zhang, R. and Shu, J.-C. 2014. A new alkaloid from the fruit of Nandina domestica Thunb. Nat. Prod.
Res. 28: 1159–1164.
Perdue, G.P. and Blomster, R.N. 1978. South American plants III: Isolation of fulvoplumierin from Himatanthus sucuuba (M.
Arg.) Woodson (Apocynaceae). J. Pharm. Sci. 67: 1322–1323.
Priyadarsini, R.V., Murugan, R.S., Sripriya, P., Karunagaran, D. and Nagini, S. 2010. The neem limonoids azadirachtin and
nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells. Free
Radic. Res. 44: 624–634.
Rai, M., Jogee, P.S., Agarkar, G. and dos Santos, C.A. 2016. Anticancer activities of Withania somnifera: current research,
formulations, and future perspectives. Pharm. Biol. 54: 189–197.
Ravipati, A.S., Zhang, L., Koyyalamudi, S.R., Jeong, S.-C., Reddy, N., Bartlett, J.R., Smith, P.T., de Pedro, N., Melguizo, A.,
Cantizani, J., Asensio, F. and Vicente, F. 2013. Anti-proliferative activities of selected Chinese medicinal herbs against
human cancer cell lines. Phytopharmacology 4: 206–219.
Réthy, B., Csupor-Löffler, B., Zupkó, I., Hajdú, Z., Máthé, I., Hohmann, J., Rédei, T. and Falkay, G. 2007. Antiproliferative
activity of Hungarian Asteraceae species against human cancer cell lines. Part I. Phytother. Res. 21: 1200–1208.
Rodríguez, F.M., López, M.R., Jiménez, I.A., Moujir, L., Ravelo, A.G. and Bazzocchi, I.L. 2005. New phenolic triterpenes
from Maytenus blepharodes. Semisynthesis of 6-deoxoblepharodol from pristimerin. Tetrahedron 61: 2513–2519.
Rossi, V., Jovicevic, L., Troiani, M.P., Bonanomi, M. and Mazzanti, G. 1990. Antiproliferative effects of Petiveria alliacea
on several tumor cell lines. Pharmacol. Res. 22(Suppl. 2): 434.
Rossi, V., Marini, S., Jovicevic, L., D’Atri, S., Turri, M. and Giardina, B. 1993. Effects of Petiveria alliacea L. on cell immunity.
Pharmacol. Res. 27(Suppl. 1): 111–112.
Roy, M.K., Kobori, M., Takenaka, M., Nakahara, K., Shinmoto, H., Isobe, S. and Tsushida, T. 2007. Antiproliferative effect
on human cancer cell lines after treatment with nimbolide extracted from an edible part of the neem tree (Azadirachta
indica). Phytother. Res. 21: 245–250.
Sagwan, S., Rao, D.V. and Sharma, R.A. 2011. In vitro antioxidant activity of Maytenus emarginata (Willd.) using DPPH
assay. J. Pharm. Res. 4: 2276–2278.
Scheck, A.C., Perry, K., Hank, N.C. and Clark, W.D. 2006. Anticancer activity of extracts derived from the mature roots of
Scutellaria baicalensis on human malignant brain tumor cells. BMC Complement. Altern. Med. 6: 27 (9 p.).
Schmidt, B.M., and Cheng, D.M.K. 2017. Ethnobotany: A phytochemical Perspective. John Wiley & Sons, Hoboken.
Shao, Z.-M., Shen, Z.-Z., Liu, C.-H., Sartippour, M.R., Go, V.L., Heber, D. and Nguyen, M. 2002. Curcumin exerts multiple
suppressive effects on human breast carcinoma cells. Int. J. Cancer 98: 234–240.
Sharma, J.V., Pitchaiah, G., Satyavati, D., Rao, J., Kumar, H. and Sanjay, H. 2011. In vitro anticancer of methanolic extract
of roots of Glochidion zeylanicum (Gaertn). Int. J. Pharma. Bio. Sci. 2: 760–764.
Shi, G., MacDougal, J.M. and McLaughlin, J.L. 1997. Bioactive annonaceous acetogenins from Rollinia mucosa.
Phytochemistry 45: 719–723.
Shi, G., Ye, Q., He, K., McLaughlin, J.L. and MacDougal, J.M. 1996. Rollinecins A and B: two new bioactive annonaceous
acetogenins from Rollinia mucosa. J. Nat. Prod. 59: 548–551.
Shi, M., Cai, Q., Yao, L., Mao, Y., Ming, Y. and Ouyang, G. 2006. Antiproliferation and apoptosis induced by curcumin in
human ovarian cancer cells. Cell Biol. Int. 30: 221–226.
Sichaem, J., Kaennakam, S., Siripong, P. and Tip-pyang, S. 2012. Tabebuialdehydes A-C, cyclopentene dialdehyde derivatives
from the roots of Tabebuia rosea. Fitoterapia 83: 1456–1459.
Singleterry, J. 2017. The costs of cancer. Available on-line https://www.acscan.org/policy-resources/costs-cancer.
Su, S., Wang, T., Chen, T., Duan, J., Yu, L. and Tang, Y. 2011. Cytotoxicity activity of extracts and compounds from Commiphora
myrrha resin against human gynecologic cancer cells. J. Med. Plants Res. 5: 1382–1389.
Sultana, S., Asif, H.M., Nazar, H.M., Akhtar, N., Rehman, J.U. and Rehman, R.U. 2014. Medicinal plants combating against
cancer—a green anticancer approach. Asian Pac. J. Cancer Prev. 15: 4385–4394.
Takagi, M., Tachi, Y., Zhang, J., Shinozaki, T., Ishii, K., Kikuchi, T., Ukiya, M., Banno, N., Tokuda, H. and Akihisa, T. 2014.
Cytotoxic and melanogenesis-inhibitory activities of limonoids from the leaves of Azadirachta indica (Neem). Chem.
Biodivers 11: 451–468.
Takemoto, T., Nishimoto, N., Nakai, S., Takagi, N., Hayashi, S., Odashima, S. and Wada, Y. 1983. Pfaffic acid, a novel
nortriterpene from Pfaffia paniculata Kuntze. Tetrahedron Lett. 24: 1057–1060.
Tan, M., Sulaiman, S. and Najimudin, N. 2007. Anticancer medicinal plant, Epipremnum pinnatum (L.) Engl. chloroform extracts
elicited both apoptotic and non-apoptotic cell deaths in T-47D mammary carcinoma cells. KMITL Sci. Tech. J. 7: 24–43.
Tan, M.L., Muhammad, T.S.T., Najimudin, N. and Sulaiman, S.F. 2005. Growth arrest and non-apoptotic programmed cell
death associated with the up-regulation of c-myc mRNA expression in T-47D breast tumor cells following exposure to
Epipremnum pinnatum (L.). Engl. hexane extract. J. Ethnopharmacol. 96: 375–383.
Tsui, W.-Y. and Brown, G.D. 1996. Cycloeudesmanolides from Sarcandra glabra. Phytochemistry 43: 819–821.
Tzeng, C.C., Wu, Y.C., Su, T.L., Watanabe, K.A., Lu, S.T. and Chou, T.C. 1990. Inhibitory effects of isoquinoline-type alkaloids
on leukemic cell growth and macromolecule biosynthesis. Kaohsiung J. Med. Sci. 6: 58–65.
Ukiya, M., Akihisa, T., Yasukawa, K., Tokuda, H., Suzuki, T. and Kimura, Y. 2006. Anti-inflammatory, anti-tumor-promoting,
and cytotoxic activities of constituents of marigold (Calendula officinalis) flowers. J. Nat. Prod. 69: 1692–1696.
Vega-Ávila, E., Tapia-Aguilar, R., Jiménez-Estrada, M., Villareal, M.L. and Ramos, R.R. 2004. Cytotoxic activity of Cuphea
aequipetala. Proc. West. Pharmacol. Soc. 47: 129–133.
Wang, W., Zhao, Y., Rayburn, E.R., Hill, D.L., Wang, H. and Zhang, R. 2007. In vitro anti-cancer activity and structure-activity
relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemother. Pharmacol. 59: 589–601.
Weissenstein, U., Kunz, M., Urech, K., Regueiro, U. and Baumgartner, S. 2016. Interaction of a standardized mistletoe (Viscum
album) preparation with antitumor effects of Trastuzumab in vitro. BMC Complement. Altern. Med. 16: 271 (10 p.).
Widowati, W., Mozef, T., Risdian, C. and Yellianty, Y. 2013. Anticancer and free radical scavenging potency of Catharanthus
roseus, Dendrophthoe petandra, Piper betle and Curcuma mangga extracts in breast cancer cell lines. Oxid. Antioxid.
Med. Sci. 2: 137–142.
Wong, K.T. and Tan, B.K.H. 1996a. In vitro cytotoxicity and immunomodulating property of Rhaphidophora korthalsii. J.
Wong, K.T., Tan, B.K.H., Sim, K.Y. and Goh, S.H. 1996b. A cytotoxic melanin precursor, 5,6-dihydroxyindole, from the
folkloric anti-cancer plant Rhaphidophora korthalsii. Nat. Prod. Lett. 9: 137–140.
WHO. 2015. Globocan 2012: Estimated Incidence, Mortality and Prevalence Worldwide in 2012.
Wu, F.E., Gu, Z.M., Zeng, L., Zhao, G.X., Zhang, Y., McLaughlin, J.L. and Sastrodihardjo, S. 1995. Two new cytotoxic
monotetrahydrofuran Annonaceous acetogenins, annomuricins A and B, from the leaves of Annona muricata. J. Nat.
Prod. 58: 830–836.
Wu, J.-B., Cheng, Y.-D., Chiu, N.-Y., Huang, S.-C. and Kuo, S.-C. 1993. A novel morphinandienone alkaloid from Fissistigma
oldhamii. Planta Med. 59: 179–180.
Wu, J.-T., Lu, S.M., Lu, C.-H., Gong, J. and An, J.-B. 2015. Effect of 3,3’-biisofraxidin on apoptosis of human gastric cancer
BGC-823 cells. Trop. J. Pharm. Res. 14: 1803–1811.
Wu, Q., Kohli, M., Bergen, H.R., Cheville, J.C., Karnes, R.J., Cao, H., Young, C.Y., Tindall, D.J., McNiven, M.A. and Donkena,
K.V. 2014. Preclinical evaluation of the supercritical extract of Azadirachta indica (neem) leaves in vitro and in vivo on
inhibition of prostate cancer tumor growth. Mol. Cancer Ther. 13: 1067–1077.
Yamashita, M., Kaneko, M., Iida, A., Tokuda, H. and Nishimura, K. 2007. Stereoselective synthesis and cytotoxicity of a cancer
chemopreventive naphthoquinone from Tabebuia avellanedae. Bioorg. Med. Chem. Lett. 17: 6417–6420.
Yamashita, M., Kaneko, M., Tokuda, H., Nishimura, K., Kumeda, Y. and Iida, A. 2009. Synthesis and evaluation of bioactive
naphthoquinones from the Brazilian medicinal plant, Tabebuia avellanedae. Bioorg. Med. Chem. 17: 6286–6291.
Yang, H.-S., Kim, J.-Y., Lee, J.-H., Lee, B.-W., Park, K.-H., Shim, K.-H., Lee, M.-K. and Seo, K.-I. 2011. Celastrol isolated
from Tripterygium regelii induces apoptosis through both caspase-dependent and -independent pathways in human breast
cancer cells. Food Chem. Toxicol. 49: 527–532.
Yen, C.-Y., Chiu, C.-C., Chang, F.-R., Chen, J.Y.-F., Hwang, C.-C., Hseu, Y.-C., Yang, H.-L., Lee, A.Y.-L., Tsai, M.-
T., Guo, Z.-L., Cheng, Y.-S., Liu, Y.-C., Lan, Y.-H., Chang, Y.-C., Ko, Y.-C., Chang, H.-W. and Wu, Y.-C. 2010.
4β-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through
DNA damage, apoptosis and G2/M arrest. BMC Cancer 10: 46 (8 p.).
Zeng, L., Wu, F.-E., Oberlies, N.H., McLaughlin, J.L. and Sastrodihadjo, S. 1996. Five new monotetrahydrofuran ring
acetogenins from the leaves of Annona muricata. J. Nat. Prod. 59: 1035–1042.
Zhang, L., Tatsuno, T., Hasegawa, I., Tadano, T. and Ohta, T. 2015. Furanonaphthoquinones from Tabebuia avellanedae
induce cell cycle arrest and apoptosis in the human non-small cell lung cancer cell line A549. Phytochem. Lett. 11: 9–17.
Zhang, P., Liang, D., Jin, W., Qu, H., Cheng, Y., Li, X. and Ma, Z. 2009. Cytotoxic thiophenes from the root of Echinops
grijisii Hance. Z. Naturforsch. C 64: 193–196.
Zhao, W., Entschladen, F., Liu, H., Niggemann, B., Fang, Q., Zaenker, K.S. and Han, R. 2003. Boswellic acid acetate induces
differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells. Cancer Detect. Prev. 27: 67–75.
Zhao, W., Wang, Y., Wang, Y., Gao, N., Han, Z. and Yu, H. 2015. Potential anti-cancer effect of curcumin in human lung
squamous cell carcinoma. Thorac. Cancer 6: 508–516.
Zhou, S., Yao, D., Guo, L. and Teng, L. 2017. Curcumin suppresses gastric cancer by inhibiting gastrin-mediated acid secretion.
FEBS Open Bio. 7: 1078–1084.
2
Use of Ethnomedicinal Herbs to
Treat and Manage Schistosomiasis in
Zimbabwe: Past Trends and
Future Directions
Alfred Maroyi
Introduction
Schistosomiasis also known as bilharzia is a freshwater snail transmitted intravascular debilitating disease
resulting from infection by the parasitic dimorphic Schistosoma trematode worms which live in the
bloodstream of humans (Steinmann et al. 2006, Inobaya et al. 2014, Adenowo et al. 2015, WHO 2017a).
Schistosomiasis is a neglected tropical disease that ranks second only to malaria in terms of human suffering
in the tropics and subtropics (Inobaya et al. 2014). Reports by the World Health Organization (WHO
2017a) showed that at least 218 million people required preventive treatment for schistosomiasis and
more than 66.5 million people were reported to have been treated for the disease in 2015. Schistosomiasis
transmission has been reported from 78 countries while preventive chemotherapy for schistosomiasis is
required in 52 countries where the disease is endemic with moderate-to-high transmission (WHO 2017a).
According to WHO (2017b), schistosomiasis causes more than 200,000 deaths per year in sub-Saharan
Africa. Previous reports by Adenowo et al. (2015) revealed that sub-Saharan Africa accounted for 93% (192
million) of the world estimated 207 million cases of schistosomiasis in 2014 with the highest prevalence of
this infection recorded in Nigeria (29 million), followed by Tanzania (19 million), Ghana and Democratic
Republic of Congo with 15 million each and Mozambique with 13 million. Schistosomiasis causes great
health, social and financial burden on economies of households and governments in sub-Saharan Africa
with profound negative effects on child development, outcome of pregnancy, and agricultural productivity
(Adenowo et al. 2015). Schistosomiasis is more rampant in poor and marginalized rural communities where
fishing and agricultural activities are dominant (Adenowo et al. 2015, WHO 2017a). Women and children
Medicinal Plants and Economic Development (MPED) Research Center, Department of Botany, University of Fort Hare,
Private Bag X1314, Alice 5700, South Africa.
E-mail: amaroyi@ufh.ac.za
doing domestic chores such as washing clothes and fetching water in infected water sources are at risk
as inadequate hygiene and contact with infected water expose such people to schistosomiasis infection.
There are two major forms of schistosomiasis, namely intestinal and urogenital caused by five digenean
blood flukes of the genus Schistosoma (WHO 2017a). Schistosoma haematobium causes urogenital
schistosomiasis in Africa, the Middle East and Corsica in France (WHO 2017a) affecting about 54 countries
in total (Ojewole 2004). The other four Schistosoma species are responsible for intestinal schistosomiasis
with Schistosoma mansoni distributed in Africa, Brazil, the Caribbean, the Middle East, Suriname and
Venezuela, Schistosoma japonicum (China, Indonesia and the Philippines), Schistosoma mekongi (several
districts in Cambodia and Lao People’s Democratic Republic), Schistosoma guineensis and closely related
Schistosoma intercalatum (confined to the rain forest areas of central Africa) (WHO 2017a). Schistosomiasis
is spread when the larvae of Schistosoma species are liberated by the infected snail, intermediary host, get
in contact with the human host and subsequently penetrate the skin. Therefore, in humans, schistosomiasis
is spread through skin contact with fresh water containing infectious larvae of Schistosoma species.
Biomphalaria snails are responsible for the transmission of Schistosoma mansoni, Bulinus snails transmit
Schistosoma haematobium while Schistosoma japonicum is spread by the freshwater snail Oncomelania
(Adenowo et al. 2015). Once inside the human body, the pathogens differentiate into schistosomules, which
migrate via the bloodstream to the liver and develop into male and female mature forms (Ndjonka et al.
2013). After mating, the worms migrate again and relocate at the mesenteric intestinal veins or the venous
plexus of the urinary system. The females release eggs, which are able to pass epithel of the blood vessels
and reach the intestinal lumen, the bladder or urethra lumen in order to be expelled by faeces or urine.
Some of these eggs also remain in these tissues and the damage of blood vessels, together with immune
reactions against the retained eggs are responsible for the clinical forms of schistosomiasis (Ndjonka et
al. 2013). According to WHO (2017a), intestinal schistosomiasis can result in abdominal pain, diarrhoea,
and blood in the stool. Liver enlargement is common in advanced cases, and is frequently associated with
an accumulation of fluid in the peritoneal cavity and hypertension of the abdominal blood vessels. The
classic sign of urogenital schistosomiasis is haematuria (blood in urine), fibrosis of the bladder and ureter,
and kidney damage are sometimes diagnosed in advanced cases of urogenital schistosomiasis (WHO
2017a). Bladder cancer is another possible complication in the later stages of urogenital schistosomiasis.
In women, urogenital schistosomiasis may present with genital lesions, vaginal bleeding, pain during
sexual intercourse and nodules in the vulva. In men, urogenital schistosomiasis can induce pathology of
the seminal vesicles, prostate and other organs. This disease may also have other long-term irreversible
consequences such as infertility in both men and women (WHO 2017a). The economic and health effects
of schistosomiasis are considerable and the disease disables more than it kills. In children, schistosomiasis
can cause anaemia, stunting and a reduced ability to learn, although the effects are usually reversible with
treatment and chronic schistosomiasis may affect people’s ability to work and in some cases can result
in death (WHO 2017a).
Schistosomiasis in Zimbabwe
Before the advent of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome
(AIDS), schistosomiasis was ranked second after malaria in terms of public health importance in Zimbabwe
(Chimbari 2012). Schistosomiasis has for several years been among the top 10 causes of hospital admissions
in Zimbabwe, an indication of its public health importance (Chimbari 2012). Both urinary and intestinal
schistosomiasis are endemic in Zimbabwe, caused by Schistosoma haematobium and Schistosoma
mansoni respectively. The disease is widespread throughout the country in both rural and urban areas
with Schistosoma haematobium more widespread than Schistosoma mansoni at prevalences of 18.0% and
7.2% respectively (Midzi et al. 2014). In Zimbabwe, Schistosoma haematobium and Schistosoma mansoni
are transmitted by the intermediate snail hosts Bulinus globosus and Biomphalaria pfeifferi respectively
(Pedersen et al. 2017) with both snail species common in most bodies of fresh water in the country.
Schistosomiasis control in Zimbabwe included control of intermediate host snails Biomphalaria pfeifferi
and Bulinus globosus and treatment based approach (Chimbari 2012), see Table 2.1.
Use of Ethnomedicinal Herbs to Treat and Manage Schistosomiasis in Zimbabwe 37
Table 2.1 Schistosomiasis control in Zimbabwe.
Control model Relevant notes

Two plant-based molluscides Phytolacca dodecandra has been studied in sufficient detail to justify its application
(Phytolacca dodecandra L’Hér. while Jatropha curcas studies were only done in the laboratory (Chimbari 2012). The
and Jatropha curcas L.) have potency of water extracts of Jatropha curcas is much lower (75 ppm) compared to that
been studied with a view to use of Phytolacca dodecandra (10 ppm) implying that larger quantities of the former would
them in preference to the WHO be required to sustain snail control activities. This control model has been characterized
recommended molluscicide, by low level community participation, poor leadership, low economic value of the
niclosamide plant, inaccessible fields, and lack of tangible benefits (Chimbari 2012). Other plant
species that have been used for schistosomiasis control in Zimbabwe with known
molluscicidal properties include Combretum imberbe Wawra, Ricinus communis L.,
Trichilia emetica Vahl, Vernonia amygdalina Delile and Ximenia caffra Sond (Ojewole
2004).
Ducks were introduced as a According to Chimbari (2012) ducks made significant impact in reducing snail numbers
strategy to control intermediate in ponds but the costs associated with transportation of the ducks and looking after
host snails for schistosomiasis them to avoid poaching were high. Furthermore, the breeding and maintenance costs of
the ducks were high as they were exotic species (Chimbari 2012).
Fish (Sargochromis Comprehensive studies showed that pulmonates and not necessarily intermediate host
codringtonii) was introduced as snails were preferred by the fish (Sargochromis codringronii) and that vegetation
a strategy to control intermediate provided refugia for snails against the predator fish (Chimbari 2012). Sargochromis
host snails for schistosomiasis codringronii was often attacked by a fish herbivore (Tilapia rendalli), and Sargochromis
codringronii could only acclimatize to small ponds (100 m X 100 m X 1–1.5 m depth)
in some regions of the country (Chimbari 2012).
Competitor snail (Bulinus Laboratory studies showed significant reduction in reproductivity of Bulinus globosus
tropicus) was introduced as a in the presence of the competitor snail (Bulinus tropicus) and evidence of Bulinus
strategy to control intermediate tropicus preying on Bulinus globosus eggs, but further enclosure studies did not show
host snails for schistosomiasis any significant effect of Bulinus tropicus on Bulinus globosus population density
suggesting the competition between the two snail species was not an important control
strategy of schistosomiasis in Zimbabwe (Chimbari 2012).
Use of praziquantel
Praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis in Zimbabwe. According to
Magnussen (2003), a single dose of 40 mg/kg has been widely accepted as the standard dosage resulting
in cure rates of 60 to 95%. Research done by Doenhoff et al. (2008) and Aragon et al. (2009) revealed that
PZQ is not 100% curative in killing adult worms, cannot kill migrating schistosomulae or the early stages
of the disease and does not prevent re-infection. Until recently, children aged five years and below were
excluded from schistosome treatment using PZQ, creating a health inequity in affected populations (Mutapi
et al. 2011). Research by Mutapi et al. (2011) revealed that PZQ treatment is as safe and efficacious in
children aged one to five years as it is in older children in whom PZQ is the drug of choice for control of
schistosome infections. In affected populations, children carry the heaviest burden of schistosome infection
(Gryseels and de Vlas 1996, Midzi et al. 2008, Mutapi et al. 2011) with urogenital schistosomiasis causing
haematuria, dysurea, nutritional deficiencies, anaemia, growth retardation, decreased physical performance
and impaired memory and cognition in young children (Mutapi et al. 2011). Control of schistosome
infections is through treatment of infected people with a single dose of the anthelmintic drug PZQ which
is safe, cheap (costing less than US$0.50/dose) and can reverse schistosome-related morbidity particularly
in the early stages of disease progression (King 2006, Mutapi et al. 2011). In South Africa, only Bayer’s
Biltricide® (PZQ) is available for the treatment of schistosomiasis at a cost of US$4.49 per tablet making
mass treatment programmes unaffordable and almost impossible to run in the country (Magaisa et al.
2015). Research by Magaisa et al. (2015) revealed that PZQ is not fully stocked in local clinics in South
Africa as the drug is considered to be too expensive. In 2010, the WHO updated their recommendations
for the treatment of schistosomiasis in children aged five years and below, allowing regular pre-school
based deworming using PZQ, aimed at reducing morbidity and promoting child health (Mutapi 2015).
Previous research by Midzi et al. (2008) and Mutapi et al. (2011) showed that PZQ usage in Zimbabwe is
efficacious, with schistosome cure and egg reduction rates typically greater than 90%.
According to Ross et al. (2017), the PZQ strategy of eliminating schistosomiasis is failing and will not
lead to disease elimination as only 5% of the reservoir human population is actually receiving intermittent
chemotherapy. This strategy is failing because the drugs are not getting to the people who need them the
most, the current global coverage is 20%, the drug compliance rate is less than 50% and the drug efficacy
is approximately 50% (Ross et al. 2017). Adverse effects associated with PZQ usage including fatigue,
urticaria, gastrointestinal and abdominal pains, nausea, vomiting, headache and dizziness (Mutapi 2015).
Researchers such as Neves et al. (2015) are concerned about reliance on a single PZQ drug for treating and
managing schistosome infections which are known to be affecting 249 million people. Praziquantel is now
facing the threat of drug resistance as revealed by both laboratory and field trials (Fallon and Doenhoff
1994, Ismail et al. 1994, Fallon et al. 1995, Ismail et al. 1996, Melman et al. 2009, Couto et al. 2011). These
reports of PZQ resistance indicates the need for new effective compounds to treat and manage schistosome
infections, and globally, there is renewed interest in natural products as a starting point for drug discovery
and development for schistosome infections (Ndjonka et al. 2013, Neves et al. 2015).
Potential of herbal medicines in treating and managing schistosomiasis in

Zimbabwe
The only control method of schistosomiasis in Zimbabwe that has been successful is the use of PZQ. Other
strategies meant to reduce schistosome infection include educating the public about sanitation, use of
clean water and avoiding infected water bodies. The interest in medicinal plants used as herbal medicines
for shistosomiasis or bilharzia (Gelfand et al. 1985, Hedberg and Staugard 1989, Ndamba et al. 1994,
Hutchings et al. 1996, Mavi 1996, Clark et al. 1997, Sparg et al. 2000, Mølgaard et al. 2001, Maroyi 2011,
Aremu et al. 2012) and PZQ developing drug resistances (Fallon and Doenhoff 1994, Ismail et al. 1994,
Fallon et al. 1995, Ismail et al. 1996, Melman et al. 2009, Couto et al. 2011), and the limited access of
poor communities and those in marginalized areas to PZQ have stimulated renewed interest in the current
use and future potential of plant products in treating schistosomiasis, both as part of traditional health
care practices and in developing new conventional medicines. In this study, 35 plant species belonging to
16 families and 32 genera are known to be widely used in the treatment and management of schistosomiasis
in Zimbabwe (Table 2.2). Plant species recorded in Table 2.2 have been cited by at least two independent
researchers as herbal medicines for schistosomiasis or cited by at least one researcher but are also known
to have anthelmintic bioactivity based on in vitro or in vivo studies. The majority of these plant species
(65.7%) are from four families, Fabaceae with 13 species, followed by Anacardiaceae with four species,
and Asteraceae and Combretaceae families with three species each. The rest of the plant families are
represented by a single species each, and the most common genera are Lannea, Terminalia and Vernonia
with two species each (Table 2.2).
Shrubs (42.8%) and trees (40.0%) appear to be the primary sources of herbal medicines used for
treating and managing schistosomiasis in Zimbabwe (Fig. 2.1A). The roots are the most frequently used
plant parts (91.4%), followed by the bark (22.9%) and leaves (14.3%) (Fig. 2.1B). All plant remedies are
usually utilized in the form of extracts and taken orally (Table 2.2). Monotherapy preparations made from
a single plant species are the most dominant (74.3%) form of herbal preparations (Table 2.2). Apart from
roots of Elephantorrhiza goetzei (Harms) Harms which are mixed with those of Piliostigma thonningii
(Schumach.) Milne-Redh. (Gelfand et al. 1985, Ndamba et al. 1994), the remainder of the species (17.1%)
are mixed with Vigna unguiculata (L.) Walp. (Table 2.2). Research conducted by Gelfand et al. (1985) and
Ndamba et al. (1994) revealed that roots of Vigna unguiculata are usually mixed with Eriosema englerianum
Harms, Erythrina abyssinica Lam. ex DC., Euclea divinorum Hiern, Lannea edulis (Sond.) Engl., Terminalia
sericea Burch. ex DC. and Vernonia amygdalina Delile as herbal medicine for schistosomiasis.
More than three quarters (88.6%) of the plant species widely used as herbal medicines for treating and
managing schistosomiasis in Zimbabwe exhibited various degrees of anthelmintic activities (Table 2.3).
Research conducted by Molgaard et al. (2001) which evaluated anthelmintic activities of Zimbabwean
plants traditionally used against schistosomiasis revealed that the extracts of stem and root of Abrus
precatorius, root bark and leaves of Ozoroa insignis and root bark of Ziziphus mucronata showed the best
Table 2.2 Zimbabwean medicinal plants with potential value as schistosomiasis remedies.
Plant species Family Habit Plant parts used Other countries with References
similar uses
Abrus precatorius L. Fabaceae Climber Root DRC, South Africa Staner and Boutique 1937, Ndamba et al.
1994, Hutchings et al. 1996
Acacia karroo Hayne Fabaceae Tree Roots Ndamba et al. 1994
Albizia antunesiana Harms Fabaceae Tree Bark Ndamba et al. 1994
Cassia abbreviata Oliver Fabaceae Shrub Bark, roots Ndamba et al. 1994
Celtis africanus N. L. Burm. Ulmaceae Tree Leaves, roots Ndamba et al. 1994
Cissampelos mucronata A. Rich. Menispermaceae Climber Roots South Africa Gelfand et al. 1985, Hutchings et al.
1996, van Wyk and Gericke 2000, Sparg
et al. 2000
Combretum imberbe Wawra Combretaceae Tree Roots Mozambique, South Gelfand et al. 1985, Venter and Venter
Africa 1996, Ribeiro et al. 2010
Dicoma anomala Sonder Asteraceae Herb Roots South Africa, Tanzania Watt and Breyer-Brandwijk 1962,
Ndamba et al. 1994
Elephantorrhiza goetzei (Harms) Harms Fabaceae Shrub Roots mixed with Piliostigma thonningii Gelfand et al. 1985, Ndamba et al. 1994,
(Schumach.) Milne-Redh. Maroyi 2011
Eriosema englerianum Harms Fabaceae Herb Roots taken orally mixed with Vigna Gelfand et al. 1985
unguiculata (L.) Walp.
Erythrina abyssinica Lam. ex DC. Fabaceae Tree Roots taken orally mixed with Vigna Kenya Kokwaro 1976, Gelfand et al. 1985
unguiculata
Euclea divinorum Hiern Ebenaceae Shrub Roots taken orally mixed with Vigna South Africa, Kenya Kokwaro 1976, Gelfand et al. 1985,
unguiculata Ndamba et al. 1994, Hutchings et al.
1996
Flacourtia indica (Burm. f.) Merr. Salicaceae Shrub Roots Malawi Williamson 1975, Gelfand et al. 1985
Gymnosporia senegalensis (Lam.) Loes. Celastraceae Shrub Roots South Africa, Tanzania Burkill 1985, Gelfand et al. 1985,
Ndamba et al. 1994, Hutchings et al.
1996
Lannea discolor (Sond.) Engl. Anacardiaceae Tree Bark, leaves Ndamba et al. 1994
Lannea edulis (Sond.) Engl. Anacardiaceae Shrub Roots taken orally mixed with Vigna Malawi Gelfand et al. 1985, Ndamba et al. 1994,
unguiculata Chigora et al. 2007
Lecaniodiscus fraxinifolius Baker Sapindaceae Shrub Bark, roots Ndamba et al. 1994
Mondia whitei (Hook. f.) Skeels Apocynaceae Climber Roots South Africa Gelfand et al. 1985, Hutchings et al. 1996

...Table 2.2 contd.
Plant species Family Habit Plant parts used Other countries with References
similar uses
Ozoroa insignis Delile Anacardiaceae Tree Roots Gelfand et al. 1985, Ndamba et al. 1994
Peltophorum africanum Sonder Fabaceae Tree Bark, roots Ndamba et al. 1994
Piliostigma thonningii (Schumach.) Milne- Fabaceae Tree Roots mixed with Elephantorrhiza Ndamba et al. 1994, Maroyi 2011
Redh. goetzei
Pterocarpus angolensis DC. Fabaceae Tree Bark, roots South Africa, Zambia Watt and Breyer-Brandwijk 1962,
Gelfand et al. 1985, Ndamba et al. 1994,
Hutchings et al. 1996, Mavi 1996, Venter
and Venter 1996
Ricinus communis L. Euphorbiaceae Shrub Roots Gelfand et al. 1985, Ndamba et al. 1994
Sclerocarya birrea (A. Rich.) Hochst. Anacardiaceae Tree Roots South Africa Gelfand et al. 1985, Hutchings et al. 1996
Senna singueana (Delile) Lock Fabaceae Shrub Bark, roots Ndamba et al. 1994
Solanum delagoense Dunal Solanaceae Shrub Roots Ndamba et al. 1994
Steganotaenia araliacea Hochst Apiaceae Shrub Bark, leaves, roots Zambia Storrs 1979, Ndamba et al. 1994
Terminalia brachystemma Welw. Combretaceae Shrub Roots Ndamba et al. 1994

Terminalia sericea Burch. ex DC. Combretaceae Tree Roots taken orally mixed with Vigna Kenya, South Africa, Watt and Breyer-Brandwijk 1962,
unguiculata Tanzania Kokwaro 1976, Gelfand et al. 1985,
Mavi 1996
Trichilia emetica Vahl Meliaceae Tree Bark, leaves Ndamba et al. 1994
Vernonia amygdalina Delile Asteraceae Shrub Roots taken orally mixed with Vigna Kenya Kokwaro 1976, Gelfand et al. 1985,
unguiculata Ndamba et al. 1994
Vernonia colorata (Willd.) Drake Asteraceae Shrub Roots Ivory Coast Burkill 1985, Gelfand et al. 1985
Vigna unguiculata (L.) Walp. Fabaceae Herb Roots taken orally mixed with Eriosema Gelfand et al. 1985, Ndamba et al. 1994
englerianum, Erythrina abyssinica,
Euclea divinorum, Lannea edulis,
Terminalia sericea and Vernonia
amygdalina
Ximenia caffra Sond. Ximeniaceae Shrub Leaves, roots South Africa Ndamba et al. 1994, Hutchings et al.
1996, Chauke et al. 2015
Ziziphus mucronata Willd. Rhamnaceae Tree Roots Gelfand et al. 1985, Ndamba et al. 1994
Table 2.3 Zimbabwean medicinal plants used against schistosomiasis that have been screened for anthelmintic activities.
Plant species Plant parts tested Test organism Concentration Safety findings References
(mg/mL)
Abrus precatorius Leaves, roots, stem Hymenolepis diminuta 0.2–4.9 Positive - brine shrimp toxicity assay Molgaard et al. 2001, Maregesi et al.
Schistosoma mansoni 0.6–1.5 2016
Acacia karroo Leaves, roots Hymenolepis diminuta 0.8–2.1 Positive - brine shrimp toxicity assay Sparg et al. 2000, Molgaard et al. 2001,
Schistosoma haematobium 50.0 Positive/negative - acute and sub-acute Adedapo et al. 2008, Cock and van
mammalian toxicity tests Vuuren 2015
Albizia antunesiana Bark, leaves, roots, stem Hymenolepis diminuta 1.1–6.3 Negative - MTT assay Molgaard et al. 2001, Chipiti et al. 2013
Cassia abbreviata Bark, leaves, roots Hymenolepis diminuta 0.5–67.5 Positive - brine shrimp toxicity assay Molgaard et al. 2001, Moshi et al. 2007
Celtis africanus Leaves, roots Hymenolepis diminuta 0.5–3.9 Negative - ames and VITOTOX® and Molgaard et al. 2001, Elgorashi et al.
positive - micronucleus test 2003, Taylor et al. 2003
Combretum imberbe Leaves, roots Schistosoma haematobium 12.5 Negative - biochemical induction assay McGaw et al. 2001, Sparg et al. 2001
Dicoma anomala Roots Hymenolepis diminuta 1.0 Negative - brine shrimp toxicity assay Molgaard et al. 2001, Munodawafa et
al. 2017
Elephantorrhiza Bark, fruits, leaves, roots, stem Hymenolepis diminuta 0.5–42.2 Positive - brine shrimp toxicity assay Molgaard et al. 2001, Wanjala and
goetzei Bark Schistosoma mansoni 0.8 Majinda 2001
Erythrina abyssinica Bark, leaves, stem Ascaridia galli 0.8–1.7 Positive - in vivo haematinic activity Lagu and Kayanja 2013, Musyoka et
al. 2016
Euclea divinorum Bark Caenorhabditis elegans 1.0 Positive (toxic) - ames and VITOTOX® McGaw et al. 2000, Sparg et al. 2000,
Root Schistosoma haematobium 25.0 Elgorashi et al. 2003
Gymnosporia Bark, leaves, roots, stem Hymenolepis diminuta 2.5–6.3 Positive - vero cells Molgaard et al. 2001, Nabende et al.
senegalensis Bark Schistosoma mansoni 100 2015
Lannea discolor Leaves, stem Hymenolepis diminuta 2.5 Positive - MTT assay and vero African Molgaard et al. 2001, Kabongo-Kayoka
monkey kidney cells et al. 2016
Lannea edulis Leaves, stem Hymenolepis diminuta 3 Negative - brine shrimp toxicity assay Molgaard et al. 2001, Munodawafa et
al. 2017
Lecaniodiscus Leaves, roots, stem Hymenolepis diminuta 1.6–3.1 - Molgaard et al. 2001
fraxinifolius
Mondia whitei Roots Schistosoma haematobium 50 Positive - acute and sub-acute mammalian Sparg et al. 2000, Joseph et al. 2015
toxicity tests
Ozoroa insignis Bark, leaves, roots, stem Hymenolepis diminuta 0.8–51.3 Positive - brine shrimp toxicity assay Molgaard et al. 2001, Haule et al. 2012
Bark, leaves, roots Schistosoma mansoni 25.3–33.8

...Table 2.3 contd.
Plant species Plant parts tested Test organism Concentration Safety findings References
(mg/mL)
Peltophorum Bark, leaves, roots, stem Hymenolepis diminuta 0.5–0.8 Positive - vero cells Molgaard et al. 2001, Bizimenyera et
africanum Bark, leaves, roots Hymenolepis contortus 1.0–5.0 Negative - brine shrimp toxicity assay; al. 2006b, Bizimenyera 2007, Samie et
and vero monkey kidney cells cytotoxicity al. 2009
assay
Piliostigma thonningii Bark, leaves, roots, stem Hymenolepis diminuta 0.3–2.2 Positive - acute and sub-acute mammalian Molgaard et al. 2001, Ukwuani et al.
toxicity tests 2012
Pterocarpus Bark, leaves, stem Hymenolepis diminuta 12.8–67.6 Positive - brine shrimp toxicity assay Molgaard et al. 2001, McGaw et al.
angolensis Bark Schistosoma mansoni 70.0 2007
Ricinus communis Leaves Caenorhabditis elegans 1.0 Negative - ames and VITOTOX®; and Sparg et al. 2000, Elgorashi et al. 2003,
Leaves + stem positive - brine shrimp toxicity assay Taylor et al. 2003, McGaw et al. 2007
Roots Schistosoma haematobium 25.0 Positive - micronucleus test
Sclerocarya birrea Bark Caenorhabditis elegans 0.5–2.0 Negative - brine shrimp toxicity assay McGaw et al. 2007
Senna singueana Bark, leaves, roots, stem Hymenolepis diminuta 0.5–4.0 Negative - modified Lorke’s method Molgaard et al. 2001, Ior et al. 2015
Solanum delagoense Leaves, roots Hymenolepis diminuta 0.4–4.2 - Molgaard et al. 2001
Steganotaenia Bark, leaves, roots, stem Hymenolepis diminuta 7.8–33.8 Positive - acute and sub-acute mammalian Molgaard et al. 2001, Agunu et al. 2003
araliacea toxicity tests
Terminalia Fruits, leaves, roots Hymenolepis diminuta 0.5–1.7 - Molgaard et al. 2001
brachystemma
Trichilia emetica Bark, leaves, roots Hymenolepis diminuta 21.2–25.6 Negative - ames and VITOTOX®; Molgaard et al. 2001, Elgorashi et al.
positive - micronucleus test 2003, Taylor et al. 2003
Vernonia amygdalina Bark, leaves, roots, stem Hymenolepis diminuta 3.4–11.6 Negative - acute and sub-acute Molgaard et al. 2001, Amole et al. 2006
mammalian toxicity tests
Vernonia colorata Roots Schistosoma haematobium 50.0 Negative - ames and VITOTOX®; and Sparg et al. 2000, Elgorashi et al. 2003,
positive (toxic) - micronucleus test and Taylor et al. 2003
comet assay
Ximenia caffra Bark, leaves, roots, stem Hymenolepis diminuta 0.5–0.8 Positive - vero cells Kamuhabwa et al. 2000, Sparg et al.
Roots Schistosoma haematobium 50.0 Positive - antiproliferative assay with 2000, Molgaard et al. 2001, Samie et
three human cell lines (HeLa, HT29 and al. 2009
A431)
Ziziphus mucronata Bark, leaves, roots, stem Hymenolepis diminuta 0.02–51.8 Positive - ames and VITOTOX®; Sparg et al. 2000, Molgaard et al. 2001,
Roots Schistosoma haematobium 12.5 micronucleus test and comet assay; and Elgorashi et al. 2003, Taylor et al. 2003,
brine shrimp toxicity assay McGaw et al. 2007
Fig. 2.1 Characteristics of the plants used as herbal medicines in treating and managing schistosomiasis in Zimbabwe. (A)
Growth form habit represented in pie diagram and (B) plant parts used represented in bar chart.
results against tapeworms. According to Molgaard et al. (2001), the best results against schistosomules
were obtained with stem and root extracts of Abrus precatorius and stem bark of Elephantorrhiza goetzei.
Similarly, Ndamba et al. (1994) investigated herbal medicines used against schistosomiasis in Zimbabwe
based on interviews with 286 traditional healers and the authors documented a total of 47 plant species.
Based on this survey, the seven most commonly used plant species Abrus precatorius, Ozoroa insignis,
Dicoma anomala, Ximenia caffra, Lannea edulis, Elephantorrhiza goetzei and Pterocarpus angolensis were
collected, prepared as described by the traditional healers, their efficacy was evaluated using laboratory
animals previously exposed to Schistosoma haematobium cercariae. The anthelmintic activity from the
extract of the bark of Pterocarpus angolensis was found to be comparable to that of PZQ, the root bark
of Ozoroa insignis and the root of Abrus precatorius were also lethal to adult schistosomes (Ndamba
et al. 1994).
Future research and conclusion

From a research and development point of view, many herbal medicines used against schistosome infections
have not received any major emphasis from government departments, non-governmental organisations
in Zimbabwe, and as such, plant species used against schistosomiasis have remained underutilized.
Nevertheless, the majority of the medicinal plants documented in this study achieve their efficacies
by reducing Schistosoma species egg-hatching and larval motility or metabolism (Ndamba et al. 1994,
Sparg et al. 2000, Mølgaard et al. 2001). Unfortunately, the modes of action of these medicinal plants
have not been fully explored. Therefore, contemporary research involving herbal medicines used against
schistosomiasis is promising, the results obtained so far are too preliminary and sometimes too general to
be used to explain and support usage of such species against schistosome infections. In addition to this,
most of the anthelmintic evaluations done so far, are routine screenings using standard procedures lacking
molecular mechanisms of the pharmacological effects of the herbal medicines. There is not yet enough
systematic data regarding the pharmacokinetics and clinical research on medicinal species used against
schistosome infections. There are also very few experimental animal studies, randomized clinical trials
and target-organ toxicity studies involving some of these herbal medicines and their derivatives that have
been carried out so far. Therefore, future studies should identify the bioactive components, details of the
molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for speciﬁc
bioactives of the documented plant species that are used against schistosome infections.
Acknowledgement
The author would like to express his gratitude to the National Research Foundation and Govan Mbeki
Research and Development Centre, University of Fort Hare for financial support to conduct this research.
References
Adenowo, A.F., Oyinloye, B.E., Ogunyinka, B.I. and Kappo, A.P. 2015. Impact of human schistosomiasis in sub-Saharan
Africa. Braz. J. Infect. Dis. 19: 196–205.
Adedapo, A.A., Sofidiya, M.O., Masika, P.J. and Afolayan, A.J. 2008. Safety evaluations of the aqueous extract of Acacia
karroo stem bark in rats and mice. Rec. Nat. Prod. 2: 128–134.
Agunu, A., Ibrahim, N.D.G., Onyiloyi, G.A. and Abdurahman, E.M. 2003. Toxicity of stem-bark extract of Steganotaenia
araliacea in rats. Niger. J. Nat. Prod. Med. 7: 65–67.
Amole, O.O., Izegbu, M.C., Onakoya, J.A.A. and Dada, M.O. 2006. Toxicity studies of the aqueous extract of Vernonia
amygdalina. Biomed. Res. 17: 39–40.
Aragon, A.D., Imani, R.A., Blackburn, V.R., Cupit, P.M., Melman, S.D., Goronga, T., Webb, T., Loker, E.S. and Cunningham,
C. 2009. Towards an understanding of the mechanism of action of praziquantel. Mol. Biochem. Parasit. 164: 57–65.
Aremu, A.O., Finnie, J.F. and van Staden, J. 2012. Potential of South African medicinal plants used as anthelmintics: their
efficacy, safety concerns and reappraisal of current screening methods. S. Afr. J. Bot. 82: 134–150.
Bizimenyera, E.S. 2007. The potential role of antibacterial, antioxidant and antiparasitic activity of Peltophorum africanum
Sond. (Fabaceae) extracts in ethnoveterinary. PhD Thesis, University of Pretoria, Pretoria.
Bizimenyera, E.S., Githiori, J.B., Swan, G.E. and Eloff, J.N. 2006. In vitro ovicidal and larvicidal activity of the leaf, bark and
root extracts of Peltophorum africanum Sond. (Fabaceae) on Haemonchus contortus. J. Anim. Vet. Adv. 5: 608–614.
Burkill, H.M. 1985. The useful plants of West Tropical Africa. Royal Botanic Gardens, Kew, London.
Chauke, M.A., Shai, L.J., Mogale, M.A., Tshisikhawe, M.P. and Mokgotho, M.P. 2015. Medicinal plant use of villagers in
the Mopani district, Limpopo province, South Africa. Afr. J. Tradit. Complem. 12: 9–26.
Chimbari, M.J. 2012. Enhancing schistosomiasis control strategy for Zimbabwe: Building on past experiences. J. Parasit.
Res. Volume 2012, Article ID 353768.
Chigora, P., Masocha, R. and Mutenheri, F. 2007. The role of indigenous medicinal knowledge (IMK) in the treatment of
ailments in rural Zimbabwe: the case of Mutirikwi communal lands. J. Sustain. Dev. in Africa 9: 26–43.
Chipiti, T., Ibrahim, M.A., Koorbanally, N.A. and Islam, S. 2013. In vitro antioxidant activities of leaf and root extracts of
Albizia antunesiana Harms. Acta Pol. Pharm. 70: 1035–1043.
Clark, T.E., Appleton, C.C. and Kvalsvig, J.D. 1997. Schistosomiasis and the use of indigenous plant molluscicides: a rural
South African perspective. Acta Trop. 66: 93–107.
Cock, I.E. and van Vuuren, S.F. 2015. South African food and medicinal plant extracts as potential antimicrobial food agents.
J. Food Sci. Tech. 52: 6879–6899.
Couto, F.F.B., Coelho, P.M.Z., Araújo, N,, Kusel, J.R., Katz, N., Jannotti-Passos, L.K. and Mattos, A.C.A. 2011. Schistosoma
mansoni: a method for inducing resistance to praziquantel using infected Biomphalaria glabrata snails. Mem. I. Oswaldo
Cruz 106: 153–157.
Doenhoff, M.J., Cioli, D. and Utzinger, J. 2008. Praziquantel: mechanisms of action, resistance and new derivatives for
schistosomiasis. Current Opinion Infectious Diseases 21: 659–667.
Elgorashi, E.E., Taylor, J.L.S., Maes, A., van Staden, J., De Kimpe, N. and Verschaeve, L. 2003. Screening of medicinal plants
used in South African traditional medicine for genotoxic effects. Toxicol. Lett. 143: 195–207.
Fallon, P.G., Sturrock, R.F., Niang, A.C. and Doenhoff, M.J. 1995. Short report: diminished susceptibility to praziquantel in
a Senegal isolate of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 53: 61–62.
Fallon, P.G. and Doenhoff, M.J. 1994. Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in
Schistosoma mansoni in mice is drug specific. Am. J. Trop. Med. Hyg. 51: 83–88.
Gelfand, M., Drummond, R.B., Mavi, S. and Ndemera, B. 1985. The traditional medical practitioner in Zimbabwe: his
principles of practice and pharmacopoeia. Mambo Press, Gweru.
Gryseels, B. and de Vlas, S.J. 1996. Worm burdens in schistosome infections. Parasitol. Today 12: 115–119.
Haule, E.E., Moshi, M.J., Nondo, R.S.O., Mwangomo, D.T. and Mahunnah, R.L.A. 2012. A study of antimicrobial activity, acute
toxicity and cytoprotective effect of a polyherbal extract in a rat ethanol-HCl gastric ulcer model. BMC Res. Notes 5: 546.
Hedberg, I. and Staugård, F. 1989. Traditional medicinal plants: traditional medicine in Botswana. Ipeleng Publishers, Gaborone.
Hutchings, A., Scott, A.H., Lewis, G. and Cunningham, A. 1996. Zulu medicinal plants. University of Natal Press, Natal.
Inobaya, M.T., Olveda, R.M., Chau, T.N.P., Olveda, D.U. and Ross, A.G.P. 2014. Prevention and control of schistosomiasis:
a current perspective. Res. Rep. Trop. Med. 5: 65–75.
Ior, L.D., Wannang, N.N., Ior, C.A. and Amagon, K.I. 2015. In vivo assessment of the antimalarial activity of Cassia singueana
and Cymbopogon citrutus. Der Pharma Chemica 7: 272–278.
Ismail, M., Metwally, A., Farghaly, A., Bruce, J., Tao, L.F. and Bennett, J.L. 1996. Characterization of isolates of Schistosoma
mansoni from Egyptian villagers that tolerate high doses of praziquantel. Am. J. Trop. Med. Hyg. 55: 214–218.
Ismail, M.M., Taha, S.A., Farghaly, A.M. and El-Azony, A.S. 1994. Laboratory induced resistance to praziquantel in
experimental schistosomiasis. J. Egypt. Soc. Parasitol. 24: 685–695.
Joseph, O., Kihdze, T.J., Katusiime, B., Imanirampa, L., Waako, P., Bajunirwe, F. and Ganafa, A.A. 2015. Toxicity of four
herbs used in erectile dysfunction, Mondia whiteii, Cola acuminata, Urtica massaica and Tarenna graveolens in male
rats. Afr. J. Pharm. Pharmaco. 9: 756–763.
Kabongo-Kayoka, P.N., Eloff, J.N., Obi, C.L. and McGaw, L.J. 2016. Antimycobacterial activity and low cytotoxicity of leaf
extracts of some African Anacardiaceae tree species. Phytother. Res. 30: 2001–2011.
Kamuhabwa, A., Nshimo, C. and DeWitte, P. 2000. Cytotoxicity of some medicinal plant extracts used in Tanzanian traditional
medicine. J. Ethnopharmacol. 70: 143–149.
King, C.H. 2006. Long-term outcomes of school-based treatment for control of urinary schistosomiasis: a review of experience
in Coast province, Kenya. Mem. I. Oswaldo Cruz 101(Suppl): 299–306.
Kokwaro, J.O. 1976. Medicinal plants of East Africa. East African Literature Bureau, Nairobi.
Lagu, C. and Kayanja, F.B.I. 2013. The in vitro antihelminthic efficacy of Erythrina abyssinica extracts on Ascaridia galli.
pp. 269–281. In: Carreira, R.P. (ed.). Insights from Veterinary Medicine, InTech, Rejeka.
Magaisa, K., Taylor, M., Kjetland, E.F. and Naidoo, P.J. 2015. A review of the control of schistosomiasis in South Africa. S.
Afr. J. Sci. 111(11/12), Art. #2014–0427.
Magnussen, P. 2003. Treatment and re-treatment strategies for schistosomiasis control in different epidemiological settings:
a review of 10 years’ experiences. Acta Trop. 86: 243–254.
Maregesi, S.M., Mwakigonja, A.R. and Urio, P. 2016. Toxicity evaluation of Abrus precatorius seeds collected from Bunda
district, Tanzania. Schol. Acad. J. Pharm. 5: 399–405.
Maroyi, A. 2011. Ethnobotanical study of medicinal plants used by people in Nhema communal area, Zimbabwe. J.
Mavi, S. 1996. Medicinal plants and their uses in Zimbabwe. pp. 67–73. In: Norman, H., Snyman, I. and Cohen, M. (eds.).
Indigenous knowledge and its uses in Southern Africa. Human Sciences Research Council, Pretoria.
McGaw, L.J., Jäger, A.K. and van Staden, J. 2000. Antibacterial, anthelmintic and anti-amoebic activity in South African
medicinal plants. J. Ethnopharmacol. 72: 247–263.
McGaw, L.J., Rabe, T., Sparg, S.G., Jäger, A.K., Eloff, J.N. and van Staden, J. 2001. An investigation on the biological activity
of Combretum species. J. Ethnopharmacol. 75: 45–50.
McGaw, L.J., van der Merwe, D. and Eloff, J.N. 2007. In vitro anthelmintic, antibacterial and cytotoxic effects of extracts
from plants used in South African ethnoveterinary medicine. Vet. J. 173: 366–372.
Melman, S.D., Steinauer, M.L., Cunningham, C., Kubatko, L.S., Mwangi, I.N., Wynn, N.B., Mutuku, M.W., Karanja, D.M.S.,
Colley, D.G., Black, C.L., Secor, W.E., Mkoji, G.M. and Loker, E.S. 2009. Reduced susceptibility to praziquantel among
naturally occurring Kenyan isolates of Schistosoma mansoni. PLOS Neglect. Trop. D. 3: e504.
Midzi, N., Sangweme, D., Zinyowera, S., Mapingure, M.P., Brouwer, K.C., Munatsi, A., Mutapi, F., Mudzori, J., Kumar, N.,
Woelk, G. and Mduluza, T. 2008. The burden of polyparasitism among primary schoolchildren in rural and farming
areas in Zimbabwe. T. Roy. Soc. Trop. Med. H. 102: 1039–1045.
Midzi, N., Mduluza, T., Chimbari, M.J., Tshuma, C., Charimari, L., Mhlanga, G., Manangazira, P., Munyati, S.M., Phiri, I.,
Mutambu, S.L., Midzi, S.S., Ncube, A., Muranzi, L.P., Rusakaniko, S. and Mutapi, F. 2014. Distribution of schistosomiasis
and soil transmitted helminthiasis in Zimbabwe: towards a national plan of action for control and elimination. PLOS
Neglect. Trop. D. 8: e3014.
Moshi, M.J., van der Beukel, C.J.P., Hamza, O.J.M., Mbwambo, Z.H., Nondo, R.O.S., Masimba, P.J., Matee, M.I.N., Kapingu,
M.C., Mikx, F., Verweij, P.E. and van der Ven, A.J.AM. 2007. Brine shrimp toxicity evaluation of some Tanzanian plants
used traditionally for the treatment of fungal infections. Afr. J. Tradit. Complem. 4: 219–225.
Mølgaard, P., Nielsen, S.B., Rasmussen, D.E., Drummond, R.B., Makaza, N. and Andreassen, J. 2001. Anthelmintic screening
of Zimbabwean plants traditionally used against schistosomiasis. J. Ethnopharmacol. 74: 257–264.
Munodawafa, T., Moyo, S., Chipurura, B. and Chagonda, L. 2017. Brine shrimp lethality bioassay of some selected Zimbabwean
traditional medicinal plants. Int. J. Phytopharmacol. 8: 8–12.
Musyoka, T.M., Dorothy, N.W., Wycliffe, A.M., Juma, K.K., Nzioka, M.D., Maina, D., Waithaka, S.K., Ngugi, M.P., Orinda,
G.O., Karau, G.M. and Njagi, E.N.M. 2016. In vivo antianaemic effect and safety of aqueous extracts of Erythrina
abyssinica and Zanthoxylum usambarensis in mice models. J. Hematol. Thromb. Dis. 4: 242.
Mutapi, F. 2015. Changing policy and practice in the control of pediatric schistosomiasis. Pediatrics 135: 1–9.
Mutapi, F., Rujeni, N., Bourke, C., Mitchell, K., Appleby, L., Nausch, N., Midzi, N. and Mduluza, T. 2011. Schistosoma
haematobium treatment in 1–5 year old children: safety and efficacy of the antihelminthic drug praziquantel. PLOS
Neglect. Trop. D. 5: e1143.
Nabende, P.N., Karanja, S.M., Mwatha, J.K. and Wachira, S.W. 2015. Anti-proliferative activity of Prunus africana, Warburgia
stuhlmannii and Maytenus senegalensis extracts in breast and colon cancer cell lines. Eur. J. Med. Plant. 5: 366–376.
Ndamba, J., Nyazema, N., Makaza, N., Anderson, C. and Kaondera, K.C. 1994. Traditional herbal remedies used for the
treatment of urinary schistosomiasis in Zimbabwe. J. Ethnopharmacol. 42: 125–132.
Ndjonka, D., Rapado, L.N., Silber, A.M., Liebau, E. and Wrenger, C. 2013. Natural products as a source for treating neglected
parasitic diseases. Int. J. Mol. Sci. 14: 3395–3439.
Neves, B.J., Andrade, C.H. and Cravo, P.V.L. 2015. Natural products as leads in schistosome drug discovery. Molecules
20: 1872–1903.
Ojewole, O.J.A. 2004. Indigenous plants and schistosomiasis control in south africa: molluscicidal activity of some Zulu
medicinal plants. B. Latinoam. Caribe Pl. 3: 8–22.
Pedersen, U.B., Karagiannis-Voules, D.-A., Midzi, N., Mduluza, T., Mukaratirwa, S., Fensholt, R., Vennervald, B.J., Kristensen,
T.K., Vounatsou, P. and Stensgaard, A.-S. 2017. Comparison of the spatial patterns of schistosomiasis in Zimbabwe
at two points in time, spaced twenty-nine years apart: is climate variability of importance? Geospatial Health 12: 505.
Ribeiro, A., Romeiras, M.M., Tavares, J. and Faria, M.T. 2010. Ethnobotanical survey in Canhane village, district of Massingir,
Mozambique: medicinal plants and traditional knowledge. J. Ethnobiol. Ethnomed. 6: 33.
Ross, A.G., Chau, T.N., Inobaya, M.T., Olveda, R.M., Li, Y. and Harn, D.A. 2017. A new global strategy for the elimination
of schistosomiasis. Int. J. Infect. Dis. 54: 130–137.
Samie, A., Obi, C.L., Lall, N. and Meyer, J.J.M. 2009. In vitro cytotoxicity and antimicrobial activities, against clinical isolates
of Campylobacter species and Entamoeba histolitica, of local medicinal plants from Venda region, in South Africa.
Ann. Trop. Med. Parasit. 103: 159–170.
Sparg, S.G., van Staden, J. and Jäger, A.K. 2000. Efficiency of traditionally used South African plants against schistosomiasis.
J. Ethnopharmacol. 72: 1–6.
Staner, P. and Boutique, R. 1937. Matériaux pour l’ étude des plantes médicinales indigènes du Congo Belge. Académie
Royale de Belgique, Bruxelles.
Steinmann, P., Keiser, J., Bos, R., Tanner, M. and Utzinger, J. 2006. Schistosomiasis and water resources development:
systematic review, meta-analysis, and estimates of people at risk. Lancet Infect. Dis. 6: 411–425.
Storrs, A.E.G. 1979. Know your trees: some of the most common trees found in Zambia. The Forest Department, Ndola.
Taylor, J.L.S., Elgorashi, E.E., Maes, A., van Gorp, U., De Kimpe, N., van Staden, J. and Verschaeve, L. 2003. Investigating
the safety of plants used in South African traditional medicine: testing for genotoxicity in the micronucleus and alkaline
comet assays. Environ. Mol. Mutag. 42: 144–154.
Ukwuani, A.N., Ihebunna, O., Samuel, R.M. and Peni, I.J. 2012. Acute oral toxicity and antiulcer activity of Piliostigma
thonningii leaf fraction in Albino rats. B. Environ. Pharmacol. Life Sci. 2: 41–45.
Van Wyk, B.-E. and Gericke, N. 2000. People’s plants: a guide to useful plants of southern Africa. Briza Publications, Pretoria.
Venter F and Venter J. 1996. Making the most of indigenous trees. Briza Publications, Pretoria.
Wanjala, C.C.W. and Majinda, R.R.T. 2001. A new stilbene glycoside from Elephantorrhiza goetzei. Fitoterapia 72: 649–655.
Watt, J.M. and Breyer-Bradwijk, M.G. 1962. The medicinal and poisonous plants of southern and eastern Africa. E. & S.
Livingstone, Edinburgh.
Williamson, J. 1975. Useful plants of Malawi. University of Malawi, Zomba.
World Health Organization (WHO). 2017a. Schistosomiasis fact sheet. World Health Organization Media Centre, Geneva.
Available from: http://www.who.int/mediacentre/factsheets/fs115/en/, accessed on 29 July 2017.
World Health Organization (WHOb). 2017. Schistosomiasis: epidemiological situation. World Health Organization Media
Centre, Geneva. Available from: http://www.who.int/schistosomiasis/epidemiology/en/, accessed on 29 July 2017.
3
Ethnobotany: Medicinal Plants Used in
the Management of Hypertension
Patricia Landazuri,1,* Nelsy Loango Chamorro2 and
Beatriz Restrepo Cortes1
Introduction
Hypertension is a worldwide disease, and it is the most common serious chronic health problem and also
a high risk factor for myocardial infarction, arteriosclerosis, stroke, and end-stage renal disease. Twenty
five percent of the world’s adult population has hypertension and this is likely to increase by 30% by 2025
(WHO 2013, World Heart Federation 2015).
The primary treatment for hypertension is: stress management, maintaining proper weight, reducing
salt intake, limiting alcohol consumption, aerobic physical activity and dietary control. The hypertension
guidelines indicated that when these treatments are not enough, drugs should be administered (Mancia
et al. 2013, James et al. 2014); antihypertensive drugs have proved to be effective, but they have many
side effects, such as reduced renal function, dry cough, angioedema among others effects (Kiriyama et
al. 2016). Hence, the management of hypertension by herbal medicine can be a complementary treatment
(Landázuri et al. 2017, Leung et al. 2017), and ethnobotanical studies for use of medicinal plants for the
management of hypertension can be of great help (Baharvand-Ahmadi et al. 2016, Rawat et al. 2016).
Ethnobotany is a specific field of scientific study of the plants, and also their relationship with people.
Modern ethnobotanists strive to collect all available data on the use of plants, to document the biodiversity
of medicinal plants and the methods of use (Popovi et al. 2016).
Blood pressure (BP) is controlled by several mechanism: local mechanisms of BP control (i.e.,
nitric oxide (NO), endothelin), neural mechanisms (i.e., sympathetic nervous system), renal-endocrine
mechanisms (i.e., Renin-Angiotensin-Aldosterone-System (RAAS), and a variety of other hormones (i.e.,
antidiuretic hormone)).
RAAS activation is a very important mechanism responsible for regulation of BP and the Angiotensin
Converting Enzyme (ACE), is the key enzyme that regulates RAAS, which is a system that is also involved
in the regulation of plasma sodium concentration.
Bioactive compounds in plants, such as polyphenols and peptides, may be useful in the prevention of
cardiovascular diseases, such as hypertension (Medina-Remón et al. 2015, Shayganni et al. 2016, Ferreira
et al. 2017).
1
Faculty of Health Sciences. Medicine, and Biomedical Science programs, Universidad Del Quindío, Armenia-Quindío,
Colombia.
2
Faculty of Basic Science and Technologies, Biology carrer program, Universidad Del Quindío, Armenia-Quindío, Colombia.
* Corresponding author: plandazu@uniquindío.edu.co
Bioactive compounds in plants including polyphenols and peptides, may be useful in the prevention
of cardiovascular diseases, such as hypertension; thus, the antihypertensive activity of several of these
metabolites result from inhibition of ACE, or calcium channel blockade, among other mechanisms of
action (Rawat et al. 2016). Thus in recent years, the inhibitory effect on ACE activity of Passiflora edulis,
Phthirusa pyrifolia, and Eucommia ulmoides Oliver has been demonstrated (Restrepo et al. 2013, Restrepo
et al. 2014, Yan et al. 2017) and calcium channel blockade of Achillea wilhelmsii (Niazmand et al. 2014,
Rawat et al. 2016).
Thus, the objective of this chapter is to contribute to the review of some medicinal plants, whose
extracts or active compounds have demonstrated efficacy on blood pressure regulation systems, such as
the RAAS, the blocking of calcium channels, nitric oxide release and arterial vasorelaxation.
Ethnobotanical studies and hypertension

Ethnobotanical studies can be defined as the scientific research of plants, as they are used in native cultures
for food, medicine, spiritual therapies, rituals, pesticides or other applications, used alone or in combination
to diagnose, treat, and prevent diseases or maintain well-being (Olowokudejo et al. 2008).
Ethnobotanical studies have provided reliable guides for use of herbal medicines that nature offers;
nature is the greatest source of medicaments for many health problems, consequently, today herbal medicines
are used alone or in combination with traditional pharmaceutical compounds to treat various ailments
(Falzon et al. 2017, Lin et al. 2017), without forgetting that a high percentage of the new medicaments
approved, have been derived directly or indirectly from natural products (Dutra et al. 2016, Gerwick 2017,
Petroni et al. 2017); in these ethnobotanical studies, there are many medicinal plants recommended by native
communities for the treatment of hypertension; this general knowledge provides new areas of research
related to the active principles and mechanisms of action of these plants in hypertension management
(Ahmad et al. 2015, Baharvand-Ahmadi et al. 2016, Lee and Hur 2017).
Hypertension
Blood pressure is the force exerted by circulating blood on the artery walls, which originates in the pumping
action of the heart, and is produced primarily by the contraction of the heart (James et al. 2014). BP is
measured in millimeters of mercury (mm Hg). It is recorded as two indexes: Systolic Blood Pressure
(SBP), which shows the force that blood exerts against artery walls when the heart beats to pump blood to
the peripheral organs and tissues, and Diastolic Blood Pressure (DBP), indicates the force that the blood
is exerting against artery walls while the heart is resting between beats. It is postulated that the normal
values of systolic pressure for healthy individuals should vary between 100 mm Hg and 140 mm Hg and
the diastolic pressure values varies between 60 mm Hg and 100 mm Hg (Mancia et al. 2013, WHO 2013,
James et al. 2014, Vardanyan et al. 2016).
High blood pressure or arterial hypertension is a serious medical condition. Hypertension has been
called the “silent killer”, because people with hypertension do not have any signs or symptoms, and many
do not even know they have it. According to the American or European Societies of Hypertension a person
suffers this condition when its SBP is consistently higher than 140 mm Hg and/or its DBP is ≥ 90 mm Hg
(Mancia et al. 2013, James et al. 2014).
For 90 to 95% of patients, the causes of hypertension are unknown, this hypertension is classified as
essential or primary hypertension. The remaining 5 to 10% are cases of secondary hypertension caused by
underlying heart, kidney, or endocrinal diseases, certain cancers, or use of cocaine, amphetamines, thyroid
supplements, or corticosteroids (Mancia et al. 2013, James et al. 2014).
WHO estimates that approximately one billion people all over the world suffer from hypertension.
It is further estimated that this number will escalate to more than 1.56 billion by the year 2025 (WHO
2013) and that hypertension occurrence is around 20–30% in the adult population in developed countries
(Chockalingam et al. 2006, WHO 2013, Ahmad et al. 2015, World Heart Federation 2015).
On the other hand, in a large number of studies the relationships between high BP values and fatal
cardiovascular and renal events have been addressed (Nangia et al. 2016, Textor 2017, Torlasco et al. 2017).
Ethnobotany: Medicinal Plants Used in the Management of Hypertension 49
WHO also estimates that hypertension is responsible for at least 45% of deaths due to heart diseases, and
that 51% of deaths worldwide are due to hypertension, which is one of the most important causes (WHO
2013, Lima Prando et al. 2015).
Many antihypertensive agents, such as diuretics, β blockers, calcium-channel blockers, and RAAS
blockers as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers among others,
are used separately or in combination to treat this disease (Charlton and Thompson 2015, Vardanyan et al.
2016). However and despite its effectiveness, these medications can cause serious side effects, like adverse
cardiovascular outcomes, diabetes, dry coughing, bradycardia, arrhythmia, electrolyte disturbances, fluid
retention and headache among others (Ahmed et al. 2015, Charlton and Thompson 2015, Nishioka et al.
2015, Kiriyama et al. 2016). Also non adherence to antihypertensive treatment is a critical contributor to
suboptimal blood pressure control (Alsabbagh et al. 2014).
These problems have motivated researchers to find new medicines from medicinal plants, to control
hypertension and with fewer side effects (Nunes et al. 2015, Baharvand-Ahmadi et al. 2016, Popovi et al.
2016). Recently, several ethnobotanical studies showed that hundreds of plants are used worldwide for
empirical hypertension treatment (Ahmad et al. 2015, Nunes et al. 2015, Baharvand-Ahmadi et al. 2016,
Lee et al. 2017). On the other hand, the results of several ethnobotanical surveys indicated that interviewed
patients used medicinal plants to treat hypertension because phytotherapy is cheaper, more efficient and
better than modern medicine (Charlton and Thomson 2015, Eddouks et al. 2017).
In this context, the treatment adherence, the cost-benefit ratio, cultural beliefs and well-being, achieved
by the use of medicinal plants for the hypertension treatment, generate the idea of reliability and safety
of these herbal medicines, contributing to improve/increase the therapeutic repository tools and helping
adherence to antihypertensive medications (Lima Prando et al. 2015).
Blood pressure control by medicinal plants

Various mechanisms have been suggested for the maintenance of blood pressure in humans. One such
well known system is the RAAS, another mechanisms for reduction of hypertension are blocking Ca2+
channels in cellular membrane (by calcium antagonists), or blocking, the sympathetic and parasympathetic
nervous system, because some blood vessels are innervated by sympathetic adrenergic nerves, which
release norepinephrine (NE) as a neurotransmitter. Other blood vessels are innervated by parasympathetic
or sympathetic cholinergic nerves, both which release acetylcholine as their primary neurotransmitter.
NE binds alpha-1 and alpha-2 adrenoceptors to cause smooth muscle contraction and vasoconstriction;
while acetylcholine binds to muscarinic receptors on the smooth muscle and/or endothelium and results
in vasodilation.
On the other hand, ACE inhibition is largely related to two types of blood pressure control, RAAS
and Nitric Oxide System (NOS). In the first control, ACE cleaves the C-terminal dipeptide His-Leu of
Angiotensin Ι (ANG I), resulting in Angiotensin II (ANG II), that increases blood pressure through binding
to receptors AT1 and AT2, especially, AT1 receptor to induce vasoconstriction (Patel et al. 2017). ACE is
also the main enzyme that destroys bradykinin which binds to beta-2-receptors that cause an increase in
intracellular Ca2+ level. The increased Ca2+ level and bradykinin lead to nitric oxide synthase to convert
L-arginine to nitric oxide, the second system, which is a potent vasodilator (Balakumar and Jugadeesh 2014).
Ethnobotanical studies have described hundreds of plants used by communities for hypertension
management, 99 plants were found in only four papers (2015–2016), Baharvand-Ahmadi et al. (2016)
reported 27 medicinal plants from 22 families, Polat et al. (2015) found five plants from three families,
Ahmad et al. (2015) reported 46 plants from 29 families and Rawat et al. (2016), described 21 plants. In
the last report they described the action mode of the plants and their clinical evidences.
In this chapter we included 10 plants, which were chosen because they were cited three or more times
in the reviewed literature and have described compounds and a possible mechanism of action.
Achillea wilhelmsii C. Koch. (A. wilhelmsii), Asteraceae family. Common name yarrow. This plant
contains flavonoids and sesquiterpene lactones, which have shown to be effective in lowering hypertension
in men and women (Asgary et al. 2000). They showed that hypertensive subjects treated with hydroalcoholic
extract (15–20 drops) twice daily for more than 6 months, had decreased diastolic and systolic blood
pressure after 2 and 6 months, respectively (p < 0.05).
Allium sativum L. (A. sativum), Liliaceae family. Common name: garlic. Several epidemiological
studies suggest an antihypertensive effect of A. sativum and its bioactive components, principally S-allyl
cysteine and allicin (Ried et al. 2014). These authors proposed that garlic-derived polysulfides stimulate
the production of the vascular gaso-transmitter hydrogen sulfide (H2S) and enhance the regulation of
endothelial Nitric Oxide (NO), which induce smooth muscle cell relaxation, vasodilation, and blood
pressure reduction. On the other hand, Ashraf et al. (2013), evaluated the effects of garlic on blood pressure
in patients with essential hypertension; patients received between 300 and 1500 mg in divided doses per
day for 24 weeks; the study showed significant decrease for both systolic and diastolic blood pressure in
a dose dependent manner.
Annona muricata L. (A. muricata), Annonaceae family. Common name: soursop graviola or guanabana.
The tree grows natively in the Caribbean and Central America; more than 200 compounds have been isolated
and identified from different parts of this plant, phenols, alkaloids and acetogenins were the most important
and effective compounds isolated from leaves, barks, seeds, roots and fruits (Patel and Patel 2016). The
leaf extract of the plant (9.17–48.5 mg/kg body weight) administered to normotensive Sprague-Dawley
rats has been reported to lower an elevated blood pressure through peripheral mechanisms involving
antagonism of Ca+2 (Nwokocha et al. 2012).
Artemisia campestris L. (A. campestris), Asteraceae family. Common names: field sagewort, beach
wormwood, field sagebrush, field wormwood; it is a medicinal herb traditionally used to treat hypertension.
The oil of the air-dried (AcEO) plant has the spathulenol (10.19%) as main component, followed by
ß-eudesmol (Dib et al. 2017); this study showed evidence about the signaling mechanism of vasorelaxation
induced by AcEO, showing that essential oil acts via L-type calcium channels.
Apium graveolens L. (A. graveolens), Apiaceae family. Common name: Celery. This plant has
demonstrated antioxidant activity. The n-butylphthalide (NBP) is one of the chemical constituents in
celery oil (Houston 2005). Extract of A. graveolens was administered as an antihypertensive agent in
folk medicine (Gharouni and Sarkati 2000, Moghadam et al. 2013, Vergara-Galicia et al. 2013). Vergara-
Galicia et al. (2013) in their study concluded that extracts caused concentration-dependent relaxation in
precontracted aortic rings with and without endothelium; for this, the authors suggested that the effect
induced by dichloromethane and ethyl acetate extracts from A. graveolens is mediated probably by calcium
antagonism.
Avena sativa L. (A. sativa). Poaceae family. Common names: Oats, avoine, hafer, avena;
Avenanthramides are one of the chemical constituents of A. sativa, avenanthramides are a group of alkaloids,
consisting of an anthranilic acid derivative linked to hydroxycinnamic acid derivative. The three major
avenanthramides reported in oat are avenanthramides 1, 3, and 4 (Peterson et al. 2002). These compounds
are bioavailable and have anti-inflammatory, anti-atherogenic and antioxidant properties (Peterson et al.
2002, Fu 2015, Martinez-Villaluenga and Penas 2017). Nie et al. (2006) showed that avenanthramides of
oats inhibit vascular smooth muscle cell proliferation and enhance nitric the oxide production.
Berberis vulgaris L. (B. vulgaris), (berberidaceae family). Common name: barberry. Berberine
(BBR), a type of isoquinoline alkaloid, is the major active component of B. vulgaris, BBR exhibits several
pharmacological activities such as antioxidant activity and has a broad range of therapeutic potential uses
including hypertension (Tabeshpour et al. 2017); while Fatehi-Hassanabad et al. (2005), showed that
aqueous extract from Berberis vulgaris fruit lowers blood pressure in rats (DOCA-induced hypertension)
and suggested that the antihypertensive and vasodilatory effects of B. vulgaris fruit extract are mainly
endothelial-independent.
Morus alba L. (M. alba), Moraceae family. Common name: mulberry. Both the fruits and roots have
been used traditionally to prevent and treat symptoms associated with cardiovascular disease as hypertension
in eastern countries. Rutin and quercetin, were two of the primary components of the leaf (Aminah et al.
2014). In a study Xia et al. (2008) showed that the ethyl acetate extract from leaves (ELM) of M. alba
on rat thoracic aorta (0.125–32 g/L) induced a concentration-dependent relaxation (P < 0.01 vs. control),
their results also showed that ELM has vasoactive effects and was mediated by inhibition of voltage- and
receptor-dependent Ca2+ channels; similar to that found by Khan et al. (2014) in anaesthetized rats. On
the other hand, Carrizzo et al. (2016) described that M. alba extract through its action on eNOS signaling,
could act for the regulation of arterial hypertension.
Myrtus communis L. (M. communis), Myrtaceae family; common name: Myrtle. Is an evergreen
shrub; phytochemical analysis of ethyl acetate extract from this plant revealed the isolation of myricetin-
3-O-rhamnoside, a major flavonol in this plant. The results of Bouaziz et al. (2015) study showed that
intravenous injection of methanol and ethyl acetate extract at 0.04 to 12 mg/kg body weight, induced
a dose-dependent and transitory decrease in SBP, DBP of the anesthetized rats and that the maximum
decrease in SBP and DBP was 19 ± 2%; 22 ± 3% and 30 ± 3%; 34 ± 1% for methanol and ethyl acetate
extract respectively at the dose of 12 mg/kg.
Passiflora edulis Sims. (P. edulis) Passifloraceae family. Common name: passion fruit. Extracts of the
family are known to have several important physiological effects in humans, such as anxiolytic, antitussive,
antitumoral and antihypertensive properties (Li et al. 2001, Deng et al. 2010, Aguillón et al. 2013, Konta
et al. 2014, Restrepo et al. 2014). Passifloraceae genus contains several compounds including alkaloids,
phenols, glycosyl flavonoids and cyanogenic compounds (Dhawan et al. 2004, Ichimura et al. 2006,
Restrepo et al. 2014); flavonoids as luteolin-6-C-chinovoside and luteolin-6-C-fucoside and aminoacids
as gamma aminobutyric acid (GABA) have been isolated from leaves of P edulis (Martinez-Villaluenga
and Peñas 1991). Flavonoids exhibit diverse biological effects, including inhibition of protein kinase C,
inhibition of cyclic nucleotide phosphodiesterase, decrease in Ca+2 uptake, and vasodilatory actions (Chan
et al. 2000, Ichimura et al. 2006; Tiwaria and Husain 2017). About the antihypertensive properties of P.
edulis extracts, Ichimura et al. (2006), postulated that the antihypertensive effect of the extract (10 mg/kg)
in SHRs might be due mostly to the GABA induced antihypertensive effect and partially to the vasodilatory
effect of polyphenols including luteolin.
Zingiber officinale Roscoe. (Z. officinale), Zingiberaceae family. Common name: Ginger. It is a
well-known spice plant, used traditionally in a wide variety of ailments including management and
prevention hypertension (Fugh-Berman 2000, Tabassum and Ahmad 2011, Akinyemi et al. 2013). The
main components of ginger are 6-gingerol, 6-shogaol, 8-gingerol and 10-gingerol, these constituents exhibit
strong antioxidant activity in vitro (Rahmani et al. 2014, Ghayur and Gilani 2005). The crude extract of
ginger (Zo.Cr) induced a dose-dependent (0.3–3 mg/kg) fall in the arterial blood pressure of anesthetized
rats (Fugh-Berman 2000); this vasodilator effect of Zo.Cr was endothelium-independent. These data and
data from different authors indicate that the blood pressure-lowering effect of ginger is mediated through
blockade of voltage-dependent calcium channels (Fugh-Berman 2000, Ghayur et al. 2005, Akinyemi et al.
2013). Ginger also inhibited ACE in a dose-dependent manner (25–125 μg/mL) (Akinyemi et al. 2013).
Table 3.1 summarizes and includes these 10 plants and Fig. 3.1 shows some of its active compounds.
Fig. 3.1 Some active compounds of medicinal plants used in the treatment and management of hypertension. Source: National
Center for Biotechnology Information. PubChem Compound Database. Accessed Jan 10, 2018.
Table 3.1 Medicinal plants used for the treatment of hypertension; scientific name, family name, plant parts used.
Scientific name Family name Part use Active compound (AC) or action mechanisms (AM)
Achillea wilhelmsii Asteraceae Aerial parts AC = flavonoids and sesquiterpene lactones
C Koch. AM = antioxidant
Allium sativum L. Amaryllidaceae Bulb AC = S-allyl L-cysteine and allicin.
AM = endothelial nitric oxide (NO) regulation; ACE
inhibition
Annona muricata L. Annonaceae Leaves AC = phenols, alkaloids and acetogenins
AM = antagonism of Ca2+
Artemisia campestris L. Asteraceae Aerial part AC = spathulenol, ß-eudesmol
AM = L-type Ca2+ channels inhibition.
Apium graveolens L. Apiaceae Leaves AC = n-butylphthalide
AM = ND
Avena sativa L. Poaceae/ Whole Cereal AC = Polyphenols (avenanthramides).
Gramineae AM = free radicals and inflammation reduction, enhances
nitric oxide production
Berberis vulgaris L. Berberidaceae Fruit, leaves, AC = Berberine and related derivatives
roots AM = Vasoldilatory activity
Morus alba L. Moraceae Fruit AC = Rutin, quercetin.
AM = vasorelaxation (voltage- and receptor-dependent Ca2+
channels inhibition)
Increase NO serum level
Myrtus communis L. Myrtaceae Leaves AC = myricetin-3-Orhamnoside
AM = ND
Passiflora edulis Sims. Passifloraceae Leaves, fruit AC = Luteolin-6-C-chinovoside and luteolin-6-C-fucoside;
GABA
AM = ACE inhibition; antioxidant status enhancement
Zingiber officinale Rosc Zingiberaceae Rhizomes AC = 6-gingerol, 6-shogaol, 8-gingerol, and 10-gingerol
AM = ACE inhibition; blockade of voltage-dependent
calcium channels
ND = Not determined.
These plants are used as infusion, decoction, beverages and fresh fruits or raw, but many of them have
no scientific validation about their effectiveness or action mechanism or active compound.
Conclusion
There were many plants in folkloric or traditional medicine that were used for the management of
hypertension, some had clinical evidence, some had scientific evidence of their mechanism of action and
others did not, but it is undeniable that these plants are the best source of drugs and therefore need to be
studied in depth.
This work provides knowledge in medicinal plants used for hypertension treatment; describes some
metabolites from these plants to inhibit ACE and calcium channel, or to increased nitric oxide release or/
and vasorelaxation.
References
Aguillón, J., Maldonado, M.E, Loango, N., Arango, S.S. and Landázuri, P. 2013. Antioxidant and antiproliferative activity
of ethanolic and aqueous extracts from leaves and fruits juice. Passiflora edulis. Perspect Nutr. Humana 15: 13–25.
Ahmad, L., Semotiuk, A., Zafar, M., Ahmad, M., Sultana, S., Liu, Q-R. and Yaseen, G. 2015. Ethnopharmacological
documentation of medicinal plants used for hypertension among the local communities of DIR Lower, Pakistan. J.
Ahmed, N., Martinelli, A. and Kiruthi, C. 2015. Chapter 20 – Antihypertensive drugs. In book: Side Effects of Drugs Annual
37: 227–236.
Alsabbagh, M.H.D.W., Lemstra, M., Eurich, D., Lix, L.M., Wilson, T.W., Watson, E. and Blackburn, D.F. 2014. Socioeconomic
status and non-adherence to antihypertensive drugs: a systematic review and meta-analysis. Value in Health 17(2):
288–296.
Akinyemi, A.J., Ademiluyi, A.O. and Oboh, G. 2013. Aqueous extracts of two varieties of ginger (zingiber officinale) inhibit
angiotensin I–converting enzyme, iron (II), and sodium nitroprusside-induced lipid peroxidation in the rat heart in
vitro. J. Med. Food 16(7): 641–646.
Aminah, S., Suwaldi, S., Fudholi, A. and Wahyono, W. 2014. The effect of encapsulated mulberry (Morus alba L.) leaves
extract on arterial blood pressure in rats. Trad. Med. J. 19(3): 149–155.
Asgary, S., Naderi, G.H., Sarrafzadegan, N., Mohammadifard, N., Mostafavi, S. and Vakili, R. 2000. Antihypertensive and
antihyperlipidemic effects of Achillea wilhelmsii. Drugs Exp. Clin. Res. 26(3): 89–93.
Ashraf, R., Khan, R.A., Ashraf, I. and Qureshi, A.A. 2013. Effects of Allium sativum (garlic) on systolic and diastolic blood
pressure in patients with essential hypertension. Pak. J. Pharm. Sci. 26(5): 859–63.
Baharvand-Ahmadi, B., Bahmani, M., Tajeddini, P., Rafieian-Kopaei, M. and Naghdi, N. 2016. An ethnobotanical study of
medicinal plants administered for the treatment of hypertension. J. Renal. Inj. Prev. 5(3): 123–128.
Balakumar, P. and Jagadeesh, G. 2014. A century old renin-angiotensin system still grows with endless possibilities: AT1
receptor signaling cascades in cardiovascular physiopathology. Cell Signal 26(10): 2147–2160.
Bouaziz, A., Khennouf, S., Abu zarga, M., Abdalla, S., Baghiani, A. and Charef, N. 2015. Phytochemical analysis, hypotensive
effect and antioxidant properties of Myrtus communis L. growing in Algeria. Asian Pac. J. Trop. Biomed. 5(1): 19–28.
Carrizzo, A., Ambrosio, M., Damato, A., Madonna, M., Storto, M., Capocci, L. et al. 2016 Morus alba extract modulates blood
pressure homeostasis through eNOS signaling. Mol. Nutr. Food Res. 60(10): 2304–2311.
Chan, E.C., Pannangpetch, P. and Woodman, O.L. 2000. Relaxation to flavones and flavonols in rat isolated thoracic aorta:
mechanism of action and structure activity relationships. J. Cardiovasc. Pharmacol. 35: 326–333.
Charlton, M. and Thompson, J.P. 2015. Drugs acting on the heart: Antihypertensive drugs. Anaesth. Intensive Care Med.
16(5): 227–231.
Chockalingam, A., Campbell, N.R. and George, F.J. 2006. Worldwide epidemic of hypertension. Can. J. Cardiol. 22(7): 553–555.
Deng, J., Zhou, Y., Bai, M., Li. H. and Li, L. 2010. Anxiolytic and sedative activities of Passiflora edulis f. flavicarpa. J.
Ethnopharmacol. 128(1): 148–153.
Dhawan, K., Dhawan, S. and Sharma, A. 2004. Passiflora: a review update. J. Ethnopharmacol. 94: 1–23.
Dib, I., Fauconnier, M.L., Sindic, M., Belmekki, F., Assaidi, A., Berrabah, M. et al. 2017. Chemical composition, vasorelaxant,
antioxidant and antiplatelet effects of essential oil of Artemisia campestris L. from Oriental Morocco. BMC Complem.
Alternat. Med. 17(82): 2–15.
Dutra, R.C., Campos, M.M., Santos, A.R.S. and Calixto. J.B. 2016. Medicinal plants in Brazil: Pharmacological studies, drug
discovery, challenges and perspectives. Pharmacol. Res. 112: 4–29.
Eddouks, M., Ajebli, M. and Hebi, M. 2017. Ethnopharmacological survey of medicinal plants used in Daraa-Tafilalet region
(Province of Errachidia). Morocco. J. Ethnopharmacol. 198: 516–530.
Falzon, C.C. and Balabanova, A. 2017. Phytotherapy: An Introduction to Herbal Medicine. Prim. Care 44(2): 217–227.
Fatehi-Hassanabad, Z., Jafarzadeh, M., Tarhini, A. and Fatehi, M. 2005. The antihypertensive and vasodilator effects of aqueous
extract from Berberis vulgaris fruit on hypertensive rats. Phytother. Res. 19(3): 222–225.
Ferreira, L.G., Evora, P.R.B., Capellini, V.K., Albuquerque, A.A., Carvalho, M.T.M., Da Silva Gomes, R.A., Parolini, M.T.
and Celotto, A.C. 2018. Effect of rosmarinic acid on the arterial blood pressure in normotensive and hypertensive
rats: role of ACE. Phytomedicine 38: 158–65.
Fu, J., Zhu, Y., Yerke, A., Wise, M.L., Johnson, J., Chu, Y. and Sang, S. 2015. Oat avenanthramides induce heme oxygenase-1
expression via Nrf2-mediated signaling in HK-2 cells. Mol. Nutr. Food Res. 59: 2471–2479.
Fugh-Berman, A. 2000. Herbs and dietary supplements in the prevention and treatment of cardiovascular disease. Prev.
Cardiol. 3(1): 24–32.
Gharouni, M. and Sarkati, A. 2000. Application of Apium graveolens in treatment of hypertension. J. Tehran. Univ. Med.
Sci. 3: 67–69.
Ghayur, M.N. and Gilani, A.H. 2005. Ginger lowers blood pressure through blockade of voltage-dependent calcium channels.
J. Cardiovasc. Pharmacol. 45(1): 74–80.
Houston, M.C. 2005 Nutraceuticals, vitamins, antioxidants, and minerals in the prevention and treatment of hypertension.
Prog. Cardiovasc. Dis. 47(6): 396–449.
Gerwick, W.H. 2017. Plant sources of drugs and chemicals. In book: Reference module in life sciences. DOI:10.1016/B978-
0-12-809633-8.02306-2.
Ichimura, T., Yamanaka. A., Ichiba, T., Toyokawa, T., Kamada, Y., Tamamura, T. and Maruyama, S. 2006 Antihypertensive
Effect of an extract of Passiflora edulis rind in spontaneously hypertensive rats. Biosci. Biotechnol. Biochem.
70(3): 718–721.
James, P.A., Oparil, S., Carter, B.L., Cushman, W.C., Dennison-Himmelfarb, C., Handler, J. and Ortiz, E. 2014. Evidence-
based guideline for the management of high blood pressure in adults. JAMA, 311(5): 507–520.
Khan, M., Khan, A-U., Rehman, N-Ur. and Gilani, A-H. 2014. Blood pressure lowering effect of Morus alba is mediated
through Ca++ antagonist pathway. Int. J. Pharmacol. 10(4): 225–230.
Kiriyama, A., Honbo, A., Nishimura, A., Shibata, N. and Iga, K. 2016. Pharmacokinetic-pharmacodynamic analyses of
antihypertensive drugs, nifedipine and propranolol, in spontaneously hypertensive rats to investigate characteristics
of effect and side effects. Regul. Toxicol. Pharm. 76: 21–29.
Konta, E.M., Almeida, M.R., do Amaral, C.L., Darin, J.D., de Rosso. V.V., Mercadante, A.Z., Antunes, L.M. and Bianchi,
M.L. 2014. Evaluation of the antihypertensive properties of yellow passion fruit pulp (Passiflora edulis Sims f.
flavicarpa Deg.) in spontaneously hypertensive rats. Phytother. Res. 28(1): 28–32.
Landazuri, P., Loango, N. and Restrepo, B. 2017. Medicinal plants used in the management hypertension. J. Anal. Pharm.
Res. Med. 5(2): 5–7.
Lee, S.Y. and Hur, S. 2017. Antihypertensive peptides from animal products, marine organisms, and plants. Food Chem.
228: 506–517.
Leung, A.A., Daskalopoulou, S.S., Dasgupta, K., McBrien, K., Butalia. S., Zarnke, K.B. and Rabi, D.M. 2017. Hypertension
Canada’s 2017 Guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults. Can.
J. Cardiol. 33(5): 557–576.
Li, H., Zhou, P., Yang, Q., Shen, Y., Deng, J., Li, L. and Zhao, D. 2001. Comparative studies on anxiolytic activities and
flavonoid compositions of Passiflora edulis ‘edulis’ and Passiflora edulis ‘flavicarpa’. J. Ethnopharmacol. 16:
133(3): 1085–1090.
Lima Prando, T.B., Barboza, L.N., Gasparotto, F.M., De Oliveira Araujo, V., Signor Tirloni, C.A., De Souza, L.M. and
Gasparotto Junior, A. 2015. Ethnopharmacological investigation of the diuretic and hemodynamic properties of
native species of the Brazilian biodiversity. J. Ethnopharmacol. 174: 369–378.
Lin, T., Yen, H., Chiang, J., Sun, M. and Chang, H. 2017. The use of Chinese herbal medicine as an adjuvant therapy to reduce
incidence of chronic hepatitis in colon cancer patients: A Taiwanese population-based cohort. J. Ethnopharmacol.
202: 225–233.
Mancia, G., Fagard, R., Narkiewicz, K., Redon, J., Zanchetti, A, Buhm. M. and Wood, D.A. 2013. ESH/ESC guidelines for
the management of arterial hypertension: The task force for the management of arterial hypertension of the European
Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur. Heart J. 34(28): 2159–2219.
Mareck, U., Herrmann, K., Galensa. R. and Wray, V. 1991. The 6-C-chinovoside and 6-C-fucoside of luteolin from Passiflora
edulis. Phytochemistry 30: 3486–3487.
Martınez-Villaluenga, C. and Peñas. E. 2017. Health benefits of oat: current evidence and molecular mechanisms. Current
Opinion. Food Sci. 14: 26–31.
Medina-Remón, A., Tresserra-Rimbau, A., Pons, A., Tur, J.A., Martorell, M., Ros, E. and Lamuela-Raventos, R.M. 2015.
Effects of total dietary polyphenols on plasma nitric oxide and blood pressure in a high cardiovascular risk cohort.
The PREDIMED randomized trial. Nutr. Metab. Cardiovasc. Dis. 25(1): 60–67.
Moghadam, M.H., Imenshahidi, M. and Mohajeri, S.A. 2013. Antihypertensive effect of celery seed on rat blood pressure in
chronic administration. J. Med. Food 16(6): 558–563.
Nangia, R., Singh, H. and Kaur, K. 2016. Prevalence of cardiovascular disease (CVD) risk factors. Med. J. Armed. Forces
India 72(4): 315–319.
Niazmand, S., Harandizadeh, F., Mahmoudabady, M., Hasanzadeh. M. and Fereidouni, E. 2014. Mechanism of vasorelaxation
induced by Achillea wilhelmsii in rat isolated thoracic aorta. Adv. Biomed. Res. 3(91): 1–7.
Nie, L., Wise, M.L., Peterson, D.M. and Meydani, M. 2006. Avenanthramide, a polyphenol from oats, inhibits vascular smooth
muscle cell proliferation and enhances nitric oxide production. Atherosclerosis 186(2): 260–266.
Nishioka, R., Kinoshita, S., Shiibashi, M., Shimazu, T., Nakazato, Y., Yamamoto, T. and Araki, N. 2015. Evaluation of the
differences in the effects of antihypertensive drugs on blood pressure variability by 24-hour ambulatory blood pressure
monitoring in chronic Ccerebrovascular disease. J. Stroke Cerebrovasc. Dis. 24(8): 1848–1854.
Nunes, M.G.S., Bernardino, A. and Martins, R.D. 2015. Use of medicinal plants by people with hypertension. Rev. RENE
16(6): 775–781.
Nwokocha, C.R., Owu, D.U., Gordon, A., Thaxter, K., McCalla, G., Ozolua, R.I. and Young. L. 2012. Possible mechanisms
of action of the hypotensive effect of Annona muricata (soursop) in normotensive Sprague–Dawley rats. Pharm.
Biol. 50(11): 1436–41.
Olowokudejo, J.D., Kadiri, A.B. and Travih, V.A. 2008 An ethnobotanical survey of herbal markets and medicinal plants in
Lagos State of Nigeria. Ethnobotanical. Leaflets 12: 851865.
Patel, S. and Patel, J.K. 2016. A review on a miracle fruits of Annona muricata. J. Pharmacogn. Phytochem. 5(1): 137–148.
Patel, S., Rauf, A., Khan, H. and Abu-Izneid, T. 2017. Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for
homeostasis and pathologies. Biomed. Pharmacother. 94: 317–325.
Peterson, D.M., Hahn, M.J. and Ammonds, C.L. 2002. Oat avenanthramides exhibit antioxidant activities in vitro. Food
Chem. 79(4): 473–478.
Petroni, L.M., Huffman, M.A. and Rodrigues, E. 2017. Medicinal plants in the diet of woolly spider monkeys (Brachyteles
arachnoides, E. Geoffroy, 1806)-a biorational for the search of new medicines for human use?. Rev. Bras. Farmacogn.
27(2): 135–142.
Polat, R., Cakilcioglu, U., Kaltalioglu. K., Ulusan, M.D. and Turkmen, Z. 2015. An ethnobotanical study on medicinal plants
in Espiye and its surrounding (Giresun-Turkey). J. Ethnopharmacol. 163: 1–11.
Popovi, Z., Mati, R., Bojovi, S., Stefanovi, M. and Vidakovi, V. 2016. Ethnobotany and herbal medicine in modern
complementary and alternative medicine: An overview of publications in the field of I & C medicine 2001–2013.
Rahmani, A.H., Al shabrmi, F.M. and Aly, S.M. 2014. Active ingredients of ginger as potential candidates in the prevention and
treatment of diseases via modulation of biological activities. Int. J. Physiol. Pathophysiol. Pharmacol. 6(2): 125–136.
Rawat, P., Singh, P.K. and Kumar, V. 2016. Anti-hypertensive medicinal plants and their mode of action. J. Herbal. Medicine
6(3): 107–118.
Restrepo, R.A., Loango, N., Moncada, M.V. and Landázuri, P. 2013. Angiotensin-converting enzyme inhibitory activity of
Passiflora edulis flavicarpa and Petroselinum crispum (Mill) Fuss. Br. J. Pharm. Res. 3(4): 776–785.
Restrepo, R.A, Nieto, O.A., Aristizabal, J. and Landázuri, P. 2014. Angiotensin-converting enzyme inhibition by Phthirusa
pyrifolia (Kunth) Eicher. World J. Pharm. Sci. 3(6): 352–363.
Ried, K. and Fakler, P. 2014. Potential of garlic (Allium sativum) in lowering high blood pressure: mechanisms of action and
clinical relevance. Integr. Blood Press. Control. 7: 71–82.
Shayganni, E., Bahmani, M., Asgary, S. and Rafieian-Kopaei, M. 2016. Inflammaging and cardiovascular disease: Management
by medicinal plants. Phytomedicine 23(11): 1119–1126.
Tabassum, N. and Ahmad, F. 2011. Role of natural herbs in the treatment of hypertension. Phcog. Rev. 5(9): 30–40.
Tabeshpour, J., Imenshahidi, M. and Hosseinzadeh, H.A. 2017. Review of the effects of Berberis vulgaris and its major
component, berberine, in metabolic syndrome, Iran. J. Basic. Med. Sci. 20(5): 557–568.
Textor, S.C. 2017. Renal arterial disease and hypertension. Med. Clin. North Am. 101(1): 65–79.
Tiwaria, S.C. and Husain, N. 2017. Biological activities and role of flavonoids in human health—a review. Indian J. Sci. Res.
12(2): 193–196.
Torlasco, C., Faini, A., Makil, E., Ferri, C., Borghi, C., Veglio, F. and Parati, G. 2017. Cardiovascular risk and hypertension
control in Italy. Data from the 2015 World Hypertension Day. Int. J. Cardiol. 243: 529–532.
Vardanyan, R., Hruby, V., Vardanyan, R. and Hruby, V. 2016. Chapter 22 Antihypertensive drugs. pp. 329–356. In: Synthesis
of Best-Seller Drugs.
Vergara-Galicia, J., Jimenez-Ramirez, L.Á., Tun-Suarez, A., Aguirre-Crespo, F., Salazar-Gómez, A., Estrada-Soto, S. et al.
2013. Vasorelaxant activity of extracts obtained from Apium graveolens: Possible source for vasorelaxant molecules
isolation with potential antihypertensive effect. Asian Pac. J. Trop. Biomed. 3(10): 776–779.
WHO 2013. A global brief on hypertension. A global brief on hypertension 40.
World Heart Federation. 2015. Cardiovascular disease risk factors - Hypertension World Heart Federation 1–2. Retrieved
from http://www.world-heart-federation.org/cardiovascular-health/cardiovascular-disease-risk-factors/hypertension/
Xia, M., Qian, L., Zhou, X., Gao, Q., Bruce, I.C. and Xia, Q. 2008. Endothelium-independent relaxation and contraction of
rat aorta induced by ethyl acetate extract from leaves of Morus alba (L.). J. Ethnopharmacol. 120(3): 442–446.
Yan, J.K., Ding, L.Q., Shi, X.L., Donkor, P.O., Chen, L.X. and Qiu, F. 2017. Megastigmane glycosides from leaves of Eucommia
ulmoides Oliver with ACE inhibitory activity. Fitoterapia 116: 121–125.
4
Plants Used for Central Nervous
System Disorders by Brazilian Indians
Priscila Yazbek,1,* Thamara Sauini,1 Fernando Cassas,1
Giuseppina Negri2 and Eliana Rodrigues1
Introduction
Ethnopharmacology is a recent discipline in the Academia. Although the term ethnopharmacology had
firstly appeared in 1967, “Ethnopharmacological search for new psychoactive drugs”, the ‘idea’ of this
discipline had already been presented in 1924 by Louis Lewin in his work entitled ‘Phantastica’.
Originally, ethnopharmacology was defined as a science that sought to understand, from field works,
the natural resources’ (plants, animals) universe used as drugs from human groups’ point of view. One of
these definitions was given by Schultes (1988) “...ethnopharmacology, sub area of ethnobotany, is a recent
discipline in the academic world, and it refers to medical or pseudomedical use of plants and animals by
pre-literate societies”.
However, over time, some researchers have defined it in the context of pharmacological and
phytochemical studies and not field work. That is, the plants or animals indicated during the field work
among Indians, for example, should be investigated by these sciences in order to prove or not their
‘empirical’ use; however, the field work itself would not be considered an ethnopharmacological study. One
of these definition was employed by Holmstedt and Bruhn as “...the interdisciplinary scientific exploration
of biologically active agents traditionally employed or observed by men” (Holmstedt and Bruhn 1983). This
view has been reinforced by current concepts, such as the International Society for Ethnopharmacology
(2005), “... interdisciplinary study of the physiological actions of plants, animals and other substances
used in indigenous medicines of past and present cultures”.
These latter definitions, somehow, establish a link between ‘traditional and/or popular’ and ‘academic’
knowledge. In this way, data from field work studies must be tested and proven or not by academic science.
However, this was not the original idea which intended to describe other cultures’ medicine. The uses of
plants and animals, as well as their effects, were seen in the context of a particular human group, whether or
not official medicine could use it for its benefit. The historical trajectory of ethnopharmacology definitions
makes us think that ethnopharmacology is only science if tested and approved by our science; not seeing
or recognizing other cultures knowledge as a science in itself.
1
Center for Ethnobotanical and Ethnopharmacological Studies-Institute of Environmental Sciences, Chemical and
Pharmaceutical, Federal University of São Paulo, SP, Brazil.
2
Federal University of São Paulo, SP, Brazil.
* Corresponding author: pbyazbek@gmail.com
Plants Used for Central Nervous System Disorders by Brazilian Indians 57
Ethnopharmacology does not deal with superstitions, but with popular knowledge related to traditional
systems of medicine. To appreciate this knowledge it must be admitted, without prejudice, as a body of
knowledge, a product of the human intellect (Elisabetsky 2003). Therefore, traditional and/or popular
knowledge does not need to be validated by ‘our’ science to be legitimate. It exists regardless of its
judgment, criticism or evaluation by ‘our medicine’.
Considering that ethnopharmacology, inserted in the context of ethnobiology, is the study of developed
knowledge and conceptualizations by any culture about its medical practices, the relations between human
populations and medicinal plants and the remedies used in traditional medical systems (Elisabetsky 2003,
Albuquerque 2005). This chapter aims to highlight the importance of studying indigenous communities,
their knowledge and culture in order to guide future pharmacological studies of plants with possible action
on the Central Nervous System (CNS).
Ethnopharmacology: approaches and cultural context

Ethnopharmacology includes diverse approaches as ethnopharmacological surveys carried out during
field work among diverse cultures in order to rescue aspects of local medicine; studies that relate human
displacement to popular and/or traditional knowledge; studies that depart from popular and/or traditional
knowledge to rescue plants (and other resources) that present use restriction, bringing elements to evaluate
risks in these medicines consumption; studies comparing knowledge among different cultures (even in
the same biome); and finally studies that depart from ancient literature reports to rescue the knowledge of
medicinal resources used centuries ago.
The development of these approaches is based on methods and techniques of anthropology
(ethnography) and biology (botany and zoology). Ethnography is used to record the complexity of local
medicines, as mentioned above, including medicinal uses of plants and animals in most cases (but also
fungi, minerals, algae and other substances). While botanical and zoological methods are used to collect
the resources (plants and animals) mentioned through the indications (Rodrigues and Otsuka 2012). As in
ethnobotanical studies, methods and analyses of data may be qualitative or quantitative, or—more rarely—it
can involve both approaches. For more details, see (Bernard 1988, Alexiades 1996).
According to Balick and Cox (1996) two different approaches can be followed in order to select a
plant species for investigation. The first one is the random selection where any plant can be choosen for
the screening of its substances without taking into account its taxonomic kinship, intrisic qualities or
ethnobotanical context. Even though some drugs, such as taxol used to treat ovarian and breast cancer,
have been discovered through random selection, this approach has low success rates. The other is the target
approach which can be done by various ways as the selection of a plant from a taxonomic family or genus
with known medicinal properties, a particular habitat or assertive characteristics as immunity to predation
by animals, and a plant indicated through an ethnobotanical survey. When both approaches are compared,
authors contest that drug discovery are more likely to succeed when ethnobotanical surveys are conducted.
Svetaz et al. (2010) tested plant species indicated by Latin America traditional medicine against fungal
pathogens and concluded that plants indicated by the communities inhibited growth of pathogenic fungi in a
higher percentage than the plants choosen randomly (40 against 21%). The study conducted by Gyllenhaal
et al. (2012) compared the bioassay activity of plants selected through the random approach and the ones
indicated by ethnomedicine from Laos and Vietnam and they observed a higher activity rate in the plants
collected according to the indications. Although some of the specific uses were not confirmed by the assays.
The lack of expected effects on pharmacological tests may occur because laboratory tests do not address
cultural contexts in which medicinal species are used, in other words, they are not accompanied by local
practices and beliefs that provide the meaning to medicinal plants, animals, and minerals. Therefore, even
a species having active therapeutic principles as indicated by a certain culture, do not act alone on healing
contexts. The cultural therapeutic meaning contributes to its effect. Thus, pharmacological tests should be
conducted considering this cultural context, avoiding misinterpretations of inefficiency for having been
tested separately from beliefs and practices involved in their uses (Moerman 2007, Reyes-Garcia 2010).
Besides which, a plant’s efficacy failure on clinical tests can be related to translation gaps from
“emic1” to “etic”2 terms. Often ethnopharmacological indications refer to “local diseases” or cultural-bound
syndromes that require rigorous observations and interpretation so they can be correlated with the correct
“etic” term used by conventional medicine. Nevertheless, the correct interpretation can be very hard to
be achieved, since cultural-bound systems often link clinical manifestations to conditions influenced by
cultural factors (Tseng 2006, Quinlan 2010), that do not always take into account conventional medicine.
Thus as defended by Pagani et al. (2017): “The correlation between the “emic” terms used by the
local populations, with their correspondent “etic” terms and the natural resources used for the healing, may
give insights to guide further pharmacological studies. One main role of ethnopharmacology is to address
these correlations, since they are the bases for suggesting the potential bioactivity of these resources”.
The evolution of ethnopharmacology as a discipline has taken great strides in the understanding
of traditional cosmologies and it may contribute to guide the development of new drugs. Some papers
have brought discussions on the relevance of theoretical and methodological contributions, as well as the
importance of interdisciplinarity to the success of studies conducted (Waldstein 2006, de Oliveira et al.
2009, Reyes-Garcia 2010).
Reyes-Garcia (2010), as an example, draws attention for the potential contribution of social sciences
and traditional knowledge systems, defined by: “[...] the knowledge of resource and ecosystem dynamics
and associated management practices existing among people of communities that, on a daily basis and
over long periods of time, interact for their benefit and livelihood with ecosystems. The term does not
merely refer to information about human uses of plants and animals. Rather, it includes a system of
classifications, a set of empirical observations about the local environment, and a system of resource use
and management. It also includes believes in non-human beings (i.e., spirits, ancestors, ghosts, gods) and
on how they relate to society”.
Moreover, many papers have been published about plants’ knowledge transmission, exchange of
knowledge between different communities and between traditional and conventional medicines, meaning of
cultural-bound syndromes and hypothesis to plants’ selection (Albuquerque and Lucena 2005, Leonti 2011,
de Medeiros et al. 2015, Pagani et al. 2017). These questions are essential to understand the use of certain
species in function of others, forms of use, dosage, choice of plants and, in later stages, these informations
can contribute for the reproduction of clinical assays that resemble cultural practices, since the efficacy
of medicinal plants are not only due to the plants, but also due to the cultural contexts they are inserted.
In this case, in addition to register and value cultural diversity and traditional knowledge, the need of
this knowledge guides scientific and technological development of drugs through the study of bioactive
potential, allowing flora to provide drugs widely used in the clinic, for example, artemisinin, colchicine,
emetin, forskolin, rutin, taxol and vincristine (Cechihinel Filho and Rosendo 1998). However, in most cases,
methods of pharmacology are lacking in achieving the logic of these medicines, which draws attention to the
cultural context understanding in order to consider these cultural elements for conduction of clinical tests.
Indigenous people and shamanism

Brazil began its history in the year 1503 with the discovery of a new world by the Portuguese. However,
this new world had already inhabitants who, according to estimates, totaled approximately 8 million people
scattered in at least 126 ethnic groups. The Tupi-Guaranis, who lived in the Atlantic forest bordering the
ocean, had already called it the territory of Pindorama, for example. Currently, according to the Brazilian
government, there are about 896,900 indigenous people distributed in 305 ethnic groups spread across
Brazil’s six main biomes (FUNAI 2017). There are 505 indigenous territories recognized by the National
Indian Foundation (FUNAI 2017), corresponding to 106.7 million hectares, or 12.5% of the country’s
territory. The largest concentration of these people is in the north, totaling 251.9 thousand indigenous
(48.7%), where the largest population is the Yanomami (25.7 thousand) in the states of Amazonas and
Roraima, living in the Amazon forest biome (FUNAI 2017).
1
Attempt to describe the behavioral system of a given culture using its own terms.
2
Attempt to describe the behavioral system of a given culture using academic terms.
These indigenous people, or nations, have an ancestral origin which, according to the two main theories
of peoples’ migration to Americas, have settled in the region between 12 and 14 thousand years ago and
continue to survive to this day. Throughout the development of each culture we can consider general topics
in common for its establishment and survival, as: coexistence in family nuclei; religious practices; healing
practices; music; dance and manufactured artifacts (technology). All these topics are practised by the 305
ethnic groups that differ in most ways, primarily, by the language and the biome where they are located.
The country is world renowned for its biodiversity, and it is among the 17 megadiverse in the world,
which together account for 70% of the planet’s biodiversity (Scarano 2009). The six main Brazilian biomes
are: Atlantic forest, Amazonian forest, Cerrado, Caatinga, the Pampa and the Pantanais-Matogrossenses
macro biome (IBGE 2017). It has the richest flora in the world, with approximately 55,000 species of
superior plants already described (Giulietti et al. 2005).
In each of these biomes there are endemic and native plant species. Their estimated numbers makes
it possible to measure the size of its biodiversity. For example, the Atlantic Forest has around 20 thousand
species of which 8 thousand are endemic, Cerrado possesses 11 thousand species of which 6 thousand
are endemic. While according to the study published by Giulietti et al. (2005), the Amazon possesses 30
thousand species, Caatinga 5 thousand species, and Pantanais-Matogrossenses 2 thousand species. In
this way we can understand that relation bioma versus human group, considering the 305 ethnicities and
biomes where they are established over the millennia, results in a great variety of cultural knowledge and
understanding about fauna and flora. Mainly access to these communities are very hard, with no roads
connecting them to cities, and thus makes the access of public and/or private health very tough, contributing
to the strengthening of traditional and popular local medicines (Rodrigues and Otsuka 2012).
However, in the last decades, the accelerated globalization process, global economy development and
the modernization of rural areas have been promoting the homogenization of societies, and, consequently,
cultural changes of traditional practices and knowledge. The consequences of these processes remain
under-explored (Cavalli-Sforza and Feldman 1981, Balick and Cox 1996).
Urbanization can impact local knowledge of these communities in two different ways, as discussed
by de Medeiros et al. (2015). The first one suggests that after having contact with external resources the
people give up their healing practices and allopathic medicines are replacing medicinal plants, since the
element incorporated is considered competitive and not complementary to a population knowledge. In
this case, and as time passes, the knowledge practices present before the urbanization process may be
replaced. The other possibility is the coexistence of both systems. In this case, new elements are added
in the medical system and do not replace medicinal plants (Soldati and Albuquerque 2012). People will
still use the traditional practices and medicinal plants, but they will also administer allopathic medicine
or drugs prescribed by the doctors.
Both situations illustrate that knowledge is always changing, incorporating elements from other
cultures and sometimes replacing practices and customs. In this context, we highlight the importance of
“learning” from these communities techniques for the selection of medicinal plants and not only listing
the medicinal plants used by them.
In the case of Brazil, 305 indigenous ethnicities identified, as it is evident, until their first contact
with the Advanced Industrial Society Ideology (Marcuse 1973, FUNAI 2017) or with the culture of non-
Indians, established different relations in their everyday life. All intellectual and natural material used to
come from tradition or ancestry and natural resources were native of forests in which they lived. Since
clothing, food, tools, medicines and utensils used to come only from their culture and region.
In this way, we can note the intrinsic relationship, mystical and the close proximity with the forest
and the relations that were established in the values of each community subject. Generally, we can
establish the main elements that form the social organization of these peoples making analogies with the
non-Indian culture. In the villages (neighborhoods, towns, communities, cities) there are Pajés (political
leaders, groups’ representatives), hunters (meat producers, farmers), planters and collectors (farmers, rural
producers), warriors (police, military, security), singers and rattle players (musicians, instrumentalists and
artists), family members who teach the youngest (teachers, educators) and Shamans (doctors, pharmacists,
nurses, health professionals).
Shamans and Shamanism are the names designated by non-Indians to healing practitioners of
indigenous communities. Since each culture establishes a different language, the names are also different.
The practice differs from non-Indian culture because beyond therapeutic practice and cure of diseases, it
involves religious aspects that are instrinsically linked to the process. It is important to highlight at this
point that, all the daily practices of Indians are linked to a religious and spiritual symbolism almost entirely.
Thus, decisions made on a daily basis are not interpreted according to the logic of empirical-theoretical-
technical rationality of western thought, but rather to a non-linear abstraction of facts interpretation,
resulting in a logic contained in metaphysical or mystical universes. To understand this type of thinking
and how relationships are established we will quote the example below:
The Krahô indigenous nation belongs to the macro-jê trunk, jê family and timbira language. In their
ascension, the Krahô suffered influences of the ethnic groups Canela, Xerente and Apinayé. Currently,
there are approximately 3,000 Krahôs, distributed in 19 villages and occupying 302,533 hectares in the
cerrado of Goiatins and Itacajá municipalities, at the north of Tocantins state. The villages are located far
from the nearest towns. In addition to not having public transport, the roads leading to them are precarious
and difficult to access, especially during the winter season, when there are strong rains (between October
and April). These factors reinforce the need to use plants for diseases’ treatments. According to Melatti
(1978), the Krahô are divided in two groups, one of them is the pair-wakměye (summer) and the other
the pair-katamye (winter). These divisions are characterized by a series of ritual and symbolic acts that
distinguish members of the half of each pair:
• Wakměye whose symbols are: day; dry season; summer; east of the village courtyard; straws for
light-colored garnishment; vertical stripes of body painting and parakeet;
• Katamye has the following symbols: night; rainy season; west; outskirts of the village; straws for
dark-colored garnishment; horizontal stripes and sucuruju snakes.
According to Rodrigues (2001), in the same way, the Krahô classify the plants and animals as belonging
to one or the other seasonal half, depending on the symbology that each one represents. Thus, plants that
flourish or fruit in the summer, belong to the wakmĕye half and those that bloom or fruit in the winter,
belong to the katamye. They explain that mid-summer plants are “more powerful” remedies than those of
winter, as rainwater, which is frequent in winter, they say, “dilutes” the “force” of these plants. According
to the interviewees, “wajaca is the person recognized by the Krahô people as holder of herbal remedies and
healing processes knowledge, by which he receives instructions and assistance from his respective pahí,
spiritual guide, generally represented by the spirit of an animal, plant, mineral, object or even of someone
that has passed away. He can cure or kill other person, acting as a wajaca or as a sorcerer. Smoking act
can help to communicate with their pahí or to produce more power at the time of healing”.
The most striking characteristics of this ethnic group are the richness of rituals and the use of medicinal
plants in healing processes (Melatti 1978). The anthropologist laments the lack of technical investment
in the collection and taxonomic identification of vegetal species used in magical rituals by these Indians
on that occasion, since:
“I found it was useful to identify those plants that the Krahô use for magical purposes, since a
laboratory analysis might prove that some of them actually contain some substance that would
produce the effects sought by the indians”
(translated from Melatti 1978).
In his work “Ritos de uma tribo Timbira” (Rites of a Timbira tribe), the author describes more than 40
rites observed among this group, most of them involving the use of animals and plants. In this sense, 20
years after this work, two researchers dedicated themselves to the survey of medicinal plants used during
rituals by this ethnic group. They described about 138 plants divided into 10 classes related to Central
Nervous System disorders (Rodrigues and Carlini 2005, 2006).
As mentioned above, the use of plants with possible effects on the central nervous system by Indians
has a strict relation with shamanism, since, as defended by Schultes and Hofmann (1993), indigenous
communities do not differentiate between physiological and supernatural causes of diseases. Many
ethnicities believe that illnesses are the result of some interference, pendency, or trouble in the spirit world.
Therefore, they believe that effective cure of diseases can only be carried out in this plan and for this they
must access it with the aid of plants, in most cases, psychoactive plants (Júnior et al. 2015).
Also on the spiritual level, the wajacas of Krahô ethnicity access their respective pahí and shamans
from other ethnic groups contacting their spiritual guides through dreams, rituals and the use of plants,
usually hallucinogenic, that act on the CNS. In these moments, spiritual revelations indicate the use of
effective plants for different diseases and for each sick person (Rodrigues 2001, Júnior et al. 2015), leading
to a treatment that considers specificities and characteristics of each patient, that is, an individualized
treatment. In the case of the Krahô Indians, each wajaca uses different plants for the same condition, this
differentiation is due to the different guides accessed by each curator who teach different applications for
plants species, as observed by Rodrigues and Carlini (2006). However, each indigenous ethnicity has a
different relationship with the spiritual plan and the spiritual guides, and few ethnopharmacological surveys
detail the contexts behind the curators’ choice of medicinal plants.
Because access to the spiritual plan is of great importance for diseases’ treatments in indigenous
communities, and considering that several medicinal plants are indicated for the same pathological
conditions, it is expected that the number of plants indicated for the CNS by these cultures will be ample.
Whereas Brazil has many endemic species in its biomes, the use of these plants by these communities can
provide a great variety of potential bioactive compounds for the CNS.
However, if the intention is to investigate whether these plants are effective in diseases treatments
designated by biomedicine, we must understand the different ways of seeing, recognizing and approaching
diseases by these people, considering the use contexts of these species and their cultural meanings.
Plants used in Central Nervous System disorders by Brazilian Indians

In 2006, Rodrigues et al. carried out a bibliographical review in order to analyze species of plants used by
several Brazilian indigenous ethnicities, as well as the relation between their chemical constituents and
their uses for Central Nervous System (CNS) disorders. These data were updated, and among studies found
from the 70s to the present day, 358 plant species, belonging to 97 botanical families, used by Indians for
different diseases were listed. These indications are available in 36 publications (for more information see
Rodrigues et al. 2006, Cunha et al. 2012, Kffuri et al. 2016).
Of the 97 taxonomic families listed, the most cited were: Fabaceae (60 registered species), Asteraceae
(23), Rubiaceae (18), Poaceae (14), Euphorbiaceae (14), Bignoniaceae (11), Apocynaceae (10), Solanaceae
(10), Lamiaceae (10), Piperaceae (10), Rutaceae (10), Verbenaceae (10), Cyperaceae (7) and Moraceae
(7). The families Fabaceae, Euphorbiaceae, Asteraceae, Bignoniaceae and Rubiaceae were also the most
cited during the research conducted by Rodrigues and Carlini (2005), who have also investigated the
plants used for CNS disorders.
According to Socio-Environmental Institute (ISA 2017), 48 Brazilian indigenous ethnic groups have
part of their population residing in other countries. In this manner, studies described here were carried
out with a total of 27 indiginous ethnic groups, who inhabit four of the Brazilian biomes (Amazon Forest,
Caatinga, Cerrado and Atlantic Forest), and some also inhabit other countries of South America; such as
the Yanomami, whose geographical distribution comprises a region of Amazon located in Brazilian and
Venezuelan territory. They are: Araraibo, Asurini, Baniwa, Deni, Fulniô, Guajajara, Jamamadi, Kaapor,
Krahô, Kubeo, Kuikuro, Maku, Makuna, Pankararu, Pareci, Pataxó, Paumari, Tembé, Terena, Ticuna,
Tiriyó, Tukano, Xokleng, Xukuru, Yanomami and Yawalapiti (Rodrigues et al. 2006), and Pataxós (Cunha
et al. 2012). The study was conducted with five multiethinic indigenous communities at the municipality
of São Gabriel da Cachoeira, Amazonas. The communities are called: Cunuri, Tapira Ponta, Ilha das
Flores, Curicuriari, and São Jorge. People interviewed in these communities belong to 10 different ethnic
groups: Tukano, Dessana, Baré, Tariano, Piratapuia, Arapaço, Baniwa, Hupda, Curripaco and Bara (Kffuri
et al. 2016).
Until 2006, few ethnopharmacological surveys were conducted among the Brazilian Indians (Rodrigues
et al. 2006). Upto the present, only two new studies have been found indicating plants used for the CNS by
Brazilian indians (Kufuri et al. 2016, Cunha et al. 2012). In these studies, 66 plants with possible effects
on the CNS were listed, of which 46 were indicated as antimalarial, without specifying which symptoms
they were acting on, and 20 as analgesics, stimulants, for headaches and fever.
The 358 cited plants are used to treat complaints and/or different diseases that may act actively on
the CNS. All uses for the 68 mentioned diseases were classified according to Rodrigues et al. (2006), in
accordance with the possible effect/action; grouping for example the plants destined for different pains,
such as for headache and earache, in the category “Analgesic”. Thus, 12 categories were defined, according
to the similarities between their effects expected on the CNS. Categories defined were: analgesics,
anticonvulsants, anxiolytics, hallucinogens, head illnesses, hypnotics, memory enhancers, stimulants, to
counteract fever, tonic and/or adaptogens, weight control, and others (without defined effect). Also, a new
category was added for antimalarial plants, since it was not indicated for which specific symptoms they
were used in the study. The categories and the number of plants indicated in each caterory are avaiable on
Figure 4.1, where six of them (marked by an asterisk) appear to exert possible psychoactive effect/action:
hallucinogens, anxiolytics, head illnesses, stimulants, hypnotics, and memory enhancers.
As examples, category “Analgesics” encompasses 21 different uses (arthritis, analgesics, body aches,
chest pain, anus pain, muscle pain, backbone pain, pain in the foot’s sole, pain in the ribs, ear pain, lower
uterine pain, rheumatic pain, headache, toothache, pain, lower extremity pain, otitis, painful joints, kidney
pain, back pain and heart pain), totaling 145 plants used to relieve all these kind of pains. Category “Fever”
refers to three uses (fever, fever in children and fever with pain), with 120 indicated plants. Category “Tonics
and/or Adaptogens” includes 15 uses (aphrodisiac, physical debility resulted from malaria combat, age
or general illness, to combat tiredness, drowsiness and inability to concentrate, elderly people who have
difficulty to understand instructions and physical degeneration, general debility, slow elderly, tonics, to
purify and strengthen the body, to restore virility, strengthen those who are weak and are no longer interested
in life because of age, tonic for the elderly, neuromuscular problems and sexual weakness), with a total of
40 species used. Thereby, the same species may have been cited for more than one use.
Considering all these classifications and the various uses and indications attributed to plants, we see
that categories “Analgesics” and “Fever” were the ones with the highest number of plants indicated, 145
and 120 species, respectively. The great number of indications to category “Analgesics” may be related to
the non-specificity of this group that includes all kinds of pain. However, category “Fever” may be related
to the high occurrence of malaria in the Amazon region, which has a characteristic symptom of elevated
body temperature, thus leaving this category within the most indicated. Another class that is evident related
to the indiginous culture is the category “Hallucinogens”. Many of the plants indicated to this section are
used by Indians in practices of shamanism, which supposedly alter the shaman’s perception, in order to
facilitate contact with the spiritual world, to perform their rituals (Rodrigues et al. 2006). As shown by
Analgesics 145
Fever 120
Antimalarial 46
Tonics and/or adaptogens 40
Hallucinogens* 25
Anxiolytics* 10
Anticonvulsants 9
Stimulants* 8
Hypnotics* 7
Weight control 6
Others 6
Head illnesses* 2
Memory enhancers* 2
Fig. 4.1 Number of plants indicated, for each of the 13 categories, with possible effect on the CNS (adapted from Rodrigues
et al. 2006).
Rodrigues et al. (2006), these plants’ uses by Brazilian Indians may be directly related to their customs.
The Krahô Indians, for example, were the ones who most indicated plants in the category “Tonics and/or
Adaptogens” because they have the status of “champion runner” as extremely important for their culture,
so, they use plants to be stronger and more able to win the competitions.
Among the plants phytochemically studied it was observed that seven phytochemical classes appeared
more frequently: flavonoids (analgesia, anxiety, fever, hypnotic, stimulant, and weight control), alkaloids
(head illnesses, hallucinogens, and as stimulant), essential oils (anxiety and fever), lignans (hallucinogens),
tannins (anxiety), triterpenes and saponins (hypnotics). According to Rodrigues et al. (2006), these classes
may be more common because they probably have a greater number of phytochemical constituents, which
may contribute to Indians determining their uses. Table 4.1 shows the frequency of the 13 phytochemical
classes among the plants indicated by Brazilian Indians, with possible effects on the Central Nervous
System, together with the number of indicated species and their chemical constituents, which were found
in the scientific literature until the year of 2006.
Table 4.1 Frequency of different phytochemical classes among the plants indicated by Brazilian indigenous people, with
possible effects on the Central Nervous System until 2006 (adapted from Rodrigues et al. 2006).
Categories of use (number of uses cited in the Number Chemical constituents found in the scientific
literature) of species literature (number of plants that present the
chemical constituent listed)
1-Analgesics: (21 different indications) 1-arthritis 145 flavonoids (28); alkaloids (18); essential oil (18);
(pain); 2-analgesic; 3-body ache; 4-chest pain; 5-pain phenolic acids (9); triterpenoid (9); tannins (6);
in the anus; 6-muscle pain; 7-pain in the backbone; coumarin (5); terpenes (5); diterpenoids (4); steroids
8-pain in the sole of the foot; 9-pain in the ribs; 10-ear (3); glycosides (2); saponins (2); iridoids (2);
ache; 11-pain in the lower womb; 12-rheumatic pain; sesquiterpene lactones (2); lactones (2); labdane
13-headache; 14-toothache; 15-pain; 16-lower extremity diterpenes (2); diterpene galactoside (1); eudesmane
pain; 17-otitis (pain); 18-painful joints, 19-kidney pain; acids (1); kava-pyrones (1); ketones (1); lignans (1);
20-back pain; 21-heart pain. aliphatic compounds (1); polyacetylene compounds
(1); sesquiterpene alcohols (1); lignan (1); aldehydes
(1); anthocyanins (1); cardenolides (1); furanone (1).
2-Fever: (3 different indications) 1-fever; 2-fever 120 flavonoids (26); essential oil (22); triterpenoid
(children); 3-fever with pain. (17); tannins (13); alkaloids (12); saponins (6);
coumarins (5); phenolic acids (7); iridoids (4);
steroids (5); anthraquinones (2); terpenes (2);
polysaccharides (2); sesquiterpene (2); lactones
(2); lignans (2); diterpenoids neocucurbitacins (1);
furanone (1); furanocoumarin (1); kava-pyrones (1);
ketones (1); labdane diterpenes (1); naphthopyrone
derivative (1); phenylpropanoid (1); phorbolesters
(1); podocarpane diterpenoids (1); sesquiterpenic
lactones (1); xanthones (1); diterpenoids (1);
fatty acids (1); alkylresorcinols (1); amides (1);
chromenes (1).
3-Tonics and/or adaptogens: (15 different indications) 40 alkaloids (4); coumarins (2); triterpenoids (2);
1-aphrodisiac; 2-combat physical debilitation resulting flavonoids (1); lignans (1); essential oils (1);
from malaria; 3-age or general infirmity; 4-to combat clerodane diterpenes (1); xanthones (1); terpenes
tiredness; 5-drowsiness and inability to concentrate; (1); labdane diterpenoids (1).
6-elderly who suffer difficulty in understanding
instructions and physical degeneration; 7-general
debility; 8-old people who are slow; 9-tonic; 10-to
purify and fortify the body; 11-re-establishing virility;
12-to strengthening those who are weak and who no
longer are interested in life because of age; 13-tonic
for the elderly; 14-neuromuscular problems; 15-sexual
debility.
4-Hallucinogens: (7 different indications) 25 alkaloids (10); lignans (5); coumarin (3); phenolic
1-hallucinogen; 2-additive; 3-inebriating snuff; acids (3); flavonoids (2); cardiac glycoside (2);
4-narcotic; 5-psychoactive; 6-substitute for Nicotiana steroids (2); diterpenes (1); triterpenoids (1); tannins
tabacum; 7-to see far (shamanism). (1); O-methoxylated-C-glycosylflavones lactones
(1); neolignans (1); furanocoumarins (1).
...Table 4.1 contd.

Categories of use (number of uses cited in the Number Chemical constituents found in the scientific
literature) of species literature (number of plants that present the
chemical constituent listed)
5-Anxiolytics: (3 different indications) 1-calmative; 10 flavonoids (4); essential oils (4); tannins (2);
2-irritability and crying in small children; 3-to calm. alkaloids (2); triterpenoids (2); saponins (1); sterols
(1); naphtoquinones (1); iridoids (1); glycosides (1)
6-Anticonvulsants: (4 different indications) 1-seizures 9 essential oil (1).
(children); 2-seizures; 3-periodic attacks of an epileptic-
like nature; 4-dizziness and blurred/darkened vision
(seizure).
7-Hypnotics: (4 different indications) 1-to induce sleep; 7 flavonoids (3); triterpenoids (2); saponins (2);
2-insomnia; 3-sedative; 4-elderly find difficult to sleep. phenolic acids (1); essential oils (1); tannins (1);
steroids (1); alkaloids (1).
8-Stimulants: (1 different indications) 1-stimulant. 8 flavonoids (3); alkaloids (2); steroids (1); lignans
(1); proanthocyanidins (1); essential oils (1); purine
alkaloids (1); indole alkylamines (1).
9-Weight control: (4 different indications) 1-to fatten 6 flavonoids (2); alkaloids (1).
dogs; 2-to lose weight; 3-to stimulate appetite; 4-when
they refuse to eat and lose appetite.
10-Others: (3 different indications) 1-antidote against 6 flavonoids (4); tannins (3), ginkgolides (1); alkyl
curare; 2-antidote against Dioclea spp.; 3-as stimulant and arylalkyl-1,3-diols (1); saponins (1); alcohols
for growth of breasts. (1); aldehydes (1); terpenes (1); triterpene (1).
11-Head illnesses: (1 different indications) 1-Craziness. 2 curare alkaloids (1).
12-Memory enhancers: (2 different indications) 2 No studies found
1-improve memory; 2-old people who are forgetful.
Plants used by indigenous communities cited in the literature and

pharmacology studies
Based on the review published by Rodrigues et al. (2006) and updating the data for 2017, we found 358
plant species with possible CNS-related activity. In order to verify which species have already been
studied or related to studies, and which are unprecedented for future studies, the number of pharmacology
studies were searched in the current literature that have already been conducted with these 358 species.
The search was performed in Pubmed databases by species’ name followed by the word “pharmacology”.
Figure 4.2 shows the number of publications found for species indicated by Brazilian indigenous people
with possible effect on the CNS.
Total 358
> 180 13
100 to 179 8
50 to 99 11
20 to 49 28
10 to 19 25
3 to 9 35
1 or 2 37
0 201
Fig. 4.2 Number of studies found (axis y) versus number of species (axis x) when searching for species’ name followed by
the word “pharmacology”.
Table 4.2 An average of studies found in PubMed for each species with possible effect on the Central Nervous System.
Number of Species with possible action on the Central Nervous System

publications
More than 180 Aloe vera (L.) Burm.f.; Carica papaya L.; Citrus sinensis (L.) Osbeck; Cymbopogon citratus (DC.) Stapf; Cymbopogon citratus Stapf.; Helianthus annuus L.; Ipomoea
publications batatas (L.) Lam.; Jatropha curcas L.; Melissa officinalis L.; Nicotiana tabacum L.; Ocimum basilicum L.; Ocimum gratissimum L.; Zingiber officinale Roscoe.
Between Ananas sp.; Carapa guianensis Aubl.; Cajanus cajan (L.) Millsp.; Mangifera indica L.; Mimosa pudica L.; Persea americana Mill.; Ruta graveolens L.; Terminalia
100 and 179 catappa L.
publications
Between Achillea millefolium L.; Argemone mexicana L.; Bixa orellana L.; Citrus aurantifolia (Christm.); Lactuca sativa L.; Lippia alba L.; Lippia alba (Mill.) N.E. Br; Musa
50 and 99 paradisiaca L.; Passiflora edulis Sims; Paullinia cupana Kunth; Pimpinella anisum L.
publications
Between Achyrocline satureioides (Lam.) DC.; Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm.; Anacardium occidentale L.; Artemisia vulgaris L.; Banisteriopsis caapi (Spruce
20 and 49 ex Griseb.) C.V. Morton; Cocos nucifera L.; Copaifera langsdorffii Desf.; Casearia silvestris Sw.; Erithroxylum coca Lam.; Erythroxylum coca L. var. Ipadu; Eugenia
publications uniflora L.; Gossypium barbadense L.; Jathropa gossypiifolia C.; Ocimum canum Sims; Petiveria alliacea L.; Pithecellobium dinizii Ducke; Physalis angulata L.;
Plectranthus amboinicus (Lour.); Protium heptaphyllum (Aubl.) March; Psychotria viridis Ruiz & Pav.; Schinus terebinthifolius Raddi; Senna alata (L.) Roxb.; Senna
obtusifolia (L.) H.S. Irwin & Barneby; Solanum americanum Mill.; Tagetes erecta L.; Terebinthifolius Raddi; Turnera ulmifolia L.; Uncaria guianensis (Aubl.) J.F. Gmel.
Between Acanthospermum hispidum DC.; Anadenanthera macrocarpa (Benth.) Brenan; Citrus sp.; Chondrodendron tomentosum Ruiz & Pav.; Cyperus articulatus L.; Dipteryx
10 and 19 odorata (Aubl.) Willd.; Euphorbia prostrata Aiton; Hedychium coronarium Koen.; Hymenaea courbaril L.; Justicia pectoralis Jacq.; Kielmeyera coriacea Mart. & Zucc.;
publications Lantana trifolia L.; Lutea L.; Mimosa tenuiflora (Willd.) Poir.; Myrcia multiflora (Lam.) DC.; Neurolaena lobata (L.) R. Br. ex Cass; Passiflora alata Curtis; Porophyllum
ruderale (Jacq.) Cass.; Pterodon emarginatus Vogel; Ptychopetalum olacoides Benth.; Sambucus australis Cham. & Schltdl.; Swartzia sp.; Urena lobata L.; Waltheria
indica L.; Zanthoxylum rhoifolium Lam.
Between 3 and Acca sellowiana (O. Berg) Burret; Ampelozizyphus amazonicus Ducke; Anadenanthera peregrina (L.) Speg.; Aniba canelilla (Kunth); Annona mucosa Jacq.; Asclepias
9 publications curassavica L.; Baccharis uncinella DC.; Borreria verticillata (L.) G. Mey.; Canna indica L.; Conyza floribunda Kunth; Costus spiralis (Jacq.) Roscoe; Coutarea
hexandra (Jacq.) K. Schum.; Euterpe precatoria Mart.; Genipa americana L.; Hedyosmum brasiliense Miq.; Himatanthus lancifolius (Müll. Arg.) Woodson; Leonotis
nepetifolia (L.) R. Br.; Libidibia ferrea (Mart. Ex Tul.) L.P.Queiroz; Luffa operculata (L.) Cogn.; Mandevilla illustris (Vell.); Ocimum micranthum Willd.; Piper arboreum
Aubl.; Piper sp.; Polypodium polypodioides (L.) Watt; Pothomorphe umbellata (L.) Miq.; Psidium quineense Sw.; Renealmia alpinia (Rottb.) Maas; Rubus brasiliensis
Mart.; Schwenkia americana L.; Siparuna guianensis Aubl.; Spiranthera odoratissima A. St.-Hil.; Strychnos guianensis (Aubl.) Mart.; Tachia grandiflora Maguire &
Weaver; Tachigalia paniculata Aubl.; Urera baccifera (L.) Gaudich. ex Wedd.
1 or 2 Alpinia nutans Roscoe; Andropogon leucostachyus Kunth; Annona hypoglauca Mart.; Arrabidaea brachypoda (DC.) Bureau; Aspidosperma nitidum Benth. ex Müll.
publication(s) Arg.; Astrocaryum aculeatum G. Mey.; Boerhavia coccinea Mill.; Cassia quinquangulata Rich.; Chaptalia nutans (L.) Pol.; Chelonanthus alatus (Aubl.) Pulle; Cordia
trichotoma (Vell.) Arrab. ex Steud.; Crateva tapia L.; Cyathula prostrata (L.) Blume Blume; Desmodium incanum DC.; Derris floribunda B. (Benth.) Ducke; Diospyros
guianensis (Aubl.) Gürke.; Epidendrum nocturnum Jacq.; Himatanthus bracteatus (A. DC.) Woodson; Laetia procera (Poepp.) Eichler; Licania heteromorpha Benth.;
Lilium sp.; Ludwigia nervosa (Poir.) H. Hara; Miconia rubiginosa (Bonpl.) DC.; Montrichardia arborescens (L.) Schott; Omphalea diandra L.; Panopsis rubescens (Pohl)
Rusby; Passiflora laurifolia L.; Parahancornia amapa (Huber) Ducke; Peperomia macrostachya (Vahl) A Dietr.; Phyllanthus acuminatus Vahl; Rolandra fruticosa (L.)
Kuntze; Solanum asperum Rich; Solanum crinitum Lam.; Solanum mauritianum Scop.; Tanaecium nocturnum (Barb.); Virola calophylla (Spruce) Warb.; Wulffia baccata
(L.) Kuntze; Zanthoxylum pentandrum (Aubl.) R.A. Howard.

...Table 4.2 contd.
Number of Species with possible action on the Central Nervous System

publications
no publications Abuta concolor Poepp. & Endl.; Abuta imene (Mart.) Eichler; Abuta grisebachii Triana & Planch.; Abuta rufescens Aubl.; Adiantum serratodentatum Humb. & Bonpl. ex Willd.;
found Alexa grandiflorsa Ducke; Alsodeia guianensis (Aubl.) Eichler.; Alternanthera dentata (Moench) Stuchlik ex R.E. Fr.; Amasonia angustifolia Mart. & Schauer; Amasonia campestris
(Aubl.) Moldenke; Anacardium giganteum W. Hancock ex Engl.; Aristolochia medicinalis R.E. Schult.; Arrabidaea trailii Sprague; Aspidosperma discolor A DC.; Aspidosperma
schultesii Woodson; Asplenium formosum Willd.; Attalea maripa (Aubl.) Mart.; Axonopus pulcher (Nees) Kuhlm.; Baccharis cylindrica (Less.) DC.; Banara guianensis Aubl.;
Bauhinia acreana Harms; Bertiera guianensis Aubl.; Brosimum acutifolium Huber; Brugmansia insignis (Barb. Rodr.) R.E. Schult.; Bulbostylis junciformis (Kunth) C.B. Clarke;
Bulbostylis lanata (Kunth) C.B. Clarke; Calliandra tenuiflora Benth; Callichlamys latifolia (Rich.) K. Schum.; Canna sp.; Cassia latifolia G. Mey.; Centropogon surinamensis
(L.) C. Presl; Cestrum laevigatum Schltdl.; Chondrodendron platiphyllum (A. St.-Hil.) Miers; Cissus sulcicaulis (Baker) Planch.; Clavija membranacea Mez; Clitoria guianensis
(Aubl.) Benth.; Clitoria javitensis (Kunth) Benth.; Coccocypselum guianense (Aubl.) K. Schum.; Cochlospermum orinocense (Kunth) Steud; Cochlospermum regium (Mart.);
Comolia microphylla Benth.; Complaya trilobata (L.) Strother; Connellia virginica L.; Conomorpha obovata (Ruiz Lopez & Pavon) Werdermann; Coussapoa intermedia Miq.;
Coutoubea ramosa Aubl.; Crateva benthamii Eichler; Crepidospermum goudotianum (Tul.) Triana & Planch.; Crotalaria maypurensis Kunth; Curculigo scorzoneraefolia (Lam.)
Baker; Cybianthus subspicatus Benth. ex Miq.; Cymbopogon densiflorus (Steud.) Stapf.; Cyperus flavus J. Presl & C. Presl; Declieuxia fruticosa (Willd. ex Roem. & Schult.)
Kuntze; Deguelia amazonica Killip; Desmodium axilare (Sw.) DC.; Dialium guianense (Aubl.) Sandwith; Dichorisandra affinis Mart.; Dioclea elliptica R.H. Maxwell; Dioclea
erecta Hoehne; Dioclea glabra Benth.; Dioclea latifolia Benth.; Dioclea scabra (Rich.) R.H. Maxwell; Dioclea ucayalina Harms; Diodia ocimifolia (Willd. ex Roem. & Schult.)
Bremek.; Discolobium leptophyllum Benth.; Dorstenia asaroides Hook.; Duguetia duckei R.E. Fr.; Elionurus adustus (Trin.) Ekman; Elizabetha princeps Schomburgk ex Benth.;
Eperua campestris (Ducke) Ducke; Eriochrysis cayennensis P. Beauv.; Erythrina glauca Willd.; Eugenia cauliflora O. Berg; Euterpe catinga Wallace; Ficus anthelmintica
Mart.; Ficus paraensis (Miq.); Galipea jasminiflora (A. St.-Hil.) Engl.; Glycydendron amazonicum Ducke; Guatteria guianensis (Aubl.) R.E.Fr.; Guettarda viburnoides Cham. &
Schltdl.; Gurania pachypoda Harms; Helicostylis tomentosa (Poepp. & Endl.) Rusby; Henriettea granulata O. Berg & Triana; Heteropsis tenuispadix G.S.Bunting ; Humiriastrum
piraparanense Cuatrec.; Hybanthus calceolaria (L.) Schulze-Menz; Hymenaea aurea Y.T. Lee & Langenh.; Hyptis hirsuta Kunth; Imperata brasiliensis Trin.; Ipomoea schomburgkii
Choisy; Ipomoea wrighti A.Gray; Iriartea deltoidea Ruiz &Pav; Jacaranda copaia (Aubl.) D. Don; Justicia pectoralis Jacq. var. stenophylla Leonard; Kielmeyera rugosa Choisy;
Licania humilis Cham. & Schltdl.; Lonchocarpus floribundus Benth; Macrolobium bifolium (Aubl.) Pers.; Macrolobium campestre Huber; Malachra capitata (L.) L.; Manihot
salicifolia Pohl; Mansoa standleyi (Steyerm.) A.H. Gentry; Maprounea guianensis Aubl.; Maquira calophylla (Poepp. & Endl.) C.C. Berg; Maquira sclerophylla (Ducke) C.C.
Berg; Marcgraviastrum elegans de Roon; Mauritia minor Burret; Memora flavida (DC.) Bureau & K. Schum.; Mesechites trifidus (Jacq.) Müll. Arg.; Miconia holosericea (L.) DC;
Micropholis cyrtobotrya (Mart. ex Miq.) Baill.; Micropholis guyanensis (A. DC.) Pierre; Mikania divaricata Poepp.; Mimosa hostilis (Mart.) Benth.; Monopteryx uaucu Spruce
ex Benth.; Mucuna altisima (Jacq.) DC.; Nectandra pisi Miq.; Ocotea aciphylla (Nees) Mez; Odontocarya tripetala Diels; Oncidium nanum Lindl.; Operculina alata (Ham.)
Urb.; Ormosia discolor Spruce ex Benth.; Ouratea castaneifolia (DC.) Engl.; Palicourea coriacea (Cham.) K. Schum; Panicum cyanescens Nees ex Trin.; Panicum nervosum
Lam.; Panopsis sessilifolia (Rich.) Sandwith; Paspalum serpentinum Hochst. ex Steud.; Passiflora costata Mast.; Pavonia rosa-campestris A.St.-Hil; Peperomia magnoliifolia
(Jacq.) A. Dietr.; Peperomia obtusifolia (L.) A. Dietr.; Perama hirsuta Aubl.; Periandra pujalu Emmerich & Senna; Phanera splendens (Kunth) Vaz; Phaseolus linearis Kunth;
Phenakospermum guianensis (A. Rich.) Endl. exMiq.; Phyllanthus dinizii Huber; Phyllanthus orbiculatus Rich.; Pilocarpus pennatifolius Lem.; Piper arborea Aubl.; Piper asimum
(Spr.) Angely; Piper daguanum C. DC.; Piptocarpha rotundifolia (Less.) Baker; Piresia leptophylla Soderstr.; Pleurothallis rubens Lindl.; Polygala asperuloides Kunth; Pouteria
ucuqui Pires & R.E. Schult.; Protium pallidum Cuatrec.; Protium paraense Cuatrec.; Pterocarpus michelii Britton; Randia armata (Sw.) DC.; Rhynchospora barbata (Vahl) Kunth;
Rhynchospora nervosa (Vahl) Boeck.; Roupala obtusata Klotzsch; Ruellia aff. malacosperma Greenm.; Ruellia geminiflora Kunth; Sabicea amazonenses Wernham; Sagotia
brachysepala (Müll.Arg.) Secco; Salvertia convallariodora A. St.-Hil; Schizaea pennula Sw.; Schizolobium amazonicum Huber ex Ducke; Schlegelia macrophylla Ducke; Schlegelia
roseiflora Ducke; Schoenobiblus daphnoides Mart.; Sciadotenia pachnococca Krukoff & Barneby; Scleria hirtella Sw.; Sipanea pratensis Aubl.; Sloanea rufa Planch. ex Benth.;
Smilax aequatorialis (Griseb.) A. DC.; Spondias mombin L.; Stachytarpheta sprucei Moldenke; Stachytarpheta straminea Moldenke; Struthanthus flexicaulis Mart.; Strychnos
javariensis Krukoff; Swartzia argentea Spruce ex Benth.; Swartzia picta Benth.; Swartzia recurva Poepp.; Syngonanthus oblongus (Körn.) Ruhland; Tabebuia barbata (E.Mey.)
Sandwith; Tabernaemontana heterophylla Vahl; Tabernaemontana sananho Ruiz; Tachigalia myrmecophila Ducke; Talisia cerasina (Benth.) Radlk.; Tephrosia senna Kunth;
Tetrapteris methystica; Theobroma subincanum Martius in Buchner; Tococa formicaria Mart.; Tocoyena formosa (Cham. & Schltdl.) K. Schum.; Trachypogon plumosus (Humb. &
Bonpl. ex Willd.) Nees; Trichilia macrophylla Benth.; Trichilia tocacheana C. DC.; Unxia camphorata L.f.; Verbena erinoides Lam.; Virola calophylloidea Markgr.; Virola michelii
Heckel; Virola theiodora (Spruce ex Benth.) Warb.; Vismia tomentosa Ruiz & Pav.; Xylopia nitida Dunal; Zornia gemella Vogel.
Of the 358 species sought, no study was found for 201. Such plants are indicated in Table 4.2,
together with the number of studies found for each species. This result indicates that more than half of the
vegetal species, indicated by Brazilian indigenous populations in the ethnopharmacological surveys, with
therapeutic purpose and possible action on the CNS were not studied, which reveals a great study potential.
Conclusion
Brazil has a great endemic diversity of vegetal species, added to the numerous indigenous ethnic groups
which use these plants as medicine for CNS disorders. Therefore, the use of these species by these cultures
points out several bioactive potential that must be pharmacologically and phytochemically studied in
order to develop new therapies and medicines for diseases recognized by biomedicine. However, for 176
species out of 358 reported in the literature, no pharmacological studies have been conducted to verify
the efficacy and safety of its uses.
Still, few studies that list medicinal plant used by indigenous Brazilian describe their contexts of use,
practices, beliefs involved in medico-religious treatments and the possible ways of choosing these plants
by the curators. Thus, when conducted, many of pharmacological studies are erroneously interpreted
as ‘non-effective’, since tests do not reproduce the circumstances in which species are used and do not
embrace their cultural meanings.
Therefore, in order to successfully develop new medicines and therapeutic practices from vegetable
species used by indigenous people, we must firstly understand, appreciate and admit this millenarian
knowledge for later investigating the efficacy and safety of these species, considering the context, practices
and values involved in their uses.
References
Albuquerque, U.P. 2005. Introdução à etnobotânica. Rio de Janeiro: Editora Interciência.
Albuquerque, U.P. and Lucena, R.F.P. 2005. Can apparency affect the use of plants by local people in tropical forests?
Interciencia. 30: 506–511.
Alexiades, M.N. 1996. Selected Guidelines for Ethnobotanical Research: A Field Manual. New York: The New York Botanical
Garden.
Balick, M.J. and Cox, P.A. 1996. Plants, people, and culture: the science of ethnobotany. Scientific American Library.
Bernard, H.R. 1988. Research methods in cultural anthropology. California: Sage Publications.
Cavalli-Sforza, L.L. and Feldman, M.W. 1981. Cultural transmission and evolution: a quantitative approach. Princeton
University Press, Princeton, NJ.
Cechinel Filho, V. and Yunes, A.R. 1998. Estratégias para a obtenção de compostos farmacologicamente ativos a partir de
plantas medicinais. Conceitos sobre modificação estrutural para otimização da atividade. Quim. Nova 21(1): 99–105.
Cunha Lima, S.T., Rodrigues, E.D., Alves, C., Merrigan, T.L., Melo, T., Guedes, M.L.S., Nascimento, A.F. and Toralles, M.B.
2012. The use of medicinal plants by an indigenous Pataxó community in NE Brazil. Rev. Bras. Plantas Med. 14(1): 84–91.
de Oliveira, F. C., Albuquerque, U. P., da Fonseca-Kruel, V.S. and Hanazaki, N. 2009. Avanços nas pesquisas etnobotânicas
no Brasil. Acta Bot. Bras. 23(2): 590–605
de Medeiros, P.M., Ladio, A.H. and Abuquerque, U.P. 2015. Local criteria for medicinal plant selection. pp. 149–162.
In: Albuquerque, U.P., de Medeiros, P.M. and Casas, A. (eds.). Evolutionary Ethnobiology. Springer International
Publishing.
Elisabetsky, E. 2003. Etnofarmacologia. Ciênc. Cult. 55(3): 35–36.
FUNAI - Fundação Nacional do Índio. Índios no Brasil. 2016. Available at http://www.funai.gov.br/index.php/indios-no-brasil/
quem-sao. Accessed on 10 Jun 2017.
Giulietti, A.M., Harley, R.M., Queiroz, L.P., Wanderley, M.G.L. and Van Den Berg, C. 2005. Biodiversidade e Conservação
das Plantas no Brasil. Megadiversidade, Belo Horizonte 1(1): 52–61.
Gyllenhaal, C., Kadushin, M.R., Southavong, B., Sydara, K., Bouamanivong, S., Xaiveu, M. and Dac, L.X. 2012. Ethnobotanical
approach versus random approach in the search for new bioactive compounds: support of a hypothesis. Pharm. Biol.
50(1): 30–41.
Heinrich, M., Ankli, A., Frei, B., Weimann, C. and Sticher, O. 1998. Medicinal plants in Mexico: Healers’ consensus and
cultural importance. Soc. Sci. Med. 47: 1859–1871.
Holmstedt, B. and Bruhn, J.G. 1983. Ethnopharmacology—a challenge. J. Ethnopharmacol. 8: 251–256.
IBGE - Instituto Brasileiro de Geografia e Estatística. Manual Técnico da Vegetação Brasileira. 2017. Available at: http://
www.ibge.gov.br/home/geociencias/recursosnaturais/vegetacao/manual_vegetacao.shtm. Accessed on 04 Jun 2017.
International Society For Ethnopharmacology. Available at: www.ethnopharmacology.org/. Accessed on 10 Jun 2017.
ISA - Instituto Socioambiental. Povos Indígenas no Brasil. Available at: https://pib.socioambiental.org/pt/c/0/1/2/populacao-

indigena-no-brasil. Accessed on 19 Jun 2017.
Júnior, W.S.F., Cruz, M.P., Vieira, F.J. and Albuquerque, U.P. 2015. An evolutionary perspective on the use of hallucinogens.
pp. 185–197. In: Albuquerque, U.P., de Medeiros, P.M. and Casas, A. (eds.). Evolutionary Ethnobiology. Springer
International Publishing.
Kffuri, C.W., Lopes, M.A., Ming, L.C., Odonne, G. and Kinupp, V.F. 2016. Antimalarial plants used by indigenous people of
the Upper Rio Negro in Amazonas, Brazil. J. Ethnopharmacol. 178: 188–198.
Leonti, M. 2011. The future is written: Impact of scripts on the cognition, selection, knowledge and transmission of medicinal
plant use and its implications for ethnobotany and ethnopharmacology. J. Ethnopharmacol. 134(3): 542–555.
Leonti, M., Fernando, R., Sticher, O. and Heinrich, M. 2003. Medicinal Flora of the Popoluca, Mexico: a Botanical Systematical
Perspective. Econ. Bot. 57(2): 218–230.
Lewin, L. 1924. Phantastica: die betäubenden und erregenden Genussmittel.
Marcuse, H. 1973. A ideologia da sociedade industrial: o homem unidimensional. Giasone Rebuá’s traduction. Rio de Janeiro:
Zahar.
Melatti, J.C. 1978. Ritos de uma tribo timbira. São Paulo: Editora Ática.
Moerman, D. 2007. Agreement and meaning: Rethinking consensus analysis. J. Ethnopharmacol. 112: 451–460.
Pagani, E., Santos, J. de F.L. and Rodrigues, E. 2017. Culture-Bound Syndromes of a Brazilian Amazon Riverine population:
Tentative correspondence between traditional and conventional medicine terms and possible ethnopharmacological
implications. J. Ethnopharmacol. 203: 80–89.
Quinlan, M.B. 2010. Ethnomedicine and ethnobotany of fright, a Caribbean culture-bound psychiatric syndrome. J. Ethnobiol.
Ethnomed. 6(1): 9.
Reyes-García, V. 2010. The relevance of traditional knowledge systems for ethnopharmacological research: theoretical and
methodological contributions. J. Ethnobiol. Ethnomed. 6(1): 32.
Rodrigues, E. 2001. Usos rituais de plantas que indicam ações sobre o Sistema Nervoso Central pelos índios Krahô, com
ênfase nas psicoativas. Doctoral dissertation, Universidade Federal de Säo Paulo. Escola Paulista de Medicina. Curso
de Psicobiologia.
Rodrigues, E. and Carlini, E.A. 2005. Ritual use of plants with possible action on the central nervous system by the Krahô
Indians, Brazil. PTR. Phytother. Res. 19: 129–135.
Rodrigues, E. and Carlini, E.A. 2006. A comparison of plants utilized in ritual healing by two Brazilian cultures: Quilombolas
and Kraho Indians. J. Psychoactive Drugs 38: 285–295.
Rodrigues, E., Mendes, F.R. and Negri, G. 2006. Plants indicated by Brazilian Indians to Central Nervous System disturbances:
a bibliographical approach. Curr. Med. Chem. 6: 211–244.
Rodrigues, E. and Otsuka, D.R. 2012. Estratégias utilizadas para a seleção de plantas com potencial bioativo com ênfase
nos métodos da etnobotânica e etnofarmacologia. pp. 39–64. In: Carlini, E.A. and Mendes, F.R. 2011. Protocolos em
psicofarmacologia comportamental: um guia para a pesquisa de drogas com ação sobre o SNC, com ênfase nas plantas
medicinais. São Paulo: FAP-UNIFESP.
Scarano, F.R. 2009. Plant communities at the periphery of the Atlantic rain forest: rare-species bias and its risks for
conservation. Biol. Conserv. 142(6): 1201–1208.
Schultes, R.E. 1988. Ethnopharmacological Conservation: A key to progress in medicine. Acta Amaz. 18: 393–406.
Schultes, R.E. and Hofmann, A. 1993. Plantas de los Dioses, orígenes del uso de los alucinógenos. Fondo de Cultura Económica.
Shephard, G.H. Jr. 2004. A sensory ecology of medicinal plant therapy in two amazonian societies. Am. Anthropol. 106: 252–266.
Soldati, G.T. and Albuquerque, U.P. 2012. Ethnobotany in intermedical spaces: the case of the Fulni-ô Indians (Northeastern
Brazil). Evid.-Based Compl. Alt. 2012.
Svetaz, L., Zuljan, F., Derita, M., Petenatti, E., Tamayo, G., Cáceres, A., Cechinel Filho, V., Giménez, A., Pinzón, R., Zacchino,
S.A. and Gupta, M. 2010. Value of the ethnomedical information for the discovery of plants with antifungal properties.
A survey among seven Latin American countries. J. Ethnopharmacol. 127: 137–158.
Tseng, W.S. 2006. From peculiar psychiatric disorders through culture-bound syndromes to culture-related specific syndromes.
Transcult. Psychiatry 43(4): 554–576.
Waldstein, A. 2006. Mexican migrant ethnopharmacology: pharmacopoeia, classification of medicines and explanations of
efficacy. J. Ethnopharmacol. 108(2): 299–310.
5
Ethnobotanical Retrospective and
Features of the Multipurpose Plant
Genipa americana L. (Rubiaceae)
Kyria Cilene de Andrade Bortoleti,1 Roberta Lane de Oliveira Silva,2
Silvany de Sousa Araújo,2,3 Ana Christina Brasileiro-Vidal2 and
Ana Maria Benko-Iseppon2,*
Introduction
Genipa americana L. is an edible species of the Rubiaceae Juss. family, native to the northern part of South
America occurring from the Caribbean region and southern Mexico to the Brazilian Atlantic coast and up to
southern Peru. It is popularly called genipap, jenipapo, huito, or jaguar, among other names. This species
was already used by the Incas (under the name of wituq or hawa) who used this plant for many purposes,
with emphasis on body painting during rituals. It is generally a small tree (8–20 m), but representatives
with up to 40 m have been described in Atlantic and Amazonian rainforests. Flowers are large (up to 15
cm diameter) round berries, with up to 400 g in weight pollinated by bees and flies. In addition to being
edible and medicinal, the fruit is used for the production of dyes, syrup, sugar, as liqueurs, wine, ethanol
and non-alcoholic beverages. Bark and resin are used in perfumery, pharmacy or for insecticide, fungicide,
and antimicrobial or similar applications, fresh or dried, whether or not cut, powdered or crushed (Barbosa
2008, Codignoto et al. 2017). The wood is a source of tannins and their salts, esters, ethers are used for the
production of natural blue and black dyes. The flowers are used in the manufacture of essential oils for the
perfumery industry (Borges and Rezende 2000), and the leaves are used for feeding animals.
This species is rarely cultivated, being thus exploited through extractive practices, i.e., plant material
is collected from natural populations and no traditional cultivation exists. Such practices have contributed
to some loss of diversity due to deforestation, forest fragmentation and some reproductive problems due
to the genetic features of this species.
Most of the existing ethnobotanical bibliography about G. americana is published in Portuguese
or Spanish, thus being unavailable to the wide scientific community. The present chapter describes the
1
UNIVASF, Universidade Federal do Vale do São Francisco, Petrolina, Pernambuco, Brazil.
2
UFPE, Universidade Federal de Pernambuco, Genetics Department, Center of Biosciences, Av. Prof. Moraes Rego, 1235,
50.670-423, Recife, Pernambuco, Brazil.
3
UFRPE, Universidade Federal Rural de Pernambuco, Recife, Pernambuco, Brazil.
* Corresponding author: ana.benko.iseppon@pq.cnpq.br
traditional use of this species by human populations. It also highlights available studies of this medicinal
and edible plant, as well as implications associated with genetic, environmental, and market potential for
derivatives from this interesting species.
Taxonomy and morphological features of G. americana L.

The genus Genipa L. is classified in the tribe Gardenieae, subfamily Ixoroideae of the family Rubiaceae
Juss. (Barroso et al. 1991). Gentry (1993) described six distinct species of the genus. Later, Pierozzi and
Mendaçolli (1997) recognized only three species (G. americana, G. infundibuliformis Zappi & Semir,
and G. williamsii Standl.). However, based on phylogenetic studies, Persson (2000a, 2003) replaced
G. williamsii in the genus Agouticarpa [Agouticarpa williamsii (Standl.) C.H. Perss.]. Therefore, the
genus Genipa includes only two species, being G. americana the most dispersed. Among the species cited,
G. americana (Fig. 5.1) is widely distributed in tropical America and is considered the most known tree
species of the genus (Guerra 1993, Zappi et al. 1995). In an inventory of the Amazonian angiosperms, Gentry
(1993) highlighted the participation of the genus as a component of the Amazonian canopy, presenting
fleshy and indehiscent fruits (Fig. 5.1a) with many seeds, which are dispersed by mammals. Its leaves are
broad (Fig. 5.1e) with triangular subfoliar stipules. The color of the corolla varies from cream to yellow,
with a tube approximately 1 cm wide and anthers inserted between the bases of the corolla lobes (Fig. 5.1b).
G. americana stands out as a woody dicotyledonous plant with high ecological plasticity, reaching up
to 40 m in height. The upright trunk is 40 to 60 cm in diameter and its crown is branched and quite leafy,
with an abundant verticillate branching (Fig. 5.1c), and bark is usually glabrous, smooth, thick and colored
grayish-green with gray spots (Corrêa 1984, Figueiredo et al. 1986, Silva et al. 1998). Its leaves are simple,
opposite, densified at the extremities of the branches, with triangular, sub-coriaceous, oblong-obovate,
triangular-shaped, glabrous, and with irregularly reticulated secondary veins. It presents hermaphrodite
flowers, axillary or terminal, slightly aromatic, tubular-campanulate calyx, yellow-white corolla (Figs. 5.1b,
5.2a), and bilocular ovary (Corrêa 1984, Figueiredo et al. 1986, Silva et al. 1998). The fruit is an ovoid
Fig. 5.1 Botanical illustration of Genipa americana. (a) fruit; (b) flower; (c) habit; (d) seeds and (e) leaf with nervures. Source:
a-b/d-e from Johann Wilhelm Weinmann: Phytanthoza iconographia, Augsburg 1735–1745 (public domain). c. present work.
Ethnobotanical Retrospective and Features of the Multipurpose Plant Genipa americana L. (Rubiaceae) 71
berry (Fig. 5.1a) of brown color, 5 to 12 cm in diameter, with a soft bark, thin and wrinkled membrane. It
presents a delicate pulp of vinous dark color, juicy, aromatic and edible.
The seeds are located in the central portion of the fruit (Fig. 5.1a), being light-brown, flat and polished
(Fig. 5.1d), surrounded by a colored aril, with viability of up to 90 days after fruit removal and zoochoric
or hydrochoric dispersion (Braga 1960, Figueiredo et al. 1986, Silva et al. 1998). Seed germination is
epigynous, that is, cotyledons rise above the soil surface. According to Nascimento et al. (2000), genipap
seeds germinate more efficiently on a substrate with filter paper or vermiculite at a temperature of 30°C.
Despite the massive production and wide seed dispersal, there is a high mortality rate after germination.
Therefore, rare seedlings of this species are found in advanced stages in the natural habitat (Francis 1993,
present work).
This species also exhibits peculiar reproductive mechanisms. Salomão and Allem (2001) reported
that G. americana would present apomictic reproduction and polyembryony. In apomixis, meiosis and
fertilization are altered, with seed formation without fertilization, that is, the offspring receives genetic
material from a parent, while the other gametes, usually male, stimulate the division of the zygote. In
turn, polyembryony is the formation of more than one embryo per egg. In their experiments, Salomão
and Allem (2001) observed that G. americana seedlings from polyembryony had a uniform development.
Origin and geographical distribution of G. americana

There are controversies as to the origin of G. americana. Based on a bibliographical survey, Xavier (1976)
suggested that this plant originated from humid areas of Cuba and Puerto Rico, while other researchers
believe that the center of origin of genipap is tropical America. According to Cavalcante (1991), the
American Genipa species originated from northern South America, where it is found both in the wild and
cultivated forms, since pre-Columbian times. However, it may be emphasized that this situation applies to
several areas of current occurrence of the species, for example, the Brazilian Atlantic coast till the state of
Bahia, in Brazil. Considering that the Amazonian region hosts the greatest diversity of Genipa species, it
can be considered that this is the most probable region of origin of the genus and probably of G. americana.
Due to the lack of fossil records, the original limits of Genipa distribution are unknown. Currently,
the natural distribution of the species is restricted to areas with annual rainfall of 1200 to 4000 mm and
average annual temperature between 18 and 28°C (Francis 1993). According to Sebbenn et al. (1998),
genipap is distributed naturally between latitudes 20 °N (Mexico) to 20 °S (Brazil, SP). Its culture extends
throughout the South American continent, Central America and the Antilles, being common in all the
Brazilian Amazon, in the natural and cultivated state. The expressive dispersion of this species throughout
America must be attributed to its being one of the checked main plants cultivated by the Indians in pre-
Columbian times (Francis 1993). This use was reported in several letters sent from Brazil to Europe in
the 16th century (Cavalcante 1991).
In Brazil, G. americana occurs in semi-deciduous seasonal forests, with greater abundance in wetlands
and riverbanks, supporting long-lasting floods, being also found in dry lands of the slopes or colonizing
open areas, behaving as a secondary pioneer (Andrade et al. 2000, Lorenzi 2002).
Phylogenetic studies on Genipa and G. americana

Phylogenetic analyses are determinant for ecological, evolutionary and biogeographic inferences, as
well as for morphological and anatomical investigations of different species (Bremer 2009). With the
advancement of genetic sequencing techniques, the growing generation of nuclear and organellar DNA
sequences associated with the morphological characteristics has provided valuable data, which supports
the phylogenetic evaluation of plant species at different taxonomic levels.
The genus Genipa is grouped in the tribe Gardenieae, subfamily Ixoroideae that is designated as
monophyletic (Kainulainen et al. 2013) and diverged to 73.1 Mya (million years ago) within the Rubiaceae
(Bremer and Eriksson 2009). In order to determine the phylogeny and to evaluate the tribal delimitations
within Ixoroideae, Kainulainen et al. (2013) used information from six coding (matK, ndhF, rbcL) and non-
coding plastid DNA regions (the rps16 intron, trnS-G and trnT-F) obtained for 110 species, representative
of 87 genera, for phylogenetic reconstructions using Bayesian analysis and Maximum Parsimony. These
authors concluded that the Ixoroideae was composed of three groups, among them the Coffeeae-alliance,
which involves the Gardenieae tribe (including Genipa), designated as the largest of the subfamily
(Bremer and Eriksson 2009). Different morphological and molecular evaluations point the Gardenieae as a
polyphyletic group (Bremer 2009, Bremer and Eriksson 2009, Kainulainen et al. 2013, Mouly et al. 2014),
being recognized as an unresolved group, both in terms of intertribal relations and in tribal boundaries.
Originally, the Gardenieae tribe was described by de Candolle (1830) and was constituted by 28 genera
whose representatives were characterized by the presence of biloculated ovaries and indiscriminate fruits
with many seeds, like Genipa. Later, also using morphological data, Robbrecht and Puff (1986) recognized
two subtribes (1) Diplosporinae and (2) Gardeniinae, composed of 20 and 60 genera, respectively. In
the Gardeniinae subtribe, three groups were recognized (1) Tetrad-, (2) Aidia and (3) Alibertia, the latter
being composed of six Neotropical genera including Genipa. With the addition of plasmidial DNA data
to the morphological matrix, a later phylogeny proposed by Persson (1996) supported the three groups
mentioned. However, it suggested the exclusion of G. americana from the Alibertia group, based on data
for rps16 intron and the intergenic spacer trnL-F, confirming the proposed by Andreasen and Bremer
(1996, 1997) with morphological and molecular data such as RbcL gene. Another phylogenetic study with
38 species from the Alibertia group using the untranscribed spacer of 5S rDNA and Internal Transcribed
Spacers (ITS) revealed a clustering of Genipa aff. willianssi in a basal clade of the group Alibertia. In
turn, G. americana was grouped with the paleotropical group. According to the authors, the plastid DNA
data indicate that the Genipa genus is paraphyletic (Persson 1996, Persson 2000), a fact that needs to be
evaluated with other phylogenetically informative sequences.
Up to date, no infrageneric evaluation was carried out using molecular markers in the genus Genipa.
Therefore, important questions, such as the number of species, monophyly, and infrageneric relations
remain unresolved.
Cytogenetic studies
Previous reports on mitotic and meiotic chromosomes of G. americana have revealed very unusual
karyotypic features for this species. The chromosome number 2n = 2x = 22 was reported for G. americana
by Gibbs and Ingram (1982) and was confirmed by several other authors (Guerra 1986, Kiehn 1986,
Pierozzi and Da Cruz 1988, Guerra 1993, Pierozzi and Mendaçolli 1997, Corrêa and Forni-Martins 2004)
and also the present work (Fig. 5.2b), being recognized as a common number in the family Rubiaceae.
Fig. 5.2 Genipa americana. (a) Detail of a branch with a flower, flower buds and leaves, collected in Pernambuco, Brazil.
(b) Mitotic chromosomes (2n = 22) after standard staining with Giemsa, and (c) after CMA3 (chromomycin A3) fluorochrome
staining. Bars in (b) and (c) = 10 μm.
Diploid genipap individuals present an asymmetric karyotype with the presence of four to seven
metacentric and submetacentric chromosomes, respectively, with a chromosome size of 2.42 to 6.77 μm
(Corrêa and Forni-Martins 2004). These data, except the chromosome count, diverged from that observed
by Pierozzi and Mendaçolli (1997) who suggested smaller chromosomes and the occurrence of three and
eight metacentric and submetacentric chromosomes, respectively.
Also regarding the heterochromatic bands evidenced by C-banding, some divergences among distinct
studies are evident. Pierozzi and Da Cruz (1988) emphasized centromeric and telomeric heterochromatic
blocks in the genipap chromosomal complement, while Pierozzi and Mendaçolli (1997) showed the
predominance of pericentromeric bands. A preliminary evaluation carried out by our group indicated some
variation in the distribution of heterochromatic bands in populations collected in Pernambuco (Brazil).
A hallmark feature for G. americana was revealed by staining with the CMA3/DAPI (4’-6’-diamidino-
2-phenylindole) base-specific fluorochromes. A high amount of constitutive GC-rich heterochromatin
(Guanine-Cytosine) was evidenced by the CMA3+ (CMA3 positive) bands pattern (Guerra 1993). In some
chromosomes, these heterochromatic segments constituted about 50% of their extent, as can be observed
in Fig. 5.2c (present work), which makes G. americana the plant species with the highest known amount
of heterochromatin in tropical America (Guerra 2001).
We presume that such an intraspecific variation and the large amounts of satellite repetitive DNA
may result in meiotic instabilities, leading to the generation of unbalanced gametes, which could justify
the reports of low seed germination rate fertility for the species. This could be in consonance with the
proposed occurrence of apomixis as a reproductive strategy of G. americana, as suggested by Salomão
and Allem (2001). To clarify this question, additional meiotic studies should be carried out as well as
population studies.
Molecular diversity
Studies aimed at acquiring knowledge about the genetic diversity of a particular native species provide
valuable information for the improvement of ex situ and in situ conservation strategies, especially concerning
species considered vulnerable due to the reduction of genetic diversity (Sebbenn et al. 1998). This is the case
of G. americana, which has been affected by extractive practices and has also been used for the recovery
of degraded areas, mainly in the restoration of riparian forests (Sebbenn et al. 1998, Rabbani et al. 2012).
Molecular studies with genipap are still scarce and involve the use of different markers, including
isoenzymes (Sebbenn et al. 1998, Sebbenn et al. 2003, Sebbenn 2004), RAPD (Random Amplified
Polymorphic DNA; Rabbani et al. 2012), ISSR (Inter Simple Sequence Repeats; Santos 2012, Moura 2014,
Silva et al. 2014) and SSRs (Simple Sequence Repeats; Manoel 2014, Manoel et al. 2014, Manoel et al.
2015). Existing reports with molecular markers aimed at obtaining information about genetic structure
and diversity, breeding system and gene flow of the species in question, for the purposes of forest recovery
strategies, conservation, management and breeding programs (Rabanni et al. 2012, Santos 2012).
The isoenzyme electrophoresis was used to evaluate the genetic variability, reproductive system
and spatial distribution of a natural population of G. americana located in the riparian forest of the Mogi
Guaçu River (São Paulo, Brazil). The evaluation included 42 adult plants and 300 seedlings from 15
matrices (20 seedlings per matrix). The evaluated isoenzymatic loci were: PGM (Phosphoglucose), 6PGDH
(6-phosphogluconate dehydrogenase), PGI (Phosphoglucose isomerase), MDH (Malate dehydrogenase)
and PRX (Peroxidase). Polymorphism levels indicated that this population presented some potential for
exploration in future breeding programs and for seed collection for the purpose of recovery of degraded areas
(Sebbenn et al. 1998, Sebbenn et al. 2003). Additionally, the authors evidenced an excess of heterozygotes in
adult plants, as compared with seedlings, suggesting the existence of selection in favor of the heterozygotes
between the adult plants in different development stages. On the other hand, an excess of homozygotes
was noticed among the seedlings, indicating the occurrence of inbreeding, leading to deviations from
the Hardy-Weinberg equilibrium, raising the assumption that the population would be reproductively
subdivided into two groups with a certain degree of relatedness, possibly due to preferential crosses and/
or genetic drift. Finally, the estimate of the crossing rate of the population in question showed that 81.6%
of the G. americana seedlings were generated by crossing, being 61.7% random, 19.9% between related
and 18.4% regarded possible apomictic (Sebbenn et al. 1998).
Later, Sebbenn (2004) studied the inheritance and linkage disequilibrium in four polymorphic
isoenzymatic loci (6pghd-1, Pgi-2, Mdh-1 and Mdh-2) in a population of G. americana. Segregation was
homogeneous among individuals, regarding two to three alleles. However, significant deviations of the 1:1
expected ratio were detected in the Mdh-2 and 6pghd-1 whose causes may be selection, meiotic distortion,
inter-allelic interactions and gene drift. Signs of linkage disequilibrium were not detected for any of the
loci, so the author suggested that they can be used for studying the breeding system, diversity and genetic
structure of populations of G. americana (Sebbenn 2004).
RAPD molecular markers were used to evaluate the genetic diversity of two natural populations located
along the lower São Francisco River (Rabanni et al. 2012) and in Arauá (Silva et al. 2015) in the state
of Sergipe (Brazil). In both studies, a high level of polymorphism among the evaluated individuals was
noticed, emphasizing that these markers regard useful tools to infer about the population genetic diversity.
Rabanni et al. (2012) also correlated the average genetic distances with the increase in geographic distances,
pointing out that studied genipap populations would be differentiated by a random process, suffering the
effects of genetic drift due to fragmentation and decrease of gene flow (Telles and Bastos 2009). Also,
UPGMA (Unweighted Pair Group Method using Arithmetic Averages) analyses allowed the identification
of adequate individuals to be used as seed matrices for germplasm bank generation, seedling production
and restoration programs in degraded areas (Rabanni et al. 2012).
Another approach identified 32 microsatellite loci used to characterize 40 adult G. americana trees
from two populations located in a small forest fragment at the Mogi Guaçu Ecological Station (São Paulo,
Brazil) and in Selvíria (Mato Grosso, Brazil). Most of the loci identified regarded dinucleotides (80.49%),
followed by mono- (10.97%), tetra- (4.88%), tri- (2.44%) and pentanucleotides (1.22%). Of these, 17 were
polymorphic and 15 monomorphic (Manoel et al. 2014). This predominance of dinucleotides was also
highlighted in genipap DNA sequences deposited in the public GenBank database (www.ncbi.nlm.nih.
gov/genbank/) by Camargo et al. (2016). In terms of genetic structure and diversity, the number of alleles,
the expected and observed heterozygosity for the populations of Mogi Guaçu and Selvíria showed that all
loci were in Hardy-Weinberg disequilibrium (Manoel et al. 2014). This scenario is probably related to the
occurrence of sampled individuals in small forest fragments. Among the 32 microsatellite loci described
by Manoel et al. (2014), six were investigated in 188 adult and 163 regenerative trees of the Mogi Guaçu
population, showing Mendelian inheritance, absence of genetic linkage and genotypic equilibrium, being
indicated for studies of genetic structure and diversity, mating systems and pedigree analyses in this species
(Manoel et al. 2015).
22 ISSR markers have also been used to evaluate genetic diversity in 35 accessions of genipap (Santos
2012, Moura 2014, Silva et al. 2014) in an experimental field in Cruz das Almas (state of Bahia, Brazil),
revealing 86% polymorphism in the evaluated germplasm (Santos 2012). Another study accessed the
diversity, divergence and spatial genetic structure of 76 individuals collected in six regions of the Sergipe
state with 14 ISSR primers, among which seven generated 107 fragments with 100% polymorphism. The
analysis of similarity and spatial genetic structure revealed the distribution of the individuals in three
distinct groups, independent of the region of their origin, indicating that the genetic basis was distributed
randomly (Moura 2014).
The Brazilian genipap germplasm bank was created in 2009 at Embrapa (Empresa Brasileira de
Pesquisa Agropecuária) Coastal Tablelands station (Tabuleiros Costeiros, Sergipe). This germplasm bank
was sampled using 12 ISSR primers, uncovering a higher diversity within the accessions (57%) than
between (43%), indicating a strong genetic structure and a low gene flow. UPGMA phenogram showed the
formation of four groups: C1, constituted mostly by accessions from Sergipe and Bahia; C2, accessions from
Ceará and Sergipe; C3 formed by materials collected in Sergipe and Ceará, and C4, constituted by a single
genotype of Sergipe. The authors suggest that this genetic distance may indicate a strong differentiation
process, as a consequence of the genetic erosion, due to the current fragmentation of natural populations.
Finally, the low heterozygosity noted among the evaluated genotypes indicates a low diversity in the
genipap germplasm bank, suggesting the need to introduce new individuals to incorporate new alleles and
increase genetic diversity (Silva et al. 2014).
Folk medicinal applications

South American populations still have a significant dependence on natural resources, with emphasis on
plants for various purposes, including food and phytomedicines (Benko-Iseppon and Crovella 2010). In
this scenario Rubiaceae members stand out, exhibiting a variety of chemical constituents of medicinal
importance, being used in the treatment of bronchitis, asthma, pneumonia, as well as anti-rheumatic,
emetic, purgative, diuretic, anti-inflammatory, antiviral and anti-edeogenic activity, among others (Lorenzi
and Matos 2002, Dias et al. 2013). Within the family, genipap occupies a prominent position due to its
recognized popular use, with some pharmacological studies that have confirmed part of its properties, also
uncovering new therapeutic potentialities.
According to Cordeiro and Felix (2014), G. americana is among the most cited plant species by the
population of Paraíba state (Northeastern Brazil), highlighting the use of genipap fruits in folk medicine
for the treatment of osteoporosis, anemia, stomach problems, nervousness, diabetes, cholesterol, besides
being an excellent tonic in the fight against indisposition, fatigue and weakness.
A compilation of the main uses of G. americana reported in the literature is shown in Table 5.1,
involving mostly indications based on the application of interviews and questionnaires in populations
in their areas of occurrence. All parts of the plants have medicinal activity (Table 5.1, Fig. 5.3a). For
example, tea prepared from the roots has purgative and antigonorrheic properties. Infusion of the leaves
is used for the treatment of diarrhea and syphilis, and when macerated it is also employed by some native
tribes as antifebrile.
Fig. 5.3 (a) Most used Genipa americana plant parts based on Table 5.1, including the number of citations (dark gray) and
percentage of citations (light gray). (b) Graphical representation of the main categories of indication (in percentage) based
on the number of indications. Legend for abbreviations in b: DIG = digestive tract; HEM = hematological disturbs (e.g.,
blood pressure, stimulating the lymphatic system); DEF = defense against pathogens, and parasites, antimicrobial activity;
RES = respiratory tract; SKI = skin, and muscles; KID = kidney and urinary tract; OTH = whole body, against fever, and
nervousness, among other indications.
Table 5.1 Main ethnobotanical and phytotherapeutic indications of G. americana considering literature reports and considering
no association with other plant species.
Ethnobotanical indication Plant part used Form of use Category1 Reference(s)

(or treatment of)
Against fever Leaves Maceration OTH Delprete et al. 2005
Against weakness Fruit Juice OTH Epstein 2001, Cordeiro and Felix
2014
Anemia Fruit Tonic HEM Agra et al. 2007
Anemia Stem Bark Decoction HEM Corrêa 1984, Donadio et al. 1998,
Matos 1999, Cordeiro and Felix
2014
Anthelmintic Leaves Aqueous extract DEF Nogueira et al. 2014
Antiasthmatic Fruit In natura RES Mors et al. 2000, Epstein 2001,
Moreira et al. 2002
Anti-diarrheic Leaves Tea DIG Corrêa 1984, Epstein 2001
Antigonorrheic Roots Tea DEF Mors et al. 2000, Epstein 2001,
Lorenzi and Matos 2002, Agra et al.
2007, Alves et al. 2008
Anti-inflammatory Leaves Maceration OTH Delprete et al. 2005
Antimicrobial Fruit In natura DEF Barbosa 2008, Codignoto et al.
2017
Anti-syphilitic Leaves Infusion DEF Corrêa 1984, Epstein 2001
Blood depurative Leaves Decoction HEM Alves et al. 2008
Blood depurative Stem bark Decoction HEM Alves et al. 2008
Cholesterol decrease Fruit In natura HEM Cordeiro and Felix 2014
Diabetes Fruit In natura OTH Cordeiro and Felix 2014
Diuretic Fruit Juice KID Epstein 2001
Diuretic Stem bark N.I.2 KID Donadio et al. 1998
Granular pharyngitis Stem bark Decoction RES Corrêa 1984, Matos 1999
Hypertension Fruit In natura HIM Robineau 1995
Jaundice Fruit In natura HEM Mors et al. 2000, Epstein 2001,
Moreira et al. 2002
Liver disorders Leaves Infusion DIG Agra et al. 2007
Liver disorders Fruit In natura DIG Mors et al. 2000, Epstein 2001,
Moreira et al. 2002
Muscle contusion, luxation Stem bark Decoction SKI Corrêa 1984, Matos 1999
Nervousness (calming) Fruit In natura OTH Cordeiro and Felix 2014
Osteoporosis Fruit In natura OTH Cordeiro and Felix 2014
Purgative Roots Tea DIG Mors et al. 2000, Epstein 2001,
Lorenzi and Matos 2002, Agra et al.
2007, Alves et al. 2008
Purgative Stem bark N.I.2 DIG Corrêa 1984
Respiratory clearance Sprouts N.I.2 RES Epstein 2001
Respiratory clearance Fruit Juice RES Epstein 2001
Scurvy Stem bark Decoction HEM Corrêa 1984, Matos 1999
Skin affections Fruit Juice SKI Djerassi et al. 1961
Spleen disorders Fruit In natura HEM Mors et al. 2000, Epstein 2001,
Moreira et al. 2002
Stomach pain Fruit In natura DIG Cordeiro and Felix 2014
Stomach ulcer Stem bark N.I.2 DIG Donadio et al. 1998
Venereal ulcers Stem bark Decoction DEF Corrêa 1984, Matos 1999
Vomitory Seeds N.I.2 DIG Epstein 2001
1
Category of indications: DEF = defense against pathogens, and parasites, antimicrobial; DIG = digestive tract;
HEM = hematological disturbs, blood pressure and lymphatic system; KID = kidney and urinary tract; RES = respiratory tract;
SKI = skin, and muscles; OTH = whole body, against fever, nervousness, bones, etc. 2N.I. = Not informed.
The stem and the bark, although having tannins, exhibit a predominantly purgative effect which in
decoction, is indicated for the treatment of scurvy wound, venereal ulcer, granular pharyngitis, and anemia,
besides being used in contusions and bone displacement.
Mature fruits are rich in iron and are indicated for problems like anemia, jaundice, asthma, liver and
spleen affections, and against osteoporosis, diabetes and high cholesterol. In addition, due to its high content
of mannitol, the mature fruit is recommended for the treatment of hypertension (Corrêa 1984, Matos 1999,
Mors et al. 2000, Lorenzi and Matos 2002, Moreira et al. 2002, Delprete et al. 2005, Conceição et al.
2011). In vitro studies with extracts of the fruits of G. americana showed a broad spectrum antimicrobial
activity (Barbosa 2008, Codignoto et al. 2017).
Considering the popular indications sampled, it is observed that the most used part involves the fruit
(41.3%), generally used in natura, including both mature and unripe stages. The second most used part is
the stem/bark (25.4%), followed by root (15.8%) and leaves (14.3%), while seeds and sprouts are rarely
cited, and no phytotherapeutic use of the flowers was reported (Fig. 5.3a).
An evaluation of the categories of use or indication based on Table 5.1 is presented in Fig. 5.3b. Two
categories figure among most indicated: DIG (diseases of the digestive tract) and HEM (treatment of blood
and circulation problems, hematological disturbs, high blood pressure and disorders of the lymphatic
system), both with 24.6%. The third category with 19.7% regarded defense (DEF, e.g., against pathogens,
and parasites or antimicrobial effect), followed by affections of the respiratory system (RES, 11.5%). Less
frequent indications included problems with skin and muscles (SKI = 4.9%), kidney and urinary tract (KID
= 3.3%). All remaining symptoms were placed in the “other” (OTH = 11.4%) category, including problems
that affect the whole body, including weakness, nervousness, fever, etc. (Table 5.1).
Phytochemical studies regarding G. americana — especially involving the isolation of their compounds
— are still scarce. Brigas et al. (2016) pointed out the presence of some compounds as iridoids, phytosterols,
and phenolics, all associated with different therapeutic properties. Among the iridoids isolated from mature
fruits of genipap, the genipin deserves mentioning (Djerassi et al. 1960) due to its anti-inflammatory and
antiangiogenic properties demonstrated by Ueda and Iwahashi (1991) and Koo et al. (2004).
Other compounds isolated from G. americana, including geniposide, tarenoside, gardenoside and
geniposidic acid exhibited anticancer activity in tumor-induced from the Ragi cell line by Epstein-Bar virus
(Ueda and Iwahashi 1991). In addition, genipin and geniposide demonstrated anti-inflammatory activity in
carrageenan-induced duck edema in rats (Koo et al. 2004). Additional pharmacological activities of iridoids
have been proved by scientific studies, such as hypotensive, spasmolytic, antiarrhythmic, hepatoprotective,
hypoglycemic, hypolipidemic, antitumor, antiviral, immunomodulatory, among others.
Costa et al. (2010) reported that the seeds and the pulp of genipap fruit contain phytosterols such
as campesterol, stigmasterol, and β-sitosterol. Phytosterols are present in genipap in high concentrations
and have the ability to lower serum cholesterol levels of Low-Density Lipoprotein (LDL). Phenolic
extracts obtained from G. americana fruits were evaluated by MTT [3(4,5-dimethyl-thiazol-2-yl)-2,5-
diphenyltetrazolium], MUH (4-methylumbelliferylheptanoate) and Methylene, indicating significant
antiproliferative activity for HepG2 hepatocarcinoma (Finco et al. 2013).
A long-standing tradition in Brazil involves the mixing of various herbs in ‘cachaça’ (sugar cane
brandy), a mixture called “garrafada”. Herbal sellers generally recommend the use of small daily doses,
usually one small cup (30 mL) per day (Benko-Iseppon et al. 2012), with genipap fruits, bark or leaves
being one of the elements frequently used in these infusions. Marques et al. (2015) reported the use of
genipap in ‘garrafadas’ together with six species (popular names ‘catuaba’, ‘jurubeba’, ‘jurema-preta’,
‘pau-ferro’, ‘prá-tudo’, and ‘ginseng’). The indication of use included treatment of chronic diseases;
osteoporosis; osteitis; osteomyelitis; periosteitis and back pain. Another survey by Nogueira (2005) reported
the association of up to 20 herbs in a bottle sold in open markets in Rio de Janeiro, indicated against
weakness (male or female) to “cleanse the blood”, for problems of the digestive tract and for women who
have difficulty in getting pregnant.
We have noted that ethnobotanical surveys rarely report on these mixtures or on the associations
of various plant species in a single product, although they are highly demanded and consumed by the
Brazilian population. Among the possible reasons for this lack of studies is the difficulty of identifying the
contents of these bottles, especially of establishing the botanical species they contain (Benko-Iseppon et al.
2012, Marques et al. 2015). In addition, the possible cytotoxic and allelopathic and mutagenic effects
of these mixtures have been poorly studied. Marques et al. (2015) highlight the lack of standardization
between different bottles, the poor information in the labels (if any available), emphasizing that the sale
of these products do not comply with legal regulations. We observed a similar situation for syrups sold in
the markets of the northeastern Brazilian region, with the lack of labels or in some cases including only
the popular name of species and not following the labeling regulations required.
It is important to encourage herbal producers and sellers involved in the production chain of these
products about the necessary availability of information and demand for standardization, also to preserve
valuable ethnobotanical information for the next generations.
Adverse effects and toxicity analyses

The importance of a careful evaluation of the cytotoxic, mutagenic and genotoxic potential of medicinal
plants and their compounds using in vitro and in vivo systems is evident, what can be achieved by different
types of tests using diverse types of model organisms (Araújo et al. 2015). Despite this importance, only
three evaluations were carried out to verify the possible adverse effects of G. americana. According to
Assis (2015), the hydroethanolic extract of the fruits of G. americana showed no in vivo toxicity (acute
and subchronic toxicity) for mice. Similarly, Omena et al. (2012) found that the pulp and seeds of genipap
are rich in antioxidants and did not present cytotoxic activity to ovine corneal epithelial cells. However,
Fernandez et al. (2011) reported that the extract prepared from leaves of genipap significantly inhibited
proliferation in the meristematic cells of Allium cepa. In addition, the same extract also promoted inhibition
of the cell cycle in fibroblasts of the cell line NCTC-929.
Considering the available analyses, it is possible to assume that there are significant differences
between compounds from different genipap tissues, requiring additional studies, including analyses of
diverse dosages and types of extracts. Particular care should be taken especially in the case of leaves that
present apparent toxicity, although this tissue represents only the third most consumed plant part (as tea,
infusion or maceration). It should be noted that no studies were found on the toxicity of the trunk/bark,
although this part is indicated as the second most used for therapeutic applications (Table 5.1, Fig. 5.3a).
Genipap fruit as food and source of raw material

The only part of genipap considered edible for humans is the fruit. Due to their strong taste, it is usually
said in Brazil that fresh fruits of genipap can arouse two types of reaction from consumers: love or hate,
not appealing to most people. Therefore, the mature fruits of genipap are rarely consumed in natura. They
are generally used as raw material for the production of jams, crystallized fruits, ice cream, soft drinks,
in the manufacture of liquor, jellies, juices, wines, sweets and syrups (Silva and Tassara 2005, Andrade et
al. 2016). Besides their characteristic flavor and aroma, these fruits are rich in iron, vitamins B1, B2, B5,
and C, also containing calcium and carbohydrates in their composition. Genipap fruit is a major source of
minerals as well as other bioactive compounds for the human diet (Vasco et al. 2008).
Fruit histochemical and chemical evaluations carried out by Figueiredo et al. (1986) reported that
genipap pulp presents low acidity, high moisture content, low protein and lipid content, high sugar content,
regular iron content, proper calcium and phosphorus content, high tannin content and palmitic and linoleic
acids (fatty acids) as well as traces of vitamin C and pectin.
Analyzing the frozen pulp of genipap, Souza et al. (2012) found values of 4.46% of carbohydrates,
0.21% of proteins, 0.34% of lipids and 1.15% of dietary fibers. Also the presence of minerals such as
Potassium (K) 92.55 mg/100 g, Calcium (Ca) 13.23 mg/100 g, Magnesium (Mg) 8.17 mg/100 g and Iron
(Fe) 0.22 mg/100 g was reported, proving to be a major source of nutrients.
Genipap as a source of pigments

Most reports on the traditional use of genipap regard the use of immature fruits that deliver a blue dye
employed in diverse types of application. This property of the fruits was already well known to Amerindians
who used them to tattoo their bodies in religious ceremonies, during battles, to dye fabrics, ornaments,
ceramics, spears and other artifacts (Gade 2016). Studies have shown that when the unripe fruit is cut, and
its interior is exposed to the air, its pulp gradually becomes dark, acquiring an intense blue color (Cavalcante
1991). In this way, Indians extract the juice of the genipap that at first has a citrus color, turning to green,
violet, blue, dark blue and finally almost black. The blue pigment is formed from the reaction between
genipin, a colorless iridoid present in genipap, and primary amine sources such as amino acids and proteins
(Touyama et al. 1994, Bentes and Mercadante 2014).
According to Corrêa (1984), navigators and European colonizers who reached ports in different points
of America are unanimous in registering the appreciation with which the juice was treated by the natives,
from Brazil to Mexico and the Antilles. Tattoos last a few weeks, and there are paintings on artifacts and
pictographs on rocks that have survived through the centuries to the present day.
Often the genipap dye was associated with the red dye ‘urucum’ (Bixa orellana L., Bixaceae). There
are reports that Catholic missionaries disapproved of such tattoos and fought against body paintings by
requiring the natives to wash before entering the churches. In the case of ‘urucum’ tattoos could be washed,
but the genipap tincture only disappears with time, and for this reason, the prohibitions were often dismissed
(Corrêa 1984). Cavalcante (1991) reported that according to J. Huber there are testimonies from South
American natives stating that G. americana was more valued and cultivated by Amerindians because of
its dye than as a source of food or wood.
Currently, there are some cosmetics for application to the hair and skin, that are available which are
recommended as temporary tattoo based on the dye of genipap, with a similar appearance to the tattoos
under the skin and estimated duration of 15 days.
Wood exploitation
The genipap wood has a light-colored core, extremely flexible, straight fibers and relative durability. It has
an average density of 0.68 g/cm³, being considered moderately heavy, flexible, compact, easy to work and
long lasting. It is not considered as hardwood but is much appreciated in woodworking, woodcutting, civil
and naval construction, carpentry for the manufacture of furniture, firearm stock, tool handles, and door and
window frames, being highly valued in curved pieces such as bows of barrels, tennis rackets, sieves, etc.
(Corrêa 1984, Barbosa 2008, Santos 2012). Other authors reported the use of genipap’s bark, which is rich
in tannins and is used in tanneries in the treatment of leather (Erbano and Duarte 2010, Moura et al. 2016).
Despite its promising characteristics, there is no genipap cultivation for the timber industry. Almeida
(2013) highlights the use of wood in construction and vessels in the northeastern region of Brazil in an
irregular manner, without any kind of preservation measure. We highlight that in this region there is
considerable fragmentation of the Atlantic forest, which was replaced by sugarcane fields, with great
impact on tree species such as genipap.
This species has been also indicated as valuable in urban and pastureland afforestation, providing
shade and shelter to the animals, being also used as forage (Salman et al. 2008, Santos et al. 2015), since
its leaves are well accepted by animals, including cattle, pigs, and goats (Table 5.2). Other studies have
demonstrated the ability of the genipap tree for phytoremediation, especially due to its capacity to absorb
chromium (a heavy metal), harmful to living organisms (Barbosa et al. 2007, Santana et al. 2012). Thus,
this plant can be a valuable tool in the regeneration of areas contaminated with this metal, persistent in the
surroundings of leather tanneries, being considered carcinogenic in its hexavalent form.
Patents associated to G. americana

Aiming to identify existing patents from G. americana we carried out a search using the keyword “Genipa
americana” in the US Patent and Trademark Office (USPTO) database, recovering 16 patents related to
uses of this species. The patents were categorized according to their applications, including (1) Production
of organic or synthetic compounds; (2) Method for production of organic compounds; (3) Method for
production of compounds rich in genipin; (4) Compositions and methods for hair coloring; (5) Multiple
emulsion for the stabilization of natural dyes and (6) Phytosanitary formulation for plant defense (Fig. 5.4).
Table 5.2 Non-medicinal uses of G. americana reported in the literature.
Sector Plant part Uses and applications Source

Human nutrition Mature fruits Production of jam; crystallized fruit, Corrêa 1984, Epstein 2001, Santos
soda, juice, frozen pulp, syrup, liquor, 2001, Prudente 2002
wine, alcohol, vinegar, brandy and ice
cream, etc.
Wood industry Wood Shipbuilding; construction of buildings; Corrêa 1984, Epstein 2001,
luxury carpentry; in cooperage, in Almeida 2013
foundries (molding of parts), in
woodcut, etc.
Leather tanning Wood bark Extract used for bathing in leather Epstein 2001, Erbano and Duarte
pieces (tanning). 2010, Moura et al. 2016
Leather tanning Immature fruit Extract used for bathing in leather Epstein 2001
pieces (tanning).
Reforestation Whole plant Recovery of deforested areas, provision Epstein 2001
of shade, formation of living fences and
street afforestation.
Animal feed Leaves and Feeding of cattle, goats, and pigs. Epstein 2001, Pinto-Ruiz et al.
mature fruits 2005, Salman et al. 2008
Phytoremediation Whole plant Phytostabilizer and chrome filterer, soil Barbosa et al. 2007, Santana et
recovery. al. 2012
Urban landscaping Whole plant Planting of seedlings in malls and Pinto-Ruiz et al. 2005, Salman et
squares. al. 2008, Santos et al. 2015
Fig. 5.4 Categories of patents deposited in the US Patent and Trademark Office (USPTO) databank involving Genipa americana
(http://www.uspto.gov/; access in June 2017).
The first patents related to G. americana were deposited between the 1980s and 1990s and mostly
referred to methods of isolation or production of new organic or synthetic compounds obtained from plant
extracts for pharmaceutical or pharmacological application. Such patents report the potential of iridoid
derivatives (monoterpene compounds that occur in plants), such as antihyperlipidemic and cholagogue,
and point to their potential use in the formulation of cholesterol-lowering drugs (Table 5.3, Fig. 5.4).
Table 5.3 Patents related to Genipa americana available in the database US Patent and Trademark Office (USPTO).
Patent # Title Description Inventor Deposited in

RE46,314 Genipin-rich material Method for producing new genipin-rich compounds obtained from G. americana fruit Chr. Hansen Natural Colors A/S February 2017
and its use for application in the development of dyes.
9,427,007 Multiple emulsions for Water-oil-water multiple emulsion for the stabilization of natural colorants of food, Chr. Hansen Natural Colors A/S August 2016
colorants pharmaceutical, and cosmetic products.
9,376,569 Colorant derived from Isolation method and characterization of dye compounds obtained from genipin or Ecoflora S.A.S. June 2016
genipin genipin and amine for use as a dye in foods, medicines, cosmetics, medical equipment
and textile products.
8,980,793 Phytosanitary A phytosanitary formulation and method comprising an active ingredient, an Univ. Blaise Pascal-Clermont-Ferrand March 2015
formulations alcoholic, hydroalcoholic or aqueous extract produced naturally by dyeing plants with II, CNRS
applications in agriculture and horticulture as herbicide, insecticide or fungicide.
8,945,640 Genipin-rich material Method for producing new genipin-rich compounds obtained from G. americana fruit WILD Flavors, Inc. February 2015
and its use for application as a cross-linking reagent and as a raw material in the development of
colorants.
8,632,612 Compositions for Compositions for coloring keratin fibers and their manufacturing methods for Segetis, Inc. January 2014
dyeing keratin fibers application in the cosmetics industry.
8,557,319 Stable natural color Method of producing dyes from the processing of G. americana juice with other edible WILD Flavors, Inc. October 2013
process, products and juices or extracts containing nitrogen compounds for application in the beverage, food
use thereof coloring, pharmaceutical industry, dietary supplements, cosmetics, personal hygiene
and animal food industry.
7,927,637 Blue colorant derived Method of production of liquid or powdered blue dye obtained from G. americana Ecoflora SA April 2011
from G. americana unprocessed natural juice for application in the textile, pharmaceutical, food, cosmetic
fruit and other industries.
7,699,897 Method of hair Compositions and methods for hair coloring for application in the cosmetics industry. L’Oreal April 2010
coloring
5,459,160 Iridoid derivatives Use of derivatives of iridoids synthesized from genipin with antihyperlipidemic action Tsumura & Co. October 1995
and the use thereof as and collagen for pharmaceutical application.
a drug
5,374,653 Iridoid derivatives Use of derivatives of iridoids synthesized from genipin with antihyperlipidemic action Tsumura & Co. December 1994
a drug
Table 5.3 contd.…

…Table 5.3 contd.
Patent # Title Description Inventor Deposited in

5,272,172 Iridoid derivatives Use of derivatives of iridoids synthesized from genipin with antihyperlipidemic action Tsumura & Co. December 1993
a drug
4,347,356 Novel nitrogen- Use of monoterpene derivatives with nitrogen-containing a pyridine chain, dimers, Taito Co., Ltd. August 1982
containing trimers and higher polymers as efficient and low toxicity dyes for pharmacological
monoterpene applications.
derivatives
4,247,698 Red coloring Method and production of a reddish-colored compound obtained from the reaction of Taito Co., Ltd. January 1981
composite and iridoid compounds and biological substances for application as a food pigment.
the method for its
production
4,232,159 Nitrogen-containing Use of monoterpene derivatives with nitrogen-containing a pyridine chain, dimers, Taito Co., Ltd. November 1980
monoterpene trimers and higher polymers as low toxicity dyes for pharmacological applications.
derivatives
3,932,628 Extracts from active Production of new organic compounds obtained from dried extracts of sap from trees US Department of Health January 1976
tree saps with antileukemic action in mice.
With advances in research, the use of these compounds was expanded to other areas such as food,
beverages, pharmaceuticals, dietary supplements, cosmetics, textiles, personal care products and animal
feed. This was the second most representative group of the search, with five patents for the methods and
production of compounds rich in genipin for application as dyes in the mentioned areas, emphasizing the
significant phytochemical potential of genipap (Table 5.3, Fig. 5.4).
The third group, with two patents deposited in 2010 concerned hair coloring compositions and
methods. This group emphasizes the pursuit of the cosmetic industry by plant raw materials capable of
providing low-cost, low-toxicity natural dyes as an alternative to minimize the irritating or toxic effects of
synthetic substances present in hair dyes, also allowing the creation of new shades for use in this market.
Other deposited patents included the production of a reddish coloring compound for use as a dye or
pigment in foods, a multiple emulsion for the stabilization of natural dyes, and a phytosanitary formulation
applied in agriculture and horticulture (Table 5.3, Fig. 5.4). The formulation of natural defensive substances
for phytosanitary use stands out as a new application directed to the agronomic area, presenting the herbicide,
insecticide or fungicide potential, which could minimize the toxic effects caused by commercial insecticides
for the health of workers and consumers of agricultural products, as well as for the environment.
It is interesting to note that many of the proposed uses and products patented are in consonance with
the indications and uses made by native communities in Latin America, emphasizing the great importance
of ethnobotanical studies in the indication of potential targets for bioprospecting of new compounds and
products of plant origin. Also worth mentioning is the tendency towards a greater appreciation of natural
products over synthetic products, in the area of cosmetics, food colorants, fabric dyeing, and in defense
against pests and diseases of agriculture, adding value to natural products, including derivatives of genipap.
This paradigm shift is made clear by the filing of nine recent patents for ‘non-toxic’ products of natural origin
between 2010 and 2017. The last patent before this new tendency was in 1995 (Table 5.3). Such a shift is
possibly associated with the clear consumer demands for natural products and ecologically sound sources.
Conservation, cultivation and extractive practices

The wide geographic distribution and good adaptability of G. americana in several tropical regions (Lorenzi
and Matos 2008) reinforces its ability to grow under diverse environmental conditions. In addition, this
species has been shown to be promising in the recovery of deforested and degraded areas due to its adaptive
characteristics to the ciliary environment, its rapid growth, abundant seed production and its capacity to
withstand long periods in wet soils, becoming a target of forestry studies (Barbosa et al. 1989, Sebbenn
1997, Rabbani et al. 2012).
According to Ferreira et al. (2005), due to its multiplicity of uses, and high potential for immediate use
among native fruit plants, genipap was included among the 10 species selected as priority by the program
‘Plants of the Future’ a joint initiative of the Brazilian Ministry of the Environment in conjunction with
the Global Environment Facility of the World Bank.
Although genipap is a species of recognized productive potential and socioeconomic relevance, works
evaluating its cultivation and productivity are still very limited. In addition, extractive practices have been
the main way of obtaining plant material, making the genipap tree very vulnerable and susceptible to forest
fragmentations and genetic erosion, which has contributed to a reduction of its diversity in some areas.
For example, Santos (2012) reported that the current practice is to preserve the trees that produce good
fruit, and those that do not serve this purpose are transformed into wood for various uses in the clandestine
timber market. Thus, the extractive activities are related to the broad range of applications of this species
and its logging characteristics (Santos et al. 2011, Bessa et al. 2013).
Currently, extractive practices have become one of the main threats to plants with edible fruits, being
carried out in a predatory way by practically complete removal of quality fruits (Ribeiro and Walter 2008).
Moreover, this fact accentuates the risk of extinction of these genotypes, making it essential to target
conservation and domestication efforts for species of environmental and economic interest (Gomes and
Moura 2010).
Aiming at the conservation of diversity, strategies for multiplication, conservation, and sustainable
management are essential since these species constitute an important source of genetic resources (Paunescu
2009). In this sense, studies evaluating germination capacity and seed storage are mandatory (Carvalho
and Nascimento 2000, Prado Neto et al. 2007, Magistrali et al. 2013), besides in vitro cultivation and
regeneration trials, as well as acclimatization of seedlings (Rocha et al. 2008, Yee et al. 2010, Almeida
2013, Almeida et al. 2015).
A major initiative involved the creation in 2009 of an Active Germplasm Bank of Genipap Tree
by Embrapa (Brazilian Agricultural Research Company) Coastal Tablelands station in Sergipe state,
Northeastern region of Brazil. This station includes an experimental field, where plants of different origins
are kept, aiming at their preservation (Almeida 2013). The maintenance of genetic resources of G. americana
is of particular importance considering its problematic physiology, since the seeds tolerate desiccation only
at low levels (Carvalho and Nascimento 2000, Oliveira et al. 2011), presenting low viability and absence of
germination after 60 days of storage (Vieira and Gusmão 2006). Despite this initiative, efforts to preserve
the species are still limited, requiring higher investments in research and development.
Conclusions and future perspectives

As highlighted throughout this chapter, since the earliest times of human civilization a communion exists
between genipap and the human populations in the regions where this species occurs. All parts of the plant
are used, with emphasis on its fruits (mature or immature) and the trunks. There are several products (some
patented) that, interestingly, reflect the primary uses of the parts of this plant. Considering the Convention
on Biological Diversity (CBD) and the Nagoya Protocol, the knowledge and role of traditional populations
in relation to their genetic resources should be recognized. The CBD proclaims three main objectives: (1)
conservation of biological diversity; (2) the sustainable use of its constituent parts; (3) the fair and equitable
sharing of benefits arising from the utilization of genetic resources (Rabitz 2015).
However, the scenario for achieving these goals is not promising in the case of genipap, since many
of their areas of occurrence have been devastated and replaced by plantations and pastures, with emphasis
on the Atlantic and Amazon forests, as well as Cerrado’s riparian forests in Brazil.
With regard to sustainability, there are still no established and implemented methodologies for the
propagation and scale plantation of G. americana. In this way, its use has been associated with extractive
practices or the maintenance of some individuals in pastures and backyards of private properties.
Appraisement of some populations in the last 15 years by our group draws attention to the lack of succession
by young plants in the surroundings of existing trees older than 40 years or more. In addition, the fragments
where the trees occur are gradually decreasing in size, plant density and diversity. Besides, as reported,
few seeds germinate, and most of the seedlings die few days or weeks after germination. Therefore, it is
imperative to analyze the reproductive mechanisms of this species, which may help in the definition of a
strategy for the production of useful seedlings or stocks for reforestation and to maintain their diversity.
In regard to “the fair and equitable sharing of benefits arising from the use of genetic resources”,
the reality is still far from achieving this goal. Practically all patents listed in this chapter derived from
information associated with popular knowledge of genipap, show the importance of ethnobotanical surveys
in different regions of its occurrence, especially those with greater dependence on natural resources. If the
benefits are to be shared, it remains to be seen by the next generations.
References
Agra, M.F., Freitas, P.F. and Barbosa-Filho, J.M. 2007. Synopsis of the plants known as medicinal and poisonous in Northeast
of Brazil. Braz. J. Pharmacog. 17: 114–140.
Almeida, C.S. 2013. Propagação e conservação in vitro de acessos de jenipapeiro. M.Sc. Dissertation, Universidade Federal
de Sergipe, Brazil. Available at https: //bdtd.ufs.br/bitstream/tede/656/1/camila_santos_almeida.pdf.
Almeida, C.S., Silva, A.V.C., Araújo, A.G. and Lédo, A.S. 2015. Respostas morfogenéticas de jenipapeiro em diferentes
condições de cultura in vitro. Rev Caatinga 28: 58–64.
Alves, E.O., Mota, J.H., Soares, T.S., Vieira, M.C. and Silva, C.B. 2008. Levantamento etnobotânico e caracterização de
plantas medicinais em fragmentos florestais de Dourados–MS. Ciênc. Agrotec. 32: 651–658.
Andrade, A.C.S., Souza, A.F., Ramos, F.N., Pereira, T.S. and Cruz, A.P.M. 2000. Germinação de sementes de jenipapo:
temperatura, substrato e morfologia do desenvolvimento pós-seminal. Pesq. Agropec. Bras. 35: 609–615.
Andrade, S.A.C., Metri, J.C., Barros Neto, B. and Guerra, N.B. 2016. Osmotic dehydration of jenipapo (Genipa americana
L.). Food Sci. Technol. 23: 276–281.
Andreasen, K. and Bremer, B. 1996. Phylogeny of the subfamily Ixoroideae (Rubiaceae). Opera Bot. Belg. 7: 119–138.
Andreasen, K. and Bremer, B. 1997. Combined phylogenetic analysis in the Rubiaceae-Ixoroideae: morphology and chloroplast
DNA data. In: Andreasen, K. (ed.). Phylogeny of Ixoroideae: Molecular Systematics within Rubiaceae. Ph.D. Dissertation,
Uppsala University, Uppsala, Sweden.
Araújo, S.S., Fernandes, T.C.C., Marin-Morales, M.A., Brasileiro-Vidal, A.C. and Benko-Iseppon, A.M. 2015. Mutagenicity,
genotoxicity and cytotoxicity assays of medicinal plants: first step for drug development. pp. 130–153. In: Duarte, M.C.T.
and Rai, M. (eds.). Therapeutic Medicinal Plants: From lab to the market. CRC Press, New Hampshire, United Kingdom.
Assis, C.S. 2015. Avaliação dos efeitos tóxicos in vitro e in vivo do extrato hidroetanólico dos frutos de Genipa americana
L. (Rubiaceae) em camundongos Swiss. M.Sc. Dissertation, Universidade Federal do Rio Grande do Norte, Brazil.
73 pp. Available at https: //repositorio.ufrn.br/jspui/bitstream/123456789/20796/1/cinthyasaraivadeassis_dissert.pdf.
Barbosa, D.A. 2008. Avaliação fitoquímica e farmacológica de Genipa americana L. (Rubiaceae). M.Sc. Dissertation,
Universidade Federal do Rio de Janeiro, Brazil. 136 pp. Available at http: //objdig.ufrj.br/59/teses/726901.pdf.
Barbosa, L.M., Batista, E.A., Mantovani, W., Veronese, S.A. and Andreani, R. 1989. Ensaios para estabelecimento de modelos
para recuperação de áreas degradadas de matas ciliares, Mogi-Guaçú (SP). pp. 268–283. Nota Prévia. In: Simpósio sobre
Mata Ciliar, 1. Campinas. Fundação CARGILL.
Barbosa, R.M.T., Almeida, A.A.F., Mielke, M.S., Loguercio, L.L., Mangabeira, P.A.O. and Gomes, F.P. 2007. A physiological
analysis of Genipa americana L.: a potential phytoremediator tree for chromium polluted watersheds. Environ. Exp.
Bot. 61(3): 264–271.
Barroso, G.M., Guimarães, E.F., Ichaso, C.L.F., Costa, C.G., Peixoto, A.L. and Lima, H.C. 1991. Rubiaceae. pp. 189–229.
In: Sistemática de Angiospermas do Brasil. Universidade Federal de Viçosa, Viçosa, Brazil.
Benko-Iseppon, A.M. and Crovella, S. 2010. Ethnobotanical bioprospection of candidates for potential antimicrobial drugs
from Brazilian plants: state of art and perspectives. Curr. Protein Pept. Sci. 11(3): 189–194.
Benko-Iseppon, A.M., Pinangé, D.S.B., Chang, S.C. and Morawetz, W. 2012. Ethnobotanical uses of the native flora from
Brazilian North-Eastern Region. pp. 84–105. In: Rai, M., Rastrelli, L., Marinoff, M., Martinez, J.L. and Cordell, G.
(eds.). 2012. Medicinal Plants: Biodiversity and Drugs. 1st. ed. CRC Press, New Hampshire.
Bentes, A.D.S. and Mercadante, A.Z. 2014. Influence of the stage of ripeness on the composition of iridoids and phenolic
compounds in genipap (Genipa americana L.). J. Agric. Food Chem. 62: 10800–10808.
Bessa, N.G.F., Borges, J.C.M., Beserra, F.P., Carvalho, R.H.A., Pereira, M.A.B., Fagundes, R., Campos, S.L., Ribeiro, L.U.,
Quirino, M.S., Chagas Junior, A.F. and Alves, A. 2013. Prospecção fitoquímica preliminar de plantas nativas do cerrado de
uso popular medicinal pela comunidade rural do assentamento Vale Verde – Tocantins. Rev. Bras. Pl. Med. 15: 692–707.
Borges, E. and Rezende, C.M. 2000. Main aroma constituents of genipap (Genipa americana L.) and bacuri (Platonia insignis
M.). J. Essent. Oil Res. 12(1): 71–74.
Braga, R. 1960. Plantas do Nordeste (especialmente, do Ceará). 2 ed. Imprensa Oficial, Fortaleza, p. 540.
Bremer, B. 2009. A review of molecular phylogenetic studies of Rubiaceae. Ann. Missouri Bot. Gard. 96: 4–26.
Bremer, B. and Eriksson, T. 2009. Time tree of Rubiaceae: Phylogeny and dating the family, subfamilies, and tribes. Int. J.
Pl. Sci. 170: 766–793.
Brigas, S., Costa, E. and Cabrita, S. 2016. The influence of Genipa americana L. on the adipose tissue of mice. Exp. Pathol.
Health Sci. 8: 19–22.
Camargo, N.B., Gontijo, O.J.S. and Barbosa, A.C.O.F. 2016. Characterization of microsatellite regions in native plants of the
Brazilian. Multi-Sci. J. 2(6): 41–47.
Candolle, A.P de. 1830. Prodromus systematis naturalis regni vegetabilis. Vol. 4. Treuttel & Würz, Paris.
Carvalho, J.E.U. and Nascimento, W.M.O. 2000. Sensibilidade de sementes de jenipapo (Genipa americana L.) ao dessecamento
e ao congelamento. Rev. Bras. Frutic. 22: 53–56.
Cavalcante, P.B. 1991. Frutas Comestíveis da Amazônia. Coleção Adolfo Ducke, 5th ed. CEJUP/Museu Paraense Emílio
Goeldi, Belém, p. 279.
Codignoto, P.S.C., Araújo, S.B., Bastos, N.M., Fernandes, T.O., Barbosa, T.A.S., Igidio, C.E.D., Faustino, F., Fernandes, M.J.B.
and Conceição. A.O. 2017. In vitro cytotoxicity and biological activities of Genipa americana (Rubiaceae) ethanolic
extracts. Afr. J. Microbiol. Res. 11: 385–390.
Conceição, A.O., Rossi, M.H., Oliveira, F.F., Takser, L. and Lafond, J. 2011. Genipa americana (Rubiaceae) fruit extract
affects mitogen-activated protein kinase cell pathways in human trophoblast–derived BeWo Cells: Implications for
placental development. J. Med. Food 14: 483–494.
Cordeiro, J.M.P. and Félix, L.P. 2014. Conhecimento botânico medicinal sobre espécies vegetais nativas da caatinga e plantas
espontâneas no agreste da Paraíba, Brasil. Rev. Bras. Plantas Med. 16: 685–692.
Corrêa, P.M. 1984. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. IBDF, Rio de Janeiro, p.747.
Corrêa, A.M. and Forni-Martins, E.R. 2004. Chromosome studies of species of Rubiaceae (A.L. de Jussieu) from the Brazilian
cerrado. Caryologia 57: 250–258.
Costa, P.A., Ballus, C.A., Teixeira-Filho, J. and Godoy, H.T. 2010. Phytosterols and tocopherols content of pulps and nuts of
Brazilian fruits. Food. Res. Int. 43: 1603–1606.
Delprete, P.G., Smith, L.B. and Klein, R.M. 2005. Flora Ilustrada Catarinense: Rubiáceas. Herbário Barbosa Rodrigues, Itajaí.
Dias, S.R.K., Mendonça, A.C.A.M. and Silva, M.A.P. 2013. Ethnobotanical, phytochemical and pharmacological aspects
Rubiaceae species in Brazil. RCPM 18: 140–156.
Djerassi, C., Gray, J.D. and Kincl, F. 1960. Isolation and characterization of genipin. J. Org. Chem. 25: 2174–2177.
Djerassi, C., Nakano, T., James, A.N., Zakow, L.H., Eisenbraun, E.J. and Shoolery, J.N. 1961. Terpenoids. XLVII. The structure
of Genipin. J. Org. Chem. 26: 1192–1206.
Donadio, L.C., Nachtigal, J.C. and Sacramento, C.K. 1998. Frutas exóticas. FUNEP, Jaboticabal, p. 279.
Epstein, L. 2001. Cultivo e aproveitamento do jenipapo. Rev. Bah. Agr. 4: 23–24.
Erbano, M. and Duarte, M.R. 2010. Morfoanatomia de folha e caule de Genipa americana L., Rubiaceae. Braz. J. Pharmacog.
20: 825–832.
Fernandez, V., Franco de Diana, D., Fernández, D., Vega Gómez, M.C., Segovia Abreu, J., Castiglioni, D., Sales, L., Martinez,
M., López, D., Bobadilla, N., Alfonso, J., Mojoli le quesne, A., Monges, D. and Vera, M. 2011. Efecto antimitótico y
citotóxico del extracto etanólico de Genipa americana L. sobre tejido meristematico de Allium cepa L. y cultivo celular
NCTC-929. Steviana 3: 48–53.
Ferreira, E.G., Lemos, E.E.P., Souza, F.X., Lourenço, I.P., Lederman, I.E., Bezerra, J.E.F., Silva-Junior, J.F., Barros, L.M.,
Rufino, M.S.M. and Oliveira, M.E.B. 2005. Frutíferas. pp. 49–100. In: Sampaio, E.V.S.B., Pareyn, F.G.C., de Figueirôa,
J.M. and Santos Junior, A.G. (eds.). Espécies da flora nordestina de importância econômica potencial. Associação Plantas
do Nordeste. Recife. Brazil.
Figueiredo, R.W., Maia, G.A., Holanda, L.F.F. and Monteiro, J.C.S. 1986. Características físicas e químicas do jenipapo.
Pesq. Agropec. Bras. 21: 421–428.
Finco, F.D.B.A., Boser, S. and Graeve, L. 2013. Antiproliferative activity of Bacaba (Oenocarpus bacaba) and Jenipapo
(Genipa americana L.) phenolic extracts a comparison of assays. Food Sci. Nutr. 43: 98–106.
Francis, J.K. 1993. Genipa americana L. Jagua, genipa. U.S. Department of Agriculture, Forest Service, Southern Forest
Experiment Station, New Orlands, LA, p.5.
Gade, D. 2016. Spell of the Urubamba: Anthropogeographical Essays on an Andean Valley in Space and Time. Springer
International Publishing, Switzerland, p.354.
Gentry, A.H. 1993. A field guide to the families and genera of woody plants of Northwest South America (Colombia, Ecuador,
Peru) with supplementary notes on herbaceous taxa. Conservation International, Washington, DC, p.895.
Gibbs, P.E. and R. Ingram. 1982. Chromosome numbers of some Brazilian flowering plants. Notes Roy. Bot. Gard. Edinburg
40: 229–407.
Gomes, C.C. and Moura, T.M. 2010. Estrutura genética em populações de plantas do Cerrado. Agrotec. 1: 33–51.
Guerra, M. 1986. Citogenética de Angiospermas coletadas em Pernambuco. Braz. J. Genet. 9: 21–40.
Guerra, M. 1993. Patterns of heterochromatin in a tropical tree species: Genipa americana L. (Rubiaceae). Cytologia 58:
427–432.
Guerra, M. 2001. Patterns of heterochromatin distribution in plant chromosomes. Genet. Mol. Biol. 23: 1029–1041.
Kainulainen, K., Razafimandimbison, S.G. and Bremer, B. 2013. Phylogenetic relationships and new tribal delimitations in
subfamily Ixoroideae (Rubiaceae). Bot. J. Linn. Soc. 173: 387–406.
Kiehn, M. 1986. Karyologische Untersuchungen und DNA-Messungen an Rubiaceae und ihre Bedeutung fur die Systematik
dieser Familie. Dissertation zur Erlangung des Doktorgrades, Universität Wien.
Koo, H.J., Song, Y.S., Kim, H.J., Lee, Y.H., Hong, S.M., Kim, S.J., Kim, B.C., Jim, C., Lim, C.J. and Park, E.H. 2004.
Antiinflammatory effects of genipin, an active principle of gardenia. Eur. J. Pharmacol. 495: 201–208.
Lorenzi, H. 2002. Árvores brasileiras: manual de identificação e cultivo de plantas arbóreas do Brasil. Instituto Plantarum,
Nova Odessa, São Paulo, p.368.
Lorenzi, H. and Matos, F.J.A. 2002. Plantas medicinais no Brasil: nativas e exóticas. Instituto Plantarum, São Paulo, p.512.
Lorenzi, H. and Matos, F.J.A. 2008. Plantas medicinais no Brasil: Nativas e Exóticas. Instituto Plantarum, Nova Odessa,
São Paulo, p.544.
Magistrali, P.R., Faria, J.A.C. and Gasparin, E. 2013. Physiological behavior of Genipa americana L. seeds regarding the
capacity for desiccation and storage tolerance. J. Seed Sci. 35(4): 495–500.
Manoel, R.O. 2014. Fluxo gênico, estrutura genética espacial intrapopulacional e sistema de reprodução hierárquico entre e
dentro de frutos em uma pequena população isolada de Genipa americana L., utilizando marcadores microssatélites.
Ph.D. Thesis, Universidade Estadual Paulista Júlio de Mesquita Filho, São Paulo, Brazil. 96 pp. Available at https://
repositorio.unesp.br/bitstream/handle/11449/123312/000826564.pdf?sequence=1&isAllowed=y.
Manoel, R.O., Freitas, M.L.M., Barreto, M.A., Moraes, M.L., Souza, A.P. and Sebbenn, A.M. 2014. Development and
characterization of 32 microsatellite loci in Genipa americana (Rubiaceae). Appl. Plant Sci. I 2(3): 1–6.
Manoel, R.O., Freitas, M.L.M., Tambarussi, E.V., Cambuim, J., Moraes, M.L.T. and Sebbenn, A.M. 2015. Mendelian
inheritance, genetic linkage, and genotypic 57 disequilibrium at microsatellite loci in Genipa americana L. (Rubiaceae).
Gen. Mol. Res. 14: 8161–8169.
Marques, J.O., Oliveira, M.F.F. and Lacerda, G.A. 2015. Efeito alelopático e análise dos rótulos de garrafadas comercializadas
no Mercado Municipal de Montes Claros. Rev. Bras. Plant. Med. 17(4): 1134–1141.
Matos, F.J.A. 1999. Plantas da medicina popular do nordeste. UFC, Fortaleza, p.80.
Moreira, R.C.T., Costa, L.C.B., Costa, R.C.S. and Rocha, E.A. 2002. Ethnobotanical approach on the use of medicinal plants
in Vila Cachoeira, Ilhéus, Bahia, Brasil. Acta Farm. Bonaer. 21: 205–211.
Mors, W.B., Rizzini, C.T. and Pereira, N.A. 2000. Medicinal Plants of Brazil. Reference Publications, Inc. Algonac, Michigan,
p.501.
Mouly, A., Kainulainen, K., Persson, C., Davis, A.P., Wong, K.M., Razafimandimbison, S.G. and Bremer, B. 2014. Phylogenetic
structure and clade circumscriptions in the Gardenieae complex (Rubiaceae). Taxon. 63(4): 801–818.
Moura, R.S. de. 2014. Diversidade genética e germinação de jenipapo. M.Sc. Dissertation, Universidade Federal de Sergipe,
Sergipe, Brazil. 67pp. Available at https: //bdtd.ufs.br/bitstream/tede/542/1/rafaela_santos_moura.pdf.
Moura, S.M.S., Sousa, S.R.S. and Conde Júnior, A.M. 2016. Genipa americana L.: prospecção tecnológica. JIBI 1: 31–35.
Nascimento, W.M.O., Carvalho, J.E.U. and Carvalho, M.M. 2000. Germinação de sementes de jenipapo (Genipa americana),
submetidas a diferentes temperaturas e substratos. Ver. Bras. Frut. 22: 471–473.
Nogueira, A.J. 2005. Medicina Popular. Prefeitura Municipal, Rio de Janeiro, p.49.
Nogueira, F.A., Nery, P.S., Morais-Costa, F., Oliveira, N.J.F., Martins, E.R. and Duarte, E.R. 2014. Efficacy of aqueous extracts
of Genipa americana L. (Rubiaceae) in inhibiting larval development and eclosion of gastrointestinal nematodes of
sheep. J. Appl. Anim. Res. 42: 356–360.
Oliveira, L.M., Silva, E.O., Bruno, R.L.A. and Alves, E.U. 2011. Períodos e ambientes de secagem na qualidade de sementes
de Genipa americana L. Semina (Ciênc. Agrar.). 32(2): 495–502.
Omena, C.M.B., Valentim, I.B., Guedes, G.S., Rabelo, L.A., Mano, C.M., Bechara, J.H., Sawaya, A.C.H.F., Trevisan,
M.T.S., Costa, J.G., Ferreira, R.C.S., Sant’ana, A.E.G. and Goulart, M.O.F. 2012. Antioxidant, anti-acetylcholinesterase
and cytotoxic activities of ethanol extracts of peel, pulp and seeds of exotic Brazilian fruits Antioxidant, anti-
acetylcholinesterase and cytotoxic activities in fruits. Food Res. Int. 49: 334–344.
Paunescu, A. 2009. Biotechnology for endangered plant conservation: a critical overview. Rom. Biotechnol. Lett. 14: 4095–4103.
Persson, C. 1996. Phylogeny of the Gardenieae (Rubiaceae). Bot. J. Linn. Soc. 121: 91–109.
Persson, C. 2000a. Phylogeny of Gardenieae (Rubiaceae) based on chloroplast DNA sequences from the rps16 intron and
trnL(UAA)-F(GAA) intergenic spacer. Nord. J. Bot. 20(3): 257–269.
Persson, C. 2000b. Phylogeny of the neotropical Alibertia group (Rubiaceae), with emphasis on the genus Alibertia, inferred
from ITS and 5S ribosomal DNA sequences. Amer. J. Bot. 87: 1018–1028.
Persson, C. 2003. Agouticarpa, a New Neotropical Genus of Tribe Gardenieae (Rubiaceae). Brittonia. 55(2): 176–201.
Pierozzi, N.I. and Da Cruz, N.D. 1988. Número e identificação dos cromossomos de Genipa americana L. (Rubiaceae) através
da técnica de banda-C. Ciên. Cult. 40: 802.
Pierozzi, N.I. and Mendaçolli, S.L.J. 1997. Karyotype and C-analysis in two species of Genipa L. (Rubiaceae, Gardenieae
Tribe). Cytologia 62: 81–90.
Pinto-Ruiz, R., Gómez, H., Martínez, B., Hernández, A., Medina, F.J., Gutiérrez, R., Escobar, E. and Vázquez, J. 2005. Árboles
y arbustos forrajeros del sur de Mexico. Pastos y Forrajes. 28(2): 87–97.
Prado Neto, M., Dantas, A.C.V.L., Vieira, E.L. and Almeida, V.O. 2007. Germinação de sementes de jenipapeiro submetidas
à pré-embebição em regulador e estimulante vegetal. Ciênc. Agrotec. 31(3): 693–698.
Prudente, R.M. 2002. Jenipapo (Genipa americana L.). pp. 88–114. In: Vieira Neto, R.D. (ed.). Fruteiras Potenciais Para os
Tabuleiros Costeiros e Baixadas Litorâneas, Embrapa-CPATC/ENDAGRO, Aracajú, Brazil.
Rabbani, A.R.C., Silva-Mann, R. and R.A. Ferreira. 2012. Genetic variability of Genipa americana L. belonging to the lower
course of São Francisco river. Rev. Arv. 36: 401–409.
Rabitz, F. 2015. Biopiracy after the Nagoya Protocol: problem structure, regime design and implementation challenges. Bras.
Polit. Sci. Rev. 9(2): 30–53.
Ribeiro, J.F. and Walter, B.M.T. 2008. Fitofisionomias do bioma Cerrado. pp. 151–212. In: Sano, S.M., Almeida, S.P. and
Ribeiro, J.F. (eds.). Cerrado: Ecologia e Flora, Embrapa-CPAC, Planaltina, Brazil.
Robbrecht, E. and C. Puff. 1986. A survey of the Gardenieae and related tribes (Rubiaceae). Bot. Jahrb. Syst. 108: 63–137.
Robineau, L. 1995. Hacia Una Pharmacopea Caribeña. TRAMIL 7 endacaribe UAG & Universidade de Antioquia Santo
Domingo, Santo Domingo, p.696.
Rocha, M.A.C., Costa, M.A.P.C., Silva, S.A., Lédo, C.A.S., Moreira, M.J. and Bastos, L.P. 2008. Enraizamento in vitro e
aclimatização de genótipos de jenipapeiro (Genipa americana L.). Rev. Bras. Frutic. 30(3): 769–774.
Salman, A.K.D., López, G.F.Z., Bentes-Gama, M.M. and Andrade, C.M.S. 2008. Espécies arbóreas nativas da Amazônia
Ocidental Brasileira com potencial para arborização de pastagens. Embrapa Rondônia, Porto Velho, Documentos, Vol.
127, p.23.
Salomão, A.N. and Allem, A. 2001. Polyembryony in angiospermous trees of the Brazilian Cerrado and Caatinga vegetation.
Acta Bot. Bras. 15: 369–378.
Santana, K.B., Almeida, A.A.F., Souza, V.L., Mangabeira, P.A.O., Silva, D.C., Gomes, F.P., Dutruch, L. and Loguercio, L.L.
2012. Physiological analyses of Genipa americana L. reveals a tree with ability as phytostabilizer and rhizofilterer of
chromium ions for phytoremediation of polluted watersheds. Environ. Exp. Bot. 80: 35–42.
Santos, R.O.S. 2001. Caracterização de jenipapeiros (Genipa americana L.) em Cruz das Almas – BA. M.Sc. Dissertation,
Universidade Federal da Bahia, Brazil, 65pp.
Santos, P.A. 2012. Manejo do jenipapeiro (Genipa americana L.) para produção de madeira e avaliação da diversidade genética
por meio de marcadores moleculares, Cruz das Almas-Bahia. M.Sc. Dissertation, Universidade Federal do Recôncavo
Baiano, Bahia, Brazil. 40pp. Available at https://www1.ufrb.edu.br/pgrecvegetais/images/...pedro_de_almeida.pdf.
Santos, A.R.F., Silva-Mann, R.S. and Ferreira, R.A. 2011. Restrição hídrica em sementes de jenipapo (Genipa americana
L.). Rev. Arv. 35: 213–220.
Santos, C.Z.A., Ferreira, R.A., Santos, L.R., Santos, L.I., Gomes, S.H. and Graça, D.A.S. 2015. Análise qualitativa da
arborização urbana de 25 vias públicas da cidade de Aracaju – SE. Ci. Fl. 25(3): 751–763.
Sebbenn, A.M. 1997. Estrutura genética de subpopulações de Genipa americana L. (Rubiaceae) a partir de Isoenzimas. Doctoral
Thesis, Universidade de São Paulo, Brazil, 107pp. Available at http://repository.usp.br/single.php?_id=001031068.
Sebbenn, A.M., Kageyama, P.Y. and Vencovsky, R. 1998. Estrutura genética de subpopulações de G. americana L. (Rubiaceae)
em mata ciliar a partir de isoenzimas. Ver. Inst. Flor 10: 95–108.
Sebbenn, A.M., Kageyama, P.Y. and Vencovsky, R. 2003. In situ genetic conservation and number of tree for seed collect in
Genipa americana L. population. Sci. For. 63: 13–22.
Sebbenn, A.M. 2004. Herança e ligação em locos de isoenzimas em Genipa americana L. Rev. Inst. Flor 16: 65–72.
Silva, S. and Tassara, H. 2005. Frutas Brasil frutas, 4th ed. Empresa das Artes, São Paulo, p.321.
Silva, A.P., Lima, C.L.C. and Vieites, R.L. 1998. Caracterização química e física do jenipapo (Genipa americana L.) armazenado.
Piracicaba. Sci. Agric. 55: 29–34.
Silva, A.V.C., Freire, K.C.S., Lédo, A.S. and Rabbani, A.R.C. 2014. Diversity and genetic structure of jenipapo (Genipa
americana L.) Brazilian accessions. Sci. Agric. 71(5): 345–355.
Silva, A.V.C., Muniz, E.N., Almeida, C.S., Vitória, M.F., Ledo, A.S., Melo, M.F.V. and Rabbani, A.R.C. 2015. Genetic diversity
and sex identification in Genipa americana L. Trop. Subtrop. Agroecosyt. 18: 81–86.
Souza, V.R., Pereira, P.A.P., Queiroz, F., Borges, S.V. and Carneiro, J.D.S. 2012. Determination of bioactive compounds,
antioxidant activity and chemical composition of Cerrado Brazilian fruits. Food Chem. 134: 381–386.
Telles, M.P.C. and Bastos, R.P. 2009. Estruturação genética na escala de paisagem. Megadiversidade 5(1-2): 101–110.
Touyama, R., Takeda, Y., Inoue, K., Kawamura, I., Yatsuzuka, M., Ikumoto, T., Shingu, T., Yokoi, T. and Inouye, H. 1994.
Studies on the blue pigments produced from genipin and methylamine. I. Structures of the brownish-red pigments,
intermediates leading to the blue pigments. Chem. Pharm. Bull. 42: 668–673.
Ueda, S. and Iwahashi, Y. 1991. Production of anti-tumor-promoting iridoid glucosides in Genipa americana and its cell
cultures. J. Nat. Prod. 54: 1677–1680.
Vasco, C., Ruales, J. and Kamal-Eldin, A. 2008. Total phenolic compounds and antioxidant capacities of major fruits from
Ecuador. Food Chem. 111: 816–823.
Vieira, F.A. and Gusmão, E. 2006. Efeitos de giberelinas, fungicidas e do armazenamento na germinação de sementes de
Genipa americana L. (Rubiaceae). Cerne. 12(2): 137–144.
Xavier, M. 1976. Jenipapo: uma espécie indígena para reflorestar. Cerrado 8: 20–23.
Yee, T.F., Goh, C.J. and Rao, A.N. 2010. In vitro studies on Genipa americana. JTMP 11: 71–88.
Zappi, D.C., Semir, J. and Pierozzi, N.I. 1995. Genipa infundibuliformis sp. Nov. and notes on Genipa americana (Rubiaceae).
Kew Bull. 50: 761–771.
6
Paramela
(Adesmia boronioides Hook. f.)
From Popular Uses to Commercialization
Silvia B. González,1,*, Ana H. Ladio,2 Bruno Gastaldi,1 Fresia M. Silva
Sofrás,1 Ariel Mazzoni3 and Gustavo Sánchez4
Introduction
Adesmia boronioides Hook.f. is a perennial bush belonging to the Leguminosae family (Fabaceae). Its
common name is “paramela” and is a species with a long history of use among the native societies of
the Argentinean-Chilean Patagonia. Due to its cultural and symbolic value, it stands out as part of the
biocultural heritage of the region. It is part of the knowledge and practices related mainly with the health
and subsistence of Mapuche and Tehuelche communities since pre-hispanic times (Molares and Ladio
2009, Ciampagna and Caparelli 2012). It is a plant used for human consumption as medicine (Martínez-
Crovetto 1980, Campos et al. 1997, Montes et al. 2001) as well as ornamental and melliferous (Forcone
and Muñoz 2009, Green and Ferreyra 2011).
Recently, commercial interest towards this plant has increased given its exceptional conditions and
potential, and in particular due to its fragrant odor (since 2005, its essential oil has been used as a supply
for the perfume industry). Nowadays, paramela is used in rural areas mainly as a medicinal infusion, and
in urban areas as ornament and/or as an aromatic ingredient for the preparation of an alcoholic beverage.
This native plant of the Patagonian region inhabits low irrigation sites, is of slow growth, and its
culture is of interest (Contardi et al. 2016a, 2016b). So far it is almost exclusively found in its natural state
(Barthelemy et al. 2008). However, in a great part of the rural communities, mainly those of Mapuche-
Tehuelche ascendance, the paramela is protected in family orchards either because it is tolerated and cared
for with the rest of the plants or because it has been transplanted to these spaces, thus being possible to
place it in an incipient domestication process (Ladio and Molares 2017).
A successful and sustained development of commercial products derived from native plants requires
a domestication process of the species. This process would ensure homogenous genetic material and high
1
Universidad Nacional de la Patagonia San Juan Bosco sede Esquel, Facultad de Ciencias Naturales y Ciencias de la Salud,
Ruta Nacional N°259 km 16,41 (U9200) Esquel, Chubut, Argentina.
2
Grupo de Etnobiología. Instituto de Investigaciones en Biodiversidad y Medio Ambiente CONICET.
3
Estación Experimental Agropecuaria Bariloche, Instituto Nacional de Tecnología Agropecuaria (INTA).
4
Universidad Nacional de Río Negro, Sede Andina, Tecnicatura en Viveros.
* Corresponding author: quim-esq@unpata.edu.ar
quality specimens. It would involve an improvement in the raw materials and a standardization of the
content in the active principles. Reproduction studies made from A. boronioides seeds, allowed for the
development of the species propagation protocols and the production of plants in greenhouses (González
et al. 2009, Sánchez and Riat 2012, Mazzoni et al. 2014). Since 2015, an experimental culture in the
Andean region of the Argentinean Patagonia allows for the evaluation of the productivity and quality of
the cultivated plant’s essential oil in relation to the wild population.
It is of particular interest to point out the negative consequences of unreasonable commercial
exploitation of the wild populations of the species and the substantial importance of their cultivation.
In the latter case, further studies are needed regarding the selection of chemotypes and their population
dynamics, as well as major research on the possible management and sustainable use of wild populations.
This is essential in order to be able to establish manuals of good practices for those who are engaged in
their collection.
Botanical and ecological information of the species

Botanical description
A. boronioides is a perennial bush belonging to the Leguminosae family (Fabaceae). Its common name
is “paramela”. Its habitat ranges from 0 m.a.s.l. to 2,200 m.a.s.l. It has a medium size, varying between
0.40–2 m. It is highly ramified, with glandular branches, fragrant and very resinous and sticky to the touch.
It has an axonomorph root. The leaves are 3–6 cm, shortly petiolate, 10–20-leaflets, leaf rachis with erect,
brief hair; obovate, fleshy, glabrous, toothed, shiny, 4–6 mm leaflets with crateriform glands especially at
the edge; short, amplexicaul, glabrous, glandular stipules. Clusters of 4–7 cm, densiflorous, sessile, ovate,
acute, glandular, glabrous bracts. The flowers are 7–10 mm, colorful, yellow, perfumed, with campanulate
chalice, pubescent, glandulous, with short teeth, serice-pubescent in their interior; glabrous vexillum
(banner), glabrous wings and keel shorter than vexil. Ovary with some marginal hair. Narrow, pubescent,
glandular, 3–5-articulate loments; semicircular, dehiscent 4.5–6 mm trusses.
Its anatomy was initially studied by Nájera et al. (2000). Subsequently, in an evaluation of leaves and
stems of diverse origins in their Patagonian distribution, very similar microscopic characters were found.
They all have cyclocytic stomata on the leaves’ epidermis. The secretory pores are located, in greater
number, on the abaxial surface, although some pores can be observed on the adaxial surface. On some
samples, secretion pores were found at the end of the leaves semilimbos (e.g., Los Antiguos, El Calafate,
Bariloche, Villa La Angostura) (González et al. 2014).
Fig. 6.1 Detail of the glands in the bundle and the back of the leaflets (10x). Photograph by González, S.B.
Paramela (Adesmia boronioides Hook. f): From Popular Uses to Commercialization 91
Fig. 6.2 Microscopic structure of the glandular structures in stems and leaves (40x) Guerra P.E. Photograph by González, S.B.
Geographic distribution
A. boronioides’s distribution ranges from Mendoza to Tierra del Fuego provinces, in Argentina, including
also Neuquén, Rio Negro, Chubut, and Santa Cruz, and the XI and XII Regions of Chile (http://www2.
darwin.edu.ar/Proyectos/FloraArgentina/fa.htm, Burkart 1967, Ulibarri and Burkart 2000).
It inhabits sunny areas, shrubs, river sides, roads and ravines, mainly in the Patagonian steppe, shrubland
areas and steppe-forest transition zones (https://www.sib.gov.ar/ficha/PLANTAE*adesmia*boronioides).
The forest areas where paramela can be found consist mainly of lenga (Nothofagus pumilio), ñire
(Nothofagus antarctica) and cypress (Austrocedrus chilensis) (Molares and Ladio 2012b). It has also been
found in the Atlantic littoral, in Santa Cruz province, in the Rio Gallegos area (González et al. 2014). In
slopes, near Los Molles, Mendoza, it grows in shrubland vegetation.
Generalities of the Adesmia genus
The Adesmia DC genus has only been found in South America, in approximately 240 species. These
species are distributed mainly in the center of Chile and in the south and west regions of Argentina. In
this country, more than 100 representative species have been found, which makes it the most numerous
genus of the Leguminosae, Papilionoideae. There are about 55 species in the Patagonian region (Burkart
1984, Ulibarri and Burkart 2000, Ulibarri and Simpson 2010).
A. boronioides stands out as the only species of this highly glandulous-resinous genus (Burkart 1967).
Ethnobotany
Its common name is paramela, but it is also known as té silvestre (wild tea), yerba carmelita (Carmelite
herb), éter (ether), pegapega, yagneu and lonkotrevo (González 2002, Molares and Ladio 2012a,b). Native
people of Patagonia have great respect for this plant, and use it for both medicinal and symbolic purposes.
Its use is inscribed within a holistic understanding of health in which different participants, elements and
unique worldviews that have no equivalent in western science are involved (Ladio and Molares 2014,
2017). For this reason, a “translation” of certain uses from a western perspective must be done carefully
since they could be oversimplified or interpreted as therapeutically inaccurate.
This plant is used as medicine by a large part of the Patagonian rural population. Its medicinal use
has been registered in ethnobotanical works by communities very distant from each other (Neuquén, Rio
Fig. 6.3 A. boronioides distribution map. Neri, A. and Gastaldi, B.
Negro and Chubut provinces, as well as the south regions of Chile) (González et al. 2005, Molares and
Ladio 2009). In most studies conducted in Mapuche-Tehuelche communities, the species has high levels of
consensus among inhabitants, in many cases greater than 75%, that is to say, their knowledge and use of the
plant is widely shared and disseminated among the rural population (Ladio 2006, Molares and Ladio 2014).
The species has been most recurrently cited as digestive, antirheumatic, diaphoretic and antiemetic
(Campos et al. 1997, González et al. 2004, 2005, Toledo and Kutschker 2012, Molares and Ladio 2014).
Today, it is a substantial part of these communities’ home medicine, being part of the first-aid kit of rural
families that use it to cope with health problems autonomously (Richeri et al. 2013). Traditionally, it is
collected in autumn-winter, while the animals are taken care of, and kept dry in paper bags in dark places
to use it as medicine during the whole year (Richeri et al. 2013). The people of the countryside distinguish
it by its “perfumed” character and it is listed in the group of plants with “magical soul” and “sweet smell
and bitter taste” (Molares and Ladio 2009, Ladio and Molares 2014).
It has been used since ancient times by the native people of the region mainly to relieve bruises, sprains,
cramps, and joint and muscle pains (González 2002, Estomba et al. 2006, Igon et al. 2006). It is also valued
for having the property of “heating the body” when prepared in the form of steam inhalations and baths,
with the plant submerged in hot water (González 2005). These baths are mainly used to prevent children
from urinating in bed when it is cold (Igon et al. 2006). Also, the steam inhalations are used against cold
and cough discomfort, in communities of Neuquén, Río Negro and Chubut provinces (Igon et al. 2006,
Eyssartier et al. 2011, Richeri et al. 2013). According to Richeri (2016), families in the Chubut plateau
gather paramela to treat asthmatic people or for bronchitis cases. This author also records the use of the
plant as incense (burning), perfume and to cleanse the houses of evil spirits. According to Ochoa (2005),
the species is also used in ointment as a sedative for rheumatic problems and to heal wounds.
The tea or infusion of paramela is widely used as digestive (Igon et al. 2006). It is also included in
the mate, a traditional drink of the region that is mainly composed by mate herbs (Ilex paraguariensis)
(Weigandt et al. 2004). It is marketed in businesses dedicated to the sale of medicinal plants in S.C. de
Bariloche mainly for its digestive properties (Cuassolo et al. 2010). The infusion is also used to wash the
hair in order to kill lice and is considered to be a hair vitalizer (Martínez-Crovetto 1980, Conticello et al.
1997, Igon et al. 2006). Ochoa (2008) describes that, in Arroyo Las Minas (Rio Negro), the infusion is used
for kidney problems, and women drink the infusion after childbirth to recover faster, as an invigorating
drink. The use for kidney problems has also been cited by Kutschker et al. (2002). Some studies have
also identified it as an aphrodisiac (Muñoz et al. 2001, Igon et al. 2006). In Comallo and Pilcaniyeu (Rio
Negro), people emphasize the use of the plant’s decoction to ease flu, stomach pains, diarrhea, and fever
(Eyssartier et al. 2009, 2011, 2013).
Popular uses of paramela

Infusion (tea): In most local recipes it is prepared using a tablespoon of leaves per cup. The dose is one
cup per day.
Mate: Fresh/dry leaves are added to the mate infusion.
Decoction: The twigs are boiled in water and eaten with burnt sugar or alone.
Plaster: The leaves are crushed and embedded in a gauze or rag that is placed over the sore area.
Baths and steam inhalations: A large bowl is filled with hot water and branches of the plant are added.
Incense: Branches are placed on the kitchen stove or burned slowly to release its fragrance.
Other local uses

It is cited as an excellent forage (Green and Ferreyra 2011). In their work on the Chubut plateau, Castillo
and Ladio (2014) found that it is a plant used as forage for goats and sheep, even though it is considered
by the shepherds as a problematic plant, because the animal’s meat will have an unpleasant taste after
feeding on this plant. Also, Green and Ferreyra (2011) described its moth-repellent properties.
Chemical constituents
The first chemical analysis of essential oils and resinoids obtained from leaves and stems was made
in 1963 (Montes and Peltz 1963). They described physicochemical properties of the essential oils and
chromatograms, but without mentioning any specific compounds due to the instrumental limitations of
the time.
Agnese et al. (1989, 1993) made phytochemical studies on some Adesmia species (A. grandiflora,
A. bicolor, A. retrofracta, A. trijuga, A. horrida, A. incana, A. aegiceras). They analyzed hydrophilic
compounds including flavonoids, pinitol, vanillin and glucose, and some lipophilic compounds such as
alkanes, carboxylic acids and wax.
Faini et al. (1995) reported three new triterpene glycosides of the malabaricane type in A. aconcaguensis.
The main component structure in the essential oil is a bisnorsesquiterpene called “esquelenone”.
This component was named after the city “Esquel”, in the Argentinean Patagonia, where paramela grows
naturally. Taking into account the stereochemistry of the compound, the name is (1S,4R,5S)-esquel-6-en-
9-one, whereas the IUPAC name is (3aS,1R,7aS)-1,2,3,3a,5,7a-hexahydro-1-methyl-6-(1-methylethyl)-
4H-inden-4-one (Fig. 6.4).
Fig. 6.4 Absolute configurations of esquelane derivatives 1–4 (Carlos M. Cerda-García-Rojas et al. 2015).
Essential oil composition of A. boronioides

The essential oil yielded 0.5% in average, through hydrodistillation of aerial parts. This oil is yellow-
greenish color with a pleasant sweet odor, specific gravity 0.9690 and refraction index 1.4972 at 20°C,
[α]= +6 (0.02; hexane). The essential oil had a high content of sesquiterpenoids. The main compounds
had a novel bisnorsesquiterpene structure (González et al. 2002) and were named Esquelenone and
Isoesquelenone. The other important compounds had cadinane and eudesmane skeletons, the first one
belonging to α-copaen-11-ol and the other to 10-epi-γ-eudesmol.
The relative amounts of the main components were directly influenced by the recollection sites,
phenological stage, drying time, season, among others.
The main compound might derive biogenetically from MW 236, an intermediary compound, precursor
of furopelargones, proposed by Lukas (1964). In turn, this hypothetical structure might derive from a
guaiane skeleton (6,9-guaiadiene, Fig. 6.5).
The olfactory profile of this essential oil was uncommon and interesting, with a sweet, woody and
spiced odor, with strong fixation properties (González et al. 2002).
Structural elucidation of the main components were performed through NMR (mono and bidimensional),
Vibrational Circular Dichroism (VCD) and its absolute configuration was recently reassigned (González
et al. 2002, Cerda-García-Rojas et al. 2015).
Essential oil composition includes not only novel structural components (Fig. 6.6) but also new terpene
skeletons not reported previously in other species (González et al. 2004).
The essential oil, some extracts, and the main component all have a nice, fruity odor suitable for
perfumery production. A dermal sensitivity test showed it was harmless to the skin (González 2002). Also,
some assays showed high stability of the essential oil at room temperature, even with solar exposition. These
results endorse the potential use of this natural product in the production of fragrances. An unfavorable
organoleptic modification was observed, however, when the essential oil was subjected to heat or exposed
to air. Under these conditions, the esquelenone went through an isomerization process in the first case, and
through a peroxidation process in the second case. This resulted in a decrease in the fresh and fruity odor.
Fig. 6.5 Biosynthesis of Esquelenone (González 2002).
Fig. 6.6 Main sesquiterpenes skeletons in A. boronioides’s essential oil (González 2002).
The esquelenone compound shares structural features with products which are being used currently
in the perfumery industry such as 6,7-dihydro-1,1,2,3,3-pentamethyl 4-(5H)-indanone (Cashmeran®).
Chemical variability in the essential oil of A. boronioides
A study of the volatile compounds’ chemical variability along the Patagonian distribution was conducted,
including Neuquén, Río Negro, Chubut and Santa Cruz provinces in Argentina.
Contents and regulation of secondary metabolites are very sensitive to environmental influences and
the presence of pathogens and predators. The chemical variability in natural populations of paramela in
Patagonia has been confirmed. For example, it is remarkable to find a greater concentration of hemiterpenes
(C5) in the southernmost sites and the quantitative difference of cadinane skeletons, which are preponderant
in some sites (La Hoya, Chubut 41% in 2015) and almost absent in others (Los Antiguos, Santa Cruz 0 to
3% in 2013–2015). Esquelanes/guaianes were quantitatively important in all studies, with a percentage of
the total essential oil contents ranging from 27.4 to 60.4%. (González et al. 2016). Low molecular weight
compounds were detected in Santa Cruz, Los Antiguos and El Calafate. The most noteworthy of these
compounds was 2-methylbutanenitrile, precursor of cyanogenic glycosides, present in numerous species
of plants and insects (González et al. 2014).
These findings show the importance of establishing the origin of the plant material in order to assure
the essential oil quality.
Cyanogenic glycosides
The southernmost populations of A. boronioides analyzed (Los Antiguos y el Calafate) were the only ones
which showed a positive reaction to Guignard test to detect cyanogenic glycosides. This is consistent with
the presence of 2-methylbutanenitrile, lotaustralin precursor, in volatile compounds of A. boronioides in
these locations (González et al. 2014).
According to the reference bibliography, cyanogenic plant populations were associated with lower
altitude locations, which would point towards a negative correlation between altitude and cyanogenic
plant number for a given species (de Araújo 1976, Richards and Fletcher 2002). This previous work was
consistent with our findings, where the populations in altitudes lower than 300 m a.s.l. showed a positive
reaction in the Guignard test (Silva Sofrás et al. 2016).
Paramela might be a polymorphic species regarding cyanogenic glycosides production (Kakes 1990)
and its function would be related to different endogenous or exogenous factors, for example the presence
of seed-feeding insects, very common in studied populations (Delfino et al. 2009).
The quantitative assay gave a maximum value of 0.47 µg HCN/g per plant. The lethal dose for an
adult human is 30–120 mg HCN, so it would be necessary to ingest 65 kg of this plant to reach this level.
A. boronioides is traditionally used in infusions, with barely 5 g in 100 ml of hot water, and therefore it
is safe for human consumption.
Phenolic compounds content

There is only one previous study regarding paramela phenolic compounds (Silva Sofrás et al. 2016). In
this work, 12 populations from different altitudes and latitudes in Patagonia were collected and analyzed
in two seasons: spring and autumn. The antioxidant variability found by Gastaldi et al. (2016) is consistent
with the total phenolic contents in each location.
The sites with altitudes lower than 500 m.a.s.l. had a higher value of total phenolic compounds in
autumn and the ones above 500 m a.s.l. had a higher value of flavonoids in spring.
Total phenolic contents and antioxidant activity in A. boronioides are higher in autumn than in spring.
There was a positive correlation between the number of compounds found and the site’s latitude. Seventeen
constituents were detected through qualitative analysis: three phenolic acids and 14 flavonoids.
The largest amount of compounds was detected in Rio Turbio (Santa Cruz), including a phenolic
acid exclusive of this site. Three flavonoids were detected in Bariloche and Villa La Angostura which are
exclusive of these sites.
There was no difference in the number of compounds detected in autumn and spring for the sites
analyzed in both seasons.
The phenols and flavonoids qualitative analysis was consistent with total flavonoid content quantitative
analysis (Silva Sofrás et al. 2016).
In vitro biological activity studies

Antioxidant activity
The aerial parts of the plant exhibited antioxidant activity, most likely due to the presence of phenolic
compounds and flavonoids (Gastaldi et al. 2016, Silva Sofrás et al. 2016). Estomba et al. (2010) studied
the antioxidant activity and pigments of A. boronioides using micropropagated 60-day seedlings from
sterile cultured seeds. A low amount of total chlorophyll was observed with “a” chlorophyll reduction at
the expense of the “b” chlorophyll (a/b chlorophyll: 2.98). Catalase activity (EC1.11.1.6) was low. The
authors concluded that it is possible to use these in vitro cultures as a source of bioactive metabolites.
Trypanocidal activity
The concentration of A. boronioides that inhibited the growth of parasites by 50% was lower than the
benzimidazole IC50. In the inhibition curve, the trend line coincided with a polynomial equation, which
would indicate that the growth of epimastigotes was affected by more than one variable. Villagra et al.
(2008) concluded that new tests are required to support this hypothesis and suggested that it is possible to
encourage the search for active compounds against Chagas disease from these essential oils.
Antimicrobial and antifungal activities
In vitro susceptibility assays and solid medium diffusion assays were carried out. For these assays,
extracts in methanol, ethyl acetate, dichloromethane, hexane and water were prepared. The extracts were
challenged with microorganisms (CCMA-29: Collection of Microbial Cultures of Argentina No. 29),
impregnating filter paper disks of 5.5 mm up to a total load of 0.25 mg/mL. The culture media were at two
pH (Antibiotic Medium I pH 6.6 and II and pH 7.9). The antimicrobial and antifungal activity under assay
conditions was null, except for the extract in ethyl acetate, in medium at pH 6.6, which showed activity
on Staphylococcus aureus (González 2002). In more recent studies (Blengini et al. 2016), antibacterial
activity against Gram-positive bacteria such as Staphylococcus aureus ATCC 25923 and Enterococcus
faecalis ATCC 11198 was detected, with MIC values of 62.5 μg/mL for both bacteria. These studies were
conducted with an experimental technique adapted from those suggested by the Clinical Laboratory
Standards Institute (CLSI). A panel of positive and negative Gram bacteria was used and the oil was
assayed. For the antifungal evaluation a broth microdilution method in front of a panel of standardized
fungi was used. The oil showed antifungal activity against Candida glabrata and Candida parapsilosis,
with 1,000 μg/mL MIC values against both yeasts.
Anti-inflammatory activity
A methanolic extract, an infusion and the essential oil obtained by hydro distillation were assayed in
accordance with the Argentine National Pharmacopoeia VII Edition.
The polar fractions (methanolic and aqueous) and the essential oil of A. boronioides were assayed at
concentrations of 15 and 50 μg/mL for their eicosanoid generation effect (TBX2, PGE2 and LTB4) in rat
peritoneal leukocytes. The methanolic extract and the essential oil showed a strong inhibition of LTB4
generation, whereas the aqueous extract was comparatively inactive. The methanolic extract showed
potent TXB2 inhibition while the essential oil and aqueous extract were much less active. The effect on
PGE2 production was smaller, implying that the greatest effect was produced on thromboxane synthase.
The essential oil showed a significant LDH release in rat peritoneal leukocytes which would suggest a
substantial toxicity to the cells; the other two extracts were not harmful.
Its anti-inflammatory activity has been tested in vitro, which would support one of the properties
attributed to the plant, that is, as a “medicine” for rheumatic pains (González et al. 2003).
Acute toxicity studies

The potential acute toxicity of A. boronioides infusion was recently studied using the Artemia salina
model. A 5% infusion was prepared from aerial parts of the plant following the standards of the Argentine
National Pharmacopoeia VII Edition to make an infusion. A freeze-dried product was obtained from the
infusion. The A. saline model organism was exposed to different concentrations of the freeze-dried product
in order to obtain concentration-response curves and to determine lethal concentrations 50 (LC50) in mg/mL.
LC50 ≤ 1 mg/mL in the toxicity bioassay with A. salina is considered an acute toxicity indicator for an
aqueous vegetal extract. This result can then be extrapolated to animals and humans. The value obtained
from the A. boronioides assay was 5.16 mg/mL, which would indicate that an infusion made from this
species would not present a risk of acute toxicity to humans (Mongelli et al. 1995, Pérez and Lazo 2010,
Gastaldi et al. 2016).
Allergenicity: dermal irritability test
Tests performed with A. boronioides essential oil included the analysis of erythema (non-pruritic rash,
bright red and slightly raised skin) and edema (accumulation of interstitial fluid in large amounts) in albino
rabbit skin. The results showed the safety of the essential oil under the test conditions, according to the
methodology of Draize (Gonzalez 2002).
Background of the species conservation state

In Argentina, the state of conservation of the paramela has not been systematically evaluated. According to
IUCN its status is “not evaluated” (NE). However, in Chile it is in the red book of CONAF (Corporación
Nacional Forestal, www.conaf.cl/) as a vulnerable species. In Argentina, there are no reliable studies so
far, except for the fact that it is protected in all Patagonian National Parks (https://www.sib.gov.ar/ficha/
PLANTAE*adesmia*boronioides). There is also no official information on the volumes that are subject
to commercial exploitation to date, so we consider that their conservation status should be addressed and
studied in more detail.
According to national and international standards (National Biodiversity Strategy and Plan of Action
2015–2020, IUCN and CBD), the use of goods should not affect the functioning and sustainability of
ecosystems (flora, fauna, water, etc.), nor the cultural values of the local people. Consequently, if this
species is to be used for commercial purposes, it is necessary to provide mechanisms that will ensure
that this natural resource is used in the context of sustainable development, taking into account the rights
and values of local communities. This is the current perspective on conservation, where the protection
of biodiversity is intimately related to socio-cultural and economic components through the concept of
sustainable development.
Additionally, it is important to consider the protection of the different wild populations of this species,
given that, due to its geographical extent, it shows morphological and chemical variations, particularly in
its essential oil (González et al. 2016).
Commercial use
Today, the species is commercialized in three ways: (1) as an ingredient for an alcoholic beverage; (2)
as a medicinal herb, mainly in infusions and decoctions; and (3) its essential oil as a raw material for
perfumery (Fig. 6.7).
1) As an ingredient for an alcoholic beverage: A. boronioides can be found in a product called
“Estepvka”, made in El Calafate, Santa Cruz. The labeling of the product shows that its ingredients
are water, alcohol and paramela. In addition, it is specified that the alcoholic concentration is 40%
(http://www.latiendagourmet.com.ar/bebidas/espirituosas/vodka-estepvka/).
2) As a medicinal herb: there is fragmentary information about the volumes used for commercial sales,
the existence of collection centers, and the number of marketing intermediaries involved. Empirical
works carried out in the city of S.C. Bariloche show that this plant is mainly commercialized dried,
sometimes fresh, and in very variable quantities in bulk, including branches, leaves and flowers. The
main sales destinations are Patagonian herbalists, pharmacies and houses selling naturistic products,
where the product is fractionated in the selling points (Cuassolo et al. 2010). Adesmia boronoides
appears as one of the most commercialized native medicinal plants in the urban centers of the region
(Cuassolo 2010).
3) Regarding its use as an essential oil, it has been used in perfumery since 2005, and to this purpose
it is marketed and exported. The extraction and harvesting of the material comes only from natural
populations. According to unverified sources, the amount of raw material would add to more than
300 tons to date. This material is processed solely by the distillation plants. There are audio-visual
records of the recollection in Lago Buenos Aires, Santa Cruz province, where weekly truck shipments
to the city of Esquel are mentioned (https://www.youtube.com/watch?v=mxSeFGrs30U).
In Chile, Paramela is advertised and sold as the “mapucheviagra”: a herbal preparation called Palwen
that increases sexual vigor (https://www.iucn.org/node/16897).
In 2008, the Natura cosmetic company started commercializing a perfume with a fragrance containing
essential oil of paramela. The product is called “Amor América”, and it was inspired by plants from
the Andes and Patagonia, including not only the paramela but also the palosanto of Ecuador (Bursera
graveolens (Kunth) Triana & Planch.).
Fig. 6.7 Alcoholic beverage and perfume with A. boronioides as an ingredient. Photograph by González S.B.
It is worth mentioning that the species has begun to be sold as ornamental in some regional fairs and
nurseries of Patagonia because of the beauty of its flowers and its perennial character.
Domestication experiences and propagation

Background analysis shows that A. boronioides arouses much interest in companies on a commercial scale,
and that the material is obtained only from natural populations.
Germination studies developed by the National University of Patagonia S.J.B. (UNPSJB), INTA
and the National University of Río Negro (UNRN) made it possible to identify effective and practical
methods for propagation. In order to successfully germinate A. boronioides, it is necessary to break the
physical barrier using treatments that weaken the seed coat. From seeds collected in natural populations,
pre-germination soaking treatments at 80°C yielded 85% germination success (González et al. 2009), and
pre-scarification yielded 83.7% germination success (Mazzoni et al. 2014).
These experiments and results suggest that it would be feasible to produce large-scale seedlings to
establish future crops as a productive alternative for the region.
Container cultivation was evaluated by the UNRN Tecnicatura en Viveros (Plant Nursery Technicature).
They evaluated the production of 120 plants grown from seeds in one-liter containers with a substrate
mixture of volcanic ash, peat and soil (Sánchez and Riat 2012). This plant material was transplanted in
2015 to a nursery on outdoor soil, located at INTA Bariloche to continue for future evaluations (Fig. 6.8).
Additionally, this exploratory cultivation test generated vegetal material that was harvested and is
being characterized chemically in relation to its contents of essential oils in the UNPSJB. In this way the
domestication studies carried out in the region try to make technical contributions that allow us to think
about productive alternatives, reduce the collection pressure of the environment and generate products of
commercial quality (Mazzoni et al. 2016, Contardi et al. 2016a, 2016b).
Fig. 6.8 Natural populations and stonemasons with specimens obtained from seeds of that origin. Photograph by González,
S.B. and Mazzoni, A.
Conclusions
The studies presented in this chapter confirm the long history of use that A. boronioides has in the Mapuche-
Tehuelche communities, as an aromatic and medicinal plant. Consistent with the commitment made by
Argentina to the Convention on Biological Diversity and the Nagoya Protocol, it is necessary to develop
regulations to control and protect the access to the traditional knowledge associated with this plant.
In relation to the use of paramela for human consumption, the results of the research are promising.
To date, no evidence of toxicity or allergenicity has been found in traditional forms of use in terms of
preparation and dosage. However, there are no studies on high-dose and long-term use safety. There
are chemical studies that show variability in the chemical composition (qualitative and quantitative)
of the essential oil and in the content of phenols in different populations of A. boronioides throughout
Patagonia. This means that in order to be able to recommend its consumption, the homogeneous quality
of the chemical composition of the plants used for the production of beverages must be ensured. In turn,
it would be important to develop systems for quality control and authentication of the raw material used
as an additive in edible products.
Studies showed that propagation of A. boronioides was possible from seeds. The plants produced could
be used to establish field crops in the future, and not rely on natural populations as the only alternative for
obtaining plant material intended for the production of commercial products.
Finally, in order to fully understand the current situation of this species and all its potential uses it is
necessary to adopt a multicultural and transdisciplinary approach. This approach should bring together
the academy perspective with that of the local communities, who have been the main heirs and makers of
this valuable Patagonian heritage.
Acknowledgements
The authors would like to acknowledge the financial support received through the projects: C. y T. N°
005/09, C.y T. N° 1039 UNPSJB, PIP 0466 UNCOMA and Professor Cristina Zuppa.
References
Agnese, A.M., Juliani, H.R. and Cabrera, J.L. 1989. Estudio fitoquímico en especies del género Adesmia (Fabaceae). An.
Asoc. Quím. Argent. 77(4) 287–291.
Agnese, A.M. 1993. Estudio fitoquímico de especies del género Adesmia (Leguminosae). Tesis Doctoral de la Universidad
Nacional de Córdoba 163 pp.
Bandoni, A. 2000. Los Recursos Vegetales Aromáticos en Latinoamérica, su aprovechamiento industrial para la producción
de aromas y sabores. EDULP. La Plata 410 pp.
Barthelemy, D., Brion, C. and Puntieri, J. 2008. Plantas. Patagonia. Vázquez Mazzini Ed. Buenos Aires 239 pp.
Blengini, A., Muñoz, A.V., Artola, S., Gamarra, K. and Freile, M.L. 2016. Evaluación de la actividad antimicrobiana de
Paramela (Adesmia boronioides Hook. f.). Dominguezia 32(2): 25.
Burkart, A.E. 1967. Sinopsis del género sudamericano de Leguminosas Adesmia D.C. Darwiniana 14: 463–468.
Burkart, A.E. 1984. Adesmia. En M.N. Correa (ed.). Flora Patagonica, Leguminosae. Col. Cient. INTA 4b: 92–161.
Campos, V.M, Cárdenas, E.M. and San Martín Saldias, C. 1997. Herbolaria médica de Chile. Diagnóstico de su estado actual
y perspectivas futuras para la medicina oficial chilena. Ministerio de Salud, Santiago.
Castillo, L. and Ladio, A.H. 2014. Importancia del recurso vegetal como fuente de remedios caseros de uso veterinario para los
pobladores rurales de Sierra Rosada, Sierra Ventana y El Escorial (Chubut). XXVI Reunión Argentina de Ecología.
RAE 2014. Comodoro Rivadavia.
Cerda-García-Rojas, C. M., Bucio, A., González, S.B., García Gutiérrez, H. and Joseph-Nathan, P. 2015. Absolute configuration
of esquelane derivatives from Adesmia boronioides by vibrational circular dichroism. Tetrahedron-Asymmetr.
26: 136–140.
Ciampagna, M.L. and Capparelli, A. 2012. Historia de uso de las plantas por parte de las poblaciones que habitaron la Patagonia
Continental Argentina. Rev. Arqueol. 6: 45–75.
Contardi, L.T., Silva Sofrás, F.M. and González, S.B. 2016a. Paramela, una especie nativa de la Patagonia: análisis de frutos
y semillas. Rev. Patag. For. – AÑO XXI, N°1, Junio 2016.
Contardi, L.T., Silva Sofrás, F.M. and González, S.B. 2016b. Reproducción de Adesmia boronioides, especie aromática y
medicinal actualmente cosechada de poblaciones naturales en Patagonia. Rev. Nat. Patagon. 9: 50–60.
Conticello, L., Gandullo, R., Bustamante, A. and Tartaglia, C. 1997. El uso de plantas medicinales por la comunidad Mapuche
de San Martín de los Andes, provincia de Neuquén (Argentina). Parodiana 10(1-2): 165–180.
Cuassolo, F., Ladio, A.H. and Ezcurra, C. 2010. Aspectos de la comercialización y control de calidad de las plantas medicinales
más vendidas en una comunidad urbana del NO de la Patagonia Argentina. Bol. Latinoam. Caribe Plant. Med.
Aromat. 9(3): 166–176.
de Araújo A. 1976. The relationship between altitude and cyanogenesis in white clover (Trifolium repens L.). Heredity 37(2):
291–293.
Delfino, M., Monelos, L., Peri, P. and Buffa, L. 2009. A new species of Aphis L (Hemiptera: Aphididae) from South Patagonia.
Neotrop. Entomol. 38(3): 366–369.
Estomba, D., Ladio, A.H. and Lozada, M. 2006. Medicinal wild plant knowledge and gathering patterns in a Mapuche
community from North-Western Patagonia. J. Ethnopharmacol. 103: 109–119.
Estomba, D., Mattes Fernández, H. and Stella, A.M. 2010. Antioxidantes y porfirinas de Adesmia boronioides, Larrea divaricata
y Atriplex lampa cultivadas in vitro Rev. FCA UNCuyo 42(2): 135–142.
Eyssartier, C., Ladio, A. and Lozada, M. 2009. Medicinal use of plant species cultivated in a semi-rural community of the
patagonian steppe. Bol. Latinoam. Caribe Plant. Med. Aromat. 8(2): 67–76.
Eyssartier, C., Ladio, A.H. and Lozada, M. 2011a. Traditional horticultural knowledge change in a rural population of the
Patagonian steppe. J. Arid Environ. 75: 78–86.
Eyssartier, C., Ladio, A.H. and Lozada, M. 2011b. Horticultural and gathering practices complement each other: a case study
in a rural population of Northwestern Patagonia. Ecol. Food Nutr. 50: 429–451.
Eyssartier, C., Ladio, A.H. and Lozada, M. 2013. Traditional horticultural and gathering practices in two semi-rural populations
of Northwestern Patagonia: resilience and embodied know-how. J. Arid. Environ. 97: 18–25.
Faini, F., M. Castillo, R. Torres, G. DelleMonache and Gacs-Baitz, E. 1995. Malabaricane triterpene glucosides from Adesmia
aconcaguensis. Phytochemistry 40(3): 885–890.
Forcone, A. and Muñoz, M. 2009. Floración de las especies de interés apícola en el Noroeste de Santa Cruz, Argentina. Bol.
Soc. Argent. Bot. 44(3-4): 393–403.
Gastaldi B., Assef, Y., Sofrás, F., Catalán, C. and González, S. 2016. Actividad antioxidante y toxicidad frente a Artemia salina
de infusiones de nueve especies aromáticas del noroeste de la Patagonia. Dominguezia 32(2): 39.
Gastaldi, B., Assef, Y., van Baren, C., Di Leo Lira, P., Retta, D., Bandoni, A. and González, S. 2016. Antioxidant activity
in teas, tinctures and essential oils of native species from Patagonia Argentina. Rev. Cub. Pl. Med. 21(1): 51–62
González, S.B. 2005. Adesmia boronioides Hook. f.: una especie aromática y medicinal nativa de la Patagonia. Nat. Patagon.
2(1): 85–91.
González, S.B. and Molares, S. 2004. Plantas medicinales utilizadas en comunidades rurales del Chubut, Patagonia Argentina.
S. Bol. Latinoam. Caribe Plant. Med. Aromat. 3(3): 58–62.
González, S.B., Gastaldi, B., Silva Sofrás, F., van Baren, C., Di Leo Lira, P., Retta, D. and Bandoni, A. 2016. Diversidad
química en una especie aromática y medicinal endémica de Patagonia. Dominguezia 32(2): 89–90.
González, S.B. 2002. Tesis Doctoral FFyB, UBA. Estudio de Adesmia boronioides Hook.f., una especie aromática y medicinal
nativa de la Patagonia. Doctorado en el área Productos Naturales, 219 pp.
González, S.B., Bandoni, A.L., van Baren, C., Di Leo Lira, P., Cerda-García-Rojas, C.M. and Joseph-Nathan, P. 2004. The
Essential Oil of the Aerial Parts of Adesmia boronioides Hook. f. J. Essent. Oil Res. 16: 513–516.
González, S.B., Bandoni, A.L., van Baren, C., Di Leo Lira, P., Cerda-García-Rojas, C.M. and Joseph-Nathan, P. 2002. Structure,
conformation and absolute configuration of novel bisnorsesquiterpenes from the Adesmia boronioides essential oil.
Tetrahedron, 58: 3065–3071.
González, S.B., Pasquini, N. and Contardi, L. 2009. Calidad de semillas y producción de plantas de Adesmia boronioides
Hook. f., especie aromática y medicinal nativa de la Patagonia. Proyecto de Ciencia y Técnica de la UNPSJB sede
Esquel. CAFCN N° 374/08, Resol C.S. N° 101/08.
González, S.B., Houghton, P. and Hoult, J. 2003.The activity against leukocyte eicosanoid generation of essential oil and
polar fractions of Adesmiaboronioides Hook. f. Phytother. Res. 17: 290–293.
González, S.B., Gallardo, C. and Guerra, P. 2005. Etnobotánica de plantas medicinales en comunidades rurales de la Provincia
del Chubut, Patagonia Argentina. Libro de Resúmenes V Reunión de la Sociedad Latinoamericana de Fitoquímica,
Montevideo, 28 Noviembre al 2 de Diciembre de 2005, pág. 102.
González, S.B., Gallardo, C., Recalde, J. and Guerra, P. 2005. Talleres etnobotánicos en comunidades del NO del Chubut.
Actas de las XXX Jornadas Argentinas de Botánica, Rosario, Argentina, 6 al 10 de Noviembre de 2005, pág. 83.
González, S.B., Guerra, P., Gastaldi, B., van Baren, C., Di Leo Lira, P. and Bandoni, A. 2014. Avances en el estudio de plantas
aromáticas nativas y naturalizadas en la Patagonia Argentina. Variabilidad y constancia en la composición de sus
aceites esenciales. Lilloa 52 (Suplemento): IV Jornadas Nacionales de Plantas Aromáticas Nativas y sus Aceites
Esenciales, 37–42.
Green, L. and Ferreyra, M. 2011. Flores de la Estepa patagónica. Vázquez Mazzini Ed. Buenos Aires 286 pp.
Guignard, L. 1906 “Le Haricot à acide cyanhydrique (“Phaseolus lunatus acide cy anhydrique (“Phaseolus lunatus” L.), étude
historique, botanique et chimique, nouveau procédé pour déceler l’’acidecyanhydriquel ‘’acide cy anhydrique” Rev.
Viticulture.
Igon, P., Ladio, A.H. and Lozada, M. 2006. Plantas Medicinales utilizadas en las comunidades de Villa Traful y Cuyín Manzano.
UNCOMA. Ed. Imaginaria. 67 pp.
Kakes, P. 1990. Properties and functions of the cyanogenic system in higher plants. Euphytica 48: 23–43.
Kutschker, A., Menoyo, H. and Hechem, V. 2002. Plantas medicinales de uso popular en comunidades del oeste del Chubut.
INTA-Universidad Nacional de la Patagonia S.J.B.-GTZ, Bariloche 139 pp.
Ladio, A.H. 2006. Gathering of wild plant foods with medicinal use in a mapuche community of NW patagonia. pp. 297–321.
In: Pieroni, Andrea and Lisa Price (eds.). Eating and Healing: Explorations of Traditional Food as Medicines.
Haworth Press. USA.
Ladio, A.H. and Molares, S. 2014. El paisaje patagónico y su gente. Capítulo 9. In: Raffaele, E., de Torres Curth, M., Morales ,
C.L. and Kitzberger, T. (eds.). Ecología e historia natural de la Patagonia Andina: Un cuarto de siglo de investigación
en biogeografía, ecología y conservación. Ed. Fund. Azara, C.A. de Buenos Aires, 256 pp.
Ladio, A.H. and Molares, S. 2017. Capítulo 29. Etnoconservacionismo y prácticas locales en Patagonia: avances y perspectivas.
pp. 649–672. In: Casas, A., Torres-Guevara, J. and y Parra, F. (eds.). Domesticación en el Continente Americano.
Historia y perspectivas del manejo de recursos genéticos en el Nuevo Mundo. Universidad Agraria La Molina. IIES,
Lima, Perú. ISBN 978-607-02-9334-4.
Ladio, A.H. 2006. Etnobotánica en la Patagonia: conocimiento local e importancia actual de los recursos vegetales en las
comunidades rurales. ACCB 18: 13–29.
Ladio, A.H., Lozada, M. and Weigandt, M. 2007.Comparison of traditional wild plants use between two Mapuche communities
inhabiting arid and forest environments in Patagonia, Argentina. J. Arid Environ. 69: 695–715.
Lukas G., 1964. The constitution of two new sesquiterpenic ketones. Furopelargones A and B. Tetrahedron. 20: 1789–1801.
Martínez-Crovetto, R. 1980. Apuntes sobre la vegetación de los alrededores del Lago Cholila. Publicación Técnica Nº 1, FCA
UNNE, Corrientes, pp. 1–22.
Mazzoni, A., Sánchez, G., Riat, M. and Hagiwara, J. 2014. Propagación de Adesmia boronioides Hook. f., planta nativa
medicinal de la Patagonia Argentina. Libro de resúmenes y poster presentado al XXXVII Congreso Argentino de
Horticultura (ASAHO). Mendoza.
Mazzoni, A., Sánchez, G., Riat, M. and Hagiwara, J. 2016. Propagación de Adesmia boronioides Hook. f., planta nativa
medicinal de la Patagonia Argentina. Presentación oral: Experiencias de Domesticación. V Jornadas Nacionales de
plantas aromáticas nativas y sus aceites esenciales y Iº Jornadas Nacionales de plantas medicinales nativas. Esquel.
Dominguezia 32(2): 70.
Molares, S. and Ladio, A.H. 2008. Plantas medicinales en una comunidad Mapuche del NO de la Patagonia Argentina:
clasificación y percepciones organolépticas relacionadas con su valoración. Bol. Latinoam. Caribe Plant. Med.
Aromat. 7(3): 149–155.
Molares, S. and Ladio, A.H. 2009. Ethnobotanical review of the Medicinal Mapuche Flora: use patterns on a regional scale.
Molares, S. and Ladio, A.H. 2012a. Mapuche perceptions and conservation of Andean Nothofagus forests and their medicinal
plants: A case study from a rural community in Patagonia, Argentina. Biodivers. Conserv. 21(4): 1079–1093.
Molares, S. and Ladio, A.H. 2012b. The usefulness of edible and medicinal Fabaceae in Argentine and Chilean Patagonia:
environmental availability and other sources of supply. Evid.-Based Compl. Alt. Article https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC3238373/pdf/ECAM2012-901918.pdf.
Molares, S. and Ladio, A.H. 2014. Medicinal plants in the cultural landscape of a Mapuche-Tehuelche community in arid
Argentine Patagonia: an eco-sensorial approach. J. Ethnobiol. Ethnomed. 10: 61.
Mongelli E., Coussio, J. and Ciccia, G. 1995. Estudio de toxicidad aguda de plantas medicinales argentinas mediante el
bioensayo de Artemia salina Lech. Dominguezia 12: 35–42.
Montes, A.L. and Peltz, L. 1963. Esencias de plantas aromáticas del Parque Nacional Nahuel Huapi y sus aledaños. 2. Adesmia
boronioides Hooker, o paramela. An. Soc. Cient. Argent. 175: 91–101.
Montes, O. Montes, M. and T . Wikomirsky. 2001. Plantas Medicinales de Uso en Chile. Química y Farmacología. Editorial
Universitaria, S.A. Santiago, Chile.
Muñoz, O., Montes, M. and Wilkomirsky, T. 2001 Plantas medicinales de uso en Chile. Química y Farmacología. Ed.
Universitaria. Santiago. 205 pp.
Nájera, M.T., Spegazzini, E.D., Castro, M.T., Guerra, P. and González, S. 2000. Anatomía de Adesmia boronioides Hook. f.
(Leguminosae - Papilionoideae). Acta Farm. Bonaer. 19(4): 245–250.
Ochoa, J. 2008. Aspectos ecológicos y socioculturales asociados al uso de plantas silvestres en una población rural del
Noroeste de la Patagonia.Tesis de Licenciatura. Universidad Nacional del Comahue, S.C. de Bariloche, Argentina.
Ochoa, J., Ladio, A.H. and Lozada, M. 2010. Uso de recursos herbolarios entre mapuches y criollos de la comunidad campesina
de Arroyo Las Minas (Río Negro, Patagonia Argentina). Bol. Latinoam. Caribe Plant. Med. Aromat. 9(4): 269–276.
Ochoa, J. 2015.Uso de plantas silvestres con órganos de almacenamiento subterráneos comestibles en Patagonia: perspectivas
etnoecológicas. Tesis para optar al grado de Doctor en Biología. Universidad Nacional del Comahue. S.C. de
Bariloche (Río Negro). 250 pp.
Pérez, O. and Lazo, F. 2010. Ensayo de Artemia: útil herramienta de trabajo para ecotoxicólogos y químicos de productos
naturales. Rev. Protección Veg. 22(1): 34–43.
Richards, A.J. and Fletcher, A. 2002. The effects of altitude, aspect, grazing and time on the proportion of cyanogenics in
neighbouring populations of Trifolium repens L. (white clover). Heredity 88: 432–436.
Richeri, M., Ladio, A.H. and Beeskow, A.M. 2013. Conocimiento tradicional y autosuficiencia: la herbolaria rural en la Meseta
Central del Chubut (Argentina). Bol. Latinoam. Caribe Plant. Med. Aromat. 12(1): 44–58.
Richeri, M. 2016. Evaluación de los reservorios etnobotánicos en las poblaciones rurales del centro norte de la Provincia del
Chubut. Tesis para optar al grado de Doctor en Biología. Universidad Nacional del Comahue. S.C. de Bariloche
(Río Negro). 170 pp.
Richeri, M., Cardoso, M.B. and Ladio, A.H. 2013. Soluciones locales y flexibilidad en el conocimiento ecológico tradicional
frente a procesos de cambio ambiental: estudios de caso en Patagonia. Ecol. Aust. 23: 184–193.
Sánchez, G. and Riat, M. 2012. Estudio de Adesmia boronioides Hook. f. “Paramela” (Fabáceas). Un acercamiento para su
reproducción y manejo en viveros. Informe técnico. Carrera Tecnicatura en Viveros. UNRN. Sede Andina. San
Carlos de Bariloche. Río Negro.
Silva Sofrás, F., Gastaldi, B. and González, S. 2016. Compuestos fenólicos de Adesmia boronioides Hook f.: Análisis de su
variabilidad en dos estaciones diferentes. Dominguezia (32)2: 54.
Toledo, C. and Kutschker, A. 2012. Plantas medicinales en el Parque Nacional Los Alerces, Chubut, Patagonia Argentina.
Bol. Soc. Argent. Bot. 47(3-4): 461–470.
Ulibarri, E. and Burkart, A. 2000. Sinopsis de las especies de Adesmia (Leguminosae-Adesmiae) de la Argentina. Darwiniana
38 (1-2): 59–126.
Ulibarri, E.A. and Simpson, B.B. 2010. Una nueva especie de Adesmia (Leguminosae, Papilionoideae) para la Argentina.
Darwiniana 48(2): 204–207.
Vetter, J. 2000. Plant cyanogenic glycosids.Toxicon 38: 11–36.
Villagra, S., González, S., González Rojas, S., Garriz, N., Longarzo, A., Errecalde, J. and Zaidenberg, A. 2008. Inhibición
in vitro de Tripanosoma cruzi por aceites esenciales. VIII Congreso Argentino de Protozoología y Enfermedades
Parasitarias, 2 al 5 de Noviembre de 2008, Rosario, Santa Fe, Argentina. Rev. Med. Rosario 74 (SUPL).
Weigandt, M., Ladio, A.H. and Lozada, M. 2004. Plantas medicinales utilizadas en la comunidad Mapuche Curruhuinca.
Secretaría de ExtensiónUniversitaria. UNCo. Ed. Imaginaria. Bariloche 73 pp.
7
The Genus Vismia : Geographical
Distribution, Chemical Composition
and Recent Biological Studies
Janne Rojas* and Alexis Buitrago
Introduction
Plants usage is considered an ancient practice where a religious-magical touch also took place for the
treatment of several human pathologies. Despite the modern practice of medicine and the use of prescription
drugs, nowdays, there is an increased interest to discover new medicines from natural sources (Rates
2001). Thus, plants have been under investigation to determine biological activities that might be useful
as a natural alternative for the treatment of human diseases.
Hypericaceae family comprises nine genera: Cratoxylum Blume, Eliea Cambess, Harungana Lamarck,
Hypericum L., Lianthus N. Robson, Santomasia N. Robson, Thornea Breedlove & Mc Clintock, Triadenum
Rafinesque and Vismia Vand (Crocketta and Robinson 2011). Vismia genus is composed of approximately
55 species, distributed in tropical and subtropical regions of Central and South America, although there are
some species reported in Africa (Hussain et al. 2012). Phytochemical studies conducted on different Vismia
species have reported around 161 chemical compounds, the majority of these with aromatic structures,
holding oxygenated functions such as anthrones, xanthones, anthraquinones, among others, which are
biosynthetically generated by the acetate malonate pathway. Other type of components isolated from this
genus comprises flavonoids, originated by the combination of acetate malonate-shikimate pathways and
terpenes biosynthetized by mevalonic acid pathway (Dewick 2002, Vizcaya et al. 2014).
Regarding biological properties, many of Vismia species have been used in traditional medicine to
treat ulcerations, fungus, herpes, as laxatives and to treat high fever (Vizcaya et al. 2014, Buitrago et al.
2016). Furthermore, isolated compounds have demonstrated antimicrobial, antioxidant, antinoniceptive,
leishmanicide, trypanomicide, cytotoxic, among other activities (Mbwambo et al. 2004, Salas et al. 2007a,
Salas et al. 2007b, Tala et al. 2011).
This chapter aims to summarize some taxonomic features, geographical distribution, chemical
composition and biological activitites, reported within the last 20 years for different Vismia species, in
order to give authentic information to readers that might be useful for further investigations.
Organic Biomolecular Research Group, Research Institute, Faculty of Pharmacy and Bioanalysis, University of Los Andes,
Mérida 5101, Venezuela.
* Corresponding author: janner@ula.ve
Significant botanical features

Hypericaceae family
Hypericaceae family belongs to order Malpigphiales and subclass Rosidae. It used to be included in to
Clusiaceae family (Guttiferae family, sensu lato) but it was separated due to different phylogenetic and
morphological features (Stevens 2007, Angiosperm Phylogeny Group 2009). This family comprises
three tribes; Cratoxyleae, Hypericeae and Vismieae; with around 560 species distributed in nine genera:
Cratoxylum Blume, Eliea Cambess, Harungana Lamarck, Hypericum Linneo, Lianthus N. Robson,
Santomasia N. Robson, Thornea Breedlove & McClintock, Triadenum Rafinesque and Vismia Vand.
(Stevens 2007, Angiosperm Phylogeny Group 2009, Crocketta et al. 2011).
Regarding botanical features, this family occurs as annual or perennial herbs, shrubs, and seldom
trees, holding single opposite or sessile whorled leaves, sometimes dotted with tiny black or translucent
spots. Limb with sub-parallel or cross-linked venation, yellow transparent glands turning dark yellow at
surface and borders. Bisexual actinomorph flowers, yellow, orange or red color perianth, frequently with
the presence of red streaks, arranged in branched inflorescences, four to five sepals and four to five petals;
being attached below the ovary. Stamens have long filaments and sometimes are fused together. Three to
five styles are usually fused at the base. Fruits are present as green dehiscent capsules turning to brown at
maturity where these open to release the seeds (Nürk et al. 2013).
Vismia genus
Vismia genus belongs to the Vismieae tribe, composed of aproximately 55 species that grow between
temperate to tropical climates. It is represented by trees and shrubs around 1 to 15 m of heigh. A highlight
feature of this genus is the orange latex that exudes when a cut occurs in any part of the plant. It possesses
ferruginous induments of single to starry hairs, opposite leaves with diferent forms such as lanceolate,
oblong-lanceolate and oblong-ovate. It exhibits terminal panicles, with pentamerous flowers of numerous
stamens grouped in fascicules; fruits as capsules or berries with persistant chalice (Álvarez et al. 2009).
Geographical distribution of Vismia genus
Species of Vismia genus are distributed mainly at Neotropic zones, from South of Mexico, passing through
Central America till they reach North of Brazil, in South America. However, six species have been reported
for the tropical areas of Africa. This occurrence, has been explained by the Gondwana super continent
that existed at the Permic period (Botta et al. 1986, Stevens, 2007, Angiosperm Phylogeny Group 2009,
Crocketta et al. 2011, Ruhfel et al. 2011). Table 7.1, describes the geographical distribution, synonymous
and common names of different Vismia species (Hokche et al. 2008, “Trópicos org.” 2015).
Secondary metabolites isolated from Vismia genus
Primary metabolism of plants involve different chemical processes such as photosynthesis, glycolysis,
citric acid cycle, amino acid synthesis, among others, where carbohydrates, lipids and proteins take place
to aid survival, growth and reproduction of plants, furthermore, Secondary Metabolites (SM) are designed
as part of this process (Dewick 2002, Shilpa et al. 2010).
In this regard, SM are chemical compounds biosynthesized by plants that play important roles such
as defense against herbivorous, pathogenic microorganisms, pollinators attraction and seed dispenser.
However, humans have discovered that, such a variety of compounds may possess biological activities to
treat a number of diseases (Goossens et al. 2003, Wink 2007).
There are three main biosynthetic pathways from where SM are designed; Shikimate that produces
aromatic amino acids, phenylpropanoids, cinnamic acids, lignans, coumarins, flavonoids and stilbenes;
mevalonate that generate terpenoids and steroids and acetate pathway that develops fatty acids and
polyketides (Dewick 2002, Marcano and Hasegawa 2002).
The Genus Vismia: Geographical Distribution, Chemical Composition and Recent Biological Studies 107
Table 7.1 Worldwide geographical distribution of Vismia species (Hokche et al. 2008, “Trópicos org.” 2015).
Especie Synonymous Common name Country

Vismia acuminate Hypericum acuminatum Lam -------- French Guyana
(Lam.) Pers
Vismia amazonica Vismia gracilis Hieron Pichirina Big leave Bolivia, Brazil, Colombia,
Ewan Guyana, Peru
Vismia angusta Caopia cordata Rusby, Hypericum Manchador, pichirina Bolivia, Brazil, Colombia,
(Miq.) reticulatum Poir French Guyana, Peru,
Surinam, Venezuela
Vismia angustifolia Vismia falcata Rusby, Vismia -------- Venezuela
Rusby laxiflora Reichardt
Vismia baccifera (L.) Caopia baccifera (L.) Kuntze, Carate, Belice, Bolivia, Brazil,
Triana & Planch Hypericum bacciferum L., red carate, Colombia, Costa Rica,
Vismia dealbata Kunth, spearhead, Ecuador, El Salvador,
Vismia mexicana Schltdl., achiotillo French Guyana, Guatemala,
Vismia panamensis Duchass & Walp Honduras, Mexico, Panama,
Peru, Surinam, Venezuela
Vismia baccifera subsp. Caopia dealbata (Kunth) Kuntze, Lancetillo, Brazil, Colombia, French
dealbata (Kunth) Ewan Vismia confertiflora Spruce ex onotillo, Guyana, Surinam, Venezuela
Reichardt, Vismia dealbata Kunth, spearhead
Vismia hamanii S.F. Blake
Vismia baccifera subsp. Caopia ferruginea (Kunth) Kuntze, Carate Colombia, Venezuela
ferruginea (Kunth) Ewan Vismia cuspidata Steud,
Vismia ferruginea Kunth
Vismia baccifera subsp. Vismia subcuneata Huber -------- Bolivia, Peru
subcuneata (Huber) Ewan
Vismia bemerguii -------- -------- Brazil, Bolivia
M.E. Berg
Vismia billbergiana Caopia billbergiana (Beurl.) Kuntze, Sangrillo Belice, Colombia, Costa Rica,
Beurl Vismia viridiflora Duchass. ex Triana México, Nicaragua, Panama
& Planch
Vismia boliviana -------- -------- Bolivia
Melch
Vismia brasiliensis Caopia brasiliensis (Choisy) Kuntze, Pau-de-lacre, Brazil
Choisy Vismia brasiliensis var. lasiantha purga-de-vento
Reich. in Martius, Vismia laccifera
Mart
Vismia buchtienii Vismia glaziovii Ruhland, Sangrito, puntelanza, Bolivia, Brazil,
Ewan Vismia gracilis Hieron pichirina blanca, Peru, Venezuela
bloodwood
Vismia calvescens Vismia lauriformis (Lam.) Choisy Lacre, lacre minchuba Colombia
Gilg & Hieron
Vismia camparaguey -------- -------- Belice, Guatemala,
Sprague & L. Riley Honduras, Mexico
Vismia caparosa Kunth Vismia guianensis (Aubl.) Choisy -------- Venezuela
Vismia cavalcantii -------- -------- Suriname
M.E. Berg
Vismia cavanillesiana -------- -------- Colombia,
Cuatrec Ecuador
Vismia cayennensis Caopia acuminata (Lam.) Kuntze, Pichirina negra, Bolivia, Brazil, Colombia,
(Jacq.) Pers Caopia cayennensis (Jacq.) Kuntze, Manchador, Lacre Ecuador, French Guyana,
Hypericum cayennense Jacq, Vismia blanco, spearhead Peru, Suriname, Trinidad and
floribunda Sprague Tobago, Venezuela
Table 7.1 contd.…
…Table 7.1 contd.

Vismia cayennensis var. Vismia sessilifolia -------- Guyana
sessilifolia (Aubl.) (Aubl.) DC
M.E. Berg
Vismia cearensis Huber -------- -------- Brazil
Vismia confertiflora Caopia confertiflora (Spruce ex -------- Brazil, Colombia,
Spruce ex Reichardt Reichardt) Ecuador, Guyana
Vismia crassa (Rusby) Caopia crassa -------- Bolivia
S.F. Blake Rusby
Vismia cuatrecasasii -------- -------- Colombia
Ewan
Vismia decipiens Vismia pentagyna (Spreng.) Ewan -------- Bolivia, Brazil,
Schltdl. & Cham Venezuela
Vismia falcata Vismia angustifolia -------- Brazil, Trinidad,
Rusby Rusby Tobago, Venezuela
Vismia glabra Caopia glabra -------- Bolivia, Brazil, Peru
Ruiz & Pav (Ruiz & Pav.) Kuntze
Vismia glaziovii Vismia buchtienii -------- Bolivia,
Ruhland Ewan Brazil
Vismia guaramirangae Vismia reichardtiana (Kuntze) Ewan Capianga, lacre Brazil
Huber
Vismia guianensis Caopia guianensis (Aubl.) A. Lyons, Uadama, punta de Bolivia, Brazil, Colombia,
(Aubl.) Choisy Hypericum acuminatum Lam., lanza lacre French Guyana, Surinam,
Hypericum guianense Aubl. Venezuela
Vismia guianensis subsp. -------- -------- Colombia
persicoides Ewan
Vismia japurensis Caopia japurensis (Reichardt) Lacre, picharrinha, Brazil, Colombia, Guyana,
Reichardt Kuntze purga-de-vento Surinam, Venezuela
Vismia jefensis N. Robson -------- Rastrojero, sangrito Colombia, Panama
Vismia laevis Caopia laevis (Triana & Planch.) Carate, punta de lanza Colombia, Venezuela
Triana & Planch Kuntze
Vismia latifolia Vismia humboldtiana Schltdl. & -------- Venezuela
Kunth Cham
Vismia latisepala -------- Sangrito, Panama
N. Robson achioto
Vismia macrophylla Caopia macrophylla (Kunth) Kuntze, Sangrillo, sapidalle, Belice, Bolivia, Brazil,
Kunth Vismia macrophylla var. glabrescens carachero,sapigale, Colombia, Costa Rica,
Hochr lacre hojiancho, lanzo, Ecuador, French Guyana,
fierro lanzo, lacre, Guyana, Guatemala,
manchador Panama, Surinam
Vismia mandar Hieron Caopia mandurr Hieron -------- Colombia, Ecuador
Vismia martiana Reichardt Caopia martiana (Reichardt) Kuntze -------- Brazil
Vismia micrantha Caopia micrantha (Mart. ex A. -------- Brazil
Mart. ex A. St.-Hil St.-Hil.) Kuntze
Vismia minutiflora -------- -------- Bolivia, Brazil, Colombia,
Ewan Ecuador, Peru
Vismia obtusa Caopia obtusa (Spruce ex Reichardt) -------- Brazil, Colombia, Ecuador,
Spruce ex Reichardt Kuntze Peru
Vismia orientalis Engl -------- -------- Tanzania
Vismia ovalifolia Melch -------- -------- Peru
Table 7.1 contd.…
…Table 7.1 contd.

Vismia panamensis Caopia panamensis -------- Colombia, Ecuador, Panama
Duchass. & Walp (Duchass. & Walp.) Kuntze
Vismia parviflora Caopia parviflora (Schltdl. & Cham.) -------- Brazil
Schltdl. & Cham Kuntze
Vismia pauciflora -------- -------- Tanzania
Milne-Redh
Vismia plicatifolia Caopia parvifolia -------- Bolivia
Hochr Rusby
Vismia pozuzoensis Vismia glabra subsp. pozuzoensis Pichirina Bolivia, Brazil, Ecuador, Peru
Engl (Engl.) Ewan
Vismia ramuliflora Miq Vismia sessilifolia (Aubl.) DC -------- French Guyana, Guyana,
Surinam
Vismia rubescens Oliv -------- -------- Equatorial Guinea, Gabon
Vismia rusbyi Ewan -------- -------- Bolivia, Botswana, Peru
Vismia sandwithii Ewan -------- -------- Brazil, Ecuador, French
Guyana, Guyana, Surinam
Vismia schultesii Vismia tomentosa Ruiz & Pav -------- Bolivia, Brazil, Colombia,
N. Robson Ecuador, Peru
Vismia sprucei -------- -------- Bolivia, Brazil, Colombia,
Prague Ecuador, Peru
Vismia steyermarkii -------- -------- --------
N. Robson
Vismia urceolata -------- -------- Colombia
Ewan
Vismia viridiflora Caopia viridiflora (Duchass. ex -------- Colombia, Panama
Duchass.ex Triana & Triana & Planch.) Kuntze
Planch
In this regard, Vismia genus biosynthesizes a variety of SM, mainly through acetate and shikimate
pathways, although, the mevalonate way is also used by this genus to produce terpene type components.
The biosynthetic pathways used by plants for the production of their MS are described below, and some
examples of isolated compounds from Vismia genus are also defined.
Acetate Malonate pathway

Polyketides comprises a large class of natural products with diverse structures derived from poly-β-keto
chains formed by coupling of two molecules of acetyl-CoA via Claisen reactions, giving acetoacetyl-CoA.
These compounds are fatty acids, polyacetylenes, prostaglandins, macrolide, antibiotics and many aromatic
compounds, such as anthraquinones and tetracyclines. The biosynthesis involves initial carboxylation of
acetyl-CoA to malonyl-CoA, a reaction involving ATP, CO2 and biotin, a coenzyme acting as CO2 carrier
(Dewick, 2002, Marcano and Hasegawa, 2002).
The conversion of acetyl-CoA into malonyl-CoA increases the acidity of α-hydrogens, providing a
better nucleophile for the Claisen condensation, thus, the carboxyl group introduced into malonyl-CoA is
simultaneously lost by a decarboxylation reaction during the Claisen condensation. (Dewick 2002). Figure 7.1,
illustrates part of the acetate malonate pathway from where many of anthraquinones, xanthones, anthrones
and some other derivatives, found in Vismia species, are biosynthesized.
Fig. 7.1 Acetate malonate pathway (Dewick 2002, Marcano and Hasegawa 2002).
Shikimate pathway
This pathway is considered one of the most important ways, used by plants, to produce a variety of
compounds, such as aromatic amino acids, benzoic acids, cinnamic acids, lignans, lignins, phenylpropenes,
coumarins, flavonoids and stilbenes. It begins with a coupling of phosphoenolpyruvate (PEP) and
D-erythrose-4-phosphate to give 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP).
Elimination of phosphoric acid from DAHP followed by an intramolecular aldol reaction generates
3-dehydroquinic acid. Dehydration and reduction of 3-dehydroquinic acid leads to shikimic acid. A
further molecule of PEP combines with shikimic acid 3-phosphate giving 3-enolpyruvylshikimic acid
3-phosphate (EPSP). 1,4-elimination of phosphoric acid leads to chorismic acid that is transformed into
prephenic acid by the enzyme chorismate mutase. Decarboxylative aromatization of prephenic acid yields
phenylpyruvic acid. Transamination of 4-hydroxyphenylpyruvic acid subsequently gives L-tyrosine and
L-phenylalanine, precursors of a wide range of natural products (Dewick 2002). Figure 7.2, partially
illustrates the shikimate pathway.
Vismia genus produces a majority of secondary metabolites through a combination of acetate and
shikimate pathways exhibiting aromatic structures like anthrones, anthraquinones, xanthones, flavonoids,
lignans, among others. Figures 7.3 to 7.19 show examples of isolated compounds from different Vismia
species (Hussain et al. 2012, Vizcaya et al. 2012).
Mevalonate pathway
Terpenoids are considered a large and diverse family of natural products derived from isoprene units
(C5), mainly joined through the head to the tail. These are classified, according to the number of isoprene
units incorporated, as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20),
sesterterpenes (C25), triterpenes (C30) and tetraterpenes (C40) (Dewick 2002, Marcano and Hasegawa 2002).
The biosynthesis begins with formation of two reactive units, dimethylallyl diphosphate (DMAPP)
and isopentenyl diphosphate (IPP), these are hemiterpene intermediates leading to more complex terpenoid
structures. Combination of DMAPP and IPP yields geranyl diphosphate (GPP). The resulting compounds
of this combination may be hydrocarbons, alcohols, aldehydes and esters. Addition of a further IPP unit
to geranyl diphosphate leads to farnesyl diphosphate (FPP), a sesquiterpene precursor. Diterpenes arise
from geranylgeranyl diphosphate (GGPP), which is formed by the addition of a further IPP molecule
to farnesyl diphosphate in the same manner as described before. However, triterpenes are not formed by
an extension of another IPP unit, instead, two molecules of farnesyl IPP are joined from tail to tail to
yield the hydrocarbon squalene that is a precursor of triterpenes and steroids. Figure 7.20, illustrates the
mevalonate pathway that produces the huge family of terpenoids and steroids (Dewick 2002, Marcano
and Hasegawa 2002).
Studies carried out on different Vismia species have reported a number of terpenes, especially
triterpenes, although, some sesquiterpenes have also been identified (Hussain et al. 2012, Vizcaya et al.
2012). Figures 7.21 to 7.23 show examples of sesquiterpenes and triterpenes isolated from several Vismia
species.
Studies on different biological activities conducted on species of Vismia

genus in the last twenty years
Plant extracts are considered an important source of secondary metabolites and are the starting point to
the new drugs discovery with possible therapeutic activities. In this regard, phytochemical specialized
laboratories have established preliminary biological screenings that allow obtaining rapid results, at low
costs, to acknowledge if the extract under investigation has the required activity (Rahman et al. 2001,
Marcano and Hasegawa 2002).
Furthermore, biological screening allows knowing the effect of heterogeneous samples such as
extracts as well as pure isolated compounds under specific and controlled experimental conditions. Such
studies are carried out in vivo (experimental animals, bacteria, fungus, among others) and in vitro (isolated
Fig. 7.2 Shikimate Pathway (Dewick 2002, Marcano and Hasegawa 2002).
Fig. 7.3 Anthraquinones isolated from different species of Vismia genus.



Fig. 7.6 Anthrones isolated from different species of Vismia genus.
Fig. 7.7 Anthrones isolated from different species of Vismia genus.

Fig. 7.8 Xanthones isolated from different species of Vismia genus.


Fig. 7.12 Cadensins isolated from different species of Vismia genus.
Fig. 7.13 Benzophenones isolated from different species of Vismia genus.


Fig. 7.16 Prenylated anthranoids isolated from different species of Vismia genus.
Fig. 7.17 Prenylated anthranoids isolated from different species of Vismia genus.
Fig. 7.18 Flavonoids and coumarins isolated from different species of Vismia genus.
Fig. 7.19 Lignans isolated from different species of Vismia genus.

Fig. 7.20 Mevalonate pathway (Dewick 2002, Marcano and Hasegawa 2002).
Fig. 7.21 Sesquiterpenes isolated from several Vismia especies.

Fig. 7.22 Triterpenes isolated from several Vismia especies.
Fig. 7.23 Triterpenes isolated from several Vismia especies.

organs, cells, enzymes and receptors). Different parameters are evaluated, such as; growth inhibition,
reproduction, morphological, physiological and histological changes (Rahman et al. 2001). Tables 7.2
to 7.10 describe in detail a variety of biological studies, carried out in several species of Vismia genus,
reported in the last 20 years.
Comparative analysis of secondary metabolites and biological activities

studied on species of Vismia genus
The interest for the study of Vismia genus dates back approximately 25 years, when the researcher, Delle
Monache along with his investigation group reported the first study on Vismia baccifera var. ferruginea.
In this investigation, several metabolites were isolated, such as prenylated anthranoids like harunganin
(78), ferruginin A (76) and B (75) (Delle Monache et al. 1979). The same research group reported five
years later, on an anthraquinone derivative called γ-hydroxyanthrone A3 (21), isolated and purified from
Vismia guaramirangae (Delle Monache et al. 1983).
To date, at least 161 secondary metabolites have been reported for different species of Vismia genus,
exhibiting a variety of structures. It is important to state that the majority of compounds have been described
for Vismia guineensis, V. guaramirangae and V. laurentii. Figure 7.24 shows the diversity of components
isolated from different Vismia species, standing out of 42 anthraquinones (Hussain et al. 2012, Vizcaya et
al. 2012), vismiaquinone A (1), B (2) and C (5) (Goncalves and Mors 1981, Miraglia et al. 1981, Nagem
and Faria D’ Jesús 1990, Nagen and Faustino 1997, Hussein et al. 2003, Nguemeving et al. 2006, Salas et
al. 2008, Vizcaya et al. 2012) being the most commonly isolated, as well as laurentiquinone A (3), B (4)
and C (6) (Nguemeving et al. 2006, Noungoue et al. 2008).
Furthermore, a significant number of xanthones have also been isolated, such as 1,4,8-trihydroxyxanthone
(27), euxanthone (28), 6-deoxyjacareubin (29), 1-hydroxy-3,6-dimethoxy-8-methyl-9h-xanthen-9-one
(33), among others (Dos Santos et al. 2000, Nguemeving et al. 2006, Tamokou et al. 2009, Buitrago et
al. 2010, Vizcaya et al. 2012). Compounds found in minor proportions like anthrones, bianthrones (Delle
Monache et al. 1979, Gonzales et al. 1980, Delle Monache et al. 1983, Nagem and Faria D’Jesús 1990,
Nagem and Alves 1995, Politi et al. 2004, Nguemeving et al. 2006, Hussain et al. 2012, Vizcaya et al.
2012), prenylated anthranoids (Gonzales et al. 1980, Hussein et al. 2003, Mbwambo et al. 2004, Politi et
al. 2004) and benzophenones (Delle Monache et al. 1980, Camelle et al. 1982, Delle Monache et al. 1983,
Fuller et al. 1999, Seo et al. 2000, Chilpa and Huerta 2009), have also been isolated.
Terpenes are other types of components present in Vismia species but in low concentrations, such as
triterpenes like, stigmasterol (105), lupeol (104), fridelin (110) and fridelane (113), the most commonly
isolated (Gonzales et al. 1980, Miraglia et al. 1981, Camelle et al. 1982, Nagem and Faria D’ Jesús 1990,
Nagen and Faustino 1997, Nguemeving et al. 2006, Kuete et al. 2007, Salas et al. 2008, Tamokou et al.
2009, Vizcaya et al. 2012), similarly, sesquiterpenes such as humulene (98), α-selinene (99), β-selinene
(100) and β-caryophyllene (101) have been identified in essential oils studied from several Vismia species
(Camelle et al. 1982, Botta et al. 1983, Buitrago et al. 2009, Rojas et al. 2011a, Rojas et al. 2011b, Vizcaya
et al. 2014, Buitrago et al. 2015).
Other compounds isolated from this genus are flavonois; kaempherol (93), quercetin (92), orientin
(87), lutonaretin (88); coumarins such as vismiaguianin (91) and B (89) reported for Vismia guiannensis
(Camelle et al. 1982, Botta et al. 1983, Nagem and Alves 1995, Nagen and Faustino 1997, Seo et al. 2000,
Politi et al. 2004, Nguemeving et al. 2006, Kuete et al. 2007) and lignans like sesamin (95) commonly
found in different Vismia species (Salas et al. 2008, Vizcaya et al. 2012).
There are around 31 investigations published in different areas regarding biological activities, with
antimicrobial and antioxidant being the most commonly reported mainly for Vismia guianensis, V. laurentii
and V. baccifera var. dealbata. Figures 7.25 and 7.26, displays biological activities carried out during the
last 20 years in extracts, essential oils and pure isolated compounds obtained from different Vismia species.
Concerning antimicrobial activity, an anthraquinone named fiscion isolated from Vismia rubescens
showed activity against Staphylococcus aureus, Pseudomonas aeruginosa, Candida parapsilosis and
Cryptococcus neoformans with MIC values of 7 µg/mL (Tamokou et al. 2009). Similarly, compounds like
1,8-dihydroxy-6-methoxy-3-methylanthraquinone (7) and 6-deoxyisojacareubin (29) isolated from Vismia
Table 7.2 Antimicrobial activity reported for essential oils obtained from Vismia species.
Botanical name Part of the plant Location Compounds Activity References

Vismia macrophylla Essential oil from leaves Venezuela Leaves: Leaves: Buitrago et al. 2015
and fruits γ-bisabolene (44.4%) S. aureus (150 μL/mL)
β-bisabolol (14.9%) E. faecalis (250 μL/mL)
Fruits: E. coli (740 μL/mL)
γ-bisabolene (22.3%) Fruits:
germacrene-D (12.1%) S. aureus (100 μL/mL)
δ-cadinene (10.7%) E. faecalis (500 μL/mL)
C. albicans (600 μL/mL)
C. krusei (600 μL/mL)
Vismia baccifera Essential oil from bark Venezuela caryophyllene oxyde (31.4%), C. tropicalis (1000 μg/mL) Vizcaya et al. 2014
β-caryophyllene (26.4%), C. parapsilosis (1000 μg/mL)
α-zingibirene (12.6%) C. neoformans (1000 μg/mL)
C. krusei (1.6 μg/mL)
C. glabrata (200 μg/mL)
Vismia guianensis Essential oil from fruits Africa β-caryophyllene (25.8%), B. cereus (10 µL/mL) Silvestre et al. 2012
α-copaene (13.1%) S. aureus (10 µL/mL)

δ-cadinene (11.6%) S. epidermidis (10 µL/mL)
S. lentus (10 µL/mL)
V. alginolyticus (100 µL/mL)
Vismia guianensis Leaves Venezuela Methanolic extract (M) E. coli M, DA (1 mg/mL) Nuñez et al. 2013
Dichlorometane/ethyl acetate extract (DA) K. pneumoniae DA (1mg/mL)
Table 7.3 Antimicrobial activity reported for isolated compounds from Vismia species.
Botanical name Part of the Location Compounds Activity References

plant
Vismia laurentii Leaves Camerun laurentixanthone C (43) 43: C. fusca Tala et al.
vismiaquinone A (2) MIC: 5 mg/mL 2007
bisvismiaquinone (24) B. megaterium
dammaradienol (107) MIC: 1 mg/mL.
Vismia laurentii Seeds Camerun laurenquinone A (3) laurenquinone 3, 8, 22 Wabo et al.
B (4) C. fusca 2007
xanthone V1 (46) MIC: 1 mg/mL
physcion (8) 46: B. megaterium
3-geranyloxyemodin anthrone (22), MIC: 1 mg/mL
friedelin (110)
Vismia baccifera Aerial parts Venezuela sesamin (95) E. faecalis Salas et al.
subsp. dealbata friedelin (110) 95 (2 mg/mL) 2007a
vismiaquinone A (2) 110 (4 mg/mL)
2 (4 mg/mL)
P. aeruginosa
95 (4 mg/mL)
110 (5 mg/mL)
Table 7.4 Antiinflammatory and antinoniceptive activities reported for extracts obtained from Vismia species.
Botanical name Part of the Location Extracts Activity References

plant
Vismia Leaves Brazil Hexane Concentrations of 100, 200 and 400 Ferreira et al.
guianensis Extract mg/Kg decreased 8 times the induced 2015
abdominal contortions (IAC) by
intraperitoneal injection of acetic acid in
mice in comparison to reference solution,
Indomethacin (15 mg/kg)
Biphasic analgesic activity model
(noniceptive and inflammatory).
Concentrations of 100, 200 and 400 mg/
kg, significantly diminished both phases
of pain when compared to the control
group
Vismia baccifera Leaves Venezuela Aqueous Acute toxicity (AT) was measured Salas et al.
subsp. dealbata Extract through the raised paw sign in mice. 2007b
Extract and control solution were
administrated by intraperitoneal injection.
Concentration of 420 mg/Kg lacked
of any lethal or abnormal behavior on
experimental animals
Pain was induced by applying thermal
stimuli at mice tails. Analgesic activity
was observed after 30 minutes of extract
administration, at concentration of 210
mg/kg and it was comparable to the
control, acetylsalicylic acid
laurentii, caused growth inhibition of Bacillus subtilis and Bacillus stearothermophilus at concentration
of 1.22 µg/mL (Kuete et al. 2007).
Essential oils obtained from several Vismia species like Vismia macrophylla, V. baccifera var. dealbata
and V. guianensis, composed mainly by a mixture of volatile type components such as monoterpenes and
Table 7.5 Cardiotonic activity reported for extracts obtained from Vismia species.
Botanical name Part of the Location Extracts Activity References

Plant
Vismia Leaves Brazil Ethanolic Hypotensive effect on adult mice Gomes et al. 2009
reichardtiana Extract (blood pressure 93.1 ± 3.8 mmHg)
Intravenous administration of extract at
concentrations between 0.5 to 30 mg/Kg
Reference drug:
Acetylcholine (Ach)
Noradrenaline (Nor)
0.5 μg/kg
Atropine (Atr)
1 mg/kg
Extract showed hypotensive effect
(13.8 ± 3.7 mmHg),
at concentration of
20 mg/kg, compared to Nor
(13.2 ± 3.3 mmHg)
Table 7.6 Antioxidant activity reported for extracts and isolated compounds obtained from Vismia species.
Botanical name Part Location Extracts/compounds Activity References

of the
plant
Vismia baccifera Leaves Venezuela Methanol extracts DPPH: Buitrago et al.
VB (V. baccifera) VB (IC50: 5.50 µg mL–1) 2016
VM (V. macrophylla) Folin-Ciocalteu:
VB 306.21 mg Eq AG/g Ext
Flavonoids content
VB 267.07 mg Eq Que/g Ext
Vismia DPPH:
macrophylla VM (IC50: 5.87 µg mL–1)
Folin-Ciocalteu:
VM 391.28 mg Eq AG/g Ext
Flavonoids content
VM 185.90 mg Eq Que/g Ext
Vismia Fruits Brazil Essential Oil Antioxidant activity by Silvestre et al.
guianensis emulsion discoloration of 2012
β-carotene (yellow color).
Reference: Trolox (Trx).
At concentration of 100 µL,
the essential oil showed 70%
of inhibition comparing to Trx
(60%)
Vismia Stems Cameroon friedelin (110) Extract Tala et al. 2011
rubescens friedelanol (112) IC50: 2.18 µg mL–1
lupeol (104) Compounds:
1,7-dihydroxyxanthone (4) 27 (IC50: 1.96 µg mL–1)
1,4,8-trihydroxyxanthone 32 (IC50: 1.73 µg mL–1)
(27) Reference drug
1,2,8-trihydroxyxanthone Ascorbic acid
(32) (IC50: 1.86 μg/mL)
physcion (8)
sesquiterpenes, showed a wide range of activity against several bacteria strains such as Staphylococcus
aureus at MIC values between 10 to 100 µL/mL (Silvestre et al. 2012, Buitrago et al. 2015); Escherichia
Table 7.7 Antioxidant activity reported for extracts and isolated compounds obtained from Vismia species.
Botanical name Part of the Location Extracts/compounds Activity References

plant
Vismia baccifera subsp. Fruits Colombia Petroleum ether Total Phenols: Petroleum Álvarez et al.
ferruginea Ethyl acetate ether 2009
Methanol 78.33 mg AG/g Ext
Ethyl acetate
350.56 mg AG/g Ext
Methanol
177.22 mg AG/g Ext
DPPH: IC50: 4.46 µg mL–1
ABTS: IC50: 4.16 µg mL–1
Vismia guianensis Total Phenols: Ethyl
acetate
356.67 mg AG/g Ext
Methanol
186.67 mg AG/g Ext
Petroleum ether
205 mg AG/g Ext
DPPH: IC50: 3.72 µg mL–1
ABTS: IC50: 5.86 µg mL–1
Vismia laurentii Seeds Cameroon laurenquinone A (3) Extract: Tala et al. 2011
laurenquinone B (4) (IC50: 2.57 µg mL–1)
xanthone V1 (46) Compounds
laurentixanthone C (43) 3 (IC50: 4.78 µg mL–1)
bivismiaquinone (24) 46 (IC50: 2.09 µg mL–1)
vismiaquinone A (2) 1 (IC50: 2.09 µg mL–1)
vismiaquinone B (1)
Table 7.8 Parasiticide activity reported for extracts and isolated compounds obtained from Vismia species.
Botanical name Part of Location Extracts/compounds Activity References

the plant
Vismia laurentii Bark Camerun Hexane extract (HE) Activity against Noungoue
Ethyl acetate extract (EAE) Plasmodium falciparum et al. 2009
Compounds: Reference drug
Tirucalla-7,2,4-dien-3-one Chloroquine phosphate
(108), 3-geranyloxyemodin 1 µM
(22), vismiaquinone A HE: IC50 4.6 μg/mL
(2), vismiaquinone B (1), EAE: IC50 4.6 μg/mL
bivismiaquinone (24), 108: IC50 1.18 μg/mL
epyfriedelinol (112), 2: IC50 1.42 μg/mL
betulinic acid (111)
stigmasta-7,22-dien-3-ol (106)
Vismia baccifera Leaves Colombia Ethanol In vitro activity against Gallego et
subsp. ferruginea Extract promastigotes and al. 2006
amastigotes of T. cruzi,
L. amazonensis,
L. donovani and
L. brazilensis
IC50: 42.9 to 71.7 mg/mL
coli (MIC: 740 μL/mL) and Enterococcus faecalis (MIC: 500 μL/mL), as well as yeasts like Candida
albicans (MIC: 600 μL/mL), C. krusei (MIC: 600 μL/mL) and C. glabrata (MIC: 200 μg/mL).
On the other hand, the search for natural sources with antioxidant activity has caught the attention
of scientists since oxidative stress in cells might promote several pathologies such as cancer, diabetes
mellitus, hepatic ailments, inflammation, premature aging, among others (Sarabjot and Poonam 2014).
Table 7.9 Anti-VIH activity reported for extracts and isolated compounds from Vismia species.
Botanical Part of the Location Extracts/ Activity References

name plant compounds
Vismia Leaves Mexico Dichloromethane/ VIH Reverse transcriptase Gómez-Cansino
mexicana Methanol (1:1) Positive control: Nevirapina® et al. 2015
Enzyme inhibition
Vm IC50 36.17 µg mL–1
Vismia Vb IC50 31.75 µg mL–1
baccifera
Vismia Leaves Mexico Dichloromethane/ VIH Reverse transcriptase Huerta-Reyes et
mexicana Metanol (1:1) Inhibition of viral replication al. 2004
At concentration of 50 µg/mL
Vm: IC50 72.9%
Vismia Vc, IC50 70.8%
camparaguey
Table 7.10 Anticancer activitity reported for extracts and isolated compounds from Vismia species.
Botanical Part of Location Extracts/compounds Activity References

name the plant
Vismia Leaves Colombia Aqueous Extract Anticancer activity on Lizcano et
baccifera human hepatocellular al. 2015
carcinoma
HepG2,
PLC/PRF/5
SK-HEP-1
Vb (19 µg/mL) showed
selective growth inhibition of
HepG2
Vismia baccifera Leaves Venezuela Sesamin (95) Anticancer activity on Salas et al.
subsp. dealbata SK-OV-3 2008
PC3
NCI-H292
At concentration of
IC50: 1000 mg/mL, sesamin
showed growth inhibition of
NCI-H292
Vismia baccifera Leaves Venezuela Different polarity fractions Cytotoxic activity (IC50) Rojas et al.
obtained from methanolic Vb: 2017
Vismia extracts: PC3: 2.92 µg/mL DCl
macrophylla Hexane (Hex) HeLa: 28.81 µg/mL Hex
Dichloromethane (DCl) Vm:
Ethyl Acetate (EthAc) MCF-7: 36.25 µg/mL Wt
Buthanol (But) SKBr3: 12.14 µg/mL Wt
Water (Wt) PC3: 10.91 µg/mL Wt
Ethyl Acetate/Buthanol HeLa: 6.09 µg/mL Hex
(EthAc/But)
Plant extracts have revealed to be a major source of chemical compounds with high antioxidant activity
and several assays; Folin-Ciocalteu, DPPH● and ABTS·+, among others, have been carried out in extracts
of Vismia rubescens, V. laurentii, V. baccifera ssp. ferruginea and V. guianensis and showed free radical
scavenger activity at concentrations between 4.46 to 2.18 µg/mL (Álvarez et al. 2009, Tala et al. 2011,
Silvestre et al. 2012).
Antioxidant activity has also been demonstrated in methanolic extracts of Vismia baccifera and
V. macrophylla, at IC50 values of 5.87 and 5.35 µg/mL, respectively (Buitrago et al. 2016). Isolated
Fig. 7.24 Secondary metabolites isolated from different Vismia species
Fig. 7.25 Biological activity assays reported for Vismia species in the last 20 years.
compounds; 1,4,8-trihydroxyxanthone (27) and 1,2,8-trihydroxyxanthone (32), from Vismia rubescens,

also showed free radical scavenger at IC50 of 1.96 µg/mL and 1.73 µg/mL, respectively (Tala et al. 2011).
Cardiotonic, hypotensive, noniceptive, analgesic and anti-VIH activitites has also been published for
Vismia genus. Regarding cardiotonic and hypontesive activitites, intravenous administration of Vismia
reichardtiana leaves extract at concentrations between 0.5 to 30 mg/Kg caused hypotensive effect on adult
mice comparable to the reference drugs noradrenaline® and acetylcholine® (Gomes et al. 2009). Analgesic
activity of hexanic extract of Vismia guianensis leaves was assayed in vivo in experimental animals; results
showed a decrease in pain threshold after oral administration of such extract at concentrations between
Fig. 7.26 Biological activity assays reported for different Vismia species.
100 to 400 mg/kg of animal weight (Ferreira et al. 2015). V. mexicana and V. baccifera were studied for
VIH reverse transcriptase activity, revealing inhibition of viral replication at concentration of 35 µg/mL
(Gómez-Cansino et al. 2015).
Conclusions
According to investigations published for Vismia genus, it might represent a source of natural compounds
with a wide range of biological activities. Nowdays, there is a huge interest for the search of new active
molecules that might be used to develop pharmaceutical forms for the treatment of diverse pathologies.
However, it is very important to bear in mind that natural products come from plants and excessive,
disproportionate use of these may cause the extinction of vulnerable species, thus, it is necessary to promote
the protection and conservation of natural resources focused in sustainable conditions.
References
Álvarez, E., Jímenez, J.G., Posada, M.A., Rojano, B., Gil, J.H., García, C.M. and Durango, D.L. 2008. Actividad antioxidante
y contenido fenólico de los extractos provenientes de las bayas de dos especies del género Vismia (Guttiferae). VITAE,
Revista de La Facultad de Química Farmacéutica 15(1): 165–172.
Angiosperm Phylogeny Group. 2009. An update of the Angiosperm Phylogeny Group classification for the orders and families
of flowering plants: APG III. Bot. J. Linn. Soc. 161(2): 105–121.
Bilia, A.R., Yusuf, A.W., Braca, A., Keita, A. and Morelli, I. 2000. New prenylated anthraquinones and xanthones from Vismia
guineensis. J. Nat. Prod. 63: 16–21.
Botta, B., Delle Monache, G., Delle Monache, F., Bettolo, M. and Oguakwa, U. 1983. 3-geranyloxy-6-methyl-1,8-dihydroxy
anthraquinone and Vismiones C, D and E from Psorospermum febrifugum. Phytochem. 22: 539–542.
Botta, B., Delle Monache, F., Delle Monache, G., Bettolo, M. and Menichini, F. 1986. Vismione H and prenilated Xanthones
from Vismia guineensis. Phytochem. 25: 1217–1219.
Buitrago, A., Rojas, L.B., Rojas, J., Buitrago, D., Usubillaga, A. and Morales, A. 2009. Comparative study of the chemical
composition of the essential oil of Vismia baccifera var. dealbata (Guttiferae) collected in two different locations in
Merida-Venezuela. J. Essent. Oil Bear Pl. 12(6): 651–655.
Buitrago, A., Rojas, J., Cote, V., Bruno-Colmenárez, J. and Díaz de Delgado, G. 2010. NMR elucidation and crystal structure
analysis of 1-hydroxy-3,6-dimethoxy-8-methyl-9h-xanthen-9-one (lichexanthone) isolated from Vismia baccifera
(Guttiferae). BLACPMA 9(6): 470–474.
Buitrago, A., Rojas, J., Rojas, L., Velasco, J., Morales, A., Peñaloza, Y. and Díaz, C. 2015. Essential oil composition and
antimicrobial activity of Vismia macrophylla leaves and fruits collected in Táchira-Venezuela. Nat. Prod. Commun.
10(2): 375–377.
Buitrago, A., Rojas, J., Rojas, L. and Peñaloza, Y. 2016. In Vitro antioxidant activity and qualitative phytochemical analysis
of two Vismia (Hypericaceae) species collected in Los Andes, Venezuela. Rev. Biol. Trop. 6(4): 1431–1439.
Camelle, G., Delle Monache, F., Delle Monache, G., Martini Bettolo, B. and Alves de Lima, R. 1982. 2-isoprenylemodin and
5,5´-dimethoxysesamin from Vismia guaramirangae. Phytochem. 21: 417–419.
Cardona, L., Fernández, I., Pedro, J., Seoane, E. and Vidal, R. 1986. Additional new xanthones and xanthonolignoids from
Hypericum canariensis. J. Nat. Prod. 49: 95–100.
Chilpa, R. and Reyes, M. 2009. Compuestos naturales de plantas de la familia Clusiaceae: Inhibidores del virus de
inmunodeficienciaia humana tipo 1. Interciencia 34: 385–392.
Crocketta, S.L. and Robson, N.K. 2011. Taxonomy and chemotaxonomy of the genus Hypericum. Med. Aromat Plant Sci.
Biotechnol. 5(1): 1–13.
Delle Monache, F., Marquina, M., Ferrari, F. and Martini-Bettolo, G. 1979. Ferruginin A and B and Ferruanthrone, New
triprenylated anthranoids from Vismia baccifera var. ferruginea. Tetrahedrom. 35: 2143–2149.
Delle Monache, G., Gonzales, J., Delle Monache, F. and Marini, G. 1980. Prenylated benzophenones from Vismia decipiens.
Phytochem. 19: 2025–2028.
Delle Monache, F., Marquina Mac-Quhae, M., Delle Monache, G., Marini, G. and Alves de Lima, R. 1983. Xanthones,
xanthololignoids and others constituents of the roots of Vismia guaramirangae. Phytochem. 22: 227–232.
Dewick, P.M. 2002. The biosynthesis of C5–C25 terpenoid compounds. Nat. Prod. Rep. 19: 181–222.
Doriguetto, A., Santos, M., Ellena, J. and Nagen, T. 2001. 6-deoxyjacareubin. Acta Crystallogr C 57: 109–1079.
Dos Santos, M., Nagem, T., Da Silva, M. and Silva, L. 2000. Xanthones from Vismia latifolia. J. Braz. Chem. Soc. 11: 537–539.
Epifano, F., Genovese, S., Menghini, L. and Curini, M. 2007. Chemistry and pharmacology of oxyprenylated secondary plant
metabolites. Phytochem. 68: 939–953.
Fuller, R., Westergaard, C., Collins, J., Cardellina, J. and Boyd, M. 1999. Vismiaphenones D-G from Vismia cayennensis.
J. Nat. Prod. 62: 57–69.
Ferreira Nobre, V., Marchesine Almeida, D.M., Lucchese, A.M., Lopes Rocha, M., Santos Oliveira, A.T. and Maia Barboza,
A.C. 2015. Antinociceptive and anti-inflammatory activity of hexanic extract leaves of Vismia guianensis Aubl. in mice.
Revista de Ciências Médicas e Biológicas 14(1): 69–73.
Gallego, A., Torres, F., Robledo, S., Vélez, I.D., Carrillo, L., Muñoz, D.L., Quiñones, W., Fonnegra, R., Roldán, J., Valencia,
L., Triana, O. and Echeverri, F. 2006. Actividad leishmanicida y tripanocida de Acacia farnesiana, Piper arieianum,
Piper Subpedale, Sphagnum recurvum y Vismia baccifera ferruginea. Actualidades Biológicas 28: 39–49.
Gómez-Cansino, R., Espitia-Pinzón, C.I., Campos-Lara, M.G., Guzmán-Gutiérrez, S.L., Segura-Salinas, E., Echeverría-
Valencia, G., Torras-Claveria, L., Cuevas-Figueroa, X.M. and Reyes-Chilpa, R. 2015. Antimycobacterial and HIV-1
Reverse transcriptase activity of Julianaceae and Clusiaceae plant species from Mexico. J. Evid. Based Complementary
Altern. Med. 2015: 1–8.
Gomes, M.J.N., Silva, S.N., Ribeiro, R.M., Abreu, I.C., Borges, R.M.O. and Borges, R.A.C. 2009. Screening farmacológico
das folhas de Vismia reichardtiana (O. Ktze) Ewan-Guttiferae. Revista Cadernos de Pesquisa 16(1): 5–10.
Goncalves, M. and Mors, W. 1981. Vismiaquinone A. δ-isopentenyl substituted anthraquinone from Vismia reirchartiana.
Phytochem. 20: 1947–1950.
Gonzales, J., Delle Monache, F., Delle Monache, G. and Marini Bettolo, G.B. 1980. Chemistry of the genus Vismia. VII.
Vismione A from the leaves of Vismia guianensis. Plant Med. 40: 347–350.
Goossens, A., Häkkinen, S., Laakso, I., Seppänen Laakso, T., Biondi, S, De Sutter, V., Lammertyn, F., Nuutila, A.M., Söderlund,
H., Zabeau, M., Inze, D. and Oksman-Caldentey, K. 2003. A functional genomics approach toward the understanding
of secondary metabolism in plant cells. Proc. Natl. Acad. Sci. 100: 8595–8600.
Hokche, O., Berry, P.E. and Huber, O. 2008. Nuevo catálogo de la flora vascular de Venezuela. Caracas, Venezuela: Ediciones
Fundación Instituto Botánico de Venezuela “Dr. Tobías Lasser”.
Huerta-Reyes, M., Basualdo, M.C., Lozada, L., Jiménez-Estrada, M., Soler, C. and Reyes-Chilpa, R. 2004. HIV-1 inhibition
by extracts of Clusiaceae species from México. Chem. Pharm. Bull. 27: 916–920.
Hussain, H., Hussain, J., Al-Harrasi, A., Saleem, M., Green, I.R., van Ree, T. and Ghulam, A. 2012. Chemistry and biology
of genus Vismia. Pharm. Biol. 50(11): 1448–1462.
Hussein, A., Bozzi, B., Correa, N., Capson, T., Kursar, T., Coley, P., Solis, P. and Gupta, M. 2003. Bioactive constituents from
three Vismia species. J. Nat. Prod. 66: 858–860.
Kuete, V., Nguemeving, J., Beng, V., Azebaze, A., Etoa, F., Meyer, M., Bodo, B and Nkengfack, A. 2007. Antimicrobial activity
of the methanolic extracts and compounds from Vismia laurentii De Wild (Guttiferae). J. Ethnopharmacol. 109: 372–379.
Lizcano, L.J., Siles, M., Trepiana, J., Hernández, M.L., Navarro, R.M., Ruiz-Larrea, B. and Ruiz-Sanz, J.I. 2015. Piper and
Vismia species from Colombian Amazonia differentially affect cell proliferation of hepatocarcinoma cells. Nutrients
7: 179–195.
Marcano, D. and Hasegawa, M. 2002. Fitoquímica orgánica. Caracas, Venezuela: Ediciones Vicerrectorado Académico UCV.
Mbaveng, A.T., Kuete, V., Nguemeving, J.R., Penlap Beng, V., Nkengfack, A. E., Marion Meyer, J.J., Lall, N. and Krohn,
K. 2008. Antimicrobial activity of the extracts and compounds obtained from Vismia guineensis (Guttiferae). Asian J.
Tradit. Med. 3(6): 211–223.
Mbwambo, Z.H., Apers, S., Moshi, M.J., Kapingu, M.C., Van Miert, S., Claeys, M., Brun, R., Cos, P., Pieters, L. and Vlietinck,
A. 2004. Anthranoid compounds with antiprotozoal activity from Vismia orientalis. Plant Med. 70(8): 706–710.
Miraglia, M., Mesquita, A., Varejáo, M., Gottlieb, O. and Gottlieb, H. 1981. Anthraquinones from Vismia species. Phytochem.
20: 2041–2042.
Nagem, J. and Faria de Jesús, T. 1990. Quinoids and other constituents of Vismia martiana. Phytochem. 29: 3362–3364.
Nagem, T.J. and Ferreira, M.A. 1993. Constituents of Vismia micrantha. Fitoterapia 64: 382–383.
Nagem, T. and Alves, V. 1995. Constituents of Vismia magnoliaefolia. Fitoterapia 56(3): 278–280.
Nagen, J. and Faustino, F. 1997. Xanthones and other constituents of Vismia parviflora. J. Brazil. Chem. Soc. 8: 505–508.
Nguemeving, J., Azebaze, A., Kuete, V., Carly, N., Beng, P., Meyer, M., Blond, A., Bodo, B. and Nkengfack, A. 2006.
Laurentixanthones A and B, antimicrobial xanthones from Vismia laurentii. Phytochem. 67: 1341–1346.
Noungoue, D., Antheaume, C., Chaabi, M., Ndjakou, B., Ngoule, S., Lobstein, A. and Tsamo, E. 2008. Anthraquinones from
the fruits of Vismia laurentii. Phytochem. 69: 1024–1028.
Noungoue, D.T., Chaabi, M., Ngouela, S., Antheaume, C., Boyom, F.F., Gut, J., Rosenthal, P.J., Lobstein, A. and Tsamo, E.
2009. Antimalarial compounds from the stem bark of Vismia laurentii. Z. Naturforsch. C. 64c: 210–214.
Nuñez, R., Rojas J., Lucena, M., Roa, A. and Meléndez P. 2013. Evaluación de la actividad antibacteriana y efecto citotóxico
de extractos obtenidos de la especie Vismia guianensis (Aubl.) Pers. (Hypericaceae). Revista de la Facultad de Farmacia
55(2): 29–34.
Nürk, N.M., Madriñán, S., Carine, M.A., Chase, M.W. and Blattner, F.R. 2013. Molecular phylogenetics and morphological
evolution of St. John’s wort (Hypericum; Hypericaceae). Mol. Phylogenet. Evol. 66(1): 1–16.
Peres, V. and Nagen, T. 1997. Trioxygenated naturally occurring xanthones. Phytochem. 44: 191–214.
Peres, V., Nagen, T. and Faustino, F. 2000. Tetraoxygentaed naturally occurring xanthones. Phytochem. 55: 683–710.
Pinheiro, R., Mac-Quhae, M., Bettolo, M. and Delle Monache, F. 1984. Prenylated antranoids from Vismia species. Phytochem.
23: 1737–1740.
Politi, M., Sanogo, R., Ndjoko, K., Guilet, D., Wolfender, J.L., Hostettmann, K. and Morelli, I. 2004. HPLC-UV/PAD and
HPLC-MS (n) analyses of leaf and root extracts of Vismia guineensis and isolation and identification of two new
bianthrones. Phytochem. Anal. 15: 355–364.
Rahman, A., Choudhary, M.I. and Thomson W.J. 2001. Bioassay techniques for drug development. New Jersey, United States:
Harwood Academic Publishers.
Rates, S.M.K. 2001. Review. Plants as source of drugs. Toxicon 39: 603–613.
Rojas, J., Buitrago, A., Rojas, L., Morales, A., Lucena, M. and Baldovino, S. 2011a. Essential oil composition and antibacterial
activity of Vismia baccifera fruits collected from Mérida, Venezuela. Nat. Prod. Commun. 6: 699–700.
Rojas, J., Buitrago, A., Rojas, L. and Morales, M. 2011b. Essential oil composition of Vismia macrophylla Leaves (Guttiferae).
Nat. Prod. Commun. 6: 85–86.
Rojas, J.C., Buitrago, A.A., Arvelo, F.A., Sojo, F.J. and Suarez, A.I. 2017. Cytotoxic activity of different polarity fractions
obtained from methanolic extracts of Vismia baccifera and Vismia macrophylla (Hypericaceae) collected in Venezuela.
JPPRes 5: 320–326.
Ruhfel, B., Bittrich, V., Bove, C., Gustafsson, M., Philbrick, C., Rutishauser, R., Xi, Z. and Davis, C. 2011. Phylogeny of the
clusioid clade (Malpighiales): evidence from the plastid and mitochondrial genomes. Am. J. Bot. 98: 306–325.
Salas, F., Velasco, J., Rojas, J. and Morales, A. 2007a. Antibacterial activity of the crude extract and constituents of Vismia
baccifera var. dealbata (Guttiferae) collected in Venezuela. Nat. Prod. Commun. 2(2): 185–188.
Salas, F., Ciangherotti, C., Salazar-Bookaman, M., Rojas, J. and Morales, A. 2007b. Toxicidad aguda y actividad analgésica
del extracto acuoso de hojas de Vismia baccifera L. var. dealbata (Guttiferae) en animales de experimentación. Revista
de la Facultad de Farmacia 49(1): 5–9.
Salas, F., Rojas, J., Morales, A. and Ramos-Nino, M. 2008. In Vitro cytotoxic activity of sesamin isolated from Vismia baccifera
var. dealbata Triana & Planch (Guttiferae) collected from Venezuela. Nat. Prod. Commun. 3: 1705–1708.
Schultes, R. 1993. Plants in treating senile dementia in the northwest Amazon. J. Ethnopharmacol. 38: 139–135.
Seo, E., Wani, M., Wall, M., Navarro, H., Mulkherjee, R., Farnsworth, N. and Kinghorn, D. 2000. New bioactive aromatic
compounds from Vismia guianensis. Phytochem. 55: 35–42.
Silvestre, R.G., de Moraes, M.M., Lins, A.C.S., Ralph, M.T., Lima-Filho, J.V., Camara, C.A. and Silva, T.M.S. 2012. Chemical
composition, antibacterial and antioxidant activities of the essential oil from Vismia guianensis fruits. Afr. J. Biotechnol.
11(41): 9888–9893.
Shilpa, K., Varun, K. and Lakshmi, B.S. 2010. An alternate method of natural drug production: Eliciting secondary metabolite
production using plant cell culture. Journal of Plant Sciences 5: 222–247.
Simmonds, M., Blaney, W., Delle Monache, F., Marquina, M. and Marini Bettolo, G. 1985. Insect antifeedant propiertis of
anthanoids from the genus Vismia. J. Chem. Ecol. 11: 1593–1599.
Stevens, P.F. 2007. Hypericaceae. En K. Kubitzki (Ed), The families and genera of vascular plants: (pp. 194–201). Berlin,
Alemania: Springer Verlag.
Vizcaya, M., Morales, A., Rojas, J. and Nuñez, R. 2012. Revisión bibliográfica sobre la composición química y actividades
farmacológicas del género Vismia (Guttiferae). BLACPMA 11: 12–34.
Vizcaya, M., Pérez, C., Rojas, J., Rojas-Fermín, L., Plaza, C., Morales, A. and Pérez, P. 2014. Composición química y
evaluación de la actividad antifúngica del aceite esencial de corteza de Vismia baccifera var. dealbata. Revista de la
Sociedad Venezolana de Microbiología 34: 86–90.
Tala, M.F., Krohn, K., Hussain, H., Kouam, S.F., Wabo, H.K., Tane, P., Schulzd, B. and Hu, Q. 2007. Laurentixanthone C: A
new antifungal and algicidal xanthone from stem bark of Vismia laurentii. Z. Naturforsch. 62b: 565–568.
Tala, M.F., Tamokou, J.D., Tchakam, P.D., Tane, P., Kuiate, J.R. and Wabo, H.K. 2011. Antioxidant xanthones, anthraquinoes
and semi-synthetic derivatives from Vismia rubescens and Vismia laurentii. Pharmacologyonline 3: 1410–1418.
Tamokou, J., Tala, M., Wabo, H., Kuiate, J. and Tane, P. 2009. Antmicrobial activities of methanol extract and compounds
from stem bark of Vismia rubescens. J. Ethnopharmacol. 124: 571–575.
Tchamo, D., Brelot, M., Antheaume, C., Ngouela, S. and Lobstein, A. 2008. Methyl 5,7–dihydrohy-2, 2,9–trimethyl-6,11–
dihydro-2H –anthra-[2,3-b] pyran -8- carboxylate. Acta Crystallogr. 64: 2414–2415.
Trópicos org. (Estados Unidos). Missouri Botanical Garden [en línea]: catálogo automatizado. [Saint Louis]: Missouri Botanical
Garden. <http://www.tropicos.org/Home.aspx> [Consulta: 28 de abril de 2015].
Wabo, H.K., Kouam, S.F., Krohn, K., Hussain, H., Tala, M.F., Tane, P., Ree, T., Hu, Q. and Schulz, B. 2007. Prenylated
anthraquinones and other constituents from the seeds of Vismia laurentii. Chem. Pharm. Bull. 55:1640–1642.
Wink, M. 2007. Bioprospecting: The search for bioactive lead structures from nature. pp. 97–116. In: Kayser, K. and Quax,
Q. (eds.). Medicinal Plant Biotechnology. From basic research to industrial application. Weinheim, Alemania: Wiley-
VCH Verlag GmbH & Co. KGaA.
8
Curcuma longa L.: From
Ethnomedicinal to Novel Biomedical
Applications
Mahendra Rai,1,* Avinash Ingle,1 Raksha Pandit,1 Priti Paralikar,1
Farkhanda Rehman,1 Netravati Anasane,1 Pramod Ingle1 and
Suneesh Buxy2
Introduction
Turmeric is a medicinal plant, which is also known as “golden spice” and “spice of life”. It has been utilized
as a medicinal plant and treated as sacred from the ancient Vedic period. The spice turmeric is derived
from rhizome of Curcuma longa, which is a perennial herb, belonging to the Zingiber family (Fig. 8.1).
It is originated in India and is cultivated in tropical and subtropical regions of the whole world (Kojima
et al. 1998). Curcumin is the natural, most active polyphenolic compound present in turmeric. Curcumin
is the most studied compound of turmeric because of its therapeutic properties. Curcumin is crystalline,
orange-yellow and the color of turmeric is mainly due to the presence of curcumin in Curcuma longa. The
rhizome of turmeric is documented as “herb of the sun” by the people of the Vedic period. Turmeric was
used as medicine from at least 6000 years ago. It is most extensively cultivated in India, Bangladesh, China
followed by Malaysia, Thailand (Kojima et al. 1998, Shishodia et al. 2005). The use of turmeric, known as
“Haridra” was first time stated in ‘Arthavaveda’ and turmeric has been considered as an effective drug for
skin diseases, graying of hair, etc. Even in Tibetan medicine the term “Haridra” means turmeric (Nadkarni
1976). Turmeric is one of the important spice which add flavors and color to food. In the middle-east, Iran
is a major importer of turmeric. The Food and Agriculture Organization (FAO) of United Nations projected
that approximately 5000 tons of turmeric is imported annually to Iran. The consumption of curcumin is
increasing in Iran (Nadkarni 1976, Asgharil et al. 2009).
By using ethanol and acetone, curcumin can be isolated from turmeric and the chemical analysis of
curcumin comprised of carbohydrates (69.4%), moisture (13.1%), protein (6.3%), fat (5.1%), and minerals
(3.5%). The bioactive components of turmeric is divided into two types: volatile compounds and non-
1
Department of Biotechnology, SGB Amravati University, Amravati-444602, Maharashtra, India.
2
Deputy Inspector General (Research and Training), Ministry of Environment, Forest and Climate Change, Government of
India.
* Corresponding author: mahendrarai@sgbau.ac.in; pmkrai@hotmail.com
Curcuma longa L.: From Ethnomedicinal to Novel Biomedical Applications 137
Fig. 8.1 Turmeric plant.
volatile compounds. Monoterpenoids and sesquiterpenoids, such as germacrone, elemene, furanodiene,

furanodienone, curcumol, curdione, curcumenol, curzerene, camphor, germacrene B, germacrene D,
isocurcumenol, α-phellandrene, sabinene, cineol, borneol, zingiberene, and sesquiterpenes and neocurdione
are different volatile components of Curcuma longa (Asghari et al. 2009, Lu et al. 2012). Essential oil
from Curcuma longa is responsible for its potential biological activities. Curcumin, demethoxycurcumin,
and bisdemethoxycurcumin, are the major non-volatile compounds of Curcuma longa. The concentration
of volatile compounds is more as compared with non-volatile compounds (Fujisawa et al. 2004). It was
reported that essential oil composition, biomass production and curcuminoid composition all are affected
by the cultivation conditions such as growth media, climatic conditions and nutrient availability (Asghari
et al. 2009).
History
Vogel and Pelletier about 200 years ago, defined curcumin as “substance that gives the yellow color”.
The chemical structure was determined by Roughley and Whiting in 1973. The melting point of
curcumin is 176–177°C. In the mid 1900s, curcumin was known as an active component, which exhibited
antimicrobial activity against Staphylococcus aureus, Salmonella paratyphi, Mycobacterium tuberculosis,
and Trichophyton gypseum, etc. In the last 50 years, it was found that curcumin has the potential effect
on various diseases such as diabetes, allergies, arthritis, Alzheimer’s disease, diabetic wounds, hepatic
disorders, rheumatism and sinusitis, cough and biliary disorders (Nanjwade et al. 2015). Curcumin can
also be used in disorders related to abdominal pain, etc. Ethnologically curcumin occupies a major role in
India and it has important position in Indian food. Even in religious ceremonies, the use of turmeric has
importance (Shrishail et al. 2013).
From more than 2500 years, turmeric is known for its medicinal treatment in Asian countries. It is
stated in ‘Ayurveda’ and traditional Chinese medicine that curcumin has many advantages in the prevention
and treatment of many diseases. In old Hindu texts, curcumin is ascribed for its aromatic, carminative,
stimulant properties. When turmeric is mixed with slaked lime, it is used in the treatment of sprains and
swellings caused by injury. Curcumin has many household applications as it can be applied on the locally
affected area of wound infection and other chronic illness (Hermann and Wahl 1991).
In Ayurveda, turmeric is known for its wide range of applications. Curcumin can be used to treat
flatulence, dyspepsia, liver disorders (jaundice in particular), eye and ear infections, small-pox, chicken pox,
common cold, ulcers and inflammation, intermittent fevers, eczema, sprain, bruises, wounds, inflammatory
troubles of joints, small pox, chicken pox, catarrhal and purulent ophthalmic, conjunctivitis, ring worm,
etc. (Hermann et al. 1991, Rai et al. 2015). Curcumin is known to have a cholesterol-lowering capacity,
antidiabetic, anti-inflammatory, and antioxidant properties and to have an anticancer activity. From the
clinical trials with humans, it was determined that curcumin was safe and effective. The Food and Drug
Administration (FDA) acknowledged curcumin as a compound “generally recognized as safe” (Pulido-
Moran et al. 2016).
Derivatives of curcumin
Curcumin is also known as diferuloylmethane and its chemical formula is C21H20O6. Chemical denotation
of curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione]. Curcumin is not soluble in
water at acidic or neutral pH. However, it is soluble in organic solvent such as acetone, methanol, and ethanol.
It is revealed that curcumin is highly sensitive to light and, therefore, it is suggested that biological samples
containing curcumin are to be protected from light (Pulido-Moran et al. 2016). Curcuminoid complexes
are present in the rhizome of turmeric and it comprises of curcumin (Curcumin I), demethoxycurcumin
(Curcumin II) and bisdemethoxycurcumin (Curcumin III). Demethoxycurcumin and bismethoxycurcumin
are the derivatives of curcumin in the rhizome of Curcuma longa, along with curcumin’s two derivatives
present in the rhizome of Curcuma longa. The commercially available curcumin contains Curcumin I
(77%), Curcumin II (17%) and Curcumin III (3%), etc. (Lee et al. 2013). The physicochemical properties
of curcumin and its derivatives are given in the Table 8.1.
Bioactivities of curcumin
Curcuma longa has been attributed to numerous bioactivities including antimicrobial, anticancerous,
antioxidant, anti-inflammatory, etc. During the span of 60 years, more than 3000 studies have been
reported on various bioactivities of curcumin and its existing benefits in medicine for treatment of allergy,
cardiovascular diseases, lung fibrosis, neurodegenerative diseases, inflammatory bowel diseases, arthritis,
etc. (Aggarwal and Harikumar 2009, Chandran and Goel 2012). Some of the bioactivities of curcumin
are illustrated below.
Anti-inflammatory activity
Curcuma longa has been attributed to numerous bioactivities including antimicrobial, anticancerous,
antioxidant, anti-inflammatory, psoriasis, etc. Traditionally, Curcuma longa has been used in anti-
inflammatory treatment in Ayurvedic medicine (Goel et al. 2008). The anti-inflammatory effect of curcumin
was very well reported in clinical as well as experimental studies (Menon and Sudheer 2007, Ferreira et
al. 2015, Zhang et al. 2015, Ma et al. 2017). The anti-inflammatory effect of curcumin is mediated through
enzymes which has the ability to inhibit cyclooxygenase-2 (COX-2), Nitric Oxide Synthase (NOS) and
lipoxygenase (LOX). These enzymes are important for inflammatory processes (Menon and Sudheer 2007,
Aggarwal and Harikumar 2009, Basnet and Skalko-Basnet 2011). Chainani-Wu (2004) reported the study
of anti-inflammatory activity of curcuminoid which is the main constituent of curcumin on humans. The
study revealed that curcumin exerts effective anti-inflammatory activity by inhibiting different molecules
which includes lipoxygenase, tumor necrotic factor, interleukin-12, phospholipase, collagenase and
interferon inducing proteins. Recently, Ullah et al. (2017) reported curcumin as a therapeutic option to limit
neuroinflammation in neurodegenerative disorders. Pharmacokinetic studies of curcumin have provided the
information about the bioavailability of curcumin in targeted tissues which implicate potential therapeutic
effect on neuroinflammation.
Microglia mediated neuroinflammation is an important agent in brain hemorrhage to inflammatory
injury. The study carried out by Yang et al. (2014) showed that curcumin inhibits the inflammatory cytokinine
production in brain hemorrhage induced BV2 microglial cells. Similar studies were also reported by
Cheng et al. (2001), which showed that curcumin inhibits LPS induced neuroinflammation and cytokine
production in BV2 cell line. The study revealed that pretreatment BV2 microglia cells with curcumin
resulted in microglial inflammation reduction and decrease in cytokine production in a dose dependent
manner. Curcumin analogues namely diarylpentadienone have anti-inflammatory activity against LPS
induced interleukin released in RAW264.7 cell (Wang et al. 2017). It was found that curcumin analogues
Table 8.1 Physicochemical properties of curcumin and its derivatives.
Structure Common name Chemical name Molecular mass Melting point Solubility in alcohol/
(g/mol) (°C) acetone
curcumin Di-cinnamoylmethane 368.4 183–186 Soluble
demethoxycurcumin 4-hydroxycinnamoulmethane 338 172–174 Soluble
bismethoxycurcumin Bis-4-hydroxycinnamoylmethane 308 224 Soluble

inhibit interleukin-6 and tumor necrosis factor alpha (TNF-α) which showed the highest inflammatory
activity. The study also indicates that anti-inflammatory activity of curcumin may be due to NF-kB
signaling pathway inhibition. Furthermore, the anti-inflammatory effect of curcumin was also reported
to have significant activity against Helicobacter pylori infection in mucosal disease (Santos et al. 2015).
Curcumin was found to play an important role in respiratory diseases caused by inflammation (Kurup
and Barrios 2008). Studies on acute allergic asthma in mice showed that curcumin can act as an anti-
inflammatory agent by down regulating Notch1-GATA3 signaling pathway (Chong et al. 2014). Curcumin
was also reported as a scavenger of nitric oxide and decreased nitic oxide synthase activity, which could
prevent bronchial inflammation in asthmatic patients (Nilani et al. 2009). Due to all its anti-inflammatory
properties, curcumin is able to treat various chronic diseases, autoimmune, cardiovascular, endocrine and
neurodegenerative diseases.
Wound healing activity

Curcumin is very well known for its wound healing potential because of its antioxidant, anti-infectious
and anti-inflammatory properties (Meng et al. 2013, Mun et al. 2013, Akbik et al. 2014). The important
role of any wound healing agent is to protect the wound tissue from infection, reduce inflammation and
induce reconstruction of damaged tissues (Kulac et al. 2013). Curcumin has also been found to boost the
process of wound healing via tissue remodeling, formation and collagen deposition (Akbik et al. 2014). It
was also observed that application of curcumin on wounds also accelerate epithelial tissue regeneration,
fibroblast proliferation and vascular density (Thangapazham et al. 2013). Jagetia and Rajanikant (2012)
reported that curcumin enhances the nitric oxide production, which promotes wound healing in mice.
Emiroglu et al. (2017) reported the effect of curcumin on healing of nasal mucosal wounds in mice. The
study showed that curcumin reduces the inflammatory response and accelerates wound healing in mice.
Various clinical research conducted by different groups revealed that curcumin accelerates the wound
healing process by decreasing our body’s natural reaction such as inflammation towards the wound (Gupta
et al. 2013, He et al. 2015). Curcumin is also reported to improve wound healing due to its free radical
scavenging activity. It was also reported that antioxidant property of curcumin is due to its hydroxyl and
methoxy groups (Rahman and Biswas 2009). The introduction of curcumin for targeting Reactive Oxygen
Species (ROS) to the wound site could be a vital approach to eliminate ROS and improve healing at the
wounded area (Mohanty and Sahoo 2017). Many studies showed that curcumin exerts different roles
on different wound healing stages. At the inflammation phase, curcumin was notably reported to inhibit
the activity of NF transcription factor, also inhibiting the production of TNF-α, IL-1 cytokines which
reduce the inflammation at the wounded site (Akbik et al. 2014). Joe et al. (2004) explained numerous
mechanisms by which curcumin exerts wound healing activity via various processes. Most importantly,
curcumin was reported to modulate inflammation in the wounded site by inhibiting the production of TNF
and interleukins which plays an important role in inflammatory response regulation. Curcumin was also
equally important to inhibit activity of nuclear factor kappa-light-enhancer of activated B cells (NF-(к)
B). NF-(к) B is a transcription factor that regulates many genes which are implicated in the inflammatory
response. Curcumin affects a variety of pathways implicated in activation of NF-(к) B (Joe et al. 2004).
Curcumin was also reported to show enhanced fibroblast migration, tissue formation and collagen deposition
at the wounded site (Blakytny and Jude 2006, Loughlin and Artlett 2011, Mohanty et al. 2012). Similarly,
curcumin has the ability to improve wound contraction by increasing the production of TGF-β which
ultimately increases fibroblast proliferation (Akbik et al. 2014). This property of curcumin reduces the
time needed for wound healing.
Anticancerous activity
Curcumin also possesses anticancer properties due to its ability to inhibit cell proliferation and promotes
apoptosis. Curcumin exerts its bioactivity at different stages of carcinogenesis which includes, prevention
of cancer related inflammation, inhibit oncogene activation and cell proliferation, induces apoptosis and
prevents metastasis (Pongrakhananon and Rojanasakul 2011). The influence of curcumin on cancer cells is
illustrated in Fig. 8.2. The anticancerous effect of curcumin depends on the concentration, time of treatment,
dose and cell type. At lower concentration, curcumin were reported to cause cell cycle arrest while, at higher
concentration it induces apoptosis (Kastan and Bartek 2004, Pongrakhananon and Rojanasakul 2011).
Curcumin has induced apoptosis in a number cell lines including melanoma, leukemia, cancerous
cell line of breast, colon, lungs, ovaries and the kidneys which leads to cancer cell death via mitochondrial
death pathway (Karunagaran et al. 2005). Yang et al. (2013) demonstrated that curcumin significantly
reduces the levels of CDK4 and cyclin D1, which are cell cycle regulators and suppressed the expression
of p53 in the mouse colon. The study also revealed that curcumin blocks STAT3 signaling by provoking
the anti-inflammatory effect. Curcumin was also reported to induce stress in endoplasmic reticulum and
cause apoptosis in tumor cells (Vallianou et al. 2015). Curcumin was also effectively used for treatment
of melanoma. The study carried out by Jiang et al. (2015) suggested that curcumin alters the expression
levels of p53, p38, NF-(к)B which is associated with apoptosis and also inhibits proliferation of melanoma
cells in human. Curcumin was also reported to significantly inhibit the gastric tumor cell growth via ROS
generation, which results in depletion of mtDNA, ultimately disrupts the cellular bioenergetics (Wang et
al. 2017).
Apart from the apoptosis inducing effect, curcumin also possesses chemopreventive ability to
stabilize cancer cells for chemotherapy induced cell death. Generally, the problem associated with
cancer chemotherapy is the cytotoxicity to normal cells and acquiring of apoptosis resistance of cancer
cells. For this, the combinational therapy approach is preferred to reduce the cytotoxicity using optimal
dose regimens. Curcumin is one of the agents which has been used for its effect in combination therapy.
Javvadi et al. (2008) reported curcumin as a chemopreventive agent and potent radiostabilizer of human
cervical carcinoma cells. The study showed that pretreatment of curcumin to HeLa and SiHa, a cervical
carcinoma cell lines before radiation therapy results in effective dose dependent radio stabilization of
cervical carcinoma cells. Quian et al. (2015) reported that curcumin enhances radio sensitivity of glioma
U87 human cells by upregulating the DUSP-2 expression and decreases the phosphorylation of ERK and
JNK. The study also revealed that curcumin inhibits U87 glioma human cell proliferation in a time and
dose dependent manner. Curcumin was reported as a potential anticancer agent. It is also gaining huge
acceptance due to its various bioactivities.
Fig. 8.2 The influence of curcumin on cancer cell.
Curcuma longa cures dermatological diseases

The varied biological properties and lack of toxicity even at higher doses of curcumin is one of the most
important content of Curcuma longa, which makes it attractive to explore its use in various disorders
including dermatological diseases. Dermatological diseases are diseases of skin which affect many people.
Skin is the first line of defense and is vulnerable to various adverse conditions like burns, injuries, infections
and disorders like acne, hyper or hypo pigmentation, dermatitis, psoriasis and cancer (Thangapazham et
al. 2007).
Acne
Acne is a chronic inflammatory disease of hair follicles (pilosebaceous unit) resulting from androgen-
induced increased sebum production, altered keratinisation, inflammation, and bacterial infections on the
face, neck, chest and back by Propionibacterium acnes. In addition to P. acnes, as the main causative
microorganism, Pityrosporum ovale and Staphylococcus epidermidis are also present in acne lesions
(Kanlayavattanakul and Lourith 2011, Williums et al. 2012). According to a study led by Lalla et al. (2001)
use of oral as well as topical preparations of Curcuma longa showed better efficacy than taking internal
preparations alone to treat acne. Curcuma longa along with two more herbs viz. Azadirachta indica and
Hemidesmus incidus when used in acne treatment, led to inflammation being significantly reduced and
suppressed the reactive oxygen species produced by P. acnes (Jain and Basal 2003).
Atopic dermatitis
Atopic dermatitis (eczema) is a medical condition characterized by inflammation, extreme dryness, itching,
redness, scaly patches and irritation of the skin. It is found in people who have a tendency to develop
allergic reactions to certain external compounds. It is commonly found in association with allergic rhinitis,
asthma or other symptoms of atopy. The inflammatory symptoms in different organs are observed due
to the release of leukotrienes, prostaglandins and proteases (Zari and Zari 2015). The active ingredient
curcumin present in C. longa shows anti-inflammatory and bactericidal property. It lowers the expression of
inflammatory enzymes in the body and treats skin inflammation associated with eczema. Curcumin inhibits
the occurrences of this disease by reducing the sensitivity of some inflammatory transcription factors like
NF-кB, cytokines like TNF, IL-1 and IL-6, some enzymes like cyclo-oxygenase 2 or 5-lipoxygenase. The
herbal paste of C. longa (turmeric powder mixed with sweet lime juice and salt) is applied on swellings.
This paste provides rapid and long lasting relief. It treats wounds and stops bleeding (Khiljee et al. 2011,
Zari and Zari 2015).
Facial photoaging
Facial photoaging occurs due to excessive exposure to the sun as early as the second decade of life.
Ultraviolet (UV) radiation viz. UVC, UVB and UVA causes mutations by generating reactive oxygen
species (ROS), such as superoxide anion, hydrogen peroxide and hydroxyl radical and increases the
expression of matrix metalloproteinases in skin connective tissues and dermal layers of the skin which
degrades skin collagen and contributes to photoaging. The degradation of endogenous type I collagen fibrils
was increased by 58% in the UV irradiated skin (Cleaver 1968, Kadekaro et al. 2003, Aoki et al. 2007).
A decreased collagen production in dermal fibroblasts and a subsequent fragmentation and disarray of
dermis collagen fibrils are also features of age-related phenotypic alterations in human skin (Satoh 1992,
Taylor 2002, Takashahi et al. 2017). In a study, the use of a herbal gel formulation Tricutan® containing
C. longa, Rosmarinus officinalis and Centella asiatica was evaluated in 28 women (aged 34–37 years)
suffering with photoaging which showed significant improvement in skin firmness and clinical evaluations
when applied for 4 weeks (Sommerfeld 2007).
Psoriasis
Psoriasis is a chronic, hyper proliferative, inflammatory and non-contagious skin disease caused by faulty
signals in the immune system and is generally considered an autoimmune disease mediated by T-cells
(Kastelan et al. 2006). It causes thick, whitish flakes of scale on raised pinkish red or black skin with
well-defined margins. Curcumin, the key component of C. longa extract has the ability to be developed
as an antipsoriatic drug because it reduces keratinocyte proliferation and was found to be effective in the
mouse tail animal model of psoriasis (Bosman 1994, Pol et al. 2003). Curcumin reduces the expression
of pro-inflammatory cytokines like IL-6 and IL-8 in human keratinocytes. These cytokines are both pro-
inflammatory and are growth factors for keratinocytes. Hence, their inhibition by curcumin might reduce
inflammation and keratinocyte hyperproliferation caused by psoriasis (Miquel et al. 2002).
Topical therapies such as glucocorticoid treatment is effective due to its anti-inflammatory property
but discontinuation is encouraged due to its side effects (Lebwohl 2004). Therefore, suitable alternatives
are important for treating psoriasis. The rhizome of C. longa has a beneficial effect on psoriasis due to the
polyphenolic compound curcumin and antioxidants present in it. Other than topical therapies, phototherapy
is also considered effective and safe for treating psoriasis. Curcumin has been proved as phototoxic for
Salmonella typhimurium and Escherichia coli on irradiation with visible light (Tonneson et al. 1987).
This potential photosensitizing principle of curcumin makes it applicable in the phototherapy of psoriasis.
The combination of phototherapy with curcumin might accelerate the clinical response and might even
diminish the exposure load (Thangapazham et al. 2007, Miguel et al. 2015).
Pruritus
Pruritus or simply itching is a restless sensation and emotional ordeal linked to a skin disturbance that
induces the desire to scratch. It can result from external compounds, many systemic diseases and medications
(Davidson and Giesler 2010). C. longa has been proven effective in treating pruritus (Vyas 2015). In a
study, a topical formulation containing 16% turmeric along with other herbal ingredients, was used in 64
patients of both sexes, with pruritus caused by multiple etiologies (atopic dermatitis, senile pruritus, and
ichthyosis). A significant improvement was observed in the patients with pruritus (Chatterjee et al. 2005).
Oral Lichen Planus

Lichen planus is a chronic inflammatory disease which affects the mucosal and cutaneous tissue. Lichen
planus may appear in the esophagus, mouth, vaginal mucosa or skin but mostly it is found in the oral
cavity. Often, it is found only in the oral cavity. Oral Lichen Planus (OLP) occurs more frequently than the
cutaneous form and tends to be more resistant to any treatment. Overall, lichen planus affects approximately
2% of the population. This disease most commonly affects women over the age of 50 however, it may
occur in all age groups. The exact cause of this immune mediated basal cell damage is unknown but it is
believed that it occurs due to an abnormal T-cell mediated immune response. It is often asymptomatic;
the atrophic erosive form can show symptoms like a burning sensation and severe pain, which makes it
difficult to speak, eat and swallow. Patients with these symptoms require treatment. Plaque and calculus
deposits are associated with significantly higher incidence of redness and erosive gingival OLP. Good
oral hygiene is essential and it enhances the healing process (Edwards and Kelsch 2002, Lodi et al. 2005).
A pilot study was conducted in the department of oral and maxillofacial surgery for which 10 patients
were clinically diagnosed and histopathologically confirmed as patients of OLP. The rhizome extract of
C. longa in the ointment form was made at NBRI, used for local application twice/day for a period of 3
months. The extract showed beneficial effects on patients and proved to be a better alternative to other
steroidal drugs, which shows hazardous side effects (Singh et al. 2013).
Vitiligo
Vitiligo is a skin disease in which the melanocytes (pigment producing) cells are destroyed, resulting in white
patches on the skin of different parts of the body. Although the exact cause of the damage to melanocytes is
not clear, oxidative stress has been associated in the pathogenesis of the disease (Schallreuter et al. 1996).
Narrowband UVB (NB-UVB) that uses the portion of the UVB spectrum from 311 to 312 nm is considered
as the gold standard treatment for vitiligo (Arca et al. 2006). Because of the anti-oxidant property of
curcumin, it seems to be a therapeutic option for the treatment of vitiligo. One study investigated whether
the combination of NB-UVB and tetrahydro-curcuminoid cream could result in synergistic therapeutic
effects against vitiligo (Asawanonda and Klahan 2010). Ten patients with vitiligo were enrolled in the
study. Two similar lesions were treated with either NB-UVB plus topical tetrahydro-curcuminoid cream
or with UVB alone. Results indicated a statistically significant repigmentation in both treatment groups
with slightly better repigmentation in the combination group (Asawanonda and Klahan 2010).
Curcumin application in Neurological Disorders

Parkinson’s Disease
Parkinson’s Disease (PD) is characterized by neurodegeneration of dopaminergic neurons from Substantia

Nigra (SN) part of the brain. This neurodegeneration results in reduced dopamine secretion causing tremors,
depression and bradykinesia which primarily affect body and brain coordination (Jankovic, 2008). PD
is characterized by selective loss of dopaminergic neurons and accumulation of α-syn based and other
proteins in Lewy bodies (Dauer and Przedborski 2003, Dawson and Dawson 2003). Formation of reactive
species like peroxynitrite (PN) (Mythri et al. 2011), toxic aldehydes such as 4HNE and MDA (Yoritaka et
al. 1996) mainly affects the biomolecules, thus damaging the cellular machinery, e.g., inhibition of brain
mitochondrial complex I (CI) activity and reducing mitochondrial membrane potential and integrity.
Rajeswari and Sabesan (2008) studied the inhibitory effect of polyphenolic curcumin and its metabolite
tetrahydrocurcumin on monoamine oxidase-B MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
induced PD in model mice. Both curcumin (80 mg/kg i. p.) and tetrahydrocurcumin (60 mg/kg i. p.) served
as a neuroprotectant against MPTP-induced depletion of DA and DOPAC (Rajeswari and Sabesan 2008).
Kundu and colleagues (2016) studied the anti-Parkinson activity of curcumin and piperine coloaded glyceryl
monooleate (GMO) nanoparticles encoated with various detergents pertaining higher bioavailability in
rotenone induced PD mice (Szczepanowicz et al. 2016). Mythri et al. (2011) have shown that the regular
consumption of curcumin provides neuroprotection in toxic mouse model of PD. They have studied the
neuroprotective property of different conjugates of curcumin, among which enhanced protection against
PN-dependent Mitochondrial Complex I inhibition of dopaminergic neurons (Mythri et al. 2007) and protein
nitration was shown by glutamoyl diester of curcumin as compared to other conjugates. Di-glutamoyl
curcumin protected dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP)-mediated neuronal
death (Mythri et al. 2011). The antioxidant activity of curcumin protects SN neurons, improves striatal
dopamine levels and chelates Fe2+ in the 6-OHDA rat model of PD (Jiao et al. 2009). This is probably
mediated by the phenolic rings and diketone groups of curcumin which serve as an electron trap thus
preventing formation of H2O2, OH– and superoxide (Zbarsky et al. 2005). Szczepanowicz et al. (2016)
synthesized multilayered Poly-L-Lysine (PLL) and Poly-L-Glutamic Acid (PGA) encapsulated curcumin
nanocarriers for the prevention of H2O2-induced reduction in mitochondrial membrane potential in SH-
SY5Y human neuroblastoma cell line (Szczepanowicz et al. 2016). Interestingly, curcumin treatment
restores lipid peroxidation mediated mitochondrial damage and apoptosis (Zhu et al. 2004). Curcumin
protects against 4HNE mediated alterations in mitochondrial respiratory function and redox metabolism,
cytochrome C release, DNA fragmentation and PARP activation in PC12 cells demonstrating a protective
function against lipid peroxidation mediated damage (Raza et al. 2008). Pretreatment with curcumin
reestablishes mitochondrial membrane potential, elevates in Cu/Zn SOD and modulates NFκB nuclear
translocation (Wang et al. 2009), inhibits IL-6 and TNF-alpha (Wang et al. 2009), aggregation of α-synuclein
in vitro (Pandey et al. 2008, Wang et al. 2010) and reduction in aggregation of synphilin-1 (Pal et al. 2011).
Curcumin also activates proteins involved in iron metabolism in SN of PD brains (Sofic et al. 1988), thus
suppressing levels of ferritin and hepcidin, representing its role as an iron chelator (Jiao et al. 2006).
Curcumin treatment thus increases the density of dopaminergic neurons in the SN (Vajragupta et al. 2003)
possibly due to neurogenesis (Xu et al. 2007, Kim et al. 2008).
Alzeimer’s Disease
Alzheimer’s Disease (AD) is a devastating neurodegenerative, persistent and progressive disorder. Amyloid
Proteins (AP) are necessarily required for the brain’s normal synaptic function (Hardy and Selkoe 2002).
AD is found to be the most common cause of dementia in 50–60% of all dementia cases (Blennow et al.
2006). There is an increase in the production of amyloid protein (Aβ) aggregates which forms plaques
which are feebly cleared from the system (Ghiso and Frangione 2002, Mawuenyega et al. 2010, Mathew
et al. 2011). AP degradation in the normal brain is a result of various enzymes (Iwata et al. 2005). AD
was initially elucidated by German psychiatrist Alois Alzheimer (1864–1915) in 1906 and was named by
Kraepelin (Blennow et al. 2006). Ahmed and Gilani (2009, 2014) reviewed the neuroprotective property of
each component of the curcuminoid mixture that plays an important role in AD representing curcuminoid
mixture better than the curcumin. It has been observed from the epidemiological studies the consumption
of turmeric (curcumin) by Asian Indians is perhaps the reason for the low occurrence of AD/PD as well as
40% less melanized nigral neurons in brains in India as compared to the Caucasians (Muthane et al. 1998,
Blennow et al. 2006). Pan et al. (1998) demonstrated that curcumin is the only natural compound that can
cross the blood-brain barrier, but only in traces. Begum et al. (2008) and Aggarwal and Harikumar (2009)
studied the methods of enhancing the bioavailability of hydrophobic curcumin using different approaches.
Ringman and colleagues (2005) examined the dietary curcumin for their properties like antioxidant, anti-
inflammatory, or anti-amyloidogenic on mice model, either administered chronically to aged Tg2576
APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. In both the cases, reduction
in interleukin-1β was reported. It was concluded that the curcumin is promisingly effective in reducing
amyloid plaque burden, insoluble β-amyloid peptide (A β), and carbonyls (Ringman et al. 2005). Wang
and colleagues (2008) have demonstrated the degrees of saturation, types of carbon skeleton and functional
group, and hydrophobicity plays an important role in anti-BACE-1 and behavioral activities of curcuminoids
and their derivatives from rhizomes of Curcuma longa (Zingiberaceae) (Wang et al. 2008). Curcumin has
proved its role as neuroprotective agent in models of stroke and AD (Lim et al. 2001, Yang et al. 2005,
Ringman et al. 2005). Yang et al. (2005) have confirmed inhibitory action of curcumin on amyloid beta
(Aβ) oligomers and fibrils in AD. Lim and colleagues (2001) reported the reduction in amyloid pathology,
oxidative stress and pro-inflammatory markers in transgenic AD mice model. In addition, curcumin reduces
the levels of Glial Fibrillary Acidic Protein (GFAP), a marker of astrocytic proliferation. Deposition of
amyloid β-peptide and markers of oxidative stress and inflammation was found to be reduced in cerebral
cortex of model AD mice after dietary supplementation of curcumin (160–5000 ppm) (Lim et al. 2001).
Mathew et al. (2012) demonstrated that amyloid-binding aptamer (named NN2) conjugated curcumin–poly
(lactic-co-glycolic acid) (PLGA) nanoparticle can be used as an effective plasma amyloid level minimizer,
as it binds and deteriorates amyloid plaques. Over-expression of curcumin induced RANTES, a chemokine
released by astrocytes and microglia plays a key role in neuroinflammatory pathways during AD leading to
enhanced neuronal survival (Lin et al. 2011). Cheng and coworkers (2013) have formulated stable curcumin
nanoparticles to test in vitro and in AD model Tg2576 mice. This nanocurcumin produced significantly
higher curcumin concentration than normal curcumin in plasma and better working memory in models.
Curcumin loaded polybutylcyanoacrylate nanoparticles (PBCN) encoated with polysorbate 80 were
formulated by Sun and coworkers (2010). The pharmacokinetic and bio-distribution of this nanoparticle
formulation was studied by intravenous administration in the tail vein and crossing across the blood-brain
barrier was observed (Sun et al. 2010).
Curcumin in medicine
Curcumin is a multi-functional and pharmacologically safe natural agent (Paul et al. 2016) and is extensively
used as an antibacterial, antifungal, antiviral as well as antiparasitic agent from ancient times (Morais et al.
2013, Tyagi et al. 2015, Teow et al. 2016). It inhibits growth of microbes by various routes such as inhibition
of cytokinesis and cell proliferation, increasing sensitivity of microbes towards antibiotics and perturbation
of the cell wall and membrane leading to cell lysis, inhibiting arachidonic acid metabolism, stabilization
of lysosomal membrane which causes uncoupling of oxidative phosphorylation, modulation of different
transcription factors, cytokines, enzymes, receptors, etc. (Shanmugam et al. 2015, Paul et al. 2016, Teow
et al. 2016). Lethal effect of curcumin on microbes can be evaluated by different assays such as killing
assay, membrane permeabilization assay, propidium iodide uptake assay, calcein leakage assay, scanning
electron microscopy, Plasma Membrane Fluorescence Intensity measurement, etc. (Lee et al. 2014, Tyagi
et al. 2015). Different antimicrobial and antiparasitic effects studied so far are summarized in the Table 8.2.
Curcumin, with its wide range of functions, is helpful in a variety of medical conditions. Rheumatoid
arthritis, is a condition in which inflammation leads to immunological reactions followed by tissue damage
at joints, occurrence is heightened with increased age (Kumar and Rai 2011, Johnson and Hunter 2014, Daily
Table 8.2 Antimicrobial and antiparasitic efficacy of curcumin.
Biological activity Type of curcumin Test organism Mechanism References

Antibacterial activity Curcumin S. aureus, E. coli Inhibition of biofilm production Kali et al. 2016
Curcumin I S. aureus, E. faecalis, E. coli, P. aeruginosa Cell death by damaging membrane Tyagi et al. 2015
Curcumin, Bisdemethoxy- B. subtilis, K.pneumoniae, E. coli, E. aerogenes, Singh and Jain 2012
curcumin, Demethoxycur- P. aeruginosa, S. aureus, P. mirabilis
cumin
Curcumin S. mutans, Actinomyces viscosus, Lactobacillus Mandroli and Bhat
casei, Porphyromonas gingivalis, E. faecalis 2013
Prevotella intermedia
Curcumin + cefaclor, S. aureus, B. subtilis, E. coli, P. aeruginosa, Sasidharan et al. 2014
cefodizime, and cefotaxime Vibrio cholerae
Antifungal activity Curcumin A. niger, C. albicans Singh and Jain 2012
Curcumin C. albicans, C. parapsilosis, C. tropicalis, Inhibits adhestion of Cells to BEC (human Martins et al. 2009
C. dubliniensis buccal epithelial cells)
Curcumin C. albicans Triggers early apoptosis, Inhibits Hyphal Sharma et al. 2010
development by regulating TUP1 levels
Antiviral activity Curcumin Human influenza virus Reduces influenza A viruses replication, Chen et al. 2010
Avian influenza virus Blocks haemagglutinating activity of IAV
virus particles affects an early stage of virus
infection
Curcumin Herpes simplex virus-1 (HSV-1) and Herpes Inhibits adsorption of virons on cells Flores et al. 2016
simplex virus-2 (HSV-2)
Anti HIV activity Curcumin HIV Inhibits UV induced HIV gene expression Taher et al. 2003
Curcumin HIV Inhibits HIV-1 integrase required for viral Mazumdar et al.
replication 1995, De Clercq 2000
Antiparasitic activity Curcumin Schistosoma mansoni Transcriptional repression in Notch and Morais et al. 2013
TGF pathways, Affects oviposition and egg
development
Curcumin+ Praziquantel Schistosoma mansoni Reduce fibrosis, Increases oxidative/ Aboueldahab and
(PZQ) nitrosative stress, fragmentation of nuclear Elhussieny 2016
DNA
Curcumin Giardia lamblia Antioxidant activity, Affects trophozoite Sadhana and Gupta
attachment 2013, Dyab et al.
2016
Curcumin Giardia lamblia Inhibits trophozoites attachment and growth, Filiberto et al. 2017
Destabilizes microtubules
Curcumin + benznidazole Trypanosoma cruzi Limits anti-parasitic activity Novaes et al. 2016
Antimalarial activity Curcumin + Artemisinin Plasmodium berghei Generation of ROS/IgG antibodies Padmanabhan et al.
2012
Curcumin, Curcumin + Plasmodium chabaudi Interference in Ubiquitin Proteasome Neto et al. 2013
chloroquine + piperine, System, Increases synthesis of
Curcumin + piperine + deubiquitylating Enzymes
artemisinin
Curcumin Plasmodium falciparum Disruption of Microtubules Chakrabarti et al.
2013
et al. 2016). Curcumin, shows anti-inflammatory activity by inhibiting enzyme triggering inflammation,
such as cyclooxygenase 2 (COX2). By the inhibition of COX2, it eventually reduces prostaglandins
synthesis, which mediates signaling of pain (Kumar and Rai 2011).
Alzheimer’s Disease (AD), usually observed in later stages of life, is a neurodegenerative disorder
involving aggregation of protein Aβ into fibrils and eventually amyloid plaques which deposits into the
brain, interfering with memory, thinking and behavior of the patient. Curcumin, with its antioxidant, anti-
inflammatory and antiamyloid potential, helps to overcome symptoms of AD, in vitro and in animal models.
In order to study safety, tolerability, pharmacokinetics, efficacy and effects of curcumin on biomarkers
associated with the AD, phase II, randomized, double-blind, placebo-controlled study was performed with
33 patients of AD, some were given low-dose (2 g/day) and another group with high-dose (4 g/day) for
24 weeks. After 24 weeks inspite of its low bioavailability and withdrawal of three patients developing
gastrointestinal symptoms, curcumin was well tolerated (Ringman et al. 2012). Another randomized,
double-blind, placebo-controlled study was carried out with 34 patients, by giving two different doses
1 g and 4g. Results depict that the mental condition neither improved nor any adverse effect was observed,
but it might decrease the need of vitamin E because of its antioxidant activity (Baum et al. 2008). Yao and
Xue (2014) from their study observed that curcumin can destabilize formation of Aβ plaque and increase
its phagocytosis. It reduces inflammation caused by tau protein and also interacts with cholesterol and
metal ions. Curcumin is a potent inhibitor of COX-2 and NF-κB, known for their inflammatory response
and hence is a possible remedy for AD through its versatility, with less to no side effects in animal models.
Cardiovascular Disease (CVD) is a condition with impaired functioning of the heart and vascular
system (Haldeman et al. 1999, Yach et al. 2004). CVD includes various disease conditions such as
persistent hypertension, cardiac inflammation, myocarditis (inflammation of myocardium) and endocarditis
(inflammation of endocardium), valvular insufficiency and stenosis, congenital malformations, familial
hypertrophic and dilated cardiomyopathies, diabetic cardiomyopathy and myocardial infarction or
ischemia associated with coronary artery disease, which are linked to heart attacks. It also involves arterial
diseases, e.g., atherosclerosis, inflammatory stenosis and thrombus formation (Jana and Swarnakar 2013).
Curcumin holds the ability in reducing risk of CVD by inhibiting the high fat diet related inflammation
and hematological changes in the body (El-Habibi et al. 2013). Even in coronary artery disease in humans,
curcumin decreases Very Low Density Lipoprotein (VLDL), Low Density Lipoprotein (LDL), cholesterol
and serum triglyceride without any effect on inflammatory biomarkers (Mirzabeigi et al. 2015).
Antiophidian (Antivenom) activity of any biological component can be estimated by its phospholipase
A2 (PLA2) inhibition. Snake venom contains PLA2 which exerts effect such as cardiotoxicity, myotoxicity,
pre orpostsynaptic neurotoxicity, edema, hemolysis, hypotension, convulsion, platelet aggregation inhibition
and anticoagulation (Gutiérrez and Lomonte 1995, Ownby 1998, Teixeira et al. 2009). PLA2 degrades
membrane phospholipids, which releases arachidonic acid, precursor of inflammatory compounds such as
prostaglandins and leukotrienes (Samy et al. 2012). Docking study of various plant derived compounds
including curcumin against Russell’s viper and bovine pancreatic PLA2 shows interaction with the Amino
Acid (AA) residues at the active site of both PLA2s, shows curcumin of having anti-inflammatory and
antidotes properties (Nirmal et al. 2008).
To study the effect of curcumin in gastrointestinal diseases, Holt et al. (2005) conducted a study with
five patients diagnosed with Ulcerative Colitis/proctitis (UC) and five patients with Crohn’s Disease (CD).
UC patients were treated with 5-aminosalicylic acid (5-ASA) + corticosteroids + 550 mg curcumin (twice
daily for a month and then thrice daily for the second month). CD patients were given 360 mg curcumin
(thrice daily for a month and 360 mg four times daily for the second month). Several hematological,
biochemical, and inflammatory analysis and sigmoidoscopy and biopsy depicts that the UC group showed
significant improvement followed by reduction in medication and DC group showed improvement with
lowered Crohn’s Disease Activity Index.
Curcumin, being able to perform inhibition of the pro-inflammatory cytokines NF-κB and IL-6/STAT3
signaling pathway, is useful for the various gastrointestinal inflammatory diseases, such as Inflammatory
Bowel Disease (IBD) (Hilsden et al. 2011). Hanai et al. (2006) performed a case study with 89 patients
having quiescent UC in a randomized, double-blind, multicenter trial, four week washout period followed
by random selection of patients for placebo or curcumin for six months. Curcumin showed improvement
in the Clinical Activity Index (CAI) and the Endoscopic Index (EI), well tolerated by patients and have
better clinical efficacy than placebo in the prevention of a relapse. Curcumin showed myorelaxant effect
on smooth muscles of the gallbladder, bladder, aorta and trachea and heart. It increased gall bladder and
intestinal tone and contraction with no side effects on other organs in vitro. Hence, it can be used in various
gastrointestinal tract disorders (Micucci et al. 2013).
Limitations of curcumin
Curcumin is a hydrophobic and lipophilic molecule which is not soluble in water. Even though curcumin
exhibited potential medicinal properties, there are several limitations demonstrated from pharmacological
studies. From the last few years, researchers all over the globe are interested in determining the mechanism
of action of curcumin and with this intention many studies with animal and in vitro models were studied.
For this reason, there are many studies which aim to find out the bioavailability of curcumin (Rai et al.
2015, Saikia et al. 2015). In 1978, Wahlstrom and Blennow for the first time administered curcumin in
Sprague-Dawley (1 g/kg dose) to determine biological availability of curcumin (Annon and Wahl 1990). Ryu
et al. (2006) demonstrated that when curcumin is intravenously administered in mice, it was accumulated
in various organs such as the liver, spleen, lungs and in the brain. It can be concluded that curcumin has
some affinity towards some tissues. It was stated that the metabolism of curcumin depends on the route of
administration, it was found that for oral administration 75% of curcumin metabolites were found in feces
and not in urine (Holder et al. 1979). On the other hand, when the curcumin was given intraperitoneally,
73% of curcumin metabolites were found in urine and only 11% was absorbed in body. It was observed
from human and mouse trials that oral consumption of curcumin showed lesser bioavailability, and it
undergoes intestinal metabolism, whereas the absorbed curcumin have rapid metabolism and excretion
in bile (Saikia et al. 2015).
Hence, the major limitations of curcumin include low absorption, poor solubility and relatively less
distribution property. Hence, curcumin is not absorbed properly in the body and cannot be utilized for
the treatment of diseases (Rai et al. 2015, Saikia et al. 2015). Curcumin possesses low bioavailability
due to rapid metabolism, rapid elimination, poor distribution in tissue and low serum level (Saikia et al.
2015). Curcumin has many limitations but the bioavailability of curcumin can be improved by suitable
encapsulation of curcumin. For example, if curcumin is administered by encapsulating in liposome,
polymeric nanoparticles, cyclodextrin and other lipid or polymer curcumin complexes it can improve the
biological activity of curcumin (Nanjwade et al. 2015).
Conclusions
Curcuma longa (turmeric) is one of the most important Indian spices, which is being used traditionally
since ancient times as a spice and potent medicine. The validation of turmeric proved that it contains a
yellow pigment, curcumin, which has enormous medicinal properties such as antimicrobial activity, anti-
inflammatory activity, wound healing activity, anticancerous activity, antioxidant activity, anti-arthritis,
antimalarial, chemopreventive and chemotherapeutic activity and many more. Hence, it is considered a
safe, nontoxic and effective herbal medicine for a variety of infections and diseases including those of the
skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, liver disorders, Alzheimer’s,
Parkinson’s and small-pox disease, etc. In addition, its specific role in the treatment of different types
of cancer is very promising. However, further studies are required to determine the optimal dosage,
bioavailability and bio-efficacy, which may help in popularization of curcumin for its use as one of the
ideal herbal medicines.
References
Aboueldahab, M.M. and Elhussieny, E.A. 2016. Antiparasitic and physiological evaluation of Curcuma longa extract and/or
PZQ on Schistosoma mansoni infected mice. International Int. J. Adv. Res. 4(6): 1020–1039.
Aggarwal, B.B. and Harikumar, K.B. 2009. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against
neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int. J. Biochem. Cell
B. 41: 40–59.
Ahmed, T. and Gilani, A.H. 2009. Inhibitory effect of curcuminoids on acetylcholinesterase activity and attenuation of
scopolamine induced amnesia may explain medicinal use of turmeric in Alzheimer’s disease. Pharmacol. Biochem.
Be. 91: 554–559.
Ahmed, T. and Gilani, A.H. 2014. Therapeutic Potential of Turmeric in Alzheimer’s Disease: Curcumin or Curcuminoids?
Phytother. Res. 28: 517–525.
Akbik, D., Ghadiri, M., Chrzanowski, W. and Rohanizadeh, R. 2014. Curcumin as a wound healing agent. Life Sci. 116(1): 1–7.
Aoki, H., Moro, O., Tagami, H. and Kishimoto, J. 2007. Gene expression profiling analysis of solar lentigo in relation to
immunohistochemical characteristics. Br. J. Dermatol. 156: 1214–1223.
Arca, E., Tastan, H.B., Erbil, A.H., Sezer, E., Koc, E. and Kurumlu, Z. 2006. Narrow-band ultraviolet B as monotherapy and
in combination with topical calcipotriol in the treatment of vitiligo. J. Dermatol. 33(5): 338–343.
Asawanonda, P. and Klahan, S.O. 2010. Tetrahydrocurcuminoid cream plus targeted narrowband UVB phototherapy for
vitiligo: a preliminary randomized controlled study. Photomed. Laser Surg. 28(5): 679–684.
Asghari, G., Mostajeran, A. and Shebli, M. 2009. Curcuminoid and essential oil components of turmeric at different stages
of growth cultivated in Iran. Res. Pharmac. Sci. 4(1): 55–61.
Basnet, P. and Skalko-Basnet, N. 2011. Curcumin: An anti-inflammatory molecule from a curry spice on the path to cancer
treatment. Molecules 16: 4567–4598.
Baum, L., Lam, C.W., Cheung, S.K., Kwok, T., Lui, V., Tsoh, J., Lam, L., Leung, V., Hui, E., Ng, C., Woo, J., Chiu, H.F.,
Goggins, W.B., Zee, B.C., Cheng, K.F., Fong, C.Y., Wong, A., Mok, H., Chow, M.S., Ho, P.C., Ip, S.P., Ho, C.S., Yu,
X.W., Lai, C.Y., Chan, M.H., Szeto, S., Chan, I.H. and Mok, V. 2008. Six-month randomized, placebo-controlled,
double-blind, pilot clinical trial of curcumin in patients with Alzheimer Disease. J. Clin. Psychopharmacol. 28(1): 110–3.
Begum, A.N., Jones, M.R., Lim, G.P., Morihara, T., Kim, P., Heath, D.D., Rock, C.L., Pruitt, M.A., Yang, F., Hudspeth, B.,
Hu, S., Faull, K.F., Teter, B., Cole and Frautschy, S.A. 2008. Curcumin structure-function, bioavailability, and efficacy
in models of neuroinflammation and Alzheimer’s Disease. J. Pharmacol. Exp. Ther. 326: 196–208.
Blakytny, R. and Jude, E. 2006. The molecular biology of chronic wounds and delayed healing in diabetes. Diabet. Med.
23: 594–608.
Blennow, K., de Leon, M.J. and Zetterberg, H. 2006. Alzheimer’s disease. Lancet. 368: 387–403.
Bosman, B. 1994. Testing of lipoxygenase inhibitors, cyclooxygenase inhibitors, drugs with immunomodulating properties
and some reference antipsoriatic drugs in the modified mouse tail test, an animal model of psoriasis. Skin Pharmacol.
7(6): 324–334.
Chainani-Wu, N. 2004. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J.
Altern. Complem. Med. 9(1): 161–168.
Chakrabarti, R., Rawat, P.S., Cooke, B.M., Coppel, R.L. and Patankar, S. 2013. Cellular effects of curcumin on plasmodium
falciparum include disruption of microtubules. PLoS ONE 8(3): 1–14.
Chandran, B. and Goel, A. 2012. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with
active rheumatoid arthritis. Phytother. Res. 26: 1719–1725.
Chatterjee, S., Datta, R.N., Bhattacharyya, D. and Bandhopadhyay, S.K. 2005. Emollient and antipruritic effect of Itch cream
in dermatological disorders: A randomized controlled trial. Indian J. Pharmaco. 37(4): 253–254.
Chen, D.Y., Shien, J.H., Tiley, L., Chiou, S.S.,Wang, S.Y., Chang, T.J., Lee, Y.J., Chan, K.W. and Hsu, W.L. 2010. Curcumin
inhibits influenza virus infection and haemagglutination activity. Food Chem. 119(1): 1346–1351.
Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., Ho, Y.F., Shen, T.S., Ko, J.Y., Lin, J.T., Lin, B.R., Ming-Shiang, W., Yu, H.S.,
Jee, H.S., Chen, G.S., Chen, T.M., Chen, C.A., Lai, M.K., Pu, Y.S., Pan, M.H., Wang, Y.J.,Tsai, C.C. and Hsieh, C.Y.
2001. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.
Anticancer Res. 21(4B): 2895–2900.
Cheng, K.K., Yeung, C.F., Ho, S.W., Chow, S.F., Chow, A.H.L. and Baum, L. 2013. Highly stabilized curcumin nanoparticles
tested in an in vitro blood–brain barrier model and in Alzheimer’s Disease Tg2576 Mice. The AAPS Journal. 15(2):
324–336.
Chong, L., Zhang, W., Nie, Y., Yu, G., Liu, L., Lin, L., Wen, S., Zhu, L. and Li, C. 2014. Protective effect of curcumin on acute
airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway. Inflammation 37: 1476–1485.
Cleaver, J.E. 1968. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218: 652–656.
Daily, J.W., Yang, M. and Park, S. 2016. Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint
arthritis: a systematic review and meta-analysis of randomized clinical trials. J. Med. Food 19(8): 717–729.
Dauer, W. and Przedborski, S. 2003. Parkinson’s disease mechanisms and models. Neuron. 39: 889–909.
Davidson, S. and Giesler, G.J. 2010. The multiple pathways for itch and their interactions with pain. Trends Neurosci. 33:
550–558.
Dawson, T.M. and Dawson, V.L. 2003. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302: 819–822.
De Clercq, E. 2000. Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection.
Med. Res. Rev. 20(1): 323–349.
Dyab, A.K., Yones, D.A., Ibraheim, Z.Z. and Hassan, T.M. 2016. Anti-giardial therapeutic potential of dichloromethane extracts
of Zingiber officinale and Curcuma longa in vitro and in vivo. Parasitol. Res. 115(1): 2637–2645.
Edwards, P.C. and Kelsch, R. 2002. Oral lichen planus: clinical presentation and management. J. Can. Dent. Assoc. 68(8):
494–499.
El-Habibi, E.S.M., El-Wakf, A.M. and Mogall, A. 2013. Efficacy of curcumin in reducing risk of cardiovascular disease in
high fat diet-fed rats. J. Bioanal. Biomed. 5(1): 066–070.
Emiroglu, G., Coskun, Z.O., Kalkan, Y., Erdivanli, O.C., Tumkaya, L., Terzi, S., Özgür, A., Demirci, M. and Dursun, E. 2017.
“The Effects of Curcumin on Wound Healing in a Rat Model of Nasal Mucosal Trauma,” Evid.-Based Compl. Alt., vol.
2017, Article ID 9452392, 6 pages. doi:10.1155/2017/9452392.
Ferreira, V.H., Nazli, A., Dizzell, S.E., Mueller, K. and Kaushic, C. 2015. The anti-inflammatory activity of curcumin protects
the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2. PLoS ONE 10(4):
e0124903. https://doi.org/10.1371/journal.pone.0124903.
Filiberto, G.G., Lissethe, P.L., José, M.H., Armando, P.R., Rodrigo, A.O., Alicia, H.C., Rafael, C., Flores, D.J., Lee, L.H.
and Adams, S.D. 2016. Inhibition of curcumin-treated herpes simplex virus 1 and 2 in vero cells. Adv. Microbiol. 6(1):
276–287.
Fouladvand, M., Barazesh, A. and Tahmasebi, R. 2013. Evaluation of in vitro antileishmanial activity of curcumin and its
derivatives “gallium curcumin, indium curcumin and diacethyle curcumin”. Eur. Rev. Med. Pharmaco. 17(1): 3306–3308.
Fujisawa, S., Atsumi, T., Ishihara, M. and Kadoma, Y. 2004. Activity of curcumin and related compounds. Anticancer Res.
24: 563–570.
Ghiso, J. and Frangione, B. 2002. Amyloidosis and Alzheimer’s Disease. Adv. Drug Deliver. Rev. 54: 1539–1551. doi:10.1016/
S0169-409X(02)00149-7.
Goel, A., Kunnumakkara, A.B. and Aggarwal, B.B. 2008. Curcumin as ‘‘curecumin’’: from kitchen to clinic. Biochem.
Pharmacol. 2008. 75: 787–809.
Gupta, S.C., Patchva, S. and Aggarwal, B.B. 2012. Therapeutic roles of curcumin: Lessons learned from clinical trials. AAPS
J. 15(1): 195–218.
Gutiérrez, J.M. and Lomonte, B. 1995. Phospholipase A2 myotoxins from Bothrops snake venoms. Toxicon. 33(11): 1405–1424.
Haldeman, G.A., Croft, J.B., Giles, W.H. and Rashidee, A. 1999. Hospitalization of patients with heart failure: national hospital
discharge survey, 1985 to 1995. Am. Heart J. 137(2): 352–360.
Hanai, H., Lida, T., Takeuchi, K., Watanabe, F., Maruyama, Y., Andoh, A., Tsujikawa, T., Fujiyama, Y., Mitsuyama, K., Sata,
M., Yamada, M., Iwaoka, Y., Kanke, K., Hiraishi, H., Hirayama, K., Aria, H., Yoshii, S., Uchijima, M., Nagata, T. and
Koide, Y. 2006. Curcumin maintenance therapy for ulcerative colitis: randomized, multicentre, double-blind, placebo-
controlled trial. Clin. Gastroeterol. Hepatol. 4(12): 1502–1506.
Hanselmann, C., Mauch, C. and Werner, S. 2001. Haem oxygenase-1: a novel player in cutaneous wound repair and psoriasis?
Biochem. J. 353(3): 459–466.
Hardy, J. and Selkoe, D.J. 2002. The amyloid hypothesis of Alzheimer’s Disease: Progress and problems on the road to
therapeutics. Science 297: 353–356. doi:10.1126/science.1072994.
He, Y., Yue, Y., Zheng, X., Zhang, K., Chen, S. and Du, Z. 2015. Curcumin, inflammation, and chronic diseases: how are
they linked? Molecules 20(5): 9183–9213.
Heng, M.C., Song, M.K. and Heng, M.K. 1994. Elevated phosphorylase kinase activity in psoriatic epidermis: Correlation
with increased phosphorylation and psoriatic activity. Br. J. Dermatol. 130(3): 298–306.
Heng, M.C., Song, M.K., Harker, J. and Heng, M.K. 2000. Drug-induced suppression of phosphorylase kinase activity
correlates with resolution of psoriasis as assessed by clinical, histological and immunohistochemical parameters. Br. J.
Dermatol. 143(5): 937–949.
Hermann, P.T. and Ammo Wahl, M.A. 1991. Pharmacology of Curcuma longa. Planta Med. 57: 1–7.
Hilsden, R.J., Verhoef, M.J., Rasmussen, H., Porcino, A. and DeBruyn, J.C. 2011. Use of complementary and alternative
medicine by patients with inflammatory bowel disease. Inflamm. Bowel. Dis. 17(1): 655–662.
Holder, G.M., Plummer, J.L. and Ryan, A.J. 1978. The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-
methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica 8: 761–768.
Holt, P.R., Katz, S. and Kirshoff, R. 2005. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig. Dis. Sci.
50(1): 2191–2193.
Iwata, N., Higuchi, M. and Saido, T.C. 2005. Metabolism of amyloid-β peptide and Alzheimer’s disease. Pharmacol. Therapeut.
108: 129–148. doi:10.1016/j.pharmthera.2005.03.010.
Jagetia, G. and Rajanikant, G. 2012. Acceleration of wound repair by curcumin in the excision wound of mice exposed to
different doses of fractionated gamma radiation. Int. Wound J. 9: 76–92.
Jain, A. and Basal, E. 2003. Inhibition of Propionibacterium acnes-induced mediators of inflammation by Indian
herbs. Phytomedicine 10(1): 34–38.
Jana, S. and Swarnakar, S. 2013. Cardiovascular diseases: nutritional and therapeutic interventions, publisher group; Taylor
and Francis Group, Editors; Nilanjana Maulik 1(26): 487–500.
Jankovic, J. 2008. Parkinson’s disease: clinical features and diagnosis. J. Neurol. Neurosur. Ps. 79: 368–76.
Javvadi, P., Segan, A.T., Tuttle, S.W. and Koumenis, C. 2008. The Chemopreventive agent curcumin is a potent radiosensitizer
of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated
protein kinase Pathway. Mol. Pharmacol. 73(5): 1491–1501. doi:10.1124/mol.107.043554.
Jiang, A.J., Jiang, G., Li, L.T. and Zheng, J.N. 2015. Curcumin induces apoptosis through mitochondrial pathway and caspases
activation in human melanoma cells. Mol. Biol. Rep. 42: 267–275. doi:10.1007/s11033-014-3769-2.
Jiao, Y., Wilkinson, J.I.V., Christine Pietsch, E., Buss, J.L., Wang, W., Planalp, R., Torti, F.M. and Torti, S.V. 2006. Iron
chelation in the biological activity of curcumin. Free Radical Biol. Med. 40: 1152–60.
Jiao, Y., Wilkinson, IV.J., Di, X., Wang, W., Hatcher, H., Kock, N.D., D’Agostino, R., Knovich, Jr. M.A., Torti, F.M. and Torti,
S.V. 2009. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood.
113(2): 462–469. https://dx.doi.org/10.1182%2Fblood-2008-05-155952.
Joe, B., Vijaykumar, M. and Lokesh, B. 2004. Biological properties of curcumin-cellular and molecular mechanisms of action.
Crit. Rev. Food Sci. Nutr. 44: 97–111.
Johnson, V.L. and Hunter, D.J. 2014. The epidemiology of osteoarthritis. Best Pract. Res. Clin. Rheumatol. 28(1): 5–15.
Kadekaro, A.L., Kavanagh, R.J., Wakamatsu, K., Ito, S., Pipitone, M.A. and Abdel-Malek, Z.A. 2003. Cutaneous photobiology.
The melanocyte vs. the sun: who will win the final round? Pigment. Cell Res. 16: 434–447.
Kali, A., Bhuvaneshwar, D., Charles, P.M. and Seetha, K.S. 2016. Antibacterial synergy of curcumin with antibiotics against
biofilm producing clinical bacterial isolates. J. Basic Clin. Pharma. 7(1): 93–96.
Kanlayavattanakul, M. and Lourith, N. 2011. Therapeutic agents and herbs in topical application for acne treatment. Int. J.
Cosmet. Sci. 33: 289–97.
Karunagaran, D., Rashmi, R. and Kumar, T.R. 2005. Induction of apoptosis by curcumin and its implications for cancer
therapy. Curr. Cancer Drug Targets. 5(2): 117–29.
Kastan, M.B. and Bartek, J. 2004. Cell-cycle checkpoints and cancer. Nature 432(7015): 316–23, ISSN 1476–4687.
Kastelan, L.M., Massari, P. and Brajac, I. 2006. Apoptosis mediated by cytolytic molecules might be responsible for maintenance
of psoriatic plaques. Med. Hypotheses 67(2): 336–337.
Khiljee, S., Rehman, N.U., Khiljee, T., Saeed, A.R., Khan, M.Y. and Qureshi, U.A. 2011. Use of traditional herbal medicines
in the treatment of eczema. J. Pak. Assoc. Dermatol. 21: 112–117.
Kim, S.J., Son, T.G., Park, H.R., Park, M., Kim, M.S., Kim, H.S., Chung, H.Y., Mattson, M.P. and Lee, J. 2008. Curcumin
stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J. Biol. Chem.
283: 14497–505.
Kojima, H., Yanai, T. and Toyota, A. 1998. Essential oil constituents from Japanese and Indian Curcuma aromatica rhizomes.
Planta Med. 64: 380–381.
Kulac, M., Aktas, C., Tulubas, F., Uygur, R., Kanter, M., Erboga, M., Ceber, M., Topcu, B. and Ozen, O.A. 2013. The effects
of topical treatment with curcumin on burn wound healing in rats. J. Mol. Histol. 44(1): 83–90.
Kumar, K. and Rai, A. 2011. Curcumin: a yellow magical spice of kitchen for treatment of rheumatoid arthritis. Int. Res. J.
Pharm. 2(12): 29–31.
Kundu, P., Das, M., Tripathy, K. and Sahoo, S.K. 2016. Delivery of dual drug loaded lipid based nanoparticles across the
blood−brain barrier impart enhanced neuroprotection in a rotenone induced mouse model of Parkinson’s Disease. ACS
Chem. Neurosci. 7: 1658−1670.
Kurup, V.P. and Barrios, C.S. 2008. Immunomodulatory effects of curcumin in allergy. Mol. Nutr. Food Res. 52: 1031–1039.
Lalla, J.K., Nandedkar, S.Y., Paranjape, M.H. and Talreja, N.B. 2001. Clinical trials of ayurvedic formulations in the treatment
of acne vulgaris. J. Ethnopharmacol. 78: 99–102.
Lebwohl, M. 2004. Innovations in the treatment of psoriasis. J. Am. Acad. Dermatol. 51(1): 40–41.
Lee, W.H., Loo, C.Y., Bebawy, M., Luk, F., Mason, R.S. and Rohanizadeh R. 2013. Curcumin and its derivatives: Their
application in neuropharmacology and neuroscience in the 21st century. Curr. Neuropharmacol. 11: 338–378.
Lim, G.P., Chu, T., Yang, F., Beech, W., Frautschy, S.A. and Cole, G.M. 2001. The curry spice curcumin reduces oxidative
damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci. 21: 8370–7.
Lin, M.S., Hung, K.S., Chiu, W.T., Sun, Y.Y., Tsai, S.H., Lin, J.W. and Lee, Y.H. 2011. Curcumin enhances neuronal survival
in N-methyl-d-aspartic acid toxicity by inducing RANTES expression in astrocytes via PI-3K and MAPK signaling
pathways. Prog. Neuro-Psychoph. 35: 931–8.
Lodi, G., Scully, C., Carrozzo, M., Griffiths, M., Sugerman, P.B. and Thongprasom, K. 2005. Current controversies in oral
lichen planus: Report of an international consensus meeting. Part 2. Clinical management and malignant transformation.
Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod. 100(2): 164–178.
Loughlin, D. and Artlett, C. 2004. Modification of collagen by 3-deoxyglucosone alters wound healing through differential
regulation of p38 MAP kinase. PLoS One 6(5): 18676.
Lu, J.J., YeDang, Y., Huang, M., Xu, W.S., Chen, X.P. and Wang, Y.T. 2012. Anti-cancer properties of terpenoids isolated
from Rhizoma Curcumae—a review. J. Ethnopharmacol. 143: 406–411.
Ma, F., Liu, F., Ding, L., Ming, Y., Yue, H., Zhou, Y. and Hou, Y. 2017. Anti-inflammatory effects of curcumin are associated
with down regulating microRNA-155 in LPS-treated macrophages and mice. Pharm. Biol. 55(1): 1263–1273. DOI:10
.1080/13880209.2017.1297838.
Mandroli, P.S. and Bhat, K. 2013. An in vitro evaluation of antibacterial activity of curcumin against common endodontic
bacteria. J. Appl. Pharm. Sci. 3(10): 106–108.
Martins, C.V.B., daSilva, D.S., Neres, A.T.M., Magalha, T.F.F., Watanabe, G.A., Modolo, L.V., Sabino, A.A., deFátima, A. and
deResende M.A. 2009. Curcumin as a promising antifungal of clinical interest. J. Antimicrob. Chemoth. 63(1): 337–339.
Mathew, A., Yoshida, Y., Maekawa, T. and Sakthi Kumar, D. 2011. Alzheimer’s disease: Cholesterol a menace? Brain Res.
Bull. 86: 1–12. doi:10.1016/j.brainresbull.2011.06.006.
Mathew, A., Aravind, A., Brahatheeswaran, D., Fukuda, T., Nagaoka, Y., Hasumura, T., Iwai, S., Morimoto, H., Yoshida, Y.,
Maekawa, T., Venugopal, K. and Kumar, D.S. 2012. Amyloid-binding aptamer conjugated curcumin–PLGA nanoparticle
for potential use in Alzheimer’s Disease. Bionanosci 2: 83–93. DOI:10.1007/s12668-012-0040-y.
Mawuenyega, K.G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J.C., Yarasheski, K.E. and Bateman, R.J. 2010.
Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330(6012): 1774. doi:10.1126/science.1197623.
Mazumdar, A., Raghavan, K., Weinstein, J., Kohn, K.W. and Pommer, Y. 1995. Inhibition of human immunodeficiency virus
type-1 integrase by curcumin. Biochem. Pharmacol. 49(1): 1165–1170.
Meng, B., Li, J. and Cao, H. 2013. Antioxidant and antiinflammatory activities of curcumin on diabetes mellitus and its
complications. Curr. Pharm. 19: 2101–13.
Menon,V.P. and Sudheer A.R. 2007. Antioxidant and anti-inflammatory properties of curcumin. Adv. Exp. Med. Biol. 595:
105–125.
Micucci, M., Aldini, R., Cevenini, M., Colliva, C., Spinozzi, S., Roda, G., Montagnani, M., Camborata, C., Camarda, L.,
Chiarini, A., Mazzella, G. and Budriesi, R. 2013. Curcuma longa L. as a therapeutic agent in intestinal motility disorders.
2: safety profile in mouse. PLoS ONE 8(11): 1–13.
Miguel, C.G., Ana, R.B., Vicente, N.L., Asunción, M.A., Manuel, A.L., August, B. and José, H.F. 2015. Effects of curcuma
extract and visible light on adults with plaque psoriasis. Eur. J. Dermatol. 25(3): 240–246.
Miquel, A.J., Bernd, J.M., Sempere, J., Diaz, A. and Ramirez, A. 2002. The curcuma antioxidants: Pharmacological effects
and prospects for future clinical use. A review. Arch. Gerontol. Geriatr. 34(1): 37–46.
Mirzabeigi, P., Mohammadpour, A.H., Salarifar, M., Gholami, K., Mojtahedzadeh, M. and Javadi, M.R. 2015. The effect
of curcumin on some of traditional and non-traditional cardiovascular risk factors: a pilot randomized, double-blind,
placebo-controlled trial. Iran. J. Pharm. Res. 14(1): 479–486.
Mohanty, C., Das, M. and Sahoo, S. 2012. Sustained wound healing activity of curcumin loaded oleic acid based polymeric
bandage in a rat model. Mol. Pharm. 9: 2801–11.
Mohanty, C. and Sahoo, S.K. 2017. Curcumin and its topical formulations for wound healing applications. Drug Discov.
Today. S1359-6446(16): 30437–8. doi: 10.1016/j.drudis.2017.07.001.
Morais, E.R., Oliveira, K.C., Magalhães, L.G., Moreira, E.B., Sergio, V.A. and Rodrigues, V. 2013. Effects of curcumin on
the parasite Schistosoma mansoni: A transcriptomic approach. Mol. Biochem. Parasit. 187(1): 91–97.
Mun, S.H., Joung, D.K., Kim, Y.S., Kang, O.H., Kim, S.B., Seo, Y.S., Kim, Y.C., Lee, D.S., Shin, D.W., Kweon, K.T. and
Kwon, D.Y. 2013. Synergistic antibacterial effect of curcumin againstmethicillin-resistant Staphylococcus aureus.
Phytomedicine 20(8-9): 714–718.
Muthane, U., Yasha, T.C. and Shankar, S.K. 1998. Low numbers and no loss of melanized nigral neurons with increasing age
in normal human brains from India. Ann. Neurol. 43: 283–7.
Mythri, R.B., Jagatha, B., Pradhan, N., Andersen, J. and Bharath, M.M.S. 2007. Mitochondrial complex I inhibition in
Parkinson’s disease: how can curcumin protect mitochondria? Antioxid. Redox Sign. 9(3): 399–408. doi: 10.1089/
ars.2006.1479.
Mythri, R.B., Harish, G., Dubey, S.K, Misra, K. and Bharath, M.M.S. 2011. Glutamoyl diester of the dietary polyphenol
curcumin offers improved protection against peroxynitrite-mediated nitrosative stress and damage of brain mitochondria
in vitro: implications for Parkinson’s disease. Mol. Cell. Biochem. 347: 135–143. DOI:10.1007/s11010-010-0621-4.
Nadkarni, K.M. 1976. Indian Materia Medica 1.3rd ed. Bombay: Popular Prakasan.
Nanjwade, B.K., Bellad, K.A., Mohamied, A.S., Nwaji, M.S. and Srichana, T. 2015. Curcumin: nutraceutical and pharmaceutical
applications. Adv. Pharmacog. Phytomed. 1(1): 17–26.
Neto, Z., Machado, M., Lindeza, A., Rosário, V.D., Gazarini, M.L. and Lopes, D. 2013. Treatment of Plasmodium chabaudi
parasites with curcumin in combination with antimalarial drugs: drug interactions and implications on the ubiquitin/
proteasome system. J. Parasitol. Res. (1): 1–11.
Nilani, P., Kasthuribai, N., Duraisamy, B., Dhamodaran, P., Ravichandran, S., Ilango, K. and Suresh, B. 2009. In vitro antioxidant
activity of selected antiasthmatic herbal constituents. Anc. Sci. Life 28: 3–6.
Nirmal, N., Praba, G.O. and Velmurugan, D. 2008. Modeling studies on phospholipase A2-inhibitor complexes. Indian Journal
of Biochemistry and Biophysic. 45(4): 256–262.
Novaes, R.D., Sartini, M.V.P., Rodriguesa, J.P.F., Gonçalves, R.V., Santos, E.C., Souza, R.L.M. and Caldas, I.S. 2016.
Curcumin enhances the anti-Trypanosoma Cruzi activity of benznidazole-based chemotherapy in acute experimental
chagas disease. Antimicrob. Agents Chemother. 60(6): 3355–64.
Ownby, C.L. 1998. Structure, function and biophysical aspects of the myotoxins from snake venoms. J. Toxicol Toxins Rev.
17(1): 213–238.
Padmanaban, G., Nagaraj, V.A. and Rangarajan, P.N. 2012. Artemisinin-based combination with curcumin adds a new dimension
to malaria therap. Curr. Sci. 102(5): 704–711.
Pal, R., Miranda, M. and Narayan, M. 2011. Nitrosative stress-induced parkinsonian lewy-like aggregates prevented through
polyphenolic phytochemical analog intervention. Biochem. Bioph. Res. Co. 404: 324–9.
Pan, M.H., Huang, T.M. and Lin, J.K. 1998. Biotransformation of curcumin through reduction and glucuronidation in mice.
Drug Metab. Dispos. 27: 486–494. doi:0090-9556/99/2704-0486-0494.
Pandey, N., Strider, J., Nolan, W.C., Yan, S.X. and Galvin, J.E. 2008. Curcumin inhibits aggregation of alpha-synuclein. Acta
Neuropathol. 115: 479–89.
Paul, S.C., Krishnakumar, K. and Kavitha M.P. 2016. Phyto-Pharmacology of Curcuma longa: A Review. Int. J. Pharmacol.
Res. 6: 144–147.
Pol, A., Bergers, M. and Schalkwijk, J. 2003. Comparison of antiproliferative effects of experimental and established antipsoriatic
drugs on human keratinocytes, using a simple 96-well-plate assay. In Vitro Cell Dev. Biol. Anim. 39(1-2): 36–42.
Pongrakhananon, V. and Rojanasakul, Y. 2011. Anticancer Properties of Curcumin. “Advances in Cancer Therapy”, book
edited by HalaGali-Muhtasib, ISBN 978-953-307-703-1, pp. 347–368.
Pulido-Moran, M., Moreno-Fernandez, J., Ramirez-Tortosa, C. and Ramirez-Tortosa, M. 2016. Curcumin and health.
Molecules 21(3): 264. doi: 10.3390/molecules21030264.
Qian, Y., Ma, J. and Guo X. 2015. Curcumin enhances the radiosensitivity of U87 cells by inducing DUSP-2 up-regulation.
Cell Physiol. Biochem. 35: 1381–1393.
Rahman, I. and Biswas, S.K. 2009. Regulation of inflammation, redox, and glucocorticoid signaling by dietary polyphenols.
In: Surh, Y.J., Dong, Z., Cadenas, E. and Packer, L. (eds.). Boca Raton: CRC Press.
Rai, M., Pandit, R., Gaikwad, S., Yadav, A. and Gade, A. 2015. Potential applications of curcumin and curcumin nanoparticles:
from traditional therapeutics to modern nanomedicine. Nanotechnol. Rev. 4(2): 161–172.
Rajeswari, A. and Sabesan, M. 2008. Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and
its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice.
Inflammopharmacol 16: 96–9.
Raza, H., John, A., Brown, E.M., Benedict, S. and Kambal, A. 2008. Alterations in mitochondrial respiratory functions,
redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells.
Toxicol. Appl. Pharmacol. 226: 161–8.
Ringman, J.M., Frautschy, S.A., Cole, G.M., Masterman, D.L. and Cummings, J.L. 2005. A potential role of the curry spice
curcumin in Alzheimer’s Disease. Curr. Alzheimer Res. 2(2): 131–6.
Ryu, E.K., Choe, Y.S., Lee K.H., Choi, Y. and Kim, B.T. 2006. Curcumin and dehydrozingerone derivatives: Synthesis,
radiolabeling, and evaluation for beta-amyloid plaque imaging. J. Med. Chem. 49: 6111–6119.
Sadhana, S. and Gupta, A.K. 2013. Evaluation of phenolics content, flavonoids and antioxidant activity of Curcuma amada
(Mango Ginger) and Zingiber officinale (Ginger). Res. Rev. J. Chem. 2(1): 32–35.
Saikia, C., Sarmah, M., Das, M.K., Ramteke, A. and Maji, T.K. 2015. Biodegradable Polymeric Nanocomposites: Advances
in Biomedical Applications. Chap. 8 Taylor and Francis Publication Boca Raton.
Samy, R.P., Gopalakrishnakone, P. and Chow, V.T. 2012. Therapeutic application of natural inhibitors agaisnt snake venom
phospholipase A2. Bioinformation 8(1): 048–057.
Santos, A.M., Lopes, T., Oleastro, M., Gato, I.V., Floch, P., Benejat, L., Chaves, P., Pereira, T., Seixas, E., Machado, J. and
Guerreiro, A.S. 2015. Curcumin inhibits gastric inflammation induced by Helicobacter pylori infection in a mouse
model. Nutrients 7(1): 306–320.
Sasidharan, N.K., Sreekala, S.R., Jacob, J. and Nambisan, B. 2014. In vitro synergistic effect of curcumin in combination
with third generation cephalosporins against bacteria associated with infectious diarrhea. Biomed. Res. Int. (1): 1–8.
Satoh, Y. 1992. Japanese Skin Type (JST). Proc. Jap. Comm. for Sunlight Prot. 2: 62–70.
Schallreuter, K.U., Wood, J.M., Pittelkow, M.R., Buttner, G., Swanson, N. and Korner, C. 1996. Increased monoamine oxidase
A activity in the epidermis of patients with vitiligo. Arch. Dermatol. Res. 288(1): 14–18.
Sharma, M., Manoharlal, R., Puri, N. and Prasad, R. 2010. Antifungal curcumin induces reactive oxygen species and triggers
an early apoptosis but prevents hyphae development by targeting the global repressor TUP1 in Candida albicans. Biosci.
Rep. 30(1): 391–404.
Shanmugam, M.K., Rane, G., Kanchi , M.M., Arfuso, F., Chinnathambi , A., Zayed , M.E., Alharbi , S.A., Tan , B.K.H., Kumar,
A.P. and Sethi, G. 2015. The multifaceted role of curcumin in cancer prevention and treatment. Molecules, 2728–2769.
Shishodia, S., Sethi, G. and Aggarwal, B.B. 2005. Curcumin: getting back to the roots. Ann. NY Acad. Sci. 1056(1): 206–217.
Shrishail, D.H., Harish, K., Ravichandra, H., Tulsianand, G. and Shruthi, S.D. 2013. Turmeric: Nature’s precious medicine.
Asian J. Pharm. Clin. Res. 6(3): 10–16.
Signaling by Dietary Polyphenols. In: Surh, Y.J., Dong, Z., Cadenas, E. and Packer, L. (eds.). Boca.
Singh, R.P. and Jain, D.A. 2012. Evaluation of antimicrobial activity of curcuminoids isolated from turmeric. Int. J. Pharm.
Life Sci. 3(1): 1368–1376.
Singh, V., Pal, M., Gupta, S., Tiwari, S.K., Malkunje, L. and Das, S. 2013. Turmeric—a new treatment option for lichen
planus: a pilot study. Natl. J. Maxillofac. Surg. 4: 198–201.
Sirenia, G.P., Rafael, C.Z., Mario, A.R., María, L.M. and Araceli, C.R. 2017. Curcumin alters the cytoskeleton and microtubule
organization on trophozoites of Giardia lamblia. Acta Tropica. 172(1): 113–121.
Sofic, E., Riederer, P., Heinsen, H., Beckmann, H., Reynolds, G.P., Hebenstreit, G. and Youdim, M.B.H. 1988. Increased
iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J. Neural Transm. 74: 199–205.
Sommerfeld, B. 2007. Randomised, placebo-controlled, double-blind, split-face study on the clinical efficacy of Tricutan®
on skin firmness. Phytomedicine 14(11): 711–715.
Sun, M., Gao, Y., Guo, C., Cao, F., Song, Z., Xi, Y., Yu, A., Li, A. and Zhai, G. 2010. Enhancement of transport of curcumin
to brain in mice by poly(n-butylcyanoacrylate) nanoparticle. J. Nanopart. Res. 12: 3111–3122.
Szczepanowicz, K., Jantas, D., Piotrowski, M., Staroń, J., Leśkiewicz, K., Regulska, M., Lasoń, W. and Warszyński, P. 2016.
Encapsulation of curcumin in polyelectrolyte nanocapsules and their neuroprotective activity. Nanotechnology 27: 355101.
Taher, M.M., Lammering, G., Hershey, C. and Valerie, K. 2003. Curcumin inhibits ultraviolet light induced human
immunodeficiency virus gene expression. Mol. Cell Biochem. 254(1): 289–297.
Takahashi, Y., Fukushima, Y., Kondo, K. and Ichihashi, M. 2017. Facial skin photo-aging and development of hyperpigmented
spots from children to middle-aged Japanese woman. Skin Res. Technol. 23(4): 613–618.
Taylor, J.S. 2002. New structural and mechanistic insight into the A-rule and the instructional and non-instructional behavior
of DNA photoproducts and other lesions. Mutat. Res. 510: 55–70.
Teixeira, C., Cury, Y., Moreira, V., Picolob, G. and Chaves, F. 2009. Inflammation induced by Bothrops asper venom. Toxicon.
54(1): 988–997.
Thangapazham, R., Sharad, S. and Maheshwari, R. 2013. Skin regenerative potentials of curcumin. Biofactors 39: 141–9.
Thangapazham, R.L., Sharma, A. and Maheshwari, R.K. 2007. Beneficial role of curcumin in skin diseases. In: Aggarwal,
B.B., Surh, Y.J. and Shishodia, S. (eds.). Boston: Springer.
Tonnesen, H.H., deVries, H., Karlsen, J. and Henegouwen, G.B.V. 1987. Studies on curcumin and curcuminoids. IX:
Investigation of the photobiological activity of curcumin using bacterial indicator systems. J. Pharm Sci. 76(5): 371–373.
Tyagi, P., Singh, M., Kumari, H., Kumari, A. and Mukhopadhyay, K. 2015. Bactericidal activity of curcumin I is associated
with damaging of bacterial Membrane. PLoS ONE 10(3): 1–15.
Ullah, F., Liang, A., Rangel, A., Gyengesi, E., Niedermayer, G. and Munch, G. 2017. High bioavailability curcumin: an
anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic
neurooinflammation. Arch. Toxicol. 91(4): 1623–1634. https://doi.org/10.1007/s00204-017-1939-4.
Vajragupta, O., Boonchoong, P., Watanabe, H., Tohda, M., Kummasud, N. and Sumanont, Y. 2003. Manganese complexes
of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity. Free Radical
Biol. Med. 35: 1632–44.
Vallianou, N.G., Evangelopoulos, A., Schizas, N. and Kazazis, C. 2015. Potential anticancer properties and mechanisms of
action of curcumin. Anticancer Res. 35: 645–651.
Vyas, K. 2015. The cure is in the roots: turmeric. J. Nutr. Disorders Ther. 5: 163.
Wahlstrom, B. and Blennow, G. 1978. A study on the fate of curcumin in the rat. Acta Pharmacol. Toxicol. 43(2): 86–92.
Wang, J., Du, X.X., Jiang, H. and Xie, J.X. 2009. Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-
oxidation and nuclear factor-kappa B modulation in MES23.5 cells. Biochem. Pharmacol. 78: 178–83.
Wang, L., Chen, X. and Du, Z. 2017. Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase
γ depletion disrupting cellular bioenergetics. J. Exp. Clin. Canc. Res.: CR. 36:47. doi:10.1186/s13046-017-0513-5.
Wang, M.S., Boddapati, S., Emadi, S. and Sierks, M.R. 2010. Curcumin reduces alpha-synuclein induced cytotoxicity in
Parkinson’s disease cell model. BMC Neurosci. 11: 57–67.
Wang, S.L., Li, Y., Wen, Y., Chen, Y.F., Na, L.X., Li, S.T. and Sun, C.H. 2009. Curcumin, a potential inhibitor of up-regulation
of TNF-alpha and IL-6 induced by palmitate in 3T3- L1 adipocytes through NF-kappaB and JNK pathway. Biomed.
Environ. Sci. 22: 32–9.
Wang, X., Kim, J.R., Lee, S.B., Kim, Y.J., Jung, M.Y., Kwon, H.K and Ahn, Y.J. 2014. Effects of curcuminoids identified in
rhizomes of Curcuma longa on BACE-1 inhibitory and behavioral activity and lifespan of Alzheimer’s disease Drosophila
models. BMC Complem. Altern. M. 14: 88.
Wang, Z.S., Chen, L.Z., Zhou, H.P., Liu, X.H. and Chen F.H. 2017. Diarylpentadienone derivatives (curcumin analogues):
Synthesis and anti-inflammatory activity. Bioorg. Med. Chem. Lett. 27(8): 1803–1807.
Williums, H.C., Dellavalle, R.P. and Garner, S. 2012. Acne vulgaris. Lancet 379: 361–372.
Xu, Y., Ku, B., Cui, L., Li, X., Barish, P.A., Foster, T.C. and Ogle, W.O. 2007. Curcumin reverses impaired hippocampal
neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically
stressed rats. Brain Res. 1162: 9–18.
Yach, D., Hawkes, C., Gould, C.L. and Hofman K.J. 2004. The global burden of chronic diseases overcoming impediments
to prevention and control. J. Amer. Med. Assoc. 291(21): 2616–2622.
Yang, F., Lim, G.P., Begum, A.N., Ubeda, O.J., Simmons, M.R., Ambegaokar, S.S., Chen, P.P., Kayed, R., Glabe,
C.G., Frautschy, SA. and Cole, G.M. 2005. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds
plaques, and reduces amyloid in vivo. J. Biol. Chem. 280: 5892–901.
Yang, J.Y., Zhong, X., Yum, H.W., Lee, H.J., Kundu, J.K., Na, H.K. and Surh, Y.J. 2013. Curcumin inhibits STAT3 signaling
in the colon of dextran sulfate sodium-treated mice. J. Cancer Prev. 18(2): 186–91.
Yang, Z., Zhao, T., Zou, Y., Zhang, J.H. and Feng, H. 2014. Curcumin inhibits microglia inflammation and confers
neuroprotection in intracerebral hemorrhage. Immunol. Lett. 160(1): 89–95. doi:10.1016/j.imlet.2014.03.005.
Yao, E.C. and Xue, L. 2014. Therapeutic Effects of Curcumin on Alzheimer’s Disease. Adv. Alzheimer Dis. 3(1): 145–159.
Yoritaka, A., Hattori, N., Uchida, K., Tanaka, M., Stadtman, E.R. and Mizuno, Y. 1996. Immunohistochemical detection of
4-hydroxynonenal protein adducts in Parkinson disease. Proc. Natl. Acad. Sci. USA 93: 2696–701.
Zari, S. and Zari, T. 2015. A review of four common medicinal plants used to treat eczema. J. Med. Plant. Res. 9(24): 702–711.
Zbarsky, V., Datla, K.P., Parkar, S., Rai, D.K., Aruoma, O.I. and Dexter, D.T. 2005. Neuroprotective properties of the natural
phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease.
Free Radical Res. 39: 1119–25.
Zhang, Y., Liang, D., Dong, L., Ge X., Xu, F., Chen W., Dai, Y., Li, H., Zou, P., Yang, S. and Liang, G. 2015. Anti-inflammatory
effects of novel curcumin analogs in experimental acute lung injury. Respir. Res. 16: 43–55.
Zhu, Y.G., Chen, X.C., Chen, Z.Z., Zeng, Y.Q., Shi, G.B., Su, Y.H. and Peng, X. 2004. Curcumin protects mitochondria from
oxidative damage and attenuates apoptosis in cortical neurons. Acta Pharmacol. Sin. 25: 1606–12.
9
Medicinal Plants of the Khyang Tribe of
Bandarban District, Bangladesh
Md. Shahadat Hossan,1 Christophe Wiart,2 Emratul Jannat,3
Abu Hanif,4 Prozzal Roy,5 Taufiq Rahman,6 Rownak Jahan,7
Tracey D. Bradshaw1 and Mohammed Rahmatullah8,*
Introduction
The Khyangs are a small ethnic group of people inhabiting the Chittagong Hill Tracts region in the
southeast part of Bangladesh. At present, they can be mainly found in Rangamati and Bandarban districts
of Chittagong Hill Tracts. Their total population is estimated to be around 2500. The Khyangs possibly
came to their present habitat from neighboring Burma (presently Myanmar). They are considered by
anthropologists as belonging to the Kuki-Chin race of the Tibeto-Burman group. Khyang societies are
headed by a leader for each society, the leader being known as a ‘Karbari’.
According to the Khyang elders, once upon a time they were nature worshippers but later converted to
Buddhism and presently Christianity. Khyang society is patriarchal. Their method of cultivation is known
as ‘jhum’, where a forest area is burnt completely followed by cultivation on that area for 2–3 years and
then moving on to a new area and letting the previous area to revert back slowly to a forested state.
Humans have recognized the need for medicines to treat and cure diseases since their advent. It has
been reported that humans were aware of medicinal properties of plants, possibly as early as 3000 BCE
(Sofowara 1982). Historical surveys have indicated that the eastern region of the Mediterranean may always
have been a rich source of medicinal plants and that indigenous Arab medicine was a major contributor
to the development of modern medicine in Europe (Saad et al. 2005). The Edwin Smith Papyrus and the
Ebers Papyrus indicate that the Egyptians were using herbal medicine during the 17th and 16th centuries
BCE (El-Soud 2010). Ayurveda (India), Greek and Chinese traditional medicine also developed from
around 2000 to 4000 years ago (Subbarayappa 2001).
1
School of Pharmacy, University of Nottingham, UK.
2
School of Pharmacy, University of Nottingham Malaysia Campus, Malaysia.
3
BDS, Pioneer Dental College and Hospital, Dhaka, Bangladesh.
4
Onehousing Group, London, UK.
5
Zuellig Pharma Bangladesh Limited, Bangladesh.
6
Department of Pharmacology, University of Cambridge, Tennis Court Road, CB2 1PD, UK.
7
Department of Biotechnology & Genetic Engineering, University of Development Alternative, Dhaka, Bangladesh.
8
Department of Pharmacy, University of Development Alternative, Dhaka, Bangladesh.
* Corresponding author: rahamatm@hotmail.com
Medicinal Plants of the Khyang Tribe of Bandarban District, Bangladesh 157
In modern times, it has been recognized that the ancient medicinal knowledge of human beings can
play a vital role in the discovery of efficacious drugs (Balick and Cox 1996). Since tribes and various
indigenous people have used medicines for a long time period, they are usually the best knowledge holders
of ancient forms of cure. It has also been recognized that phytotherapeutic practices, that is treatment of
diseases with plants is the most common form of practice among indigenous people, possibly partly because
of the abundance of plants, and partly because any given plant may possess hundreds of phytochemicals
with potential disease curing ability. Moreover, plants are affordable and can yield affordable medicines
in the form of simple decoctions or pastes, which can be simply used either orally or topically.
As such, it is important to document the medicinal practices of tribes before they get totally lost
due to the onslaught of ‘civilization’ and ‘globalization’. Bangladesh is possibly home to over a hundred
small or large tribes. However, ethnomedicinal data on these tribes are practically negligible. We have
previously documented the traditional medicinal practices of folk medicinal practitioners and a few tribes
of Bangladesh (Akter et al. 2014, Azad et al. 2014, Islam et al. 2015a,b, Rahman and Rahmatullah 2015,
Zaman et al. 2015, Seraj et al. 2017). The present chapter gives an account of the traditional medicinal
practices of Khyang Tribal Medicinal Practitioners (TMPs) residing in Khyaplong-para and Shuanlo-
para in Rowangchaari of Bandarban district, Bangladesh. To our knowledge, there has been scant or no
information previously on medicinal plants of the Khyang.
Loss of Khyang traditional medicinal practices including their phyto-therapeutic knowledge may
prove to be disastrous in the long run because along with ongoing rapid deforestation, this may lead to
loss of both medicinal plants and their uses. Discovery of important and vital drugs may suffer from these
dual losses. The Khyangs have inhabited their present area for a long time and so are most knowledgeable
about the local plant species. The aim of the present study was to document the Khyang tribal medicinal
practices involving mostly plants before such knowledge and plant species become irretrievably lost.
Ethnomedicinal survey
Ethnomedicinal survey is essentially the tool to collect data on tribal medicinal plants and their uses.
The present data was obtained from the Khyang tribal medicinal practitioners (TMPs) practicing among
the Khyang communities of Khyaplong-para and Shuanlo-para in Rowangchaari of Bandarban district,
Bangladesh (Fig. 9.1) through such a survey. Altogether, a total of 15 Khyang TMPs were interviewed,
thirteen of them being males and two females. The names and other details of the TMPs are given in Table 9.1.
The ages of the TMPs ranged from 37–70 years, suggesting that even today these Khyang communities
have not given up on their traditional medicinal treatments.
Ethnomedicinal information is generally collected through interviews of tribal TMPs, the present
study being no exception. Interviews were conducted with the help of a semi-structured questionnaire
and the guided field-walk method of Martin (1995) and Maundu (1995). In this method, the TMPs took
the interviewers on guided field-walks both individually and collectively through areas from where they
collected their medicinal plants or plant parts (Fig. 9.2), pointed out the plants, and described their uses.
Plant species used by the Khyangs

The Khyang TMPs were observed to use 84 plant species in their treatment. The names of the plant species
along with other taxonomic information are shown in Table 9.2. Khyang treatment appeared to be basically
monoherbal, with one whole plant or plant part being used to treat a single or multiple disease(s). The
formulations and treatment modes were also fairly simple with plant paste, decoction or juice being taken
either orally or applied topically. Gastrointestinal disorders in the form of dysentery, blood dysentery,
and diarrhea were the most common ailments treated. However, the TMPs had phytomedicines for some
serious ailments (by serious is meant that existing allopathic medicines do not bring total cure) like heart
disorders, arthritis, rheumatism, hypertension, tumor, cancer, and diabetes.
Surprisingly, although the forested regions of the Chittagong Hill Tracts are known for prevalence of
malaria (Starzengruber et al. 2014) including cerebral malaria, the Khyang TMPs did not mention malaria
among the diseases treated. The TMPs, on the other hand, treated fever, which may be a symptomatic
Fig. 9.1 Map showing Bangladesh (left) and study area (right).
Table 9.1 Information on the interviewed Khyang tribal healers.
Name of traditional healer Age Gender Area

Aung-marrak 60 M Khyaplong-para
Chaillong Khyang* 58 M Khyaplong-para
Paichong 70 M Khyaplong-para
Paisra 37 F Khyaplong-para
Prothoai Khyang (Karbari)* 63 M Khyaplong-para
Rathung 51 M Khyaplong-para
Shalashu 49 M Shuanlo-para
Shala-u khyang 39 M Shuanlo-para
Shoikh-la 44 M Shuanlo-para
Sialian Khyang* 52 F Khyaplong-para
Timraw 53 M Khyaplong-para
Tinglaw 66 M Shuanlo-para
Tonlapru 55 M Shuanlo-para
Unshalank 40 M Khyaplong-para
Vanlalshia 60 M Khyaplong-para
*Principal healers
Fig. 9.2 Collection of medicinal plants in guided field-walks with Khyang TMPs.
treatment of malaria, for malaria causes fever. It is also interesting in this aspect that fever, including fever
with convulsions (this type of fever may be malarial fever) was treated with a number of different plant
species, which indicates the importance given by the TMPs to treat fever.
Selected phytochemical constituents of Khyang medicinal plants and their

pharmacological activities
Table 9.3 gives an account of the important phytoconstituent(s) present in the Khyang medicinal plants and
shows that although a large number of medicinal plants used by the Khyang TMPs are yet to be investigated
for their phytochemical constituents, the plants that have been investigated possess bioactive compounds
relevant to their medicinal uses plus possibly other therapeutic uses. For instance, one of the plants used
to treat tumor was Amorphophallus paeoniifolius (Dennst.) Nicolson. The plant contains quercetin; the
compound can reverse pre-neoplastic lesions caused by chemical carcinogenesis (Carrasco-Torres et al.
2017). Quercetin also reportedly induces apoptosis and necroptosis in MCF-7 breast cancer cells (Khorsandi
et al. 2017). To give just one more example, Ocimum americanum was also used by the Khyang TMPs
to treat tumors. The anti-proliferative activity of the essential oils obtained from this plant collected from
Burkina Faso has been described (Bayala et al. 2014). Moreover, the plant contains rosmarinic acid, which
may be a good anti-cancer agent (Dall’Acqua et al. 2017). The plant furthermore contains ursolic acid,
which reportedly can inhibit hepatocellular carcinoma (Liu et al. 2017, Zhao et al. 2017). The structures
of some important phytoconstituents present in the Khyang medicinal plants are shown in Fig. 9.3. The
reported pharmacological activities of some of the important phytoconstituents are discussed (below).
This following discussion will be essentially based on reviews of individual phytoconstituent instead of
describing every individual paper dealing with any given pharmacological activity of the phytoconstituent.
Abelmoschus moschatus Medik. Myricetin, present in the plant, reportedly possesses anti-oxidant, anti-
carcinogen, anti-viral, anti-diabetic, anti-thrombotic, anti-microbial activities, and useful in the treatment
of gout and diarrhea (Ong and Khoo, 1997).
Acacia catechu (L.f.) Willd. Various biologically active phytocomponents present in the plant are
Catechin, Epicatechin, Epicatechin gallate, Procatechinic acid, Quercetin, Rutin, and Kaempferol. Catechin,
epicatechin, and epicatechin gallate possess anti-cancer, hypocholesterolemic and hypotensive activities
(Sonoda et al. 2015). Quercetin is antioxidant and can be beneficial in cancer, allergy, asthma, diabetes,
cardiovascular diseases, oral mucosa (mouse apthous ulcers), gastric ulceration, hypertension, immunity and
Table 9.2 Medicinal plants and formulations of the Khyang tribe.
Serial No. Botanical name Family name Local name Ailment/medical use Part utilized Mode of preparation (if known)
1. Abelmoschus moschatus Medik. Malvaceae Vomla/Mishun Aphrodisiac, Stress, Depression, Leaf, Root, Seed Juice obtained from leaf and root is taken
Sore throat, Throat pain, Tonsillitis, orally.
Scabies Seed and root paste is applied topically for pain
or scabies.
2. Acacia catechu (L.f.) Willd. Fabaceae Khangmui Acne, Leprosy, Gum pain, Chronic Fruit, Leaf Infusion obtained from leaf and fruit is taken
blood dysentery orally.
Fruit juice is applied externally.
3. Acacia farnesiana (Linn.) Willd. Fabaceae Hoija Leprosy, Gum pain Bark, Leaf Dried leaf and bark powder or concentrated
infusion of leaf and bark is applied for 7-10
days topically.
4. Achyranthes aspera L. Amaranthaceae Saikka Jaundice, Flatulence, Expectorant, Root, Leaf Root powder is taken with honey, daily 1 spoon
Constipation, Excessive bleeding twice for 5–7 days.
during menstruation, Heart disease, Leaf juice/squeezed leaf applied as coagulant.
Coagulant
5. Acorus calamus L. Acoraceae Thith Toothache Root Fresh root juice is applied.
6. Ageratum conyzoides (L.) L. Asteraceae Urr Antiseptic, Blood coagulant Leaf Squeezed leaf applied to cut area and held for
a while.
7. Allophylus cobbe (L.) Räusch. Sapindaceae Natokthum Ulcer, Gastrointestinal tract (GIT) Root Decoction of root taken orally.
problem
8. Alpinia conchigera Griff. Zingiberaceae Soilopropat Stomach ache, Boils, Wound, Leaf, Root Leaf juice taken for stomach ache.
Swelling, Inflammation Root paste applied topically or rubbed.
9. Alstonia scholaris (L.) R.Br. Apocynaceae Shijgi Acne, Blood dysentery, Bark, Flower, Acne (exudates rubbed), Blood dysentery (bark
Anthelmintic, Leprosy Exudates juice taken orally), Anthelmintic (bark juice
taken orally), Leprosy (exudates rubbed).
10. Amorphophallus paeoniifolius Araceae Boil, Piles, Tumor, Inflammation, Root Root paste is applied and infusion of root is
(Dennst.) Nicolson Bronchitis, Premature ejaculations, taken orally.
Aphrodisiac
11. Antidesma acuminatum Wall. Phyllanthaceae Chiamchi Anaemia, Constipation Fruit The fruit salad can be eaten with food/meal as
side daily once for one week to treat anaemia
and constipation.
12. Argyreia capitiformis (Poir.) Convolvulaceae Lungmulthur Insect bite, Anti-poisonous, Itch, Root, Leaf Leaf and root paste is rubbed on the affected
Ooststr. Scabies, Bone fracture, Fever area to treat insect bite, as anti-poison, and for
itch, scabies, and bone fracture.
13. Aristolochia bracteolata Linn. Aristolochiaceae Aan-h-lum Convulsion in children, Fever Leaf Infusion of leaf is boiled and cooled; the
infusion is then used for shower.
14. Bauhinia acuminata Linn. Fabaceae Laldir Epilepsy, Cough, Jaundice, Cold, Root The decoction of the root is used to gargle to
Vermifuge get relief from cough and cold.
One tea spoon decoction can be taken orally
with other drinks or water for 5–7 days
once daily to treat jaundice, epilepsy, and as
vermifuge.
15. Begonia barbata Wall. Begoniaceae Kukthur (red) Diarrhea of children Leaf, Stem Obtained juice from leaf and stem is taken 3
times with breast milk for one day.
16. Begonia silhetensis (A. DC.) C.B. Begoniaceae Kukthur (white) Diarrhea of children Leaf, Stem Obtained juice from leaf and stem is taken 3
Clarke times with breast milk for one day.
17. Belamcanda chinensis (L.) DC. Iridaceae Lily Breathing problem, Skin disorder Root, Leaf Root and leaf extract (prepared by boiling with
water and concentrating) is applied topically
for skin disorder and infusion is taken orally for
breathing problem.
18. Breynia retusa (Dennst.) Alston Phyllanthaceae Fulamulthir Cough, Flu, Toothache, Dysentery, Fruit, Root, Leaf Juice obtained from fruit & leaves taken orally
Conjunctivitis for dysentery & cough, root juice topically
applied for toothache and conjunctivitis.
19. Calotropis procera (Ait.) Ait.f. Asclepiadaceae Muru-o Joint pain, Arthritis, Muscle pain Leaf Leaves are warmed and applied to painful
areas.
20. Cassia alata L. Fabaceae Rulrijaw/ Ringworm, Eczema Leaf Leaf juice is applied topically.
Builakung
21. Casuarina equisetifolia L. Casuarinaceae Farthing Beriberi, Diarrhea, Swelling, Bark Bark paste is applied topically for swelling.
Astringent Bark juice is also taken half spoon daily for 2
days in case of diarrhoea.
22. Centella asiatica (L.) Urb. Apiaceae Mawtung Stomach ache, Stomach fullness, Whole plant Whole plant is taken orally as chutney/salad.
Insect bite or poisoning due to
insect bite
Table 9.2 contd.…

…Table 9.2 contd.
23. Citrus aurantifolia (Christm.) Rutaceae Raite Anthelmintic, Headache, Skin Fruit, Leaf Juice of fruit and leaf taken orally.
Swingle disorder
24. Clausena suffruticosa Wight & Rutaceae Changeerathing Arthritis, Joint pain Root, Bark Bark and root paste is rubbed topically.
Arn.
25. Clerodendrum indicum (L.) Verbenaceae Aanfui Tranquilizer, Mental illness Leaf, Root Paste of root and leaf is applied on top of head.
Kuntze. Clean leaves and roots are boiled with water
and the water used to take a bath to cure mental
illness.
26. Clerodendrum viscosum Vent. Verbenaceae Koidim Nausea, Vomiting, Post-partum Leaf Half tea spoon of leaf juice is taken orally
diarrhea and burning in the hand twice daily for 3 days.
and feet
27. Cocos nucifera L. Arecaceae Unchitai Anthelmintic, Malaria, Aphrodisiac, Fruit, Leaf Fresh coconut meat is taken orally. Coconut
Vermifuge water is taken orally to treat all of these
diseases.
28. Curculigo recurvata Dryand. Hypoxidaceae Nathial Aphrodisiac Rhizome Rhizome juice is taken orally.
29. Cuscuta reflexa Roxb. Cuscutaceae Chokro Jaundice, Liver disease, Uterus and Stem Obtained juice from stem is taken orally.
Liver pain Stem is cooked and taken orally as curry.
30. Cyperus difformis L. Cyperaceae Thit Mental problem, Tranquilizer Root Infusion of root used for shower. Root juice is
taken orally.
31. Delonix regia (Bojer) Raf. Fabaceae Sandri Antibacterial, Rheumatism, Fungal Root, Bark Paste of root and bark is topically applied.
infection
32. Dillenia indica L. Dilleniaceae Aitlung Edible, Blood dysentery, Flu and Fruit Fruits are eaten as pickle. Ripe fruit is taken
fever orally.
33. Dioscorea glabra Roxb. Dioscoreaceae Breng Astringent, Jaundice, Topical pain Rhizome, Leaf Rhizomes are cooked and eaten as curry,
leaf juice is taken orally in case of jaundice,
crushed leaf is applied topically to pain area to
get relief from pain.
34. Dioscorea pentaphylla L. Dioscoreaceae Manshimoklok Stomach ache, Leprosy, Fever Leaf Leaf juice is taken orally for stomach ache and
fever and applied topically for leprosy.
35. Dioscorea sp. Dioscoreaceae Toalrang Snake bite, Insect bite, Fruit Juice obtained from fruit is applied or rubbed
Anti-poisonous on affected area.
36. Elephantopus scaber L. Asteraceae Mrangkhua Heal pain, Heal inflammation Leaf Heated leaf is applied to the heal after
warming.
37. Erythrina variegate L. Fabaceae Faiseo Worm infection Root 1 teaspoon root juice is taken daily once for 3
days.
38. Eupatorium odoratum L. Asteraceae Pache-ye Astringent, Coagulant Leaf Squeezed leaf applied to cut area and held for
a while.
39. Euphorbia hirta L. Euphorbiaceae Dudhothe Scabies, Wound, Itch Leaf Leaves are boiled in water and the water used
to take a bath.
40. Globba marantina L. Zingiberaceae Aienghang Malaria, Typhoid, Chronic fever, Rhizome Juice obtained from rhizome is orally taken
Kala azar, Fever with extreme (1 tea spoon daily twice for 2 days).
convulsions
41. Gymnopetalum cochinchinense Cucurbitaceae Mansonkhirat/ Acidity, GIT problem, Leucorrhoea Fruit Infusion obtained from dried crushed fruit is
(Lour.) Kurz. Aankhate/ taken orally.
Tho-umpong
42. Hedyotis scandens Roxb. Rubiaceae Taruthing GIT problem, Boil, Stomach ache Leaf Paste obtained from leaf is applied topically
for boils.
Juice/Infusion obtained from leaves is taken
orally for GIT problem or stomach ache.
43. Hoya parasitica Wall. Asclepiadaceae Nempar Fever, Body ache Leaf Leaf juice or paste of leaf is used externally.
44. Hyptis suaveolens (L.) Poit. Lamiaceae Baish-rung Stomach fullness, GIT Seed Overnight soaked seed in water is taken orally.
45. Ixora parviflora Vahl Rubiacea Toalchu Menstrual pain Root Crushed root powder + Vomla (Abelmoschus
moschatus) plant’s crushed root powder is
mixed with 1 tea spoon water and taken orally.
46. Kalanchoe pinnata (Lam.) Pers. Crassulaceae Nasirkhaw Cough, Cold, Flu Leaf Leaf is heated over fire for 1–2 minutes and
then squeezed to obtain juice, which is taken
orally. Dose: 2 tea spoons twice daily for 3
days.
47. Lygodium flexuosum (L.) Sw. Lygodiaceae Paingjemjit Increasing of breast milk, Loss of Leaf Leaf juice is taken with coconut milk to
appetite, Diuretic, Ear infection increase breast milk for breast feeding mother.
Leaf juice is taken orally for loss of appetite
and as diuretic.
Leaf juice is applied in the ear for otitis (ear
infection).
48. Mikania cordata (Burm.f.) B.L. Asteraceae Bache-a Coagulant, Astringent Leaf Leaf is squeezed and applied to cut area.
Rob.
Table 9.2 contd.…

…Table 9.2 contd.
49. Mimosa pudica L. Fabaceae Beljak Constipation, Acidity, Gingivitis Leaf, Root Juice obtained from leaf and root is taken
orally.
50. Moghania macrophylla (Willd.) Fabaceae Thialai- Arthritis, Joint pain Leaf Leaf warmed by heat is applied on pain-
Kuntze padarkep affected area.
51. Morinda angustifolia Roxb. Rubiaceae Jongmit Bone fracture, Arthritis, Leaf Leaf paste is applied topically.
Inflammation
52. Mucuna gigantean (Willd.) DC. Fabaceae Bybra Astringent, Blood coagulant Leaf Leaf juice is applied to cut area.
53. Mussaenda corymbosa Roxb. Rubiaceae Kuthbul Tumor, Astringent Root, Leaf Extract of root and leaf is applied topically.
54. Nymphaea nouchali Burm.f. Nymphaeaceae Ba-aa Anaemia, Bile disease, Leaf, Rhizome Boiled leaf and rhizome is taken orally with
Menstruation problem food.
55. Ocimum americanum L. Lamiaceae Vipena pang Tumor, Infection, Ulcer, Cancer Leaf, Aerial part Aerial part or leaf juice is applied externally
for infection and taken orally for ulcer, cancer
and tumour.
56. Opuntia dillenii Ker-Gawl. Cactaceae Renkung Asthma, Leaf, Exudates Leaf juice is taken orally for asthma.
Anti-poisonous, Insect bite, Exudates applied topically for insect bite and
Rheumatism rheumatism.
57. Phyllanthus emblica L. Phyllanthaceae Shuanlu At the time of urination pain in Fruit Fruit juice mixed with rice washed water is
lower abdomen, Burning sensation taken orally until cure.
in urinary tract, Leucorrhoea
58. Premna scandens Roxb. Verbenaceae Aan-norai Neurological disorder, Stress, Leaf Young leaves are eaten as chutney/salad.
Tranquilizer
59. Psychotria calocarpa Kurz. Rubiaceae Shipujo-o Abscess, Scabies Root Root paste is applied or rubbed topically.
60. Sansevieria roxburghiana Schult. Asparagaceae Faackrethal Otitis, Wound, Scabies Leaf Crushed leaf is rubbed on affected area.
and Schult.f.
61. Sarcochlamys pulcherrima (Roxb.) Urticaceae Naplung Fever, Gout, Goitre Leaf, Root Infusion obtained from leaf is taken orally.
Gaud.
62. Scoparia dulcis L. Scrophulariaceae Turojot-turpang Fever (children), Stomach ache, Root Root juice at low concentration is taken with
Dysentery breast milk for fever in children.
For stomach ache and dysentery in adults, fresh
juice is taken twice daily for 2–3 days.
63. Selaginella decipiens Warb. Selaginellaceae Shikithing Gout, Vertigo Whole plant Whole plant decoction is used to rub on the
painful area.
64. Smilax macrophylla Willd. Smilacaceae Wisisong Toothache Root Root juice is applied on affected tooth.
65. Solanum lasiocarpum Dunal Solanaceae Shialmandak Mental disorder, Scabies, Piles, Leaf Leaf juice or decoction is mixed with bath
Allergy in eye, Leprosy, Fever, water while bathing to treat scabies, piles,
Cough, Nausea leprosy, allergy, fever and the rest of the
ailments.
66. Solanum torvum Sw. Solanaceae Mirem Blood dysentery, Low Blood Leaf, Root Decoction of root is taken half tea spoon daily
pressure, Arthritis for 3–5 days with meal for dysentery and blood
pressure.
Leaf juice or leaf paste is used topically for
arthritic pain.
67. Spilanthes calva DC. Asteraceae Aankhasaai Toothache Flower Flower paste is applied to affected area.
68. Spondias pinnata Kurz Anacardiaceae Thoailo-o Wound, Otitis Fruit, Bark Juice obtained from fruit and bark is applied
into the ear for otitis and topically applied to
wounds.
69. Spondias cytherea Sonn. Anacardiaceae Thoai-h-lok Excessive bleeding during Root Juice obtained from root is taken orally.
menstruation
70. Synedrella nodiflora (L.) Gaertn. Asteraceae Man-ankhasha Anthelmintic Whole plant Infusion of whole plant is taken 1 spoon orally
2–3 times a day for 3 days.
71. Syzygium cumini (L.) Skeels Myrtaceae Bulbu Diabetes, Dysentery, Antiemetic Seed Dried crushed seed powder taken orally 2
spoons daily for four weeks.
72. Tabernaemontana divaricata (L.) Apocynaceae Sisakrai Leprosy Fruit Powder of dry fruit applied topically.
R. Br. Roxb.
73. Tamarindus indica L. Fabaceae Theng-ther-le Conjunctivitis, Loss of appetite, Fruit Ripe fruit pulp is eaten for loss of appetite.
Inflammation Diluted (1:5) leaf juice is used for eye
disease. Leaf paste is applied topically for
inflammation.
74. Terminalia bellirica (Gaertn.) Combretaceae Thakbraw Expectorant, Conjunctivitis, Fruit Infusion of fruit is taken orally.
Roxb. Asthma, Aphrodisiac
75. Terminalia chebula Retz. Combretaceae Thabra Cough, Diarrhea Bark, Seed Seed pulp is taken orally for diarrhoea.
Bark juice is taken orally for cough.
76. Thunbergia grandiflora Roxb. Acanthaceae Jongrikhaw Eye problem, Cut, Astringent, Leaf, Stem Leaf and stem juice is taken orally as astringent
Wound or applied topically.
77. Thysanolaena maxima (Roxb.) Poaceae Jaruthing Boil, Abscess, Cancer (externally Leaf Leaf paste is applied topically.
Kuntze visible tumor)
Table 9.2 contd.…
…Table 9.2 contd.
78. Trichosanthes tricuspidata Lour. Cucurbitaceae Hedopang/ Tumor, stomach ulcer, cancer Fruit, Seed Sun dried fruits and seed are soaked in tribal
Mokal wine for 3 days; this wine is then taken orally 1
table spoon daily at night for 2–3 months.
79. Urena lobata L. Malvaceae Pethai/Koptorik Fever, Cold sore, Aphthae Leaf, Root Leaf juice is applied externally/topically for
cold sore and aphthae.
Infusion of leaf and root is used for shower to
cure fever.
80. Vitex negundo L. Verbenaceae Namturpung Expectorant, Flatulence, Stress, Fruit, Leaf Fume from burning dried leaf is inhaled for
Headache, Leprosy, Anthelmintic, headache and Stress.
Antipyretic Dried fruit powder is taken orally for worms
and fever.
Dried fruit powder is applied topically for
leprosy treatment.
81. Vitis pedata L. Vitaceae Jolpol Jaundice, Neurological problem, Leaf Leaf is cooked and taken as vegetable or curry
Tranquilizer (cooked with hilly crab).
82. Vitis pentagona (Roxb.) Lawson Vitaceae Dingdung Vertigo, Tranquilizer Leaf Leaf juice is warmed and after cooling topically
applied to scalp.
83. Zingiber officinale Roscoe Zingiberaceae Tumreng Blood pressure, Dyspnoea, Acidity, Rhizome Juice obtained from rhizome is taken orally.
Stomach upset
84. Ziziphus mauritiana Lam. Rhamnaceae Merai Dysentery with blood and mucus in Bark, Fruit Bark juice is taken orally.
stool, Edible Fruits are eaten.
Fig. 9.3 Bioactive phenolic present in various plants used by the Khyang tribe.
infections, inflammation, injury and pain, prostatitis/interstitial cystitis, arthritis, metabolic syndrome, and
obesity (Kelly 2011). Rutin reportedly has pharmacological benefits against cancer, diabetes, hypertension,
and hypercholesterolemia (Al-Dhabi et al. 2015). Kaempferol and some of its glycosides reportedly possess
antioxidant, anti-inflammatory, anti-cancer, anti-microbial, cardioprotective, neuroprotective, anti-diabetic,
anti-osteoporotic, anxiolytic, analgesic, and anti-allergic activities (Calderón-Montaño et al. 2011).
Acacia farnesiana (Linn.) Willd. Phytochemical constituents include Gallic acid, Ellagic acid, Kaempferol,
and Naringenin. Gallic acid has antioxidant and anti-cancer effects (Badhani et al. 2015). Ellagic acid has
antioxidant and anti-microbial properties (Vattem and Shetty 2005). Naringenin has been found to have
metal chelating property along with antioxidant, anti-microbial, anti-viral, anti-allergic, anti-estrogenic,
anti-diabetic, anti-inflammatory, anti-obesity, anti-cancer, adipolytic and hepatoprotective activities.
Moreover, the compound may be useful in hypoxia and ischemic heart disease (Vishnu Varthan et al. 2013).
Achyranthes aspera L. Some reported phytoconstituents are Achyranthine, Oleanolic acid, and Ecdysterone.
Oleanolic acid possesses hepatoprotective, anti-inflammatory, antioxidant, and anti-cancer properties
(Pollier and Goossens 2012).
Acorus calamus L. The various compounds mentioned in Table 9.3 for this plant possess anti-bacterial,
anti-fungal, insecticidal, and nematicidal activities; additionally, the plant or plant extract has in laboratory
experiments shown anti-inflammatory, anti-adipogenic, insulin sensitization, immunomodulatory,
neuroprotective, antioxidant, broncho-dilatory, and anti-proliferative effects, suggesting that more
bio-active components may be present (Mythili Avadhani et al. 2013). 1,8-Cineole has shown anti-
neoplastic, acaricide, allelopathic, anthelmintic, anti-allergic, anti-bronchitic, anti-catarrh, anti-fatigue, anti-
laryngitic, anti-pharyngitic, anti-inflammatory, anti-bacterial, and hypotensive effects (Ramya et al. 2012).
Ageratum conyzoides (L.) L. Various pharmacological studies indicate that β-sitosterol can prove useful
in heart disease, hypercholesterolemia, modulating the immune system, prevention of rheumatoid arthritis,
cervical cancer, hair loss, and benign prostatic hyperplasia (Saeidnia et al. 2014).
Alstonia scholaris (L.) R.Br. Betulinic acid reportedly has anti-retroviral, anti-malarial, anti-inflammatory,
anti-cancer, and anti-tumor properties (Ramya et al. 2012).
Aristolochia bracteolata Linn. Aristolochic acid can cause renal failure and urothelial carcinoma (Yang
et al. 2014).
Belamcanda chinensis (L.) DC. Pharmacological activity studies with mangiferin indicate that the
compound may be antioxidant, analgesic, anti-diabetic, anti-proliferative, chemopreventive, radioprotective,
cardiotonic, immunomodulatory, and diuretic (Jyotshna et al. 2016).
Cassia alata L. Emodin has been reported to give anti-cancer, hepatoprotective, anti-inflammatory,
antioxidant, and antimicrobial effects (Dong et al. 2016). Chrysophanol has been shown to demonstrate
antioxidant and anti-inflammatory activities in microglia (Lin et al. 2015).
Centella asiatica (L.) Urb. Together with madecassic acid and Asiatic acid, asiaticoside has wound healing
effect; by itself, asiaticoside is anti-microbial, cytotoxic against hepatoma and melanoma, anxiolytic and
neuroprotective; madecassoside reportedly can stimulate collagen synthesis (Alfarra and Omar 2013).
Linalool reportedly has sedative, anxiolytic, analgesic, anti-convulsant, and anti-inflammatory effects
(Aprotosoaie et al. 2014).
Citrus aurantifolia (Christm.) Swingle. β-Caryophyllene is anti-microbial and cytotoxic (anti-cancer)
(Neta et al. 2016), the compound is also hepatoprotective (Varga et al. 2017).
Cocos nucifera L. Ferulic acid has been reported to have antioxidant, anti-microbial, anti-inflammatory,
anti-thrombosis and anti-cancer properties (Ou and Kwok 2004). Amyrins are known to be anti-
hyperglycemic and hypolipidemic (Santos et al. 2012).
Cuscuta reflexa Roxb. Luteolin is an anti-inflammatory and neuroprotective agent (Nabavi et al. 2015).
The compound is also reportedly antioxidant, anti-bacterial, anti-diabetic, and anti-proliferative and inhibits
colorectal cancer (Pandurangan and Esa 2014).
Elephantopus scaber L. Lupeol reportedly has beneficial effects against inflammation, cancer, arthritis,
diabetes, heart diseases, renal toxicity, and hepatotoxicity (Wal et al. 2011).
Erythrina variegata L. Oxyresveratrol has anti-neoplastic, antioxidant, skin whitening, neuroprotective,
hepatoprotective, and hypoglycemic activities (Xu et al. 2014).
Eupatorium odoratum L. Chlorogenic acid has antioxidant, anti-inflammatory, cardioprotective,
hepatoprotective, renoprotective, anti-diabetic, and anti-lipidemic activities (Maalik et al. 2016).
Euphorbia hirta L. Reported activities of gallic acid include hepatoprotective, anti-cancer, anti-microbial,
anti-inflammatory, anti-depressant, anti-Parkinson, anti-diabetic, anti-malarial, diuretic, wound healing,
anthelmintic, and anxiolytic (Nayeem et al. 2016). Caffeic acid is carcinogen inhibitor, anti-oxidant, anti-
bacterial, and cardioprotective (Magnani et al. 2014). p-Coumaric acid is antioxidant and anti-microbial
Table 9.3 Some notable bioactive phytochemicals in the Khyang medicinal plants.
Serial No. Botanical name Notable bioactive phytochemicals

1. Abelmoschus moschatus Medik. Myricetin
2. Acacia catechu (L.f.) Willd. Catechin; Epicatechin; Epicatechin gallate; Procatechinic acid;
Quercetin; Rutin; Kaempferol
3. Acacia farnesiana (Linn.) Willd. Gallic acid; Ellagic acid; Kaempferol; Naringenin
4. Achyranthes aspera L. Achyranthine; Oleanolic acid; Ecdysterone
5. Acorus calamus L. 1,8-cineole; α-Humulene; α-Pinene; α-Terpinene; (–)-α-Terpineol;
Curcumene; Asarone; (–)-β-Elemene; Borneol; Elemicin; Eugenol;
Limonene; Linalool; Menthol; Galangin
6. Ageratum conyzoides (L.) L. α-Pinene; α-Terpinene; (–)-β-Elemene; β-Sitosterol; Borneol;
(–)-β-Caryophyllene epoxide; Eugenol; Farnesol; Friedelin; Limonene;
Quercetin; Kaempferol
7. Allophylus cobbe (L.) Räusch.) Phenolics; Alkaloids; Cyanolipids
8. Alpinia conchigera Griff. 1’S-1-acetoxychavicol acetate (ACA); various lignans such as
Conchigeranals A-E, Galanganal, Galanganols A and B
Sesquineolignans - Conchignans A, B, and C, together with Vanillin
and Phloroglucinol
Essential oils with Eucalyptol (25.85%); Chavicol (25.08%), β-Pinene
(6.71%); Caryophyllene (3.38%)as the major components
Cardamomin; 2’,4’-Dihydroxy-6’-methoxychalcone
9. Alstonia scholaris (L.) R.Br. Betulin; Betulinic acid; Oleanolic acid; Ursolic acid; β-Sitosterol;
β-Amyrin acetate; Corialstonine; Corialstonidine; Scholaricine;
Vallesamine
10. Amorphophallus paeoniifolius Quercetin
(Dennst.) Nicolson
11. Antidesma acuminatum Wall. Data not available to date
12. Argyreia capitiformis (Poir.) Data not available to date
Ooststr.
13. Aristolochia bracteolata Linn. Aristolochic acid
14. Bauhinia acuminata Linn. Essential oils containing Phytol; β-Caryophyllene and Caryophyllene
oxide
15. Begonia barbata Wall. Data not available to date
16. Begonia silhetensis (A. DC.) C.B. Data not available to date
Clarke
17. Belamcanda chinensis (L.) DC. Iridin; Irigenin; Mangiferin; Rhamnocitrin
18. Breynia retusa (Dennst.) Alston Data not available to date
19. Calotropis procera (Ait.) Ait.f. β-Amyrin; Calactin, Coroglaucigenin and various other cardenolides;
Calotroposides H-N; 2’-Epi-uscharin; Proceraside A
20. Cassia alata L. Chrysophanol; Emodin; Rhein; Aloe-emodin; Chrysophanic acid;
Kaempferol; Quercetin; Myricetin
21. Casuarina equisetifolia L. Tannins; Gallic acid; various Catechol derivatives; Kaempferol;
Quercetin
22. Centella asiatica (L.) Urb. α-Humulene; α-Pinene; α-Terpeneol; Asiatic acid; Asiaticoside;
Astragalin; β-bisabolene; β-carotene; β-elemene; β-sesquiphellandrene;
β-Sitosterol; Betulinic acid; delta-cadinene; Farnesol; Geraniol;
Isoquercetin; Kaempferol; Limonene; Linalool; Madecassoside;
Myrcene; Nerol; Nerolidol; Quercetin
Table 9.3 contd. …

…Table 9.3 contd.

23. Citrus aurantifolia (Christm.) 1,8-Cineole; 1,4-Cineole; 5-Methoxy-Psoralen; α-Phellandrene;
Swingle α-Pinene; α-Terpenene, α-Terpineol; Bergamottin; Bergapten;
β-Bisabolene; β-Pinene; Borneol; β-Caryophyllene; Citral; Citronellal;
γ-Terpinene; Geranial; Imperatorin; Isoimperatorin; Linalool; Myrcene
24. Clausena suffruticosa Wight & Coumarins, O-Methylheptaphylline, Capnolactone
Arn.
25. Clerodendrum indicum (L.) Kuntze. Scutellarein
26. Clerodendrum viscosum Vent. Quercetin; β-Sitosterol
27. Cocos nucifera L. Amyrins; α-Terpineol; β-Sitosterol; Ferulic acid; Gentisic acid;
Limonene; Menthol
28. Curculigo recurvata Dryand. Data not available to date
29. Cuscuta reflexa Roxb. Bergenin; β-Sitosterol; Kaempferol; Luteolin; Mangiferin
30. Cyperus difformis L. Essential oil containing predominantly Cyperene and Cyperotundone
31. Delonix regia (Bojer) Raf. Tannins
32. Dillenia indica L. Betulin; Betulinic Acid
33. Dioscorea glabra Roxb. Ferulic acid
34. Dioscorea pentaphylla L. Diosbulbin B
35. Dioscorea sp. Various sesquiterpenoids, polysaccharides
36. Elephantopus scaber L. Deoxyelephantopin; Isodeoxyelephantopin; Lupeol
37. Erythrina variegata L. β-Sitosterol; Erysodine; Erysovine; Erysotrine; Erythraline;
Oxyresveratrol
38. Eupatorium odoratum L. β-Amyrin; Lupeol; Chlorogenic acid; Hexacosanol; Odoratin
39. Euphorbia hirta L. α-Amyrin; β-Amyrin; β-Sitosterol; Betulin; Caffeic acid; Ellagic acid;
Ferulic acid; Gallic acid; Kaempferol; p-Coumaric acid; Quercetin;
Rhamnetin; Tannic acid
40. Globba marantina L. Essential oil containing β-Caryophyllene; α-Humulene; (Z)-N
erolidol;
(Z,Z)-Farnesol
41. Gymnopetalum cochinchinense Data not available to date
(Lour.) Kurz.
42. Hedyotis scandens Roxb. Phenolic glycosides
43. FHoya parasitica Wall. Dihydrocanaric acid
44. Hyptis suaveolens (L.) Poit. 1,8-Cineole; α-Cadinol; α-Humelene; α-Phellandrene; α-Pinene;
α-Terpinene; α-Terpineol; β-Pinene; Betulinic acid; Borneol; Camphene;
Camphor; Caryophyllene oxide; Elemene; Fenchone; γ-Terpinene;
Limonene; Menthol; Myrcene; p-Cymene; Terpinen-4-ol; Terpinolene;
Thymol
45. Ixora parviflora Vahl β-Sitosterol; β-Sitosterol-β-D-glucoside; Kaempferol; Kaempferol-7-O-
Me ether; Chlorogenic acid; Apigenin; Quercetin; Apigenin-7-O-β-D-
glucopyranoside; Quercetin-3-O-β-D-galactopyranoside
46. Kalanchoe pinnata (Lam.) Pers. α-Amyrin; β-Amyrin; β-Sitosterol; Caffeic acid; Ferulic acid; Friedelin;
Kaempferol; p-Coumaric acid; Patuletin; Quercetin
47. Lygodium flexuosum (L.) Sw. Kaempferol; Lygodinolide; Quercetin
48. Mikania cordata (Burm.f.) B.L. Deoxymikanolide
Rob.
49. Mimosa pudica L. Mimosine; β-Amyrin; β-Sitosterol
Table 9.3 contd.…

…Table 9.3 contd.

50. Moghania macrophylla (Willd.) Genistein; 2-Hydroxy Genistein
Kuntze
51. Morinda angustifolia Roxb. 1,8-dihydroxy-2-methyl-3,7-dimethoxyanthraquinone
52. Mucuna gigantean (Willd.) DC. Data not available to date
53. Mussaenda corymbosa Roxb. Data not available to date
54. Nymphaea nouchali Burm.f. Gallic acid; Myricitrin; Nymphalin
55. Ocimum americanum L. Betulinic acid; Estragole; Linalool; Cineole; Camphor; Eugenol;
Ursolic acid; Rosmarinic acid
56. Opuntia dillenii Ker-Gawl. Opuntiol; Opuntioside; Polysaccharides
57. Phyllanthus emblica L. β-Sitosterol; Corilagin; Ellagic acid; Gallic acid; Gallic acid ethyl ester;
Kaempferol; Lupeol; Quercetin; Rutin
58. Premna scandens Roxb. Data not available to date
59. Psychotria calocarpa Kurz. Data not available to date
60. Sansevieria roxburghiana Schult. Protocatechuic acid
and Schult.f.
61. Sarcochlamys pulcherrima (Roxb.) Data not available to date
Gaud.
62. Scoparia dulcis L. Betulinic acid; Coixol; Friedelin
63. Selaginella decipiens Warb. Data not available to date
64. Smilax macrophylla Willd. Data not available to date
65. Solanum lasiocarpum Dunal Data not available to date
66. Solanum torvum Sw. Methyl caffeate; some steroidal glycosides such as Torvpregnanosides
A and B; Torvanol A
67. Spilanthes calva DC.
68. Spondias pinnata Kurz Gallic acid; Methyl gallate
69. Spondias cytherea Sonn. Data not available to date
70. Synedrella nodiflora (L.) Gaertn. Data not available to date
71. Syzygium cumini (L.) Skeels Betulinic acid; Gallic acid; 1,8-Cineole; Acetyl oleanolic acid;
Bergenins; Caffeic acid; Cinnamaldehyde; Citronellol; Cyanidin
diglycoside; Delphinidin-3-gentiobioside; Ellagic acid; Eugenol;
Ferulic acid; Isoquercetin; Kaempferol; Linalool; Malvidin and
malvidin derivatives; Myricetin and myricetin derivatives; Myrtenol;
Nerol; N-hentriacontane; Petunidin; Quercetin; Terpinolene;
α-Terpenol; α-Terpinene; β-Phellandrene; β-Pinene; β-Sitosterol
72. Tabernaemontana divaricata (L.) Coronaridine; Conophylline; 3’-R/S-hydroxyvoacamine; Conolidine;
R. Br. Roxb. 19,20-dihydrotabernamine; 19,20-dihydroervahanine A.
73. Tamarindus indica L. (–) Epicatechin; α-Humulene; α-Pinene; α-Terpineol; β-Elemene;
β-Ionone; β-Pinene; β-Sitosterol; Carvacrol; Cinnamaldehyde; Geranial;
Geraniol; Hordenine; Isoorientin; Isovitexin; Limonene; Linalool; Methyl
salicylate; Myrcene; Myristic acid; Nerol; Piperitone; Safrole; Terpinen-
4-ol; Vitexin
74. Terminalia bellirica (Gaertn.) β-Sitosterol; Corilagin; Ellagic acid; Ethyl gallate; Gallic acid;
Roxb. Phyllemblin
75. Terminalia chebula Retz. β-Sitosterol; Chebulagic acid; Chebulinic acid; Corilagin; Daucosterol;
Ellagic acid; Gallic acid; p-Coumaric acid; Punicalagin; Punicalin;
Quercetin; Rutin; Terchebin
Table 9.3 contd.…

…Table 9.3 contd.

76. Thunbergia grandiflora Roxb. Iridoid glycosides - Isoundedoside and Grandifloric acid
Apigenin 7-glucuronide
77. Thysanolaena maxima (Roxb.) Data not available to date
Kuntze
78. Trichosanthes tricuspidata Lour. Trichoterol; Tricuspidatin; 2-O-glucocucurbitacin; Methyl palmitate;
Palmitic acid; Suberic acid; α-Spinasterol; α-Spinasterol 3-O-β-D-
glucopyranoside; Stigmast-7-en-3-β-ol-3-O-β-D-glucopyranoside;
Glyceryl-1-palmitate; Glyceryl-1-stearate; Bryonolic acid;
Cucurbitacin B; Isocucurbitacin B; 3-epi-Isocucurbitacin B;
23,24-Dihydrocucurbitacin D; Isocucurbitacin D; Cyclotricuspidosides
A, B and C
79. Urena lobata L. Clematoside-S
80. Vitex negundo L. β-Sitosterol; β-Sitosterol acetate; Luteolin; Vitexin and its glycosides;
Lyoniresinol; Chrysoplentin; Negundoside; Negundin B; Betulinic acid;
Ursolic acid
81. Vitis pedata L. Data not available to date
82. Vitis pentagona (Roxb.) Lawson Data not available to date
83. Zingiber officinale Roscoe 6-Gingerol; 10-Gingerol; 8-Gingerol; 8-Shogaol; 6-Shogaol;
α-Curcumene; Borneol; 1,8-Cineole; 4-Terpineol; 6-dehydrogingerdione;
α-Cadinol; α-Curumene; α-Phellandrene; α-Pinene; α-Terpinene;
α-Terpineol; α-Zingiberene; β-Bisabolene; β-Elemene; β-Eudesmol;
β-Ionone; β-Phellandrene; β-Pinene; β-Sesquiphellandrene; β-Sitosterol;
Borneol; Bornyl acetate; Caffeic acid; Camphene; Camphor; Capsaicin;
Caryophyllene; Chlorogenic acid; Citral; Citronellal; Citronellol;
Curcumin; Eugenol; Farnesol; Ferulic acid; Galanolactone; Geranial;
Geraniol; Isoeugenol; Kaempferol; Limonene; Linalool; Myrcene;
Myricetin; Myristic acid; Nerol; Nerolidol; p-Coumaric acid; p-Cymene;
Quercetin; Zingerone
84. Ziziphus mauritiana Lam. Betulin; Betulinic acid; Mauritine L; Mauritine M; Nummularines H,
B; Hemsine A
[Sources: https://phytochem.nal.usda.gov; http://www.mpbd.info; PubMed (Fibers, amino acids, metal ions, vitamins, fatty
acids ignored); https://scifinder.cas.org. Blank ones represent no available information.]
(Boz 2015); furthermore, it is reported to be hepatoprotective and renoprotective (Akdemir et al. 2017). The
compound has also been shown to induce apoptosis in HCT-15 colon cancer cells (Jaganathan et al. 2013).
Ocimum americanum L. Rosmarinic acid reportedly has antioxidant, anti-inflammatory, anti-viral,
photoprotective, anti-cancer, anti-depressant, and neuroprotective actions (Bhatt et al. 2013). Eugenol is
antioxidant, anti-microbial, anti-cancer, and anti-inflammatory (Raja et al. 2015).
Phyllanthus emblica L. Corilagin is known to be antioxidant, radioprotective and anti-viral (Sarin et
al. 2014); the compound has been reported to inhibit ovarian cancer (Jia et al. 2013). Corilagin also
demonstrated anti-inflammatory and antioxidative effects in rat model of acute cholestasis (Jin et al. 2013).
Sansevieria roxburghiana Schult. and Schult.f. Protocatechuic acid has been reported to have
anti-inflammatory, antioxidant, anti-hyperglycemia, anti-bacterial, anti-viral, anti-cancer, anti-aging,
anti-atherosclerotic, anti-tumoral, anti-asthma, anti-ulcer, anti-spasmodic and neurological properties
(Khan et al. 2015).
Scoparia dulcis L. Friedelin has been described possessing anti-mycobacterial activity (Mann et al.
2011); anti-inflammatory, analgesic, and anti-pyretic effects have also been described for this compound
(Antonisamy et al. 2011).
Syzygium cumini (L.) Skeels. Bergenins are antinociceptive, anti-arrhythmic, antioxidative, anti-microbial,
hepatoprotective, anti-inflammatory,providing protection against gastric ulcers, they also possess insulin
enhancing,lipolytic, and enhances wound healing properties. Caffeic acid has anti-aging, anti-atherogenic,
anti-carcinogenic, anti-depressant, anti-edemic, anti-hepatoadenomic, anti-hepatotoxic, anti-inflammatory,
anti-tumor, and vulnerary (wound-healing) properties. Cinnamaldehyde is an anti-hyperuricemic,
acaricidal, anti-microbial, and anti-diabetic agent. Citronellol has demonstrated anti-bacterial, anti-viral,
anti-spasmodic, and antioxidant activities. Eugenol is an acaricide, anti-convulsant, anti-edemic, anti-
inflammatory, anti-mitotic, anti-mutagenic, antioxidant, anti-tumor, anti-bacterial, hepatoprotective, and
insecticidal. Malvidin has anti-neoplastic activities. Myrtenol is anti-insomnia, anti-malarial, antioxidant,
anti-plasmodial, anti-thyreotropic, aphrodisiac, gonadotrophic, hypocholesterolemic and immunostimulant.
Nerol is a sedative (Ramya et al. 2012).
Tamarindus indica L. β-Pinene possesses anti-inflammatory, antiseptic, candidicide, and insecticidal
activities (Ramya et al. 2012). Carvacrol is an antioxidant, anti-bacterial, anti-fungal, anti-cancer and anti-
inflammatory agent; it also possesses hepatoprotective, spasmolytic, and vasorelaxant properties (Suntres
et al. 2015). Geraniol is an anti-hyperglycemic (Babukumar et al. 2017). Isovitexin is an anti-inflammatory
and antioxidant (Lv et al. 2016). Vitexin has shown anti-inflammatory, anti-oxidant, cardioprotective, anti-
cancer, antinociceptive, anti-convulsant, memory enhancer, and anti-diabetic properties (Aslam et al. 2015).
Terminalia chebula Retz. Chebulagic acid is anti-hyperglycemic (Huang et al. 2012). Punicalagin(s) can
be antioxidants, anti-cancer and have beneficial effects in cardiovascular disorders (Tyagi et al. 2012).
Trichosanthes tricuspidata Lour. Tricuspidation may be a useful anti-cancer agent (Dhanabal et al. 2015).
Spinasterol has analgesic properties (Brusco et al. 2017). Cucurbitacin B reportedly has anti-microbial,
anti-cancer and anti-inflammatory properties (Chung et al. 2015).
Vitex negundo L. Lyoniresinol has strong antioxidant properties (Govind 2011). Negundoside is
hepatoprotective (Sheikh et al. 2008).
Zingiber officinale Roscoe. Gingerols, shogaols, and zingerone have antioxidant, anti-tumor, anti-
inflammatory, analgesic, anti-microbial, and hepatoprotective activities (Rahmani et al. 2014). Borneol is
antinociceptive and anti-inflammatory (da Silva Almeida et al. 2013). α-Cadinol has insecticidal properties
against yellow fever mosquito larvae, anti-termitic activity, anti-fungal activity against Candida versicolor
and Laetiporus sulphureus, and was selectively cytotoxic against human colon adenocarcinoma (Leandro et
al. 2012). Eugenol, α-pinene and β-pinene are known to inhibit growth of potential infectious endocarditis
causing Gram-positive bacteria (Leite et al. 2007). Caryophyllene can be a good antioxidant (Miguel 2010).
Conclusion
To conclude, the medicinal plants of the Khyang tribe contain multiple natural product metabolites that are
known to possess health-promoting, protective and disease-fighting properties. These agents, over millennia
have evolved diverse structural scaffolds, which may prove invaluable in drug discovery programs. It
can readily be seen from Table 9.3, that many of the Khyang medicinal plants are as yet uncharacterized
and putative bioactive components await discovery. Thus, these plants may potentially yield novel
therapeutic components. It is also important to point out that because of the twin effects of globalization
and encroachment on forest lands pose real threats, not only are habitats of these medicinal plants shrinking
but also traditional medicinal practices and the knowledge of generation of Khyangs are at risk of being
lost. It is therefore important to pay attention to the conservancy status of these medicinal plants.
References
Akdemir, F.N.E., Albayrak, M., Çalik, M., Bayir, Y. and Gülçin, I. 2017. The protective effects of p-coumaric acid on acute
liver and kidney damages induced by cisplatin. Biomedicines 5: 18.
Akter, S., Nipu, A.H., Chyti, H.N., Das, P.R., Islam, M.T. and Rahmatullah, M. 2014. Ethnomedicinal plants of the Shing tribe
of Moulvibazar district, Bangladesh. World J. Pharm. Pharmaceut. Sci. 3(10): 1529–1537.
Al-Dhabi, N.A., Arasu, M.V., Park, C.H. and Park, S.U. 2015. An up-to-date review of rutin and its biological and
pharmacological activities. EXCLI Journal 14: 59–63.
Alfarra, H.Y. and Omar, M.N. 2013. Centella asiatica: from folk remedy to the medicinal biotechnology—a state revision.
Int. J. Biosci. 3(6): 49–67.
Antonisamy, P., Duraipandiyan, V. and Ignacimuthu, S. 2011. Anti-inflammatory, analgesic and antipyretic effects of friedelin
isolated from Azima tetracantha Lam. in mouse and rat models. J. Pharm. Pharmacol. 63(8): 1070–1077.
Aprotosoaie, A.C., Hăncianu, M., Costache, I.-I. and Miron, A. 2014. Linalool: a review on a key odorant molecule with
valuable biological properties. Flavour Frag. J. 29(4): 193–219.
Aslam, M.S., Ahmad, M.S. and Mamat, A.S. 2015. Pharmacological potential of vitexin. Ind. Res. J. Pharm. Sci. 5: 114–122.
Azad, A.K., Mahmud, M.R., Parvin, A., Chakrabortty, A., Akter, F., Moury, S.I., Anny, I.P., Tarannom, S.R., Joy, S.K.,
Chowdhury, S.Y., Akter, S. and Rahmatullah, M. 2014. Medicinal plants of a Santal tribal healer in Dinajpur district,
Bangladesh. World J. Pharm. Pharmaceut. Sci. 3(10): 1597–1606.
Babukumar, S., Vinothkumar, V., Sankaranarayanan, C. and Srinivasan, S. 2017. Geraniol, a natural monoterpene, ameliorates
hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats.
Pharm. Biol. 55(1): 1442–1449.
Badhani, B., Sharma, N. and Kakkar, R. 2015. Gallic acid: a versatile antioxidant with promising therapeutic and industrial
applications. RSC Adv. 5: 27540–27557.
Balick, J.M. and Cox, P.A. 1996. Plants, People and Culture: the Science of Ethnobotany, Scientific American Library, New
York, 228 pp.
Bayala, B., Bassole, I.H., Gnoula, C., Nebie, R., Yonli, A., Morel, L., Figueredo, G., Nikiema, J.B., Lobaccaro, J.M. and
Simpore, J. 2014. Chemical composition, antioxidant, anti-inflammatory and anti-proliferative activities of essential
oils of plants from Burkina Faso. PLoS One 9(3): e92122.
Bhatt, R., Mishra, N. and Bansal, P.K. 2013. Phytochemical, pharmacological and pharmacokinetics effects of rosmarinic
acid. J. Pharm. Sci. Innov. 2(2): 28–34.
Brusco, I., Camponogara, C., Carvalho, F.B., Schetinger, M.R.C., Oliveira, M.S., Trevisan, G., Ferreira, J. and Oliveira, S.M.
2017. α-Spinasterol: a cyclooxygenase inhibitor and a TRPV1 antagonist presents an antinociceptive effect in clinically
relevant models of pain in mice. Brit. J. Pharmacol. doi: 10.1111/bph.13992.
Boz, H. 2015. p-Coumaric acid in cereals: presence, antioxidant and antimicrobial effects. Int. J. Food. Sci. Technol. 50(11):
2323–2328.
Calderón-Montaño, J.M., Burgos-Morón, E., Pérez-Guerrero, C. and López-Lázaro, M. 2011. A review on the dietary flavonoid
kaempferol. Mini-Rev. Med. Chem. 11: 298–344.
Carrasco-Torres, G., Monroy-Ramírez, H.C., Martínez-Guerra, A.A., Baltiérrez-Hoyos, R., Romero-Tlalolini, M.L.Á., Villa-
Treviño, S., Sánchez-Chino, X. and Vásquez-Garzón, V.R. 2017. Quercetin reverses rat liver preneoplastic lesions induced
by chemical carcinogenesis. Oxid. Med. Cell. Longev. 2017: 4674918.
Chung, S.O., Kim, Y.J. and Park, S.U. 2015. An updated review of cucurbitacins and their biological and pharmacological
activities. Exp. Clin. Sci. J. 14: 562–566.
Dall’Acqua, S., Peron, G., Ferrari, S., Gandin, V., Bramucci, M., Quassinti, L., Mártonfi, P. and Maggi, F. 2017. Phytochemical
investigations and antiproliferative secondary metabolites from Thymus alternans growing in Slovakia. Pharm. Biol.
55(1): 1162–1170.
da Silva Almeida, J.R.G., Souza, G.R., Silva, J.C., de Lima Saraiva, S.R.G., de Oliveira Júnior, R.G., de Souza SiqueiraQuintans,
J., de Souza SiqueiraBarreto, R., Bonjardim, L.R., de HolandaCavalcanti, S.C. and Quintans Junior, L.J. 2013. Borneol,
a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice. Sci. World J., 2013:
Article ID 808460.
Dhanabal, S.P., Lall, N., Pavithra, N. and Chaitanya, M.V.N.L. 2015. Natural products: an important leads for anticancer drug
discovery. J. Harm. Res. Pharm. 4(4): 316–328.
Dong, X., Fu, J., Yin, X., Cao, S., Li, X., Huyiligeqi and Ni, J. 2016. Emodin: a review of its pharmacology, toxicity and
pharmacokinetics. Phytother. Res. 30(8): 1207–1218.
El-Soud, N.H.A. 2010. Herbal medicine in ancient Egypt. J. Med. Plants Res. 4(2): 82–86.
Govind, P. 2011. Some important anticancer herbs: a review. Int. Res. J. Pharm. 2(7): 45–52.
Huang, Y.-N., Zhao, D.-D., Gao, B., Zhong, K., Zhu, R.-X., Zhang, Y., Xie, W.-J., Jia, L.-R. and Gao, H. 2012. Anti-
hyperglycemic effect of chebulagic acid from the fruits of Terminalia chebula Retz. Int. J. Mol. Sci. 13: 6320–6333.
Islam, A., Siddik, A.B., Hanee, U., Guha, A., Zaman, F., Mokarroma, U., Zahan, H., Jabber, S., Naurin, S., Kabir, H., Jahan, S.
and Rahmatullah, M. 2015a. Ethnomedicinal practices of a chakma tribal healer practicing among a marma community
in Rangamati district, Bangladesh. World J. Pharm. Pharmaceut. Sci. 4(3): 180–188.
Islam, A., Siddik, A.B., Hanee, U., Guha, A., Zaman, F., Mokarroma, U., Zahan, H., Jabber, S., Naurin, S., Kabir, H., Jahan, S.
and Rahmatullah, M. 2015b. Ethnomedicinal practices among a Tripura community in Rangamati district, Bangladesh.
World J. Pharm. Pharmaceut. Sci. 4(3): 189–196.
Jaganathan, S.K., Supriyanto, E. and Mandal, M. 2013. Events associated with apoptotic effect of p-coumaric acid in HCT-15
colon cancer cells. World J. Gastroenterol. 19(43): 7726–7734.
Jia, L., Jin, H., Zhou, J., Chen, L., Lu, Y., Ming, Y. and Yu, Y. 2013. A potential anti-tumour herbal medicine, Corilagin,
inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways. BMC Complem. Altern. M. 13: 33.
Jin, F., Cheng, D., Tao, J.-Y., Zhang, S.-L., Pang, R., Guo, Y.-J., Ye, P., Dong, J.-H. and Zhao, L. 2013. Anti-inflammatory and
anti-oxidative effects of corilagin in a rat model of acute cholestasis. BMC Gastroenterol. 13: 79.
Jyotshna, Khare, P. and Shanker, K. 2016. Mangiferin: A review of sources and interventions for biological activities. Biofactors
42(5): 504–514.
Kelly, G.S. 2011. Quercetin. Altern. Med. Rev. 16(2): 172–194.
Khan, A.K., Rashid, R., Fatima, N., Mahmood, S., Mir, S., Khan, S., Jabeen, N. and Murtaza, G. 2015. Pharmacological
activities of protocatechuic acid. Acta Pol. Pharm. 72(4): 643–650.
Khorsandi, L., Orazizadeh, M., Niazvand, F., Abbaspour, M.R., Mansouri, E. and Khodadadi, A. 2017. Quercetin induces
apoptosis and necroptosis in MCF-7 breast cancer cells. Bratisl. Med. J. 118(2): 123–128.
Leandro, L.M., de Sousa Vargas, F., Barbosa, P.C.S., Neves, J.K.O., da Silva, J.A. and da Veiga-Junior, V.F. 2012. Chemical
and biological activities of terpenoids from Copaiba (Copaifera spp.) oleoresins. Molecules 17: 3866–3889.
Leite, A.M., de Oliveira Lima, E., de Souza, E.L., Diniz, M.F.F. deM, Trajano, V.N. and de Medeiros, I.A. 2007. Inhibitory
effect of β-pinene, α-pinene and eugenol on the growth of potential infectious endocarditis causing Gram-positive
bacteria. Braz. J. Pharm. Sci. 43(1): 121–126.
Lin, F., Zhang, C., Chen, X., Song, E., Sun, S., Chen, M., Pan, T. and Deng, X. 2015. Chrysophanol affords neuroprotection
against microglial activation and free-radical-mediated oxidative damage in BV2 murine microglia. Int. J. Clin. Exp.
Med. 8(3): 3447–3455.
Liu, T., Ma, H., Shi, W., Duan, J., Wang, Y., Zhang, C., Li, C., Lin, J., Li, S., Lv, J. and Lin, L. 2017. Inhibition of STAT3
signaling pathway by ursolic acid suppresses growth of hepatocellular carcinoma. Int. J. Oncol. 51(2): 555–562.
Lv, H., Yu, Z., Zheng, Y., Wang, L., Qin, X., Cheng, G. and Ci, X. 2016. Isovitexin exerts anti-inflammatory and anti-oxidant
activities on lipopolysaccharide-induced acute lung injury by inhibiting MAPK and NF-κB and activating HO-1/Nrf2
pathways. Int. J. Biol. Sci. 12(1): 72–86.
Maalik, A., Bukhari, S.M., Zaidi, A., Shah, K.H. and Khan, F.A. 2016. Chlorogenic acid: A pharmacologically potent molecule.
Acta Pol. Pharm. 73(4): 851–854.
Magnani, C., Isaac, V.L.B., Correa, M.A. and Salgado, H.R.N. 2014. Caffeic acid: a review of its potential use in medications
and cosmetics. Anal. Methods 6: 3203–3210.
Mann, A., Ibrahim, K., Oyewale, A.O., Amupitan, J.O., Fatope, M.O. and Okogun, J.I. 2011. Antimycobacterialfriedelane-
terpenoid from the root bark of Terminalia avicennioides. Am. J. Chem. 1(2): 52–55.
Martin, G.J. 1995. Ethnobotany: a ‘People and Plants’ Conservation Manual, Chapman and Hall, London, pp. 268.
Maundu, P. 1995. Methodology for collecting and sharing indigenous knowledge: a case study. Indigen. Know. Developm.
Mon. 3(2): 3–5.
Miguel, M.G. 2010. Antioxidant and anti-inflammatory activities of essential oils: a short review. Molecules 15: 9252–9287.
Moreira, J., Klein-Júnior, L.C., Filho, V.C. and de Campos Buzzi, F. 2013. Anti-hyperalgesic activity of corilagin, a tannin
isolated from Phyllanthus niruri L. (Euphorbiaceae). J. Ethnopharmacol. 146(1): 318–323.
Mythili Avadhani, M.N., Immanuel Selvaraj, C., Rajasekharan, P.E. and Tharachand, C. 2013. The sweetness and bitterness
of sweet flag [Acorus calamus L.]—a review. Res. J. Pharm. Biol. Chem. Sci. 4(2): 598–610.
Nabavi, S.F., Braidy, N., Gortzi, O., Sobarzo-Sanchez, E., Daglia, M., Skalicka-Woźniak, K. and Nabavi, S.M. 2015. Luteolin
as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res. Bull. 119: 1–11.
Nayeem, N., Asdaq, S.M.B., Salem, H. and Said, A.H.E.I.-A. 2016. Gallic acid: a promising lead molecule for drug development.
J. Appl. Pharm. 8: 213.
Neta, M.C.S., Vittorazzi, C., Guimarães, A.C., Martins, J.D.L., Fronza, M., Endringer, D.C. and Scherer, R. 2016. Effects of
β-caryophyllene and Murraya paniculata essential oils in the murine hepatoma cells and in the bacteria and fungi 24-h
time-kill curve studies. Pharm. Biol. 55(1): 190–197.
Ong, K.C. and Khoo, H.E. 1997. Biological effects of myricetin. Gen. Pharmacol. 29(2): 121–126.
Ou, S. and Kwok, K.-C. 2004. Ferulic acid: pharmaceutical functions, preparation and applications in foods. J. Sci. Food
Agric. 84: 1261–1269.
Pandurangan, A.K. and Esa, N.M. 2014. Luteolin, a bioflavonoid inhibits colorectal cancer through modulation of multiple
signaling pathways: a review. Asian Pac. J. Cancer Prev. 15: 5501–5508.
Pollier, J. and Goossens, A. 2012. Oleanolic acid. Phytochemistry 77: 10–15.
Rahman, F. and Rahmatullah, M. 2015. Medicinal plant formulations of the Musohor tribe of Birganj in Dinajpur district,
Bangladesh. World J. Pharm. Pharmaceut. Sci. 4(11): 177–185.
Rahmani, A.H., Shabrmi, F.M.A. and Aly, S.M. 2014. Active ingredients of ginger as potential candidates in the prevention
and treatment of diseases via modulation of biological activities. Int. J. Physiol. Pathophys. Pharmacol. 6(2): 125–136.
Raja, M.R.C., Srinivasan, V., Selvaraj, S. and Mahapatra, S.K. 2015. Versatile and synergistic potential of eugenol: a review.
Pharm. Anal. Acta 6(5): 367.
Ramya, S., Neethirajan, K. and Jayakumararaj, R. 2012. Profile of bioactive compounds in Syzygium cumini—a review. J.
Pharm. Res. 5(8): 4548–4553.
Saad, B., Azaizeh, H. and Said, O. 2005. Tradition and perspectives of Arab herbal medicine: a review. Evid.-Based Compl.
Alt. 2: 475–479.
Saeidnia, S., Manayi, A., Gohari, A.R. and Abdollahi, M. 2014. The story of beta-sitosterol—a review. Eur. J. Med. Plant.
4(5): 590–609.
Santos, F.A., J.T. Frota, B.R. Arruda, T.S. de Melo, A.A. de Carvalho Almeida da Silva, G.A. de Castro Brito, M.H. Chaves
and V.S. Rao. 2012. Antihyperglycemic and hypolipidemic effects of α,β-amyrin, a triterpenoid mixture from Protium
heptaphyllum in mice. Lipids Health Dis. 11: 98.
Sarin, B., Verma, N., Martín, J.P. and Mohanty, A. 2014. An overview of important ethnomedicinal herbs of Phyllanthus
species: Present status and future prospects. Sci. World J. 2014: Article ID 839172.
Seraj, S., Mazumder, M.S.H., Hossan, M.S. and Rahmatullah, M. 2017. Uncommon phytotherapeutic practices in Hajiganj
Upazila of Chandpur District, Bangladesh against gastrointestinal disorders. EC Gastroenterol. Dig. Syst. 4(3): 68–74.
Sheikh, A.T., Kaiser, P.J., Gupta, B.D., Gupta, V.K. and Johri, R.K. 2008. Negundoside, an iridiod glycoside from leaves of
Vitex negundo, protects human liver cells against calcium mediated toxicity induced by carbon tetrachloride. World J.
Gastroenterol. 14(23): 3693–3709.
Sofowora, A. 1982. Medicinal Plants and Traditional Medicinal in Africa. John Wiley and Sons, New York, 256 pp.
Sonoda, J.-I., Narumi, K., Akio, K., Erisa, T. and Toshiro, M. 2015. Green tea catechins—Pharmacokinetic properties and
health beneficial effects. Pharm. Anal. Acta. 6: 2.
Starzengruber, P., Fuehrer, H.P., Ley, B., Thriemer, K., Swoboda, P., Habler, V.E., Jung, M., Graninger, W., Khan, W.A.,
Haque, R. and Noedl, H. 2014. High prevalence of asymptomatic malaria in south-eastern Bangladesh. Malaria J. 13: 16.
Subbarayappa, B.V. 2001. The roots of ancient medicine: an historical outline. J. Biosci. 26(2): 135–144.
Suntres, Z.E., Coccimiglio, J. and Alipour, M. 2015. The bioactivity and toxicological actions of carvacrol. Crit. Rev. Food
Sci. 55: 304–318.
Tyagi, S., Singh, A., Bhardwaj, P., Sahu, S., Yadav, A.P. and Kori, M.L. 2012. Punicalagins—a large polyphenol compounds
found in pomegranates: a therapeutic review. Acad. J. Plant Sci. 5(2): 45–49.
Varga, Z.V., Matyas, C., Erdelyi, K., Cinar, R., Nieri, D., Chicca, A., Nemeth, B.T., Paloczi, J., Lajtos, T., Corey, L., Hasko,
G., Gao, B., Kunos, G., Gertsch, J. and Pacher, P. 2017. β-Caryophyllene protects against alcoholic steatohepatitis by
attenuating inflammation and metabolic dysregulation in mice. Brit. J. Pharmacol. doi:10.1111/bph.13722.
Vattem, D.A. and Shetty, K. 2005. Biological functionality of ellagic acid: a review. J. Food Biochem. 29(3): 234–266.
Vishnu Varthan, V.J., Srividya, A.R. and Sathish Kumar, M.N. 2013. Int. J. Pharm. Res. Schol. 2(4): 198–212.
Wal, P., Wal, A., Sharma, G. and Rai, A.K. 2011. Biological activities of lupeol. Sys. Rev. Pharm. 2(2): 96–103.
Xu, L., Liu, C., Xiang, W., Chen, H., Qin, X. and Huang, X. 2014. Advances in the study of oxyresveratrol. Int. J. Pharmacol.
10(1): 44–54.
Yang, H.-Y., Chen, P.-C. and Wang, J.-D. 2014. Chinese herbs containing aristolochic acid associated with renal failure and
urothelial carcinoma: A review from epidemiologic observations to casual inference. BioMed Res. Int. 2014: Article
ID 569325.
Zaman, T., Keya, K.F., Akter, S., Sagar, M.H., Khan, M.S., Bhuiyan, M.B., Malek, I. and Rahmatullah, M. 2015. Plants as
Medicines: Documentation of medicinal plants used by a Khasia tribal practitioner in Habiganj district, Bangladesh.
World J. Pharm. Pharmaceut. Sci. 4(12): 55–63.
Zhao, R., Li, T., Zheng, G., Jiang, K., Fan, L. and Shao, J. 2017. Simultaneous inhibition of growth and metastasis of
hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive
chitosan-conjugated mesoporous silica nanocomplex. Biomaterials 143: 1–16.
10
Management of Cardiovascular
Diseases and Related Complications
Using Traditional Herbs and Spices
Kavisha Mooroteea and Fawzi Mahomoodally*
Introduction
The World Health Organization (WHO) defines cardiovascular diseases (CVDs) as chronic disorders that
affect the cardiovascular system, which consist of the heart and blood vessels running throughout the body
(WHO 2017). CVDs are the leading cause of mortality worldwide (WHO 2016) responsible for around
17.7 million deaths in 2015 and it is predicted that by 2030, the death toll will escalate up to 23.3 million
(WHO 2013, WHO 2017).
Estimated direct and indirect costs of CVDs in the United States are greater than US$286 billion.
Cardiovascular diseases impose direct costs including hospital and nursing home services, professional
fees, prescription drugs, and transportation costs spent to visit healthcare providers and indirect costs
including costs incurred because of disability and loss of productivity due to absence from work (Roger
and colleagues 2011).
Some of the common types of CVDs and related complications include ischaemic heart disease,
cerebrovascular disease, chronic rheumatic heart disease, hypertensive disease, hyperlipidemia, pulmonary
heart disease, diseases of the blood vessels, and other forms of heart diseases (WHO 2016).
Ischaemic Heart Disease (IHD) also called Coronary Heart Disease (CHD) is caused when the coronary
arteries present on the surface of the heart are narrowed and blocked due to fatty material deposition. As a
result, the heart muscle does not get enough blood and oxygen supply to meet its metabolic demands. IHD
can thus lead to angina pectoris, heart attack, and heart failure (Thygesen et al. 2007). IHD was found to
be the leading global cause of mortality and life-years lost in 2010 (Murray et al. 2012).
The WHO definition of cerebrovascular disease generally termed as stroke is a clinical syndrome
characterized by rapidly developing signs of focal or global disturbance of cerebral functions lasting longer
than 24 hours or resulting in mortality with no apparent causes other that of vascular origin (Eleftheriou 2012).
Department of Health Sciences, Faculty of Science, University of Mauritius, Réduit, Mauritius.

* Corresponding author: f.mahomoodally@uom.ac.mu
Stroke is the third leading cause of mortality worldwide responsible for more than 5 million deaths
annually (Eleftheriou 2012).
The two major types of stroke are:
• Ischemic stroke which occurs when a blood vessel (artery) carrying blood to the brain is blocked due
to atherosclerosis preventing blood from reaching the brain and the brain tissue dies due to lack of
oxygen (Torbey and Bhardwaj 2004).
• Brain haemorrhage which occurs when a brain artery bursts causing blood to leak into the brain
tissue (Dupont et al. 2010).
Chronic Rheumatic Heart Disease (RHD) is a common form of heart disease caused by infection.
Group A Streptococcus bacteria infects the throat which leads to Acute Rheumatic Fever (ARF) and finally
to RHD. Chronic RHD permanently affects the heart valves of a person and can lead to heart failure, sudden
cardiac death, atrial fibrillation, and embolic stroke in the future (Mackay et al. 2004, Khan and Mensah
2010). According to WHO, RHD is responsible for around 1.5% of deaths yearly (WHO Department of
Child and Adolescent Health and Development 2005, Khan and Mensah 2010).
Hypertension also called high Blood Pressure (BP) is a chronic disorder in which the BP in the arteries
is above normal (Tabassum and Ahmad 2011). It affects more than 1 billion people globally (Chobanian
et al. 2003).
Two main types of hypertension are known which include:
• Essential hypertension: It is the most common one affecting 90 to 95% of hypertensive patients
without a known cause but there are many factors such as nutrition, age, lifestyle, neurohumoral
activity, and interactions that increase the risk of acquiring essential hypertension (Tabassum and
Ahmad 2011).
• Secondary hypertension: It affects 5–10% of hypertensive patients and has a well-established cause
such as diabetes and renal damage and therefore is more likely to be managed compared to essential
hypertension (Tabassum and Ahmad 2011).
Hyperlipidemia refers to raised blood lipid concentration. Elevation in Low Density Lipoproteins
(LDL), cholesterol (esters derivatives) and triglycerides are primarily responsible for hyperlipidemia. These
lipids are coupled with blood plasma proteins and remain in the dissolved state in the blood. The main reason
for hyperlipidemia is faulty lipid metabolism which is caused by the defect in the activity of lipoprotein
lipase enzyme or lack of the surface Apoprotein C-II. Different types of hyperlipidemia exist depending
on which lipid levels are high in the blood (Nirosha et al. 2014). For instance, hypercholesterolemia results
when there is a high level of cholesterol, whereas hypertriglyceridemia results when there is a high amount
of triglycerides, the most common form of fat.
The main focus of this chapter is to provide an overview of common cardiovascular diseases and to
highlight the potential of traditional medicines, particularly herbs and spices, in the management of CVDs
and related complications.
Risk factors associated with cardiovascular diseases

Various risk factors contribute to developing CVDs and these risk factors may be classified as either non
modifiable or modifiable. Non modifiable risk factors are conditions that cannot be changed whereas
modifiable risk factors are conditions that can be altered through lifestyle changes (Buttar et al. 2005).
• Non modifiable risk factors
Age, heredity or genetic makeup, and type 1 diabetes are classified as non-modifiable risk factors.
Age is a process of wear and tear the body undergoes with time making a person more susceptible
to chronic diseases such as CVDs. Further ageing makes the body exposed to multiple stressors and
oxidative stress which cause harm to the body. According to epidemiological research, people with
a family history of heart disease are more vulnerable to develop CVDs. Moreover, a type 1 diabetic
has abnormal fat metabolism and impaired glucose tolerance increasing the risk of developing CVDs
(Buttar et al. 2005).
Herbs and Spices for Cardiovascular Diseases 179
• Modifiable risk factors

Nine major modifiable risk factors for CVDs which are tobacco smoking, excessive alcohol, lack of
physical activity, poor nutrition, obesity, hypertension, high amount of dietary fat, and high blood
sugar level were identified by the Canadian Heart and Stroke Foundation in 2003 (Heart and Stroke
Foundation 2005, cited Buttar et al. 2005). Also, sudden stress, recurrent migraine, and the use of
oral contraceptives were linked with CVDs (Buttar et al. 2005).
Traditional medicine
The WHO stated that Traditional Medicine (TM) refers to health practices, approaches, knowledge, and
beliefs encompassing animal and mineral based medicines, spiritual therapies, manual techniques, and
exercises applied singularly or in amalgamation to cure, diagnose, and prevent diseases or to restore good
health (WHO 2003).
Herbal medicines have subsisted throughout the world with a prolonged recorded history since the
prehistoric period. Herbs were used in ancient Chinese, Greek, Egyptian, and Indian medicine for several
remedial purposes. However, the Native Americans and Africans use them in their healing rituals as a part
of their culture. The traditional Indian system has incorporated herbs as one of its most potent therapeutic
components, which are documented in the literature such as Vedas and Samhitas (Ehrlich 2011).
In the early 19th century, scientists had access to chemical analysis methods and thus they isolated
and modified active constituents from the herbs, resulting in transition from raw herbals to artificial
pharmaceuticals. During that phase, there was a fall in the use of medicinal herbs (Ehrlich 2011). However,
artificial pharmaceuticals were relatively more costly and generated many unwanted side effects despite their
powerful pharmacological activity. This is why nowadays both consumers and the scientific community
are shifting back to herbal medicines, which are derived from the nature and claim to be safer (Oreagba
et al. 2011).
Use of traditional medicine worldwide

Since the beginning of mankind, TM largely medicinal herbs and spices have been used to manage ailments.
Undoubtedly, they are still being utilized for prophylactic and curative purposes all throughout the world.
TM has sustained its popularity in all areas of the developing world. According to WHO, 70% of Indians
rely on TM for their primary health care needs. In China, TM accounts for about 40% of all health care
provided and more than 90% of general hospitals in China have units for TM (WHO 2005, Fig. 10.1).
Populations using TM/CAM worlwide
Australia 48
France 49
Chile 71
Africa 80
0 20 40 60 80 100
Percentage (%)
Fig. 10.1 Populations using TM/CAM worldwide.
Nonetheless, use of TM is not limited to developing countries only and its use is rapidly spreading in
developed countries. In the United States, 158 million adults depend on natural remedies and according
to the USA Commission for Alternative and Complementary medicines, US $17 billion were expended
on TM in 2000 (WHO 2003).
Factors influencing use of traditional medicine

There is no denying to the clear-cut fact that use of TM is growing worldwide and public interest in
traditional remedies has been ascribed to various factors including:
• lower cost and fewer side effects compared to allopathic drugs
• strong perception on the safety and efficacy of TM
• burden of diseases and failure of conventional treatment
• family tradition or culture
• regional biodiversity
Systems of traditional medicine

Throughout history, a variety of TM systems have been developed and the prevailing conditions,
environment, and geographic area affect the philosophy and practices of each system (WHO 2005). The
main systems of TM include Traditional Chinese Medicine (TCM), traditional Indian medicine, Traditional
Arabic Medicine (TAM), and traditional African medicine (TAM).
• Traditional Chinese medicine
Traditional Chinese medicine originated from China and has a history of several thousands of years
(Xutian et al. 2009, Wachtel-Galor and Benzie 2011). Yin and Yang is an important theory in TCM as
it is the foundation of diagnosis and treatment which are based on a holistic view. TCM incorporates
a range of practices such as herbal medicines (Ginkgo biloba, Allium sativum, and Panax ginseng),
acupuncture, moxibustion, mind/body exercises, and massage which are being used worldwide for
supporting good health and for prophylaxis of ailments (Wachtel-Galor and Benzie 2011).
• Traditional Indian medicine
Traditional Indian medicine also known as Ayurveda originated years ago in India (Prasad, 2002)
and is a unique and distinct health care system due to its universal and holistic approach. This
system emphasizes on living in harmony with the Universe which constitutes five basic elements
namely Earth, Water, Fire, Air, and Space. Along with these five elements, Ayurveda also uses herbs
(Curcuma longa, Magnifera indica, and Phyllanthus emblica), massage, diet, yoga, and detoxification
for sustaining physical, psychological, philosophical, ethical, and spiritual well-being of mankind
and maintaining good health (Kurup 2004, Ravishankar and Shukla 2007).
• Traditional Arabic medicine
Traditional Arabic medicine also known as Unani medicine or Greco-Arab medicine originated in
Greece and was developed by Arabs and Persians into an elaborate medical science. Unani system of
medicine aims at treating the whole body, the mind, and the soul. This system is based on hippocratic
theory of four humors: blood, phlegm, yellow bile, and black bile which have different temperaments:
hot, cold, wet, and dry (Rahman et al. 2008). In Unani, techniques such as regimental therapy (Ilaj-
bil-Tadbeer), diet therapy (Ilaj-bil-Ghiza), massage (Dalak), pharmacotherapy (Ilaj-bid-Dawa), and
surgery (Jarahat) are used for health rehabilitation (Ahmed et al. 2014).
• Traditional African medicine
Traditional African medicine is the most ancient and maybe the most varied of all medicinal systems.
Africa is regarded as the cradle of mankind with a substantial natural and cultural diversity marked
by regional differences in curative practices (Gurib-Fakim 2006). African traditional medicine in
its diverse forms is holistic consisting of the body and the mind. The traditional healer generally
identifies and treats the psychological basis of a disease prior to prescribing medicines to cure the
symptoms (Gurib-Fakim 2006, Gurib-Fakim et al. 2010).
According to Mahomoodally (2013), two significant reasons advocate the continuous enthusiasm in
TM in the African healthcare system, primarily:
1. Deficient access to conventional prescriptions and western types of medications, whereby access
to modern medical care cannot be afforded by most people in Africa either in light of the fact that
it is too expensive or on the grounds that there are no medical service providers.
2. Absence of powerful modern medical treatment for some sicknesses such as, malaria and/or HIV/
AIDS, which inordinately influence Africa more than other areas in the world although worldwide
in distribution.
Some of the commonly used African medicinal plants include Acacia senegal, Aloe ferox, Artemisia
herba-alba, Aspalathus linearis, Centella asiatica, Catharanthus roseus, Cyclopia genistoides,
Harpagophytum procumbens, Momordica charantia, and Pelargonium sidoides.
Regulation of herbal medicines

Herbal medicines are normally sold as food supplements, but there is a lack of a standard regulatory
framework in different countries thereby impeding the international trade and expansion of the herbal
products segment. The present law in United States, Canada, and Europe could be used to direct the legal
features of the herbal medicine industry in other countries (Benzie and Wachtel-Galor 2011).
In the United States, under the Dietary Supplement Health and Education Act (DSHEA) of 1994,
herbal medicines, which are categorized as dietary supplements, are assumed safe, and do not require
authorization from the Food and Drug Administration (FDA) for safety and effectiveness before they are
marketed. Nevertheless, a dietary supplement manufacturer or distributor of a supplement with a “new
dietary ingredient” may need to go across premarket review for safety and other data. In addition, all
domestic and foreign companies that produce package labels or hold dietary supplements must obey the
FDA’s ongoing Good Manufacturing Practice (GMP) regulations, which outline procedures for ascertaining
the quality of supplements planned for sale (FDA 2010, Gao 2010).
In Canada, herbal remedies and traditional medicines for instance, Ayurvedic medicine, must follow
the natural health products regulations. The regulations command that a manufacturer, packer, labeller or
importer require a preliminary registration with Health Canada prior to starting any such activity. Also,
GMPs must be employed to make sure that the product is safe and of good quality. This requires that
suitable standards and practices apropos the manufacture, storage, handling, and distribution of natural
health products be met (Benzie and Wachtel-Galor 2011, Health Canada 2013).
In Europe, the European Directive 2004/24/EC provides instructions for herbal medicines usage.
The directive establishes that herbal medicines released on the market require approval by the national
regulatory authorities of each European country. Also, suitable use of these products is due to evidence
of safety and efficacy (Calapai 2008).
Standardization of herbal medicines

Traditional herbs and spices are being used as medicines since time immemorial. The widespread use of
herbal medicines and issues regarding their safety and efficacy has indisputably increased the need of
standardization of these medicines. Guidelines which are set by the WHO are utilized as a standard by most
countries. The standardization involves the external (macroscopy/microscopy) and internal examination/ash
values, extractive values and many other parameters to identify, verify, and study its chemical composition.
Standardization of the therapeutic flora will ascertain indirectly that the flora is protected for their medicinal
and nutritive value. Standardization affirms the safety of the therapeutic taxa but effectiveness has to be
determined clinically or in the laboratory (Pradhan et al. 2015).
Phytotherapy and its importance

Phytotherapy or herbalism considered as being the world’s oldest medical practice used by our ancestors
to treat their illnesses is still utilized today by many cultures for medicinal purposes. Herbal medicines
involve herbs, herbal materials, herbal preparations, and finished herbal products that contain plants or
parts of plants rich in active ingredients which are responsible for disease management (WHO 2008,
Laelago et al. 2016).
It is approximated that almost 75% of the medicinal flora used globally were included from traditional
medicine. In India, around 70% of current pharmaceuticals are discovered from natural resources and
a large number of other man-made analogues has been made from prototype compounds isolated from
botanicals (Sen et al. 2011, Pan et al. 2014).
To date, around 80% of cardiovascular drugs are obtained from plant sources. In the year 2005 to
2007, 13 drugs of natural origin were accepted in the United States, and clinical assays on more than 100
natural product-based drugs are ongoing (Pan et al. 2013).
A large number of plants are used in traditional Indian medicine. It was approximated that Ayurveda
utilizes 1200 to 1800 plants, Siddha uses 500 to 900 plants, Unani involves 400 to 700 plants, and Amchi
utilizes 300 plants (Fig. 10.2). Interestingly, folk healers of India practice more than 7500 therapeutic flora
in different medicines (Sen and Chakraborty 2015, Debnath et al. 2015).
1600 1500
1400
Average number of plants used
1200
1000
800 700
600 550
400 300
200
0
Ayurveda Siddha Unani Amchi
Traditional Indian medicines
Fig. 10.2 Average number of plants used by Traditional Indian medicines.
Polyherbal formulation and its importance

Polyherbal formulations (PHF) refer to the combination of various medicinal herbs and their active
constituents to gain additional therapeutic efficacy, usually known as polyherbalism (Parasuraman et
al. 2014). Abana is a polyherbal Ayurvedic formulation containing several herbs such as Terminalia
arjuna, Withania somnifera, and Zingiber officinale to name a few, which protect against hypertensive
and coronary heart diseases (Sheela and Shyamala 2000). This positive herb-herb interaction is called
synergism whereby poly-herbalism provides some advantages that are absent in single herbal formulation
(Parasuraman et al. 2014).
Two types of synergism are known namely pharmacokinetic synergism which occurs when an
herb helps in facilitating the absorption, distribution, metabolism, or elimination of other herbs and
pharmacodynamic synergism which occurs when active phytochemical constituents having the same
medicinal activity act at the same receptor sites. PHF act on multiple targets simultaneously to relief people
from symptoms caused by diseases (Chorgade 2007, Parasuraman et al. 2014).
Overall, efficacy, safety, low cost, ubiquity, and better acceptance made PHF a desirable therapeutic
alternative which is being used globally (Parasuraman et al. 2014).
Safety issues of traditional medicine

Although TMs are natural remedies and have been used since ancient times, this does not imply that they
are always safe. Inappropriate use of TMs or practices can cause serious health problems particularly when
used in concomitance with conventional drugs, they may reduce the effectiveness of allopathic drugs and
even cause serious drug-herb interactions (Tachjian et al. 2010). Furthermore, intrinsic or extrinsic toxicity
of some herbs can produce harmful effects. Ephedra, Aristolochia, and Aconitum herbs are known to cause
adverse reactions upon administration (Zhang et al. 2015).
Also, factors such as lack of scientific evidence of safety and effectiveness, quality control, and
regulatory surveillance have been identified which complicate the use of TMs (Shi and Klotz 2012,
Suroowan and Mahomoodally 2015) and therefore, there is a need to conduct further research in the field
of TMs in order to deal with these challenges.
Mechanism of action of some traditional used herbs/spices for CVDs

Welsh onion
Welsh onion (Allium fistulosum) is extensively grown in southern China. Fistular onion stalk, derived from
welsh onion, leads to a reduction in the average injured area of atherosclerosis and protects the vascular
wall and immune cell infiltration. In addition, the crude extract decreases the amount of the inflammatory
cytokines interleukin 1 beta (IL-1β), IL-6, Monocyte Chemotactic Protein 1(MCP1), and tumour necrosis
factor alpha (TNFα) and suppresses the local activity of the rennin-angiotensin-aldosterone system in the
aortic tissue. Also, treatment with the extract represses various local inflammatory signalling pathways
by blocking its activation, including phosphorylation of the nuclear factor kappa B (NFκB), Janus kinase/
signal transducers and activators of transcription and mitogen-activated protein kinase pathways (He et al.
2014). These facts demonstrate that fistular onion stalk extract may be helpful in reducing atherosclerosis,
and the mechanism involves the regulation of the local inflammatory responses.
Chinese ginseng
The root of Chinese ginseng (Panax notoginseng), known as Sanqi, Sanchi or Tianqi in East Asian countries,
has been identified over 80 variants according to distinct substitute patterns. Five primary saponins namely
R1, Rb1, Rg1, Rd, and Re, represent 90% of the total ginseng employed in pharmacological experiments.
The protective effect of ginseng in cardiac injury has been demonstrated in numerous studies. It ameliorates
rats’ heart function evidenced by left ventricular ejection fractions, left ventricular fractional shortening,
left ventricular dimensions at end diastole and left ventricular dimensions at end systole (Chen et al. 2011).
Furthermore, it diminishes infarction size and blood level of creatine kinase in rats with myocardial ischemia
(Yue et al. 2012, Han et al.2013). In addition, it lowers blood levels of lactate dehydrogenase, cardiac
troponin I, malondialdehyde, and various cytokines, including TNF-α, IL-1β and C-reactive protein (Han
et al. 2013). These studies reveal the curative potentials of ginseng for myocardial infarction.
Hawthorn
The hypolipidemic effect of hawthorn (Crataegus) has been explored largely in animal studies. A
decrement in blood lipid was observed upon oral administration of a whole hawthorn extract at a dosage of
250 mg/kg/day for 7 days in high-fat diets fed mice (Niu et al. 2011). Then, the specific effects of aqueous
and ethanolic hawthorn extracts on lipid profiles were compared. In a high-fat emulsion fed mice, both
ethanol and aqueous extracts held anti-hyperlipidemic properties and the ethanol extract displayed more
favourable effects than the aqueous extract (Shao et al. 2016). This hypolipidemic effect of hawthorn
mainly contributes to suppression of the development of atherosclerosis which was evidenced by the
significantly hindered pathological alterations and decreased intima-media thickness in the arteries
(Zhang et al.2013). Thorough investigation indicated that the anti-hyperlipidemic action may be due to
the anti-inflammation activities, increase in Peroxisome Proliferator-Activated Receptor alpha (PPARα)
to ease β-oxidation-related enzymes in the liver resulting in fat breakdown, greater expression of hepatic
LDL receptors leading to a larger entry of blood cholesterol into the liver, and the suppressed cholesterol
production and enhanced breakdown of cholesterol to bile acids (Niu et al. 2011, Walden and Tomlinson,
2011, Zhang et al. 2013, Shao et al. 2016).
Saffron
Saffron (Crocus sativus) is a stemless plant whose medicinal properties have been sought for more than 4000
years (Srivastava et al. 2010). Saffron’s key ingredients include crocin, picrocrocin, safranal, and crocetin
(Srivastava et al. 2010, Mehdizadeh et al. 2013) and these compounds give rise to distinct mechanisms
of action (Mokhtari-Zaer et al. 2015). The anti-hypertensive benefits of saffron are supported by various
reports. According to a clinical study, one week administration of 400 mg of saffron tablets lowered the
Systolic Blood Pressure (SBP) and Mean Arterial Blood Pressure (MABP) in healthy participants by 11
and 5 mmHg, respectively (Modaghegh et al. 2008).
Saffron exhibits vasorelaxant activities in distinct animal models. Extracts of saffron petals decreased
the BP of male Sprague-Dawley rats in a dose dependent way, most probably by regulating peripheral
vascular resistance (Fatehi et al. 2003). Furthermore, saffron stigma extract, and two of its main constituents,
crocin and safranal, reduced the effect of MABP in normotensive and desoxycorticosterone acetate
(DOCA)-salt induced hypertensive male Wistar rats (Imenshahidi et al. 2010).
Saffron also relaxes non-vascular muscles. Extracts of saffron reduced contractility and cardiac
rate of guinea-pig isolated perfused hearts by inhibiting Ca2+ channels, opening potassium channels, and
antagonizing β-adrenoceptors (Boskabady et al. 2008). Moreover, safranal provides protection in a rat
model of myocardial ischemia-reperfusion lesion through enhanced phosphorylation of protein kinase B
(Akt)/glycogen synthase kinase-3β (GSK-3β)/eNOS pathway, weakening of the activity of IKK-β/NF-κB,
maintaining normal antioxidant reserve and up-regulating the anti-apoptotic pathway (Bharti et al. 2012).
Chinese goldthread
Chinese goldthread (Coptis chinensis), is extensively utilized in Chinese folk medicine (Affuso et al. 2010).
Through evidence, goldthread, and its prime ingredient, Berberine (BBR), are capable of lowering blood
pressure (Affuso et al. 2010, Xiong et al. 2013).
Various mechanisms have been suggested for Chinese goldthread’s hypotensive effect. One of which
seems to be through enhancement of oxidative stress (Zhang et al. 2011, Wan et al. 2013). BBR is known
to scavenge ROS, block NADPH oxidase (Wan et al. 2013), and upregulate the antioxidant enzyme,
superoxide dimustase (SOD), in rats with atherosclerotic renovascular disease.
Constituents of goldthread also act by relaxing arterial tissues through endothelial-dependent and
independent routes (Affuso et al. 2010). In chronic intermittent hypobaric hypoxic and normoxic animal
models, goldthread has been shown to relax norepinephrine-induced contractions in rat isolated thoracic
aortic rings (Zhang et al. 2011). The same authors also reported BBR’s vasorelaxant activity on KCl-
induced contractions using the same models (Zhang et al. 2011).
Apparently, BBR elevates the expression of endothelial Nitric Oxide Synthase (eNOS) with a
concomitant rise in NO release that leads to enhanced flow-mediated vasodilation (Affuso et al. 2010, Zhang
et al. 2011). This dilation is likely mediated by the vasodilator prostaglandin I2(PGI2) as well as the opening
of KATP channels and blockage of Ca2+ influx (Zhang et al. 2011). In a clinical study, BBR decreased the
formation of endothelial microparticles (EMPs) which are known to induce endothelial dysfunction and
pro-coagulant activity in healthy humans (Wang et al. 2009, Affuso et al. 2010). In addition, BBR isolate of
Chinese goldthread inhibits endothelial injury (Wang et al. 2009) modulates inflammatory pathways through
suppression of transcription factor NF-κB, Vascular Cell Adhesion Molecule 1 (VCAM-1) expression,
Vascular Smooth Muscle Cells (VSMC) proliferation (Affuso et al. 2010, Wan et al. 2013). It also improves
lipid profile by reducing total and LDL cholesterol, and cardiac muscle hypertrophy (Zhang et al. 2011).
Green tea
Green tea (Camellia sinensis) leaf catechins (GTC) are active polyphenolic compounds that provide vascular
protective effects through several mechanisms, namely antioxidative, lipid lowering and anti-inflammatory
effects (Velayutham et al. 2008). Environmental pollutants and certain medications may increase the
amount of Reactive Oxygen Species (ROS) which lead to vascular damage and development of other
circulatory diseases such as atherosclerosis, ischaemic heart disease, hypertension, cardiomyopathies,
cardiac hypertrophy and congestive heart failure. In this case, consumption of GTC increases the activity
of antioxidant enzymes such as catalase and superoxide dismutase which play key roles in scavenging
ROS (Velayutham et al. 2008). Moreover, high blood lipid levels contribute to progression of atherosclerotic
plaques and therefore intake of GTC prevents the action of the main enzymes playing a role in the
biosynthesis of lipid and also decreases the ability of the intestine to absorb lipid thereby improving
blood lipid profile (Velayutham et al. 2008). GTC inhibits vascular inflammation which is involved
in the development of atherosclerotic lesions. GTC presents anti-inflammatory activity by preventing
adhesion of white blood cells to endothelium and subsequent transmigration via suppression of NF-kB
which plays a role in the synthesis of cytokines and adhesion molecules in endothelial and inflammatory
cells (Velayutham et al. 2008).
Turmeric
Turmeric (Curcuma longa) is an Indian spice with a bright yellow chemical known as curcumin which has
cardioprotective effects. Curcumin influences genes leading to cardiac repair and cardiac function following
a heart attack. According to a study in the American Journal of Cardiology in 2012, curcumin possibly
minimizes post-bypass heart attack risk by 56% (Future Pharm 2017). Turmeric is a great remedy for
atherosclerosis because it has the potential to lower blood cholesterol levels and as such minimizing the risk
of plaque build-up in the arteries. Turmeric prevents atherosclerosis by the following effects (Singh 2017):
• Curcumin prevents build-up of arterial plaques and arterial blockage by inhibiting LDL cholesterol
oxidation in the body.
• Turmeric functions as a vasodilator causing dilation of the blood vessels and therefore reduces the
probability of blockage. Moreover, turmeric is capable of preventing aggregation of blood platelets
and blocks the formation of blood clots.
• Turmeric possesses anti-inflammatory properties and thereby inhibits inflammatory deposits on the
internal walls of the blood vessels.
• Turmeric has antioxidant properties which aid decreased formation of highly reactive free radicals
so as to stop further inflammation.
• Turmeric prevents the absorption of cholesterol in the gut thus suppressing LDL cholesterol oxidation
in the lining of the blood vessels.
Future prospects of herbal medicine

Despite the growing use and rapid-growing market of medicinal herbs in both developing and industrialized
countries, policy-makers, health professionals, and the public are highly concerned about the safety, efficacy,
quality, availability, conservation, and any development issues of these herbal products (Ghani 2013).
The public demands for authentication on the safety, efficacy, and quality of herbal medicines.
Therefore, to minimize these concerns and to meet the demands of the public, thorough studies on medicinal
herbs need to be carried out not solely for their considerable healthcare value but also for the commercial
advantages. Interestingly, quite in-depth phytochemical and pharmacological investigations on medicinal
herbs are being done worldwide and efforts are ongoing to separate and identify their active chemical
components and to substantiate the claims of their efficacy and safety. It has been demonstrated that herbal
medicines are not fully without scientific basis as majority hold the proper chemical constituents and exert
the claimed activity (Ghani 2013).
There is strong scientific evidence from randomized clinical studies for use of several medicinal
herbs. In spite of the concerns and the demands of the public, there is still an increase in the trend of using
herbal therapies and is likely to rise furthermore in the future with more and more scientific evidence of
their quality, efficacy and safety coming from the investigators (Ghani 2013).
However, the production, sale, and use of herbal medicines should be officially and legally modulated to
ensure quality and safety by established rules and regulations. In most countries, regulations and registration
of therapeutic herbs are less developed and their quality is not assured. Therefore, they should be brought
under legal control in all countries where they are employed for curative purposes and attempts should be
made to make the public aware of the gains and dangers of herbal medicines usage.
Appropriate use of herbal medicine of ‘guaranteed quality’ will definitely lead to beneficial therapeutic
effects on the consumers and lower the risks associated with them. Moreover, use of adulterated herbal
ingredients and improper formulation must come to a standstill as they may cause production of poor-quality
and dangerous herbal medicines. Therefore, rules and regulations of GMP should be firmly followed in
herbal medicines production. With regard to the above data, it may be safely deducted that herbal medicines
possess good upcoming prospects and hopefully one day they may come out as good substitutes or better
alternatives for man-made conventional medicines (Ghani 2013).
Conclusion
Traditional medicine use among cardiovascular patients is prevalent, with medicinal herbs and spices
being the most frequently used remedies. Nonetheless, despite the success of conventional medicines in
appeasing the suffering of cardiovascular patients further to improving the quality of life of sufferers, they
are not devoid of unwanted side-effects. Hence, interest in TMs has been rejuvenated which are presumed
to be safer than allopathic drugs. Even though herbal medicines are useful, many of them lack careful
scientific evaluation and this dearth of awareness may eventually lead to toxicity, herb-drug interactions,
side effects, and other issues. Therefore, it is recommended that all stakeholders join hands together in order
to improve the overall research quality of herbal medicines. As a conclusive note, this chapter provides
thorough information on the techniques by which medicinal plants act to prevent CVDs. It is anticipated
that these facts will open novel avenues to discover useful new drugs to allay sufferings.
References
Affuso, F., Mercurio, V., Fazio, V. and Fazio, S. 2010. Cardiovascular and metabolic effects of Berberine. World J. Cardiol.
2: 71–77.
Ahmed, K., Jahan, N., Aslam, M., Kausar, H., Khalid, M. and Ali, H. 2014. Dalak (Massage) in unani medicine: a review.
IJAYUSH 3: 162–174.
Bharti, S., Golechha, M., Kumari, S., Siddiqui, K.M. and Arya, D.S. 2012. Akt/GSK-3β/eNOS phosphorylation arbitrates
safranal-induced myocardial protection against ischemia–reperfusion injury in rats. Eur. J. Nutr. 51: 719–727.
Boskabady, M.H., Shafei, M.N., Shakiba, A. and Sefidi, H.S. 2008. Effect of aqueous-ethanol extract from Crocus sativus
(saffron) on guinea-pig isolated heart. Phytother. Res. 22: 330–334.
Buttar, H.S., Li, T. and Ravi, N. 2005. Prevention of cardiovascular diseases: Role of exercise, dietary interventions, obesity
and smoking cessation. Exp. Clin. cardiol. 10: 229–249.
Calapai, G. 2008. European legislation on herbal medicines: a look into the future. [ONLINE] Available at: https://www.ncbi.
nlm.nih.gov/pubmed/18422385. [Accessed 13 August 2017].
Chen, S., J. Liu, X. Liu, Y. Fu, M. Zhang and Q. Lin. 2011. Panax notoginseng saponins inhibit ischemia-induced apoptosis
by activating PI3K/Akt pathway in cardiomyocytes. J. Ethnopharmacol. 137: 263–270.
Chobanian, A.V., Bakris, G.L. and Black, H.R. 2003. The seventh report of the joint national committee on prevention,
detection, evaluation and treatment of high blood pressure: the JNC 7 report. JAMA 289: 2560–2572.
Dupont, S.A., E.F. Wijdicks, G. Lanzino, and A.A. Rabinstein. 2010. Aneurysmal subarachnoid hemorrhage: An overview
for the practicing neurologist. Semin. Neurol. 30: 545–554.
Ehrlich, S.D. 2011. Herbal medicine. [ONLINE] Available at: http://www.umm.edu/health/medical/altmed/treatment/herbal-
medicine. [Accessed 13 August 2017].
Eleftheriou, D. 2012. Endothelial injury and repair in childhood arterial ischaemic stroke. [ONLINE] Available at: http://
discovery.ucl.ac.uk/1378547/1/THESIS%20nov%20pdf.pdf. [Accessed 28 March 2017].
Fatehi, M., Rashidabady, T. and Fatehi-Hassanabad, Z. 2003. Effects of Crocus sativus petals’ extract on rat blood pressure
and on responses induced by electrical field stimulation in the rat isolated vas deferens and guinea-pig ileum. J.
Future Pharm. 2017. Potential Heart Healthy Benefits of Turmeric. [ONLINE] Available at: https://myfuturepharm.com/
heart-healthy-benefits-turmeric/. [Accessed 22 October 2017].
Ghani, A. 2013. Herbal medicines: Present status, future prospects. [ONLINE] Available at: http://www.pharmabiz.com/
NewsDetails.aspx?aid=78355&sid=21. [Accessed 13 August 2017].
Gurib-Fakim, A. 2006. Medicinal plants: Traditions of yesterday and drugs of tomorrow. Mol. Aspects Med. 27: 1–93.
Han, S.Y., Li, X., Ma, X., Zhang, K., Ma, Z.Z., Jiang, Y. and Tu, P.F. 2013. Evaluation of the anti-myocardial ischemia effect of
individual and combined extracts of Panax notoginseng and Carthamus tinctorius in rats. J. Ethnopharmacol. 145: 722–727.
He, B., Hao, J., Sheng, W., Xiang, Y., Zhang, J., Tian, J., Zhu, X., Feng, Y. and Xia, H. 2014. Fistular onion stalk extract
exhibits anti-atherosclerotic effects in rats. Exp. Ther. Med. 8: 785–792.
Imenshahidi, M., Hosseinzadeh, H. and Javadpour, Y. 2010. Hypotensive effect of aqueous saffron extract (Crocus sativus L.)
and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother. Res. 24: 990–994.
Khan, M. and Mensah, G.A. 2010. Epidemiology of Cardiovascular Disease. 2nd ed. Washington: National Academies Press.
Laelago, T., Yohannes, T. and Lemango, F. 2016. Prevalence of herbal medicine use and associated factors among pregnant
women attending antenatal care at public health facilities in Hossana Town, Southern Ethiopia: facility based cross
sectional study. Arch. Pub. Health 74: 1–8.
Mahomoodally, M.F. 2013. Traditional medicines in Africa: an appraisal of ten potent African medicinal plants. Evid.-Based
Compl. Alt. 2013: 1–14.
Mehdizadeh, R., Parizadeh, M.R., Khooei, A.R., Mehri, S. and Hosseinzadeh, H. 2013. Cardioprotective effect of saffron
extract and safranal in isoproterenol-induced myocardial infarction in Wistar Rats. Iran J. Basic Med. Sci. 16: 56–63.
Modaghegh, M.H., Shahabian, M., Esmaeili, H.A., Rajbai, O. and Hosseinzadeh, H. 2008. Safety evaluation of saffron (Crocus
sativus) tablets in healthy volunteers. Phytomedicine 15: 1032–1037.
Mokhtari-zaer, A., Khazdair, M.R. and Boskabady, M.H. 2015. Smooth muscle relaxant activity of Crocus sativus (saffron)
and its constituents: possible mechanisms. Avicenna J. Phytomed. 5: 365–375.
Murray, C.J., Vos, T. and Lozano, R. 2012. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions,
1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 380: 2197–2223.
Nirosha, K., Divya, M., Vamsi, S. and Sadiq, M. 2014. A review on hyperlipidemia. Int. J. Nov. Trends Pharm. Sci. 4: 1–12.
Niu, C., Chen, C., Chen, L., Cheng, K., Yeh, C. and Cheng, J. 2011. Decrease of blood lipids induced by Shan-Zha (Fruit of
Crataegus pinnatifida) is mainly related to an increase of PPARα in liver of mice fed high-fat diet. Horm. Metab. Res.
43: 625–630.
Oreagba, I.A., Oshikoya, K.A. and Amachree, M. 2011. Herbal medicine use among urban residents in Lagos, Nigeria. BMC
Complem. Altern. M. 11: 1–8.
Parasuraman, S., Thing, G.S. and Dhanaraj, S.A. 2014. Polyherbal formulation: Concept of ayurveda. Pharmacogn. Rev. 8:
73–80.
Pradhan, N., Gavali, J. and Waghmare, N. 2015. WHO (World Health Organization) guidelines for standardization of herbal
drugs. IAMJ 3: 1–7.
Rahman, S.Z., Khan, R.A. and Latif, A. 2008. Importance of pharmacovigilance in unani system of medicine. Indian J.
Pharmacol. 40: 1–3.
Ravishankar, B. and Shukla, V.J. 2007. Indian systems of medicine: a brief profile. Afr. J. Tradit. Complem. 4: 319–337.
Roger, V.L., Go, A.S., Lloyd-Jones, D.M. et al. 2011. Heart Disease and Stroke Statistics—2011 Update. Circulation. 123:
18–209.
Sharma, S. 2015. Current status of herbal product: Regulatory overview. J. Pharm. Bioallied. Sci. 7: 293–296.
Shao, F., Gu, L., Chen, H., Liu, R., Huang, H. and Ren, G. 2016. Comparison of hypolipidemic and antioxidant effects of
aqueous and ethanol extracts of Crataegus pinnatifida fruit in high-fat emulsion-induced hyperlipidemia rats. Pharmacogn.
Mag. 12: 64–69.
Singh, A. 2017. Turmeric Prevents Plaque Formation Improving Circulation in Atherosclerosis [ONLINE] Available at: https://
snec30.com/atherosclerosis-turmeric/. [Accessed 22 October 2017].
Srivastava, R., Ahmed, H., Dixit, R.K. and Saraf, S.A. 2010. Crocus sativus L.: a comprehensive review. Pharmacogn. Rev.
4: 200–208.
Suroowan, S. and Mahomoodally, F. 2015. Common phyto-remedies used against cardiovascular diseases and their potential
to induce adverse events in cardiovascular patients. Phytomedicine 1: 1–13.
Tabassum, N. and Ahmad, F. 2011. Role of natural herbs in the treatment of hypertension. Pharmacogn. Rev. 5: 30–40.
Tachjian, A., Maria, V. and Jahangir, A. 2010. Use of herbal products and potential interactions in patients with cardiovascular
Diseases. J. Am. Coll. Cardiol. 55: 515–525.
Thygesen, K., Alpert, J.S. and White, H.D. 2007. Universal definition of myocardial infarction. Circulation. 116: 1–22.
Torbey, M.T and Bhardwaj, A. 2004. Critical care neurology and neurosurgery. 2nd ed. Totowa: Humana Press.
Velayutham, P., Babu, A. and Liu, D. 2008. Green tea catechins and cardiovascular health: an update. Curr. Med. Chem. 15:
1840–1850.
Wachtel-Galor, S. and Benzie, I.F.F. 2011. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. Boca Raton: CRC Press.
Wan, X., Chen, X., Liu, L., Zhao, Y., Huang, W.J., Zhang, Q., Miao, G.G., Chen, W., Xie, H.G. and Cao, C.C. 2013.
Berberineameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of
NFκB signaling pathway in rats. PLoS One 8: 1–8.
Wang, Y., Huang, Y., Lam, K.S., Li, Y., Wong, W.T., Ye, H., Lau, C.W., Vanhoutte, P.M. and Xu, A. 2009. Berberine prevents
hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein
kinase and endothelial nitric oxide synthase. Cardiovasc. Res. 82: 484–492.
World Health Organization. 2003. Traditional medicine. [ONLINE] Available at: http://apps.who.int/gb/archive/pdf_files/
WHA56/ea5618.pdf. [Accessed 19 December 2017].
World Health Organization. 2003. Traditional medicine. [ONLINE] Available at: http://www.worldhealthorganisation.com.
[Accessed 28 March 2017].
World Health Organization. 2005. National policy on traditional medicine and regulation of herbal medicines. [ONLINE]
Available at: http://apps.who.int/iris/bitstream/10665/43229/1/9241593237.pdf. [Accessed 28 March 2017].
World Health Organization. 2013. Cardiovascular disease. [ONLINE] Available at: http://www.who.int/cardiovascular_diseases/
en/. [Accessed 21 March 2017].
World Health Organization. 2016. Cardiovascular diseases. [ONLINE] Available at: http://www.who.int/mediacentre/factsheets/
fs317/en/. [Accessed 26 March 2017].
World Health Organization. 2017. Cardiovascular disease. [ONLINE] Available at: http://www.who.int/cardiovascular_diseases/
about_cvd/en/. [Accessed 28 March 2017].
World Health Organization. 2017. Essential Medicines and Health Products Information Portal. [ONLINE] Available at: http://
apps.who.int/medicinedocs/en/d/Js2293e/. [Accessed 22 October 2017].
World Health Organization. 2017. Herbal medicine research and global health: an ethical analysis. [ONLINE] Available
at: http://www.who.int/bulletin/volumes/86/8/07-042820/en/. [Accessed 19 December 2017].
Xiong, X., Yang, X., Liu, W., Chu, F., Wang, P. and Wang, J. 2013. Trends in the treatment of hypertension from the perspective
of traditional Chinese medicine. Evid.-Based Compl. Alt. 2013: 1–13.
Yue, Q.X., Xie, F.B., Song, X.Y., Wu, W.Y., Jiang, B.H. and Guan, S.H. 2012. Proteomic studies on protective effects of salvianolic acids,
notoginsengnosides and combination of salvianolic acids and notoginsengnosides against cardiac ischemic-reperfusion injury.
Zhang, J., Cui, M., He, Y., Yu, H. and Guo, D. 2005. Chemical fingerprint and metabolic fingerprint analysis of Danshen
injection by HPLC–UV and HPLC–MS methods. J. Pharm. Biomed. Anal. 36: 1029–1035.
Zhang, J., Onakpoya, I.J., Posadzki, P. and Eddouks, M. 2015. The safety of herbal medicine: from prejudice to evidence. Evid.-
Based Compl. Alt. 2015: 1–3.
Zhang, P., Song, S.J., Liu, W.L., Li, L.L., Zhao, W.L. and Zhang, Y. 2011. Effects of coptischinensis on vasoconstrictive activity
of isolated thoracic aorta of normoxic and chronic intermittent hypobaric hypoxic rats. Evid.-Based Compl. Alt. 27: 1–5.
Zhang, J., Liang, R., Wang, L., Yan, R., Hou, R., Gao, S. and Yang, B. 2013. Effects of an aqueous extract of Crataegus
pinnatifida Bge. var. major N.E.Br. Fruit on experimental atherosclerosis in rats. J. Ethnopharmacol. 148: 563–569.
11
Use of Ethnomedicinal Plants in
Primary Health Care
Nélida Soria Rey
Introduction
The World Health Organization (WHO) considers Natural and Traditional Medicine, which includes the
treatment with ethnomedicinal plants, as the most natural, safe and effective medicine. WHO, therefore,
supports Member States in promoting the use of Traditional Medicines in Primary Health Care (PHC),
on the basis of ensuring the safety and quality of the medicine, while recommending professionals and
consumers to use ethnomedicinal plants properly because they could be effective as first-line treatment and
prevention for conditions such as colds, diarrhea, stomach pains, mild fevers, minor wounds, metabolic
and other diseases (Del Toro Garcia and Trapero Quintana 2007).
In recent years, numerous studies have been carried out to define the species used by different human
populations to analyze their possible inclusion in Primary Health Care (PHC). The results show that the uses
of plant depend on the groups studied and the habitat where communities develop. In a broad perspective,
herbal medicine can and should be considered as the shared knowledge and interaction between cultural
resources, natural resources and the preservation of biodiversity. In the Latin American context, the
experiences applied from an intercultural perspective have generally been characterized by a disconnect
of health care treatments from the rest of the societal problems, such as links with the social and economic
structure. Ancestral medicine veers away from the generally accepted definition of a modern health care
system (Almeida Vera and Almeida Vera 2014).
Although ethnomedicinal plants are used by over 90% of the population in developing countries,
their incorporation into PHC is still relegated due to the barriers of health systems, services and personnel,
and it is uncommon to integrate in the same service, traditional and allopathic medicines. Thus, many
professionals in allopathic medicine, even in countries with a strong history of ethnomedicinal plant
use, such as Latin American countries, express great reservations and often serious disbeliefs about the
benefits of Traditional Medicine (WHO 2002–2005). Nonetheless, different ethnomedicinal plants make
a significant contribution to the health system of many local communities, as they are frequently used by
the majority of the rural population and have contributed to experimental studies in the search for safety
and effectiveness (Angulo et al. 2012).
It is clear that curative and preventive treatments based on ethnomedicinal plants are the most popular
form of traditional medicine and have prevailed over time through oral transmission (Flores 2008).
Faculty of Applied Sciences, National University of Pilar, Scientific Society of Paraguay.

E-mail: nsoria@aplicadas.edu.py
Therefore, one of the current challenges consists in its incorporation within the PHC, for which constant
training for the general consumer market and for health care professionals. This training is necessary to
finally fulfill one of the fundamental strategies of PHC: their integration with the community in a process
of interculturality.
In this chapter, we analyze the parameters that influence the safe and effective use of medicinal plants
in primary care, considering that this medicine is affordable to all.
Natural medicine
For centuries, humans have sought out the flora of their surroundings, not only for food but also medicine
for diseases that afflicted them. The plants used were almost always related to their environment, and for
the said reason they identified numerous medicinal species they used for the cure of their illnesses.
Many of them continue in the present, as for example “aloe” (Aloe vera) or “ajenjo (wormwood)”
(Artemisia absinthium) to which over time properties are added, the result of studies carried out.
The spread of knowledge related to the pharmacological uses of ethnomedicinal plants is generally
transmitted orally. Sometimes there is no scientific evidence that allows its use in a safe and effective way.
Environmental changes that have taken place globally, such as increasing population in urban areas, led
to the modification of the natural habitat and contributed to the disappearance of species and the use of
others with the same common name, but without proof that it has the same effect as that attributed to the
other species. Climate change also exerts strong pressure and modifies the floristic composition making
species considered medicinal by the population disappear.
In addition borders between countries have disappeared and people move freely from one country
to another with their “natural medicines”. When they are abroad, people substitute their natural medicine
with another one that displays similar medicinal properties, using the same common name, thus expanding
the number of species used as medicinal.
All these factors contribute to the fact that the number of medicinal species continues to increase, and,
in general, we move away from the proposal of the WHO that states: “to contemplate culturally recognized
products and practices as a complement to the provision of local health services and to consider to the
public health systems of their Member States that are fundamental in determining and facilitating access
to safe practices and products” (WHO 2013), because the species used as medicinal are replaced without
evidence of their effectiveness and safety by which we cannot assure that the results of the use of the plant
is harmless for human consumption.
So, we can no longer speak of “traditional use of a species” or its “harmless” action, because, as
mentioned, plants are marketed by their common names and the species are different from those used
previously, producing different responses. In Table 11.1 we mention some species that are replaced by
others because they have the same common name.
The number of medicinal species that are marketed as medicinal is increasing and the sites in which
these products are acquired. Thus, extending the concept that they are not only medicines but also fulfill
functions of food and that therefore can be sold anywhere outside of the traditional field of medicine, which
Table 11.1 Example of species that are replaced by each other.
Generic name Species with the same common name

“Katuava” Anemopaegma arvense (Vell.) Stellfeld ex Souza (Bignoniaceae)
Psidium cinereum var. paraguariensis (Myrtaceae)
“clover” Oxalis sp. (Oxalidaceae)
Amburana cearensis (Allemão) A.C. Sm. (Leguminosae)
“Francisco Álvarez” Luehea divaricata Mart. (Tiliaceae)
Banara arguta Briq. (Flacourtiaceae)
“tiger hand” Jungia floribunda Less. (Asteraceae)
Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae)
“Cañafístula” Cassia grandis L. f (Leguminosae)
Cassia fistula L. (Leguminosae)
Use of Ethnomedicinal Plants in Primary Health Care 191
are pharmacies, such as herbalists, dieticians, naturist stores and informal fairs or street stalls complicating
their legal control and the quality of the product offered to the consumer (Acosta et al. 2017).
Although ethnomedicinal plants are effective in primary care and as a first-line medication in stomach
conditions, small wounds, control of metabolic diseases (hypertension, diabetes, others), this occurs only
when the species used are those with the secondary metabolites that act on these ailments. For this reason,
replacing one species for another makes primary care professionals hesitant to prescribe herbal medicines.
We must not forget that many times the uses attributed to medicinal species have been empirical.
Traditionally, the shape of the plant’s organ was related with the organ of the human body in which it
would exert its action. This scheme has varied and currently the use is related not only to morphology but
also to flavors or odors, for example, when plants have bitter tastes they are used to combat the increase
of glucose in the blood, starting from the assumption that bitter is opposed to sweet.
All of the above leads us to indicate that the use of ethnomedicinal plants is possible in PHC if the
parameters that allow their safe and effective use are respected.
Efficacy and safety

The efficacy and safety of ethnomedicinal plants is based on three fundamental pillars that can guarantee
their innocuousness:
1) the taxonomic identity assures us, which species is used as medicinal. It is based on taxonomy and
includes micrographic methods to certify the identity of the species used,
2) the habitat from which it comes, that is to say its origin or provenance,
3) the dose used, because people have a false idea that excessive consumption does not produce toxic
effects, thinking that the medicine by being natural does not produce negative effects and they can
consume the amount they want (Fig. 11.1).
Figure
Figure11.1
11.1 Parameters
Parametersfor
forthe
theefficacy
efficacy and safety of the use of medical plants.
Taxonomic and micro graphical identification of plants

Ethnomedicinal plants should be marketed by their scientific names ensuring that they are the same species
to obtain similar therapeutic responses depending on the medical conditions for which they are used.
The common names with which the species are known may vary from country to country, from region
to region, so therapeutic responses may be different, and marketing by the common name may lead to
confusion or adulteration, substitutions that can be intentional or not and this constitutes a major problem
because it can affect the efficacy of medicinal products and diminish credibility regarding the use of plants
as a basic medicine in primary health care (Pocchettino et al. 2008).
Although the most frequently used medicinal organ is the leaf, when the bark, root or rhizome is
used, determining the identity of the species becomes complicated and it is common to substitute one
species for another since there are few regulations related to the controls prior to the commercialization
of plant organs and when these are sliced or pulverized is even further complicated. For this reason, it is
necessary to start working with micrographic patterns to ensure the identity of the species that are used.
That is to say, for the identification of the medicinal species the tools provided by the taxonomy
are not sufficient, since in the taxonomy the floral/fruit organs of the species are used for the taxonomic
identification; in popular medicine, organs of the species are used that are cut, sliced, pulverized, then
one must look for other methods to assure the identity. That is, when you have a part of the plant, the
taxonomy can contribute little or nothing to identify the plant species. This is where plant micrograph is
of great importance, since it not only contributes the histological parameters that characterize the plant or
part of the plant used as medicinal, it also allows the identification and characterization of vegetal powders.
On the other hand, since ethnomedicinal plants are generally harvested from their natural habitat,
confusions can occur, with the substitution of one species for another, especially when the collection
is done by people without sufficient knowledge and taking into account only the characteristics, which
may be similar between two species; that is to say, it could be replaced by scientific ignorance. Also,
the substitution can be carried out premeditated, for example the intentional substitution to increase the
volume of the species that is commercialized. Consequently, the importance of marketing ethnomedicinal
plants should be encouraged by the scientific name, supported by controls that certify the identity of what
is sold (Degen et al. 2005).
There are numerous examples of adulteration or falsification of medicinal plants; we mentioned
some that can help us understand this problem. The “cangorosa” Maytenus ilicifolia (Celastraceae), has
thorny leaves and can be confused and replaced by species of Sorocea bonplandii (Moraceae), Jodina
rhombifolia (Santalaceae), also Tithonia diversifolia (Asteraceae) and Jungia floribunda (Asteraceae)
that have similar leaves can confuse one with another. That is to say they are morphologically similar,
to differentiate them, it is necessary to carry out taxonomic and micrographic studies that analyze the
histological characters that allow the separation of the species (Alonso and Desmarchelier 2007). These
species used in folk medicine as a stomach protector, to combat metabolic conditions, although there are
few studies related to their effectiveness.
In addition, the use of ethnomedicinal plants from the traditional medicines of India or China, which
is completely unknown to western people, is becoming increasingly common, without the corresponding
controls that could ensure the efficacy of these products (Veiga Junior et al. 2005), and in general the
histological parameters for identification are unknown which makes it difficult to identify species.
According to WHO (2003) reporting of adverse effects related to the use of herbal medicine increased
due to the poor quality of them, especially the medicinal plant raw materials and the idea of the general
population that the plants are harmless. As mentioned before, people believe there are no adverse effects
and they can consume as much and as long as they want. It has been acknowledged, therefore, that not
enough attention has been given to guaranteeing and controlling the quality of herbal medicines, making
it difficult to use this type of medicine in PHC.
For all of the above, we can affirm that the quality and efficiency of the plants starts with the correct
identification of the species by its Latin name. While the standardization of ethnomedicinal plants can
be a more complex task, because they contain complex mixtures and the constituents responsible for the
effects are often unknown, assuming that they act together.
As mentioned in natural medicine the plant’s organ is used, not the entire plant, therefore it is necessary
to have physical patterns where the macroscopic characteristics of the medicinal plant materials, such as
shape, size, color, surface characteristics, texture, characteristics of the fracture and appearance of the cut
surface. However, since these characteristics are judged subjectively and the substitutes or adulterants
may resemble the genuine material a lot, it is necessary to corroborate the findings by microscopy and/or
physical-chemical analysis, and then the plant histology constitutes the adequate tool for the identification
of the drug.
All this leads us to think that the update of the Herbal Pharmacopeia becomes a necessity because
our medicine is based on the consumption of ethnomedicinal plants, and in this chapter, we write the
characteristics of the organs used as medicine and the identification techniques. Microscopic inspection
of medicinal plant materials is indispensable for the identification of powdered materials. The sample
may require studies using chemical reactive and these procedures should be recorded in the monographs
of each of the species included in the Pharmacopoeias. It is important to remember that a microscopic
examination alone may not always provide complete identification, although when used in association with
other analytical methods it can often provide supporting evidence for sample identification (WHO 2005).
Thus, the botanical identity of the plant based drug must be given by the scientific name (genus,
species, subspecies or variety, author and family) and the organ considered as medicinal must be described
in detail, it may be important in addition to register the common names in the local language, if any.
In addition, specimens of ethnomedicinal plants should be collected and prepared in the form of a
herbarium for their preservation, ensuring that they include all the organs required for accurate identification:
flowers, fruits, seeds, roots and normal leaves, which should serve as patterns for their correct identification
(OMS, UICN, WWF 1993).
This must be supported by the histological descriptions of the medicinal organ and the composition
of the powder of the vegetal drug, that is to say we need patterns of the genuine species to base the
comparisons and identification.
Origin of medicinal species: natural habitat and cultivation

Ethnomedicinal plants for commercialization are extracted from their natural habitat or cultivated. In almost
all countries of Latin America, ethnomedicinal plants come mostly from their natural habitat, and few
are grown, probably due to the lack of knowledge of agricultural techniques for production. The species
introduced and acclimated, in general, the conditions for their cultivation are known and it is important
to remember that the ethnomedicinal plants constitute a significant commercial field, the reason why the
extensive exploitation of the species can take them to the limit of the extinction (WHO 2003).
On the other hand, numerous efforts have made in recent years to draw attention to the problems nature
faces because of deforestation and the destruction of ecosystems, mainly due to anthropogenic actions.
The loss of biodiversity with the consequent disappearance of species depends on factors associated with
common economic and social problems in developing countries. The disorderly growth of populations
due to urban and rural development without adequate planning processes causes pressures on available
natural resources. On the other hand, overexploitation, livestock, industrialization, construction of road
infrastructures and other characteristics have contributed significantly to the processes of extinction.
In addition, as we know, the problems that affect the conservation of biodiversity contribute to the
disappearance of species considered medicinal and in many cases, are replaced by others with similar
characteristics.
As already mentioned, in some Latin American countries, the number of plants used for medicinal
purposes is increasing, Basualdo et al. (2003, 2004) mentioned that in Paraguay, in their capital and in
the metropolitan areas, 266 species are traded for medicinal purposes, used to combat, prevent or cure
57 diseases; Pin et al. (2009) cited 500 medicinal species used for preventive and therapeutic purposes.
These lists include species introduced, acclimatized and native, not to mention the origin that is if they
come from crops or are extracted from their natural habitat. In other countries of the Americas, there is a
similar situation, in Colombia, according to Duque Villegas (2003), from 100 to 243 medicinal and aromatic
species are sold in the marketplaces of the city of Bogotá; of them, between 50 and 60% correspond to
native species (it is not known if they are wild or cultivated), while 20 and 40% are naturalized, coming
from other places.
One of the most frequent problems when collecting medicinal species from wild populations is the
confusion of species and when the “originals” are replaced with other species or parts of other plants due
to incorrect identification. Sometimes the substitution may be intended to increase the volume of marketing
and with the certainty that the user will not perceive the difference.
Another problem that we mention when we talk about quality is the contamination with agrotoxics
because it is close to agricultural production sites on a large scale, where it is sometimes fumigated, even
using small airplanes so that the product used reaches all cultivated areas. These circumstances may
adversely affect the safety of products and cause health problems in people who consume these herbs.
This type of contamination occurs in natural or cultured populations.
The safety and quality of medicinal vegetable raw materials and finished products made from this
raw material depends on factors that can be classified as intrinsic (genetic) or extrinsic (species selection,
harvesting methods, cultivation, harvesting, post-harvest processing, transportation and storage practices)
(Fig. 11.2). Inadvertent contamination by microbial or chemical agents during any stage of production
may also compromise the safety and quality (WHO 2003).
As mentioned above, obtaining the raw material from its natural habitat can produce the substitution
with native species similar to the one harvested, an example is “yerba mate” Ilex paraguayensis
(Aquifoliaceae), a species used to prepare mate, cooked mate, a brew that is made with the leaves of the
species mentioned, and is used as food in the southern part of Latin America, Paraguay, Brazil, Argentina,
Uruguay. Natural populations called “yerbales” when harvested were adulterated with other species in a
fraudulent way to increase the amount for commercialization (Keller and Giberti 2011, Horianski et al.
2012).
The cultivation of ethnomedicinal plants for use as raw material offers the advantage that it is
possible to know which species is cultivated, that is to say, the taxonomic identity, the genetic traits and
the pharmacognostic factors are handled, which determine the best moment for the collection of the raw
material, that is to say when it has more quantity and quality of its secondary metabolites.
In addition, by cultivating selected species, extrinsic factors can be managed to obtain abundant raw
material, which is homogeneous and of high quality. It is possible to control some of the variables that
affect the production (nutrient supply to the soil, pest control, humidity) and, therefore, to improve the yield
in active principles. In crops, in general, plants develop in the same way, which facilitates the collection,
drying and in some cases the extraction process (WHO 2005).
Knowing the harvesting period is fundamental to obtain good quality raw material, ethnomedicinal
plants should be harvested during the optimum season or period to ensure obtainment of the appropriate
secondary metabolites of the best possible quality. The harvesting season depends on the part of the plant
to be used. In addition, it is known that the concentration of components with biological activity, as well
as that of the undesired secondary metabolites, varies according to the stage of growth and development
of the plant, for example when harvesting flower, it is good to it collect early in the morning, before they
fully open. That is to say, the best time to harvest (the optimum season and times of day) can be managed
according to the quality and quantity of the components with biological activity, and not only the total
yield in vegetal matter of the parts of the ethnomedicinal plants subject to production.
Microbial contamination
Fig. 11.2 Factors that influence the safety and quality of plant material.
During the harvest, care must be taken to prevent foreign matter, other herbs and toxic plants from
mixing with the harvested plant material. Ethnomedicinal plants should be harvested in the best possible
conditions, in the absence of dew, rain and exceptionally high humidity levels. If the harvest is carried
out in wet conditions, the harvested material must be transported immediately to a drying plant under the
roof to accelerate drying and thus avoid the possible detrimental effects of high humidity levels, which
encourage microbial fermentation and molding, decreasing the quality of the raw material (WHO 2003).
Microbial contamination
Bacterial or fungal contamination of ethnomedicinal plants represent a serious problem because of the risk
involved for the health of the patient and for the economic losses generated when they are raw material for
the production of pharmaceuticals, food or cosmetics. This type of contamination is closely linked to the
supply chain, where some part of the process fails to obtain products that deviate from the characteristics
of what is sought.
Inappropriate values of microbial contamination are often due to a poor drying or storage process,
which can lead to both the proliferation of pathogens and the production of toxins of different nature
(aflatoxins, E. coli enterotoxin) that are capable of causing serious complications in users (Vanaclocha
and Cañigueral 2006).
Microbiological control has two very important aspects:
1. Hygienic and Sanitary Quality, that is to say that the raw materials do not contain pathogenic
microorganisms for human health.
2. Commercial quality, that the raw material does not present characteristics that make it unsuitable
for its use.
As stated, microbiological control is an important part of the quality of ethnomedicinal plants used
in primary care.
Conservation of medicinal species

As mentioned, for marketing, ethnomedicinal plants are harvested from their natural habitat. According
to Soria and Basualdo (2015), 67% of the plants mentioned as medicinal in Paraguay, come from their
natural habitat, while only 33% is cultivated, so the conservation of these plants is an aspect that must be
addressed, since extensive and uncontrolled extraction may jeopardize the sustainability of species over
time. In addition to the factors that affect the conservation of the species, there is another one, directly
linked to the medicinal organ used; so, when the root, rhizome or part of them is used, the plant must be
extracted completely even if only a part of these subterranean organs is used.
This contributes to the overexploitation to which they are submitted for commercial use, especially,
when they constitute raw material of some herbal medicine, in more industrialized processes for the
pharmaceutical, food, cosmetic industry. The development of policies for the conservation of species in
general, and of medicinal species in particular, becomes a necessity, for which studies should be carried
out to determine the degree of threat of each of the species that could be used in PHC.
The conservation status of native species is a global concern. It is necessary to understand the potential
threat of survival for species before entering a cropping program. Therefore, it is recommended that prior
to their use in the PHC; a count of raw material quantity is conducted to ensure sustained effectiveness
of a cropping program.
Due to the concern for species conservation, the Strategic Plan for Biological Conservation 2010–2020
and Aichi’s goal number 12 propose that “by 2020 the extinction of identified endangered species would
have been avoided and their conservation status would have been improved and sustained, especially
for the most declining species” and indicates the need to identify species at risk of extinction (Soria and
Basualdo 2015).
Conservation of ethnomedicinal plants is a major risk due to the lack of knowledge we have about
them. In order to effectively use and conserve ethnomedicinal plants, it is essential to know precisely
the information about the species, what the correct scientific name is, the number of individuals in the
population, whether the extraction is done from their natural habitat, and the distribution of the population.
There is no known accepted global list of ethnomedicinal plants that are used today. Many ethnomedicinal
plants are poorly identified. For this and other reasons, any national program on the use and conservation
of ethnomedicinal plants should include an herbarium specimen conservation mechanism that allows the
identification of ethnomedicinal plants in the country, their distribution and their scarcity or abundance.
Dosage
In general, medicinal herbs are prepared in infusion or decoction for their consumption, the procedure is
very important for the extraction of the active substances contained in them. When it comes to soft organs
(leaf, flower, and aerial), the preparation is done by means of infusion, that is to say the water is boiled
and it is fed on the vegetable, sometimes it is recommended to cover to avoid that the essential oils to be
vaporized. When a hard part is used (bark, stem, root, and seed) it is boiled in the water for some minutes
that can vary between five or ten, the resulting liquid is filtered and the decoction obtained is drunk. In
general, the amount of the plant to be used depends on the plant organ used and the amount of water
used is related to the contents of a 150 ml cup (Table 11.2). The extracted product is very little with this
procedure (Tyler and Robbers 2003, ANVISA 2011).
With regard to species activity, it is important to remember that the use of plants may interact with
allopathic drugs. There are studies showing that the simultaneous consumption of medicine and organs,
parts or products coming from ethnomedicinal plants may lead to interactions, which further motivates
the need to recognize that plants should be treated as medicine. It is important to know the attitudes of
users and health personnel regarding the consumption of ethnomedicinal plants as a medicine (Rodríguez
Ramos 2014).
In general, in Latin American countries, with a strong tradition in the use of ethnomedicinal plants,
99% of the population that goes to the health services, admit they use ethnomedicinal plants for medicinal
or preventive purposes, although in general they do not inform health personnel of their use because they
consider that consumption is harmless. It is important to remember that this medicine constitutes the only
form of traditional medicine widely accepted by the population in all countries of Latin America.
One of the current trends in medicine has been to incorporate Traditional Medicine into professional
practice, not as an alternative method motivated by economic causes, but as a scientific discipline that
must be studied, perfected and developed permanently, for its ethical and scientific advantages, because
it constitutes a means of recovering the cultural heritage of the people, which is in danger of disappearing
with the advance of “modern medicine” (Torres and Quintana 2004).
All of the above leads us to mention that public policies, which favor multidisciplinary investigations
in ethnomedicinal plants, are needed, prior to their use in primary care to ensure the use of a more effective
and low-cost medicine.
Table 11.2 Relationship of plant organ/grams/mL of water.
Vegetable drug Weight in grams mL

Dry leaves 3–4 150
Inflorescence 6–9 100
Roots, bark 2–5 100
Flowers 1–3 150
Fruit peel 6 150
Aerial part 2–5 150
Examples of effects of joint use of plants and allopathic drugs

In recent years, adverse effects related to the use of plants in conjunction with medicinal allopathic have
increased. Let us look at some examples. When antidepressant treatment and concomitant use of medicinal
species as “St. John’s wort” also known as “wort” (Hypericum sp., Clusiaceae), a drug popularly used as
an antidepressant, can cause complications such as decreasing the antidepressant effects of the chemical
drug and also provoke contrary effects to those sought and induce a strong anxiety in the users. In addition,
this herb is photosensitizing in animals and although there are no studies for humans, it is recommended
that people not be exposed to sunlight (Tyler and Robbers 2003).
Valerian (Valeriana officinalis L., Caprifoliaceae), popularly used as a sleep inducer, sedative, moderate
tranquilizer, used in conjunction with barbiturates, benzodiazepines and/or alcohol can cause intestinal
bleeding, potentiate the action of barbiturates and reduce symptoms of abstinence from benzodiazepines.
In addition, the use of anti-coagulants can also be affected by the consumption of ethnomedicinal
plants, such as ginger (Zingiber officinale L., Zingiberaceae), which can cause hemorrhages caused by
its consumption, considering that this plant is used in food as spice for its flavor. It can also produce high
blood pressure.
The Ginkgo biloba L., is a species considered as a living fossil. It is the only living representative of
the Ginkgoaceae family of the order of the Ginkgoales; this species coexisted with dinosaurs, in the Jurassic
era from where it comes to our days maintaining its medicinal properties, i.e., preventing and fighting the
effects of strokes, stimulating circulation, is also considered to be an antioxidant and anti-inflammatory.
This species should not be consumed along with antidepressants, anticoagulants, aspirin, warfarin,
eparin and it is recommended that epileptics do not use it. The reported side effects are interference with
serotonin, production of greater bleeding by potentiating the effect of anticoagulants, stomach discomfort,
and migraine.
Also, the “confrei” (Symphytum officinale L. Boraginaceae), a species that is used in traditional
medicine for healing effect, possesses pyrrolizidinic alkaloids which are hepatotoxic and can produce
carcinogenic cells. After several cases of death caused by cirrhosis resulting from veno-occlusive liver
disease triggered by these alkaloids, the use of this species was banned by the WHO plant safety agencies.
There are other species that produce undesirable effects due to its secondary metabolites, such as
Senecio grisebacchii Baker (Asteraceae) that is used in the traditional medicine to “renew the blood”,
coinciding with beginning of the month of August, end of the winter, in the southern hemisphere, this
species possesses pyrrolizidine alkaloids that cause hepatic damages. Likewise, “jurubeba”, Solanum
paniculatum L. (Solanaceae), can cause irritation of the gastrointestinal mucosa. Likewise, Aristolochia
species are attributed with diuretic and anti-infective properties in the urinary tract, antirheumatic, sedative
and sometimes is part of slimming preparations. Among its secondary metabolites, it has the aristolochic
acid, consumption of which can cause renal problems (Arango Toro 2005).
“Salvia”, Lippia alba (Mill.) N.E. Br. ex Britton & P. Wilson (Verbenaceae), has shown good results
for its use as an antispasmodic, hypotensive and high dose has not reported toxic effects or intolerance.
It has experimentally demonstrated analgesic, hypotensive, smooth muscle relaxant, and anti-fungal
activities against Candida albicans .This last action validates the uses in cases of infections where this
microorganism is involved. The other tested effects act in a beneficial way in the baths given to women
during the puerperium. The combination of Lippia alba extract and paracetamol in rabbits increases the
toxic effect of paracetamol on the liver, so it should not be administered in conjunction with this drug
(Argueta and Cano 1994, Gonzalez and Naranjo 2000).
Care group: Pregnant women, infants, children, and the elderly persons
In relation to the side effects that ethnomedicinal plants may have, pregnant women, infants and children
under two years should avoid the consumption of ethnomedicinal plants, especially when there is no safety
study. Nursing mothers run the risk that the drug may pass even though it is in small proportion to the child
through milk, and because the organs of the babies are not yet fully strengthened, can cause adverse effects.
There is also another important group of users: the elderly. Due to their age kidney functions decreases,
difficulty in the absorption, distribution and elimination of secondary metabolites of the plants, which can
lead to poisoning, frequently confused because people assume that products of plant origin are “harmless”.
Ethnomedicinal plants in Primary Health Care

Everything mentioned, leads us to understand that when we talk about ethnomedicinal plants in primary
care, we are talking about medicines and therefore we must consider and manage them as such respecting
the parameters that allow us to use them in first line treatment and prevention, especially in the initial phases
of colds, diarrhea, stomach pains, epidermal problems, mild fevers, metabolic diseases (hypertension, type
II diabetes and other metabolic diseases), and is also a form of affordable, accessible and available care
(Soria and Ramos 2015).
So, which plants meet the requirements for use in PHC?
Many drugs come from traditional medicine and have been used for centuries, providing some
assurance of their safety, mainly when acute toxicity is concerned. Probably, that ancestral use has
contributed to rooting in the population the generalized perception that natural is synonymous of harmless.
However, although plant drugs and derivatives often have a broad therapeutic range, they are not exempt
from possible adverse effects, interactions and contraindications. Hence, the evaluation of their safety
should be carried out with the criteria applied to other medicinal products and should be supported,
whenever possible, in the existence of relevant scientific documentation on their toxicity, side effects,
interactions, and contraindications. Many species have passed the test of efficacy and safety and could be
used as a base drug; it is convenient to remember that these species have a recommended dose and that
their indiscriminate use can cause adverse effects.
Let us look at some examples of ethnomedicinal plants that could be used in primary care, as long as
the parameters for safety and efficacy to which we referred in this chapter are respected:
“Aloe” Aloe saponaria Haw. (Asphodelaceae), is a species used since antiquity. It is mentioned in the
Bible, is native to North Africa and introduced in America, where it is grown in abundance. In external use,
it can help healing wounds, for which the mucilage of the fresh leaf on the wound is allowed to drain. It
can also be used to treat zits, acne, eczema, ulcers, itching of the skin, treatment to be repeated 3–4 times
a day. The adverse effect reported was photosensitivity and contact dermatitis (Alonso 2004).
“Boldo, false boldo” Plectranthus barbatus Andrews (Lamiaceae), the aromatic leaves of this species are
used as digestive medicine. It is recommended not to administer to people with hypertension, carriers of
obstruction of the bile ducts, patients who use drugs for the central nervous system; can lower blood pressure
and cause gastric irritation. Consumed with allopathic products such as metronidazole or disulfiram can
decrease the effects of these drugs. It should not be used by pregnant women, infants and children under
2 years of age (Anvisa 2011).
“Boldo” Peumus boldus Molina (Monimiaceae). This species is used in hepatic, vesicular ailments and it
is used for its digestive properties. At the usual doses 2–3 g of dry leaf in 150 mL of water, boldo infusion
is well tolerated. However, because of its choleretic action, it should not be used in cases of obstruction
of the bile ducts or in severe liver diseases. Some of the active ingredients have oxytocin activity and
should not be given to pregnant women. Neither should be administered to children younger than 2 years
(Alonso 2004).
“Cangorosa” Maytenus ilicifolia Mart. ex Reissek (Celastraceae), the blending of the leaves and the root
bark is used to combat dyspepsia, heartburn, gastritis. It is prepared in infusion of 3–5 g of dry drug in
150 mL of water or 5–7 g of root bark in 200 mL water and it is drunk right after main meals. Pregnant
women, infants and children under 2 years should not consume it. Prolonged use can cause nausea and/
or a strange taste in the mouth (Sharapin et al. 2006).
“Guayaba” Psidium guajava L. (Myrtaceae), the leaves are used to treat pharyngitis and in external use to
wash wounds, for which the decoction of 50 g of fresh leaves in 1 L of water is prepared and the wounds
are washed 3 times per day. To treat pharyngitis the person must gargle up to 3 times a day, without
swallowing. Use for short periods, no more than 30 days. Do not administer to pregnant women, infants
and children under 2 years of age (WHO 2010).
“Kava kava” Piper methysticum G. Forst. (Piperaceae), is used in alternative medicine in the treatment of
anxiety, insomnia, depression, attention deficit disorder, and has shown positive results when used in the
prevention of withdrawal symptoms sedatives from medicines like Valium, Xanax and others. Continued
use of this species can affect the liver and lead to hepatitis, cirrhosis and liver failure. The use of this
species is considered unsafe, especially because of the abuse of it. People do not limit their use to the
recommended dose (Alonso 2004).
“Guaco” Mikania glomerata Spreng. (Asteraceae), the leaves are used as an expectorant, according to
the form published by ANVISA of Brasil (2011), boil 150 mL of water, pour on 3 g of dry leaf, and drink
twice day. Do not use with non-steroidal anti-inflammatory drugs, as their use may interfere with blood
clotting. Higher than recommended doses can cause vomiting and diarrhea.
The leaf of sour orange Citrus auriantium L. (Rutaceae) is used in traditional medicine as antispasmodic
and sedative. In external use to combat foot odors, 10–15 g of fresh leaves are squeezed, macerated in cold
water and drank during the day. The decoction of 50 g/l of leaves boiled in water for 10 minutes is used
to wash the feet daily, decreasing the odor. It is not recommended to administrate it to pregnant women,
infants and children under 2 years (ANVISA 2011).
“Fennel, hinojo” Foeniculum vulgare L. (Apiaceae), is used as digestive, carminative and diuretic. It is
prepared in infusion, 2–3 g of seed in 150–200 mL of water and 2 cups a day is drunk after main meals.
Recommended doses do not produce adverse effects. High doses have demonstrated to have the emenagogo
effect, for which reason it should not be administered during pregnancy and the lactation period. The
essential oil can cause, in doses greater than 1 ml, convulsive or hallucinogenic effects. Do not administer
to children under 2 years of age. Do not consume for prolonged periods, that is to say for more than three
months on an ongoing basis. The aqueous extract can produce photosensitivity, so sunbathing is not
recommended when drinking the infusion of this species.
“Breaking stone” Phyllanthus niruri L. (Euphorbiaceae), the aerial part of the plant is used as a diuretic
and to combat kidney stones. An infusion of 3–4 g is prepared in 150 mL and is drunk up to 3 cups a day.
It is not recommended to use it in prolonged treatments since it can produce diarrhea, hypotension and
marked diuresis. It is not advisable to administer it to pregnant women, infants and children under 2 years
of age (ANVISA 2011).
The species Scoparia dulcis L. (Plantaginaceae) is used in popular medicine as digestive medicine;
studies show that the species has antispasmodic effect in stomach cramps. There are still few studies
regarding the toxic effects, but it is believed that it could potentiate the effect of barbiturates and act as
a selective inhibitor of serotonin reuptake. There are numerous studies related to the use of this species
for its antidiabetic action for which it has shown promising effects (De Farias Freire et al. 1993, Pari and
Latha 2004).
It is not intended to make an extensive listing; only some species are shown that could be useful in
primary care mentioning its properties and the care that should be taken for their use.
It is important to remember that the effect of ethnomedicinal plants is not immediate, so it cannot
be used in acute conditions. In addition, it is recommended that consumption of the same species does
not last for more than six months, which should be followed by a six-month waiting period as well. This
is because the metabolites are transformed into the liver and are generally removed by the urinary tract.
This waiting period allows the body to recover from the stress that could have caused the prolonged use.
An important aspect that we must not forget is that vegetable drugs can cause side effects that are
manifested with symptoms like nausea, stomach pain, diarrhea, headache, when any of these symptoms
are felt, the use of it should immediately stop. If symptoms persist, contact a physician, who should be
informed of the species used and the time of consumption to find the appropriate solution.
Conclusion
Ethnomedicinal plants can be used in primary health care as a more attainable, affordable, safe and effective
medicine if the conditions for its use are maintained.
Efficacy and safety are two main aspects to take into account when using ethnomedicinal plants
and they depend on: (i) the taxonomic identity (ii) the habitat from which it comes (iii) the dosage used.
The extraction of the species from their natural habitat can cause confusion between species of similar
morphological characteristics, resulting in adulteration and consequently different therapeutic responses.
Vegetable matter from crops has the advantage that the pharmacognostic factors can be handled and it is
also possible to obtain raw material of good quality, suitable for medicinal use.
It is necessary to continue the studies analyzing all of the above-mentioned factors. Researches should
be collaborating together through an intercultural approach that allows them to analyze and ascribe solutions
to community health problems in a dynamic viewpoint which, links existing socioeconomic structures and
ancestral medicine to the official health system that allows safe and effective use of ethnomedicinal plants.
References
Acosta, M.E., Ladio, A.H. and Vignale, N. 2017. Medicinal plants traded in San Salvador de Jujuy city (Argentina) and its
botanical quality. Bol. Latinoam. Caribe Plant. Med. Aromat. 16(1): 34–52.
Almeida Vera, L. and Almeida Vera, L. 2014. Rationale of the Ecuadorian Intercultural Management Model in Primary Health
Care. Medisan 18(8): 1201–1214.
Alonso, J. 2004. Treaty on Phytopharmaceuticals and Nutraceuticals. Ediciones Corpus. Rosario Argentina, pp. 131.
Alonso, J. and Desmarchelier, C. 2007. Maytenus ilicifolia Martius (Congorosa). Bol. Latinoam. Caribe Plant. Med. Aromat.
6(1): 11–22.
Angulo, F.A., Rosero, R.A. and González Insuasti, M.S. 2012. Ethnobotanical study of medicinal plants used by the inhabitants
of the village of Genoy, Municipality of Pasto, Colombia. Rev. Univ. Salud 14(2): 168–185.
ANVISA. 2011. National Formulary of Phytotherapy of Brazil. Brasilia, 560 p.
Arango Toro, O. 2005. The use of medicinal herbs can produce serious nephrological and urological problems. Actas Urol.
Esp. 29(8): 801–802.
Argueta, V.A. and Cano, J.A. 1994. Atlas of traditional Mexican medicine plants. México: Instituto Nacional Indigenista.
Basualdo, I., Soria, N., Ortíz, M. and Degen, R. 2003. Medicinal use of plants commercialized in the markets of asuncion and
greater asunción. Rev. Soc. Cient. Parag. 14: 5–22.
Basualdo, I., Soria, N., Ortíz, M. and Degen, R. 2004. Medicinal plants marketed in the markets of asuncion and greater
asunción. Rojasiana 6(1): 95–114.
Basualdo, I. and Soria, N. 2015. Medicinal plants marketed in the municipal market of the city of Pilar, Dpto. Ñeembucu,
Paraguay. Dominguezia 30(2): 47–53.
De Farias Freire, S.M., Da Silva Emim, J.A., Lapa, A.J., Souccar, C. and Brandao, L.M. 1993. Analgesic and anti-inflammatory
properties of Scoparia dulcis L. extracts and glutinol in rodents. Phytother. Res. 7(6): 408–414.
Del Toro García, G. and Trapero Quintana, Y.M. 2007. Natural medicine and health system in Cuba. Bol. Latinoam. Caribe
Plant. Med. Aromat. 6(3): 48–51.
Degen, R., Soria, N., Ortiz, M. and Basualdo, I. 2005. Problems of common names of medicinal plants marketed in Paraguay.
Dominguezia 21(1): 11–16.
Duque Villegas, A. 2003. National survey of medicinal and aromatic plants an approach to the market of pmya in Colombia 26 p.
Flores, A. 2008. Conflicts in the use of Traditional Medicine. Reg. Soc. XX(43): 213–217.
Gonzáles, A. and Naranjo, S. 2000. Possible hepatotoxicity induced by the association of Lippia alba and acetominofen in
rabbits. Conaplamed Info. 16: 25–35.
Horianski, M.A., Castrillo, M.L., Tayagui, A.B. and Jerke, G. 2012. Microbiological quality of canchada yerba mate. Rev.
Cienc. Tecnol. 17: 30–33.
Keller, H.A. and Giberti, G. 2011. First record for the Argentine flora of Ilex affinis (Aquifoliaceae), substitute of the “yerba
mate”. Bol. Soc. Argent. Bot. 46: 1–2.
OMS, UICN, W.W.F. 1993. Guidelines on Conservation of Medicinal Plants, 34 p.
Pari, L. and Latha, M. 2004. Protective role of Scoparia dulcis plant extract on brain antioxidant status and lipid peroxidation
in STZ diabetic male Wistar rats. BMC Complem. Altern. M. 4: 16.
Pin, A., González, G., Marín, G., Céspedes, G., Cretton, S., Christen, P. and Roguet, D. 2009. Medicinal Plants of the Botanical
Garden of Asunción. Asunción, Paraguay, 441 pp.
Pochettino M.L., Arenas, P., Sánchez, D. and Correa, R. 2008. Traditional botanical knowledge, commercial circulation and
consumption of medicinal plants in an urban area of Argentina. Bol. Latinoam. Caribe Plant. Med. Aromat. 7(3): 141–148.
Rodríguez Ramos, R. 2014. Medicina Naturista y Atención Primaria de Salud. Experiencia Cubana. Available in: http/: www.
uva.org. Ar/cuba.
Sharapin, N., Alonso, J.R., Henriquez, A., Zuanazzi, J.A., Mentz, L.A., Nunez, E., Apel, M. and Cañigueral, S. 2006. Cangorosa
Leaf (Maytenus ilicifolium). Rev. Fitoterapia 6(1): 29–43.
Soria, N. and Basualdo, I. 2015. Conservation of medicinal species in Paraguay (Part I). Dominguezia 31(1): 41–47.
Soria, N. and Ramos, P. 2015. Use of medicinal plants in primary health care in Paraguay: some considerations for safe and
effective use. Mem. Inst. Investig. Cienc. Salud 13(2): 8–17.
Torres, I.B. and Quintana, I.J. 2004. Comparative analysis on the use of medicinal plants in traditional medicine in Cuba and
Canary Islands. Rev. Cubana Plant. Med. 9(1): 9–14.
Tyler, V.E. and Robbers, J.E. 2003. Las hierbas medicinales de TYLER. Uso terapéutico de las fitomedicinas. Editorial
Acribia SA, 254 p.
Vanaclocha, B. and Cañigueral, S. 2006. Possible hepatotoxicity of rhizome of cimicífuga. Rev. Fitoterapia 6(2): 129–135.
Veiga Junior, V.F., PintoI, A.C. and Maciel, M.A. 2005. Medicinal plants: safe cure? Quim. Nova 28(3): 1–15.
World Health Organization (WHO). WHO strategy on traditional medicine 2002–2005. Geneve, Suiza. 1–75 pp.
World Health Organization (WHO). 2003. WHO Guidelines on Good Agricultural Practices and Collection (BPAR) for
Medicinal Plants. Geneve, Suiza, 79 p.
World Health Organization (WHO). 2005. Quality Control Methods for Medicinal Plant Materials. Geneve, 122 p.
World Health Organization (WHO). 2010. Who Monographs on Selected Medicinal Plants 4. pp. 108–117.
World Health Organization (WHO). 2013. WHO Strategy on Traditional Medicine 2014–2023. Geneve, Suiza, 75 pp.
12
Secondary Metabolites of Some
Ethno-medicinal Plants of Arunachal
Pradesh, India
Pallabi Kalita Hui,1,* Debmalya Das Gupta1 and Hui Tag2
Introduction
The North Eastern (NE) region of India represented by seven Indian states, viz. Assam, Arunachal Pradesh,
Manipur, Meghalaya, Mizoram, Nagaland and Tripura is a ‘Global Biodiversity Hotspot’ and represents one
of the highest biodiversity of the Indian subcontinent. The region is often referred to as the Seven Sisters
and Sikkim has also now been included in North eastern states. It is ecologically represented by the Eastern
Himalayan biome and is rich in a number of endemic flora and fauna endowed with a rich biodiversity.
Arunachal Pradesh popularly called as “Land of Rising Sun”, falls under a geographical coordinates of
26°28’ to 29°30’ North Latitude and 90°30’ to 97°30’ East Latitude spreading over a geographical area of
83,743 sq. km. It shares borders with Assam and Nagaland in the South, Tibet (China) in the North and
North East, Bhutan in the West and Myanmar in the East. The state being primarily a hilly tract is nestled
in the foothills of Himalayas situated on the Great Eastern Himalayan Mountain Range and is recognized
as the 12th Global Biodiversity Hotspots. It covers a vast diversity of flora and fauna making it one of the
richest biotic province of the Republic of India. Parallel with this, nature has exceedingly endowed the
state with rich bio-resources along with the second largest area under forest cover, i.e., the total area of
68,045 sq.km in the whole of India after Madhya Pradesh (Anonymous 2008).
Arunachal Pradesh is a tribal state comprises of 19 districts inhabited by 26 major tribes and 110 sub-
tribes of diverse culture and lifestyle, with a traditionally rich Indigenous Knowledge System (IKS), across
different geographical regions since time-immemorial (Fig. 12.1) (Tag et al. 2005). The majority of the
local tribal communities originally belonged to Mongoloid racial stock but their long history of migration
coupled with geographical isolation has altogether contributed to varied distinctive characteristics which are
reflected in their language, dress and customs and customary laws amongst different tribes and sub-tribes.
The richness of life form, i.e., the flora and fauna that occur in the pristine forest presents a panorama of
1
Department of Biotechnology, National Institute of Technology Arunachal Pradesh (NIT AP), Yupia-791112, Papum Pare,
Arunachal Pradesh, India.
2
Department of Botany, Rajiv Gandhi University, Rono Hills, Doimukh-791112, Papum Pare, Arunachal Pradesh, India.
* Corresponding author: pallabi2008rgu@gmail.com
Secondary Metabolites of Some Ethno-medicinal Plants of Arunachal Pradesh, India 203
Fig. 12.1 Map of Arunachal Pradesh showing different districts and its headquarters.
biological diversity. Such an unparalleled occurrence of life form can attributed to the peculiar location
of the state which is at the junction of Paleo Arctic, Indo-Chinese and Indo-Myanmar Biogeographical
region (Taktajan 1996).
The vegetation type of the state have been classified into different forest types by various workers
(Champion and Seth 1968, Haridasan and Rao 1985–1987) who classified the vegetation type of North
East India. Later, Haridasan made the detailed study and classified the forest type of Arunachal Pradesh
into four broad vegetation types which are further sub-classified based on prevailing plants (Haridasan
2001). The forests of Arunachal Pradesh are a powerhouse of a rich collection of medicinal plants, foods,
aromatic and other economically useful plants comprising almost all the vegetation types of the country.
The state harbors over 7000–8000 flowering plants (Hussain and Hore 2008) starting from the foothills
to the snowline alpine region. Till date, over 800 medicinal plants reported from wild habitat have been
found used in folk medicine while many others are still under exploration (Srivastava and Adi community
2009, Tag et al. 2014). Owing to its rich biodiversity new records or species are still reported by botanists
(Banik et al. 2003). However with the growing advent of science and research yielding high throughput
results researchers have come to the conclusion that certain plants that have a potent biological effect viz.
antibacterial, antifungal, anti-inflammatory, antipyretic, etc., are a result of certain secondary metabolites
that are prevalent among the plant family. However they may be or may not be directly correlated but some
kind of association does exist which renders these plants vital for mankind. It is only since the late 20th
century that secondary metabolites have been clearly recognized as having important functions in plants.
Many thousands of secondary metabolites have been isolated from plants of late, and many of them have
shown powerful physiological effects in humans and as such are used as medicines. Some of the wild
medicinal plants viz., Hedyotis scandens, Lasia spinosa, Elatostema sublaxum, Ficus semicordata, Musa
balbisiana, Bryonia grandis, Artemisia nilagirica, Dendrocnide sinuata, Clerodendrum colebrookianum,
Zanthoxylum armatum, Acorus calamus, etc., are used in treating common diseases and ailments like
dysentery, diarrhea, gastritis disorder, constipation, menstrual problem, toothache, headache, stomach
ache, fever, typhoid, pneumonia, allergy, urination problem, jaundice, diabetes, eye-infection, high blood
pressure, kidney stone, anti-dandruff, anti-lice in the hair and other uses.
Keeping in mind the broad prospect of the rich biodiversity of Arunachal Himalayas towards the global
scenario, the aim of this chapter is to provide an insight of a wide range of secondary metabolites that are
present in this biodiversity rich zone of Northeast India. The region is enriched with different medicinally
important plants across different agro-climatic zone. Here we focus on some commonly available medicinal
plants of this region with a diverse range of secondary metabolites to have an outlook of future prospect
of such rich zonal area harboring some endemic, rare and endangered flora species of the world.
Classification of secondary metabolites

Secondary metabolites largely fall into three classes of compounds: alkaloids, terpenoids, and phenolics.
However, these classes of compounds also include primary metabolites, so whether a compound is a
primary or secondary metabolite is a distinction based not only on its chemical structure but also on its
function and distribution within the plant kingdom.
Alkaloids
Alkaloids are a large group of nitrogen-containing compounds, examples of which are known to occur
in approximately 20% of all flowering plants (Secondary metabolites – Knowledge Encyclopaedia
2016). Closely related plant species often contain alkaloids of related chemical structure. The primary
metabolites from which they are derived include amino acids such as tryptophan, tyrosine, and
lysine. Alkaloid biosynthetic pathways can be long, and many alkaloids have correspondingly complex
chemical structures. Alkaloids accumulate in plant organs such as leaves or fruits and are ingested by
animals that consume those plant parts. Many alkaloids are extremely toxic, especially to mammals, and
act as potent nerve poisons, enzyme inhibitors, or membrane transport inhibitors. In addition to being toxic,
many alkaloids are also bitter or otherwise foul-tasting. Therefore, the presence of alkaloids and other
toxic secondary metabolites can serve as a deterrent to animals, who learn to avoid eating such plants.
Sometimes domesticated animals that have not previously been exposed to alkaloid-containing plants do
not have acquired avoidance mechanisms, and as such they become poisoned.
For example, Senecio vulgaris, often known by the common name ‘groundsel’ contains Pyrrolizidine
Alkaloids (PAs) one of which is named ‘senecionine’ which has resulted in many recorded cases of
livestock fatalities due to liver failure. More frequently, over time, natural selection has resulted in
animals developing biochemical mechanisms or behavioral traits that lead to avoidance of alkaloid-
containing plants. Sometimes although a less common phenomenon, animals may evolve a mechanism for
sequestering (storing) or breaking down a potentially toxic compound, thus ‘disarming’ the plant. Plants
have however with advent of time, acquired new capabilities to synthesize additional defense compounds
to combat animals that have developed resistance to the original chemicals. This type of an ‘arms race’
is a form of co-evolution and may help to account for the incredible abundance of secondary metabolites
in flowering plants.
Medicinal Alkaloids
Many potentially toxic plant-derived alkaloids have medicinal properties, as long as they are carefully
administered with regular dosage levels (Fig. 12.2). Alkaloids with important medicinal uses include
‘morphine’ and ‘codeine’ from the opium poppy (Papaver somniferum) and cocaine from the coca plant
(Erythroxylum sp.). These alkaloids act on the nervous system and are used as painkillers. ‘Atropine’
from the deadly ‘nightshade plant’ (Atropa belladonna), also acts on the nervous system and is used in
anaesthesia and ophthalmology.
Vincristine and vinblastine from the ‘periwinkle plant’ (Vinca minor) are inhibitors of cell division
and are used to treat cancers of the blood and lymphatic systems. Quinine from the bark of the ‘cinchona
tree’ (Cinchona officinalis) is toxic to the Plasmodium parasite, which causes malaria, and has long been
used in tropical and subtropical regions of the world.
Fig. 12.2 Some examples of alkaloids, a diverse group of secondary metabolites that contain nitrogen (source: Taiz and
Zeiger 2010).
Other alkaloids are used as stimulants, including caffeine, present in coffee (Coffea sp.), tea (Camellia
sinensis), and cola plants (Cola sp.), and nicotine, which is present in tobacco (Nicotiana tabacum).
Nicotine preparations are, paradoxically, also used as an aid in smoking cessation. Nicotine is also a very
potent insecticide. Ground-up tobacco leaves were used for insect control for many years, but this practice
was superseded by the use of special formulations of nicotine. More recently the use of nicotine as an
insecticide has been discouraged because of its toxicity to humans.
Terpenoids
The terpenoids sometimes called isoprenoids, are a large and diverse class of naturally occurring organic
chemicals similar to terpenes, derived from the assembly of five-carbon isoprene units with different
modifications. They are derived from acetyl CoA or from intermediates in glycolysis (Cornelia and Ludger
2012). They are classified by their number of five-carbon isoprenoid units. Monoterpenes (containing two
C5-units) are exemplified by the fragrant oils (such as menthol) contained in the leaves of members of
the mint (Lamiaceae) family. In addition to giving these plants their characteristic taste and odor, these
volatile oils have insect-repellent qualities (Fig. 12.3).
The pyrethroids, which are monoterpene esters from the flowers of ‘chrysanthemum’ and related
species, are commercially used as insecticides. In spite of being biodegradable and nontoxic to mammals,
they fatally affect the nervous systems of insects, including humans.
Fig. 12.3 Structures of limonene (A) and menthol (B): two well-known monoterpenes that serve as defenses against insects
and other organisms (source: Taiz and Zeiger 2010).
Diterpenes are formed from four C5-units. Paclitaxel (commonly known by the brand name Taxol),
a diterpene found in bark of the genus ‘Taxus’, is a potent inhibitor of cell division in animals. At the end
of the 20th century, paclitaxel was developed as a powerful new chemotherapeutic treatment for people
with solid tumors, such as ovarian cancer patients.
Triterpenoids (formed from six C5 units) comprise the plant steroids, some of which act as plant
hormones. These also can protect plants from insect attack, though their mode of action is quite different
from that of the pyrethroids. Examples include ‘phytoecdysones’, a group of plant sterols that resemble
insect molting hormones. When ingested in excess it can disrupt the normal molting cycle with often
lethal consequences to the insect.
Tetraterpenoids (eight C5 units) include important pigments such as β-carotene, which is a precursor
of vitamin A, and lycopene, which gives tomatoes (Solanum lycopersicum) their red color. Rather than
functioning in plant defense, the colored pigments that accumulate in ripening fruits can serve as attractants
to animals, which actually aid the plant in seed dispersal.
The polyterpenes are polymers that may contain several thousand isoprenoid units. Rubber, a
polyterpene in the latex of rubber trees (Hevea brasiliensis) that probably aids in wound healing in the
plant, is also very important for the manufacture of tires and other products.
Phenolic compounds
Phenolic compounds are defined by the presence of one or more aromatic rings bearing a hydroxyl
functional group. Many are synthesized from the amino acid phenylalanine. They are important for the
quality of plant based foods and are responsible for imparting color of red fruits, juices and wines and
substrates for enzymatic browning, and are also involved in flavor properties. Phenolic compounds from
medicinal herbs and dietary plants include phenolic acids, flavonoids, tannins, stilbenes, curcuminoids,
coumarins, lignans, quinones, etc.
Simple phenolic compounds, such as ‘salicylic acid’ can be important in defence against attack of
fungal pathogens. Its concentration increases in the leaves of certain plants in response to fungal attack
and enables the plant to mount a complex defense response.
Interestingly ‘aspirin’ a derivative of salicylic acid, is routinely used in humans to reduce inflammation,
pain, and fever. Other phenolic compounds, called ‘isoflavones’ are synthesized rapidly in plants of the
legume (Fabaceae) family when they are attacked by bacterial or fungal pathogens, and they have strong
antimicrobial activity.
One of the complex phenolic macromolecule, ‘Lignin’ is laid down in plant secondary cell walls and
is the main component of wood. It is a very important structural molecule in all woody plants, allowing
them to achieve height, girth, and longevity. It is also valuable for plant defense: Plant parts containing
cells with lignified walls are much less palatable to insects and other animals than are non-woody plants
and are much less easily digested by fungal enzymes than plant parts that contain only cells with primary
cellulose walls.
Other function as attractants. ‘Anthocyanins’ and ‘Anthocyanidins’ are phenolic pigments that impart
pink and purple colors to flowers and fruits. This pigmentation attracts insects and other animals that move
between individual plants and lead to pollination and fruit dispersal. Often the plant pigment and the
pollinator’s visual systems are well matched: Plants with red flowers attract birds and mammals because
these animals possess the correct photoreceptors to see red pigments.
Phenolic compounds: antioxidant activity, occurrence, and potential uses

Phenolic compounds, ubiquitous in plants are an essential part of the human diet, and are of considerable
interest due to their antioxidant properties. These compounds possess an aromatic ring bearing one or
more hydroxyl groups and their structures may range from that of a simple phenolic molecule to that of
a complex high-molecular weight polymer. Flavonoids, which bear the (C6–C3–C6) structure, account for
more than half of the over eight thousand different phenolic compounds. The antioxidant activity of phenolic
compounds depends on the structure, in particular the number and positions of the hydroxyl groups and
the nature of substitutions on the aromatic rings. Fruits, vegetables and beverages are the major sources
of phenolic compounds in the human diet (Balakumbahan et al. 2010).
Phenolic compounds are secondary metabolites that are derivatives of the pentose phosphate,
shikimate, and phenylpropanoid pathways in plants (Taiz and Zeiger 2010). These compounds, one of the
most widely occurring groups of phytochemicals, are of considerable physiological and morphological
importance in plants. These compounds play an important role in growth and reproduction, providing
protection against pathogens and predators (Alasalvar et al. 2001), besides contributing towards the color
and sensory characteristics of fruits and vegetables (Benavente-Garcia et al. 1997).
Phenolic compounds exhibit a wide range of physiological properties, such as anti-allergenic,
anti-artherogenic, anti-inflammatory, anti-microbial, antioxidant, anti-thrombotic, cardio-protective and
vasodilatory effects (Samman et al. 1998, Middleton et al. 2000, Puupponen Pimia et al. 2001, Claudine
et al. 2005). Phenolic compounds have been associated with the health benefits derived from consuming
high levels of fruits and vegetables (Harborne 1989, Parr and Bolwell 2000).
Structurally, phenolic compounds comprise an aromatic ring, bearing one or more hydroxyl
substituents, and range from simple phenolic molecules to highly polymerized compounds. Despite
this structural diversity, the groups of compounds are often referred to as ‘polyphenols’. Most naturally
occurring phenolic compounds are present as conjugates with mono and polysaccharides, linked to one or
more of the phenolic groups, and may also occur as functional derivatives such as esters and methyl esters
(Shahidi and Naczk 1995, Harborne et al. 1999, King and Young 1999). Though such structural diversity
results in a wide range of phenolic compounds that occur in nature, phenolic compounds can basically
be categorized into several classes as shown in Table 12.1 (Shahidi and Naczk 1995, King and Young
1999). Among these, phenolic acids, flavonoids and tannins are regarded as the main dietary phenolic
compounds (Bhom 1998).
Phenolic acids consist of two subgroups, i.e., the hydroxybenzoic and hydroxycinnamic acids
(Fig. 12.4). Hydroxybenzoic acids include gallic, p-hydroxybenzoic, protocatechuic, vanillic and syringic
acids, which in common have the (C6–C1) structure. Hydroxycinnamic acids, on the other hand, are aromatic
compounds with a three-carbon side chain (C6–C3), with caffeic acid, ferulic acid, p-coumaric acid and
sinapic acid being the most common.
Flavonoids constitute the largest group of plant phenolics, accounting for over half of the eight thousand
naturally occurring phenolic compounds. Flavonoids are low molecular weight compounds, consisting of
15 carbon atoms, arranged in a (C6–C3–C6) configuration. Essentially the structure consists of two aromatic
rings A and B, joined by a three carbon bridge, usually in the form of a heterocyclic ring C. The aromatic
ring A is derived from the acetate/malonate pathway, while ring B is derived from phenylalanine through
the shikimate pathway (Hollman and Katan 1999, Merken and Beecher 2000). Variations in substitution
patterns to ring C result in the major flavonoid classes, i.e., flavonols, flavones, flavanones, flavanols (or
Table 12.1 Classes of phenolic compounds in plants.
Class Structure
Simple phenolics, benzoquinones C6
Hydroxybenzoic acids (C6–C1)
Acethophenones, phenylacetic acids (C6–C2)
Hydroxycinnamic acids, phenylpropanoids (coumarins, isocoumarins, chromones, chromenes) (C6–C3)
Napthoquinones (C6–C4)
Xanthones (C6–C1–C6)
Stilbenes, anthraquinones (C6–C2–C6)
Flavonoids, isoflavonoids (C6–C3–C6)
Lignans, neolignans (C6–C3)2
Biflavonoids (C6–C3–C6)2
Lignins (C6–C3)n
Condensed tannins (proanthocyanidins or flavolans) (C6–C3–C6)n
Fig. 12.4 Examples of some hydroxybenzoic and hydroxycinnamic acids.
catechins), isoflavones, flavanonols, and anthocyanidins (Pietta 2000), of which flavones and flavonols
occur most widely and are structurally diverse. Substitutions to rings A and B give rise to the different
compounds within each class of flavonoids. These substitutions may include oxygenation, alkylation,
glycosylation, acylation, and sulfation (Pietta 2000).
Tannins, the relatively high molecular weight compounds which constitute the third important group
of phenolics may be subdivided into hydrolysable tannins and condensed tannins (Porter 1989). The former
are esters of gallic acid (gallo- and ellagi-tannins), while the latter (also known as proanthocyanidins)
are polymers of polyhydroxyflavan-3-ol monomers (Porter 1989). Some common medicinal plants of
Arunachal Pradesh with their photographs (Fig. 12.5) and types of secondary metabolites are given in
below (Table 12.2).
Understanding relationships between secondary metabolites of plants and

its associated medicinal properties for the future generation
Since last two decades, significant ethnobotanical works have been published from this region (Tiwari et
al. 1976, Thothathri and Pal 1987, Kar 2004, Tag and Das 2004, Kala 2005, Tag et al. 2005, Angami et al.
2006, Das and Tag 2006, Ramashankar and Rawat 2008, Goswami et al. 2009, Tiwari et al. 2009, Doley
et al. 2010, 2014, Kagyung et al. 2010, Rethy et al. 2010, Sarmah and Arunachalam 2010, Srivastava et
al. 2010, Srivastava and Nyishi Community 2010, Jeri et al. 2011, Namsa et al. 2011, Nimachow et al.
2011, 2012, Shrivastava et al. 2012, Dutta and Dutta 2013, Maiti et al. 2013, Monlai et al. 2013, Payum
et al. 2013, Singh and Singh 2013, Yakang et al. 2013, Boko and Narsimhan 2014, Perme et al. 2015,
Purwianingsih et al. 2015, Murtem and Chaudhry 2016, Tsering 2016, Tsering et al. 2017, Tripathi et al.
2017). However, such studies have also revealed that many tribal groups of the eastern Himalayan zone
including Arunachal Himalayas of India are either under-explored or unexplored with regards to their
ethnobotanical and ethno-medicinal research works due to communication bottleneck and topographical
disadvantage. Such unexplored plants, are rich repositories of wide range of secondary metabolites (Table
12.2). It is obvious that these secondary metabolites are useful to plants but can be catabolized. Several
of these products have shown to exert a profound physiological effect on the mammalian system and
therefore are termed bioactive compounds. An intricate understanding of relationships between secondary
A B
D
C
Fig. 12.5 Some representative ethnomedicinal plants in Arunachal Pradesh (A) Acorus calamus L. (B). Illicium griffithii
Hook.f. & Thomson (C) Rubia cordifolia L. (D) Solanum torvum Sw. (E) Zanthoxylum armatum DC. (Photographs taken by
Dr. Hui Tag during his several field surveys.)
metabolites of plants and its associated medicinal property is henceforth necessary to validate such rich
repositories of energy, food, shelter and medicinal wealth in Arunachal Pradesh that would serve as a
pioneer for future states of the country as well as other nations. It’s high time that we focus our attention
to the complex relationship between the secondary metabolites and its associated medicinal property of
these plants rather than viewing each of them in an isolated mode, because all are intermingled together
and have strong correlation between them. Such correlated studies could be the answer for the current
global concern of environmental issues, biodiversity degradation, conservation of bio-resources, hazardous
diseases, etc. Therefore keeping in mind the broad prospect of such secondary metabolites that are present in
the rich biodiversity of ethno-medicinal plants of Arunachal Pradesh, our future target must be to document
and validate such traditionally useful bio-resources and establish the relationship between the secondary
metabolites and its related bioactive compounds. Moreover extinction of traditional knowledge has been
Table 12.2 List of some common ethno-medicinal plants of Arunachal Pradesh with types of secondary metabolites.
Sl No. Name of the plant Family Traditional use Active compounds Type of
secondary
metabolites
1. Aconitum ferox Wall. ex Ser. Ranunculaceae Paste of tuber is applied at the tip of the arrows for Aconitin, Pseudo-aconitin, Diterpene
hunting animals (Tag and Das 2004). Bikh-aconitine, Diacetyl- alkaloids
pseudaconitin, Aconine (Giri et al.
1997)
2. Acorus calamus L. Acoraceae Rhizome is chewed for toothache, inhaled for congestion; β-asarone Ether
used as brain tonic, coolant and drug for colic and as (McGaw et al. 2002).
a remedy for digestive disorders (Balakumbahan et al.
2010).
3. Ageratum conyzoides (L.) L. Asteraceae Paste of entire plant is applied on wounds for healing Stigmasterol and Sterols
and blood clotting; plant juice is applied twice daily in β-sitosterol.
red eye (conjuctivitis); plants are pounded and made into (Kamboj and Saluja 2011).
pills, the size of a pea and taken to cure blood dysentery;
whole plant also used as fish poison (Srivastava and Adi

Community 2009).
4. Andrographis paniculata (Burm.f.) Nees Acanthaceae Crushed leaves mixed in warm water is administered for Andrographolide (Pholphana et al. Labdane
the treatment of malaria and cough (Sen et al. 2008). 2004). diterpenoid
5. Bryophyllum pinnatum (Lam.) Oken Crassulaceae Juice of leaves is applied on burnt parts of the body Bryotoxin A, B, C, Bufadienolides
(Boko and Narsimhan 2014). 4-hydroxy-3-methoxy-cinnamic acid, flavonoids,
4-hydroxy benzoic acid (Kamboj and Polyphenols,
Saluja 2009). Triterpenoids
6. Clerodendrum glandulosum Lindl. Verbenaceae Used for the treatment of malarial parasite (Wangpan et 1,3-dimethyl-5-(2,5,13,17- Triterpenoid,
al. 2016). tetramethyl octadeca-6,16-dien-8-yl) Sterols
benzene, β–sitosterol, Clerodolone
(Joshi et al. 1979).
7. Coptis teeta Wall. Ranunculaceae Rhizome used in eye diseases and as a good appetizer, Berberine, Coptine (Xu et al. 2010). Alkaloids
curing the digestive system.
Anti-inflammatory and is useful in skin disorders
(Bhattee and Beniwal 1988).
8. Dillenia indica L. Dilleniaceae Fruits and fleshy calyx with little salt are taken raw or Betulinic acid (Kumar et al. 2010). Pentacyclic
boiled and is used for treating stomachache (Khongsai et triterpenoid
al. 2011).
9. Dioscorea floribunda M. Martens & Dioscoreaceae Tubers powders with water used in ulcer, malaria, Diosbulbin A, B, C, D, E Diosgeninan Saponins Alkaloid
Galeotti headache, fever (Ramashankar and Rawat 2008). (Hoyer et al. 1975).
10. Drymaria cordata (L.) Willd. ex Schult. Caryophyllaceae Leaf paste is applied on forehead to get relief from Drymaritin , C-Glycoside Flavanoid Alkaloids,
headache; fresh whole plant is mixed with Psidium (Hsieh et al. 2004). Flavonoids,
guajava and is taken during gastritis (Kagyung et al.
2010).
11. Illicium griffithii Hook.f. & Thomson Schisandraceae Used as medicine to cure abdominal pain, cough, Shikimic acid (Qinh et al. 2016). Cyclohexane
dyspepsia, food poisoning, vomiting, toothache and Carboxylic acid,
sinusitis. Fruits are also used as incense, flavoring tea, to Sesquiterpene
increase the potency of alcohol, preparing butter salted lactone
tea or sugar tea for sweet fragrance. It is also used as
an antifungal agent and food preservative (Murtem and
Chaudhry 2016).
12. Oroxylum indicum (L.) Kurz. Bignoniaceae Stem bark powder used in breast cancer (Tripathi et al. Oroxylin, Baicalein, Stigmast-7-en-3-ol Flavones, Sterols
2017). (Luitel et al. 2010).
13. Paedaria foetida L. Rubiaceae Boiled leaves & twigs are taken with rice as a vegetable Linalool (Wong and Tan 1994). Monoterpenes
to cure diarrhea & dysentery, the paste of the leaves
applied to skin diseases; also useful for curing
stomachache & gastric indigestion (Chanda et al. 2013).
14. Piper longum L. Piperaceae Leaf after rubbing with mustard oil and warming over Pipernonaline, Piperoctadecalidine, Alkaloids
burning charcoal is applied to belly during stomach ache Piperine (Park et al. 2002).
of children (Perme et al. 2015).
15. Rubia cordifolia L. Rubiaceae Root used as tonic, astringent; stem used as antidote for Cordifoliol Cordifodiol, Rubiacordone Anthraquinone
cobra bite and scorpion sting, used as a blood clotting A(1),
agent (Hussain and Hore, 2008). Purpurin (Li et al, 2009).
16. Solanum torvum Sw. Solanaceae Crushed fruits are applied to gums to get relief from gum spirostanol saponins, spirostanol Saponins,
infection and toothache (Namsa et al. 2011). glycosides (Lu et al. 2008). Glycoside
conjugates
17. Terminalia bellirica (Gaertn.) Roxb. Combretaceae Ground and drunk with water; fruits are directly Termilignan, Thannilignan (Valsaraj et Lignans
consumed, helps in curing cold, cough & fever (Khongsai al. 1997).
et al. 2011).
Table 12.2 contd.…

…Table 12.2 contd.
Sl No. Name of the plant Family Traditional use Active compounds Type of
secondary
metabolites
18. Tinospora sinensis (Lour.) Merr. Menispermaceae Stem decoction for strengthening of bones Tinosinaside, Diosgenin, Cordioside Steroids,
(Srivastava and Nyishi Community 2010). (Srinivasan et al. 2008). Glycosides,
Carbohydrates
19. Zanthoxylum armatum DC. Rutaceae Crude pounded fruits are used as fish poison; tender Armatamide, Asarinin, Fargesin (Kalia Amides, Lignans
leaves are used as vegetable; infusion of seeds mixed et al. 1999).
with Allium sativum and little salt is prescribed in case of
stomach bloating (Khongsai et al. 2011).
20. Zingiber officinale Roscoe Zingiberaceae Used as edible; Rhizome is used for different religious β-sitosterol, Palmitate, Isovanillin, Sterols, Phenolic
purpose (Boko and Narsimhan 2014). Glycol mono-palmitate (Bao et al. aldehyde
2010).
witnessed in many parts of the state particularly districts of Tawang and West Kameng region because of
rapid changes and developmental process in an effort to make it a global tourist hotspot (Tsering 2016).
Therefore there is also a need to protect such medicinally important plants which can be only done by
imparting knowledge of different conservation strategies in the public domain especially to the villagers
through conducting various awareness programs. They also need to be involved in food biodiversity
based natural resource conservation by demonstrating rural biotechnology tools and methods for effective
conservation and sustainable management of these mountain plant bio-resources for rural livelihood security
and the future generations of mankind. Such an awareness campaign would also ensure significance of
such valuable botanical resources in current demand and supply trends of wild edible plants in the local
and regional markets.
Conclusion
Thus, such rare and endemic medicinal plants of Arunachal Pradesh need conservation attention in the
present decade to prevent rampant illegal collection from the wild habitat as well as for obtaining goods
and services and ecological stability. Since local communities have deep faith in traditional methods of
herbal treatment, they are still using some plants in treatment of several human ailments some of which are
not recorded in any medicinal literatures including Ayurveda. Such plants need to be explored judiciously
as well as protected from habitat destruction and other possible threats. Plant tissue culture techniques
viz. in vitro organ culture, cell suspension cultures and callus culture can be effective in curbing the cost
of production in the process of extraction, isolation and purification of secondary metabolites extracted
directly from these plants (Purwianingsih 2015). Development of appropriate agro-technology research is
urgently required to minimize wild collection and that would ensure ex situ conservation and sustainable
medicinal and commercial uses making this state undoubtedly the living encyclopaedia and cultural refugia
in biodiversity conservation of the eastern Himalayan Region.
References
Alasalvar, C., Grigor, J.M., Zhang, D., Quantick, P.C. and Shahidi, F. 2001. Comparison of volatiles, phenolics, sugars,
antioxidant vitamins, and sensory quality of different colored carrot varieties. J. Agric. Food Chem. 49: 1410–1416.
Angami, A., Gajurel, P.R., Rethy, P., Singh, B. and Kalita, S.K. 2006. Status and potential of wild edible plants of Arunachal
Pradesh. Indian J. Trad. Knowl. 5(4): 541–550.
Anonymous. Forest Statistics of Arunachal Pradesh. 2008. Department of Environment and Forest, Govt. of Arunachal
Pradesh Itanagar, pp. 3–30.
Balakumbahan, R., Rajamani, K. and Kumanan, K. 2010. Acorus calamus: an overview. J. Med. Plant Res. 4(25): 2740–2745.
Banik, A., Sarmah, A. and Muthu, J. 2003. Agapetes neriifolia (King and Prain) Airy Ashaw var. minor (King and Prain) Airy
Shaw – New record for India. Bull. Bot. Surv. India, Calcutta 45(1-4): 213–216.
Bao, L., Deng, A., Li, Z., Du, G. and Qin, H. 2010. Chemical constituents of rhizomes of Zingiber officinale. China J. Chin.
Mat. Med. 35(5): 598–601.
Benavente-Garcia, O., Castillo, J., Marin, F.R., Ortuno, A. and Del, Rio, J.A. 1997. Uses and properties of citrus flavonoids.
J. Agric. Food Chem. 45: 4505–4515.
Bhattee, S.S. and Beniwal, B.S. 1988. Coptis teeta Wall—an important and valuable medicinal plant of Arunachal Pradesh
and its cultivation. Indian For. 144(5): 251–260.
Bhom, B.A. 1998. Introduction to Flavonoids. Harwood Academic Publishers, Amsterdam.
Boko, N. and Narsimhan, D. 2014. Rapid survey of plants used by Adi tribe of Bosing-Banggo, East Siang District, Arunachal
Pradesh, India. Pleione 8(2): 271–282.
Champion, H.G. and Seth, S.K. 1968. A Revised Survey of the Forest Types of India. Manager of Publication, New Delhi, India.
Chanda, S., Sarethy, I.P. and De, B. 2013. Paederia foetida—a promising ethno-medicinal tribal plant of northeastern India.
J. For. Res. 24(4): 801.
Claudine, M., Mazur, A. and Scalbert, A. 2005. Polyphenols and prevention of cardiovascular diseases. Curr. Opin. Lipidol.
16: 77–84.
Cornelia, C. and Ludger, B. 2012. Phytoalexins of the pyrinae: biphenyls and dibenzofurans. Beilstein J. Org. Chem. 8: 613–620.
Das, A.K. and Tag, H. 2006. Ethnomedicinal studies of the Khamti tribe of Arunachal Pradesh. Indian J. Trad. Knowl. 5(3):
317–322.
Doley, B., Gajurel, P.R., Rethy, P., Singh, B. and Hazarika, H. 2010. Ethnomedicinal uses of different species of Cinnamomum
schaeffer (Lauraceae) by ethnic community in Arunachal Pradesh, India. Pleione 3(1): 9–12.
Doley, B., Gajurel, P.R., Rethy, P. and Buragohain, R. 2014. Uses of trees as medicine by the ethnic communities of Arunachal
Pradesh, India. J. Med. Pl. Res. 8(24): 857–863.
Dutta, R. and Dutta, A. 2013. Bheta fishing—a traditional community fishing practice of nocte tribe of tirap district, Arunachal
Pradesh. Indian J. Trad. Knowl. 12(1): 162 – 165.
Giri, A., Banerjee, S., Ahuja, P.S. and Giri, C.C. 1997. Production of hairy roots in Aconitum heterophyllum Wall. using
Agrobacterium rhizogenes. In Vitro Cell Dev. Biol. - Plant 33(4): 280–284.
Goswami, P., Soki, D., Jaishi, A., Das, M. and Sarma, H.N. 2009. Traditional healthcare practices among the tagin tribe of
Arunachal Pradesh. Indian J. Trad. Knowl. 8(1): 127–130.
Harborne, J.B., Baxter, H. and Moss, G.P. (eds.). 1999. Photochemical Dictionary the Handbook of Bioactive Compound
from Plants (2)1999. Taylor & Francis, London.
Harborne, J.B. 1989. General procedure and measurement of total Phenolics. Methods in Plant Biochemistry. Volume 1. Plant
phenolics. London Academic Press Ltd., 1989, pp 1–28.
Haridasan, K. and Rao, R.R. (1985–87). Forest Flora of Meghalaya. Vol. I&II. Bishen Singh Mahendra Pal Singh, Dehradun,
India.
Haridasan, K. 2001. Ethnobotanical studies in Arunachal Pradesh—A status Report. pp. 154–167. In: Gian Singh, Singh, H.B.
and Mukherjee, T.K. (eds.). Ethnomedicine of North-East India, NISCIR (CSIR), New Delhi.
Hollman, P.C.H. and Katan, M.B. 1999. Dietary flavonoids: intake, health effects and bioavailability. Food Chem. Toxicol.
37: 937–942.
Hoyer, G.A., Sucrow, W. and Winkler, D. 1975. Diosgenin saponins from Dioscorea floribunda. Phytochemistry 14(2): 539–542.
Hussain, S. and Hore, D.K. 2008. Collection and conservation of major medicinal plants of Arunachal Pradesh. Indian For.
134(12): 1663–1679.
Jeri, L., Tag, H., Tsering, J., Kalita, P., Mingki, T. and Das, A.K. 2011. Ethnobotanical Investigation of Edible and Medicinal
Plants in Pakke Wildlife Sanctuary of East Kameng District in Arunachal Pradesh, India. Pleione 5(1): 83–90.
Joshi, K.C., Singh, P. and Mehra, A. 1979. Chemical investigation of the roots of different Clerodendron species. Planta
Med. 37(9): 64–66.
Kagyung, R., Gajurel, P.R., Rethy, P. and Singh, B. 2010. Ethnomedicinal plants used for gastro-intestinal diseases by Adi
tribes of dehang-debang biosphere reserve in Arunachal Pradesh. Indian J. Trad. Knowl. 9(3): 496–501.
Kala, C.P. 2005. Ethnomedicinal Botany of Apatani in the Eastern Himalayan Region of India. J. Ethnobio. Ethnomed. 1:11.
Kalia, N.K., Singh, B. and Sood, R.P. 1999. A new amide from Zanthoxylum armatum. J. Nat. Prod. 62(2): 311–312.
Kamboj, A. and Saluja, A.K. 2009. Bryophyllum pinnatum (Lam.) Kurz.: Phytochemical and pharmacological profile: A
review. Ph. Cog. Rev. 3: 364–74.
Kamboj, A. and Saluja, A.K. 2011. Isolation of Stigmasterol and β Sitosterol from petroleum ether extract of aerial parts of
Ageratum conyzoides (Asteraceae). Int. J. Pharm. Sci. 3(1): 94–96.
Kar, A. 2004. Common Wild Vegetables of Aka tribe of Arunachal Pradesh. Indian J. Trad. Knowl. 3(3): 305–313.
Khongsai, M., Saikia, S.P and Kayang, H. 2011. Ethnomedicinal plants used by different tribes of Arunachal Pradesh. Indian
J. Trad. Knowl. 10(3): 541–546.
King, A.M.Y. and Young, G. 1999. Characteristics and occurrence of phenolic phytochemicals. J. Am. Diet. Assoc. 99: 213–218.
Kumar, D., Mallick, S., Vedasiromoni, J.R. and Pal, B.C. 2010. Anti-leukemic activity of Dillenia indica L. fruit extract and
quantification of betulinic acid by HPLC. Phytomedicine 17(6): 431–435.
Li, X., Liu, Z., Chen, Y., Wang, L.J., Zheng, Y.N., Sun, G.Z. and Ruan, C.C. 2009. Rubiacordone A: a new anthraquinone
glycoside from the roots of Rubia cordifolia. Molecules 14(1): 566–572.
Lu, Yuanyuan, Luo, J., Xu, D., Huang, X. and Kong, L. 2008. Characterization of spirostanol saponins in Solanum torvum by
high-performance liquid chromatography/evaporative light scattering detector/electrospray ionization with multi-stage
tandem mass spectrometry. Rapid Commun. Mass Sp. 22(16): 2447–2452.
Luitel, H.N., Rajbhandari, M., Kalauni, S.K., Awale, S., Masuda, K. and Gewali, M.B. 2010. Chemical constituents from
Oroxylum indicum (L.) Kurz of Nepalese Origin. Sci. World (8): 8–21.
Maiti, S., Chakravaty, P., Garai, S., Bandyopadhyay, S. and Chouhan, V.S. 2013. Ethno veterinary practices for ephemeral
fever of yak: A participatory assessment by the Monpa tribe of Arunachal Pradesh. Indian J. Trad. Knowl. 12(1): 36–39.
McGaw, L.J., Jäger, A.K. and Staden, J.V. 2002. Isolation of β-asarone, an antibacterial and anthelmintic compound, from
Acorus calamus in South Africa. S. Afr. J. Bot. 68(1): 31–35.
Merken, H.M. and Beecher, G.R. 2000. Measurement of food flavonoids by high-performance liquid chromatography: a
review. J. Agr. Food Chem. 48: 577–599.
Middleton, E., Kandaswami, C. and Theoharides, T.C. 2000. The effects of plant flavonoids on mammalian cells: implications
for inflammation, heart disease, and cancer. Pharmacol. Rev. 52: 673–751.
Monlai, S., Lalramnghinglova, H. and Arunachalam, A. 2013. Traditional Tai-Khampti medicinal plants to cure fracture
bones. Pleione 7(2): 469–472.
Murtem, G. and Chaudhry, P. 2016. An ethnobotanical note on wild edible plants of Upper Eastern Himalaya, India. Brazilian
J. Biol. Sci. 3(5): 63–81.
Namsa, N.D., Mandal, M., Tangjang, S. and Mandal, S.C. 2011. Ethnobotany of the Monpa ethnic group of Arunachal Pradesh.
J. Ethnobio. Ethnomed. 7: 31. 1746-4269-7-31.
Nimachow, G., Joshi, R.C. and Dai, O. 2011. Role of indigenous knowledge system in conservation of forest resources—a
case study of the Aka tribe of Arunachal Pradesh. Indian J. Trad. Knowl. 10(2): 276–280.
Nimasow, G., Ringu, N. and Nimasow, O.D. 2012. Ethnomedicinal Knowledge among the Adi tribes of Lower Dibang Valley,
Arunachal Pradesh, India. Int. Res. J. Pharm. 3(6): 223–229.
Park, B.S., Lee, S.E., Choi, W.S., Jeong, C.Y., Song, C. and Cho, K.Y. 2002. Insecticidal and acaricidal activity of pipernonaline
and piperoctadecalidine derived from dried fruits of Piper longum L. Crop Prot. 21: 249–251.
Parr, A.J. and Bolwell, G.P. 2000. Phenols in the plant and in man. The potential for possible nutritional enhancement of the
diet by modifying the phenols content or profile. J. Sci. Food Agr. 80: 985–1012.
Payum, T., Das, A.K., Ramashankar, R., Tamuly, T. and Hazarika, M. 2013. Ethnobotany and Antioxidant determination of
Phoebe cooperiana fruit—A highly utilized wild fruit in Arunachal Pradesh, India. Int. J. Pharm. Sci. Res. 4(8): 3196–3201.
Hsieh, P.W., Chang, F.R., Lee, K.H., Hwang, T.L., Chang, S.W. and Wu, Y.C. 2004. A new anti-HIV alkaloid, drymaritin, and
a new C-glycoside flavonoid, diandraflavone, from Drymaria cordata. J. Nat. Prod. 67(7): 1175–1177.
Perme, N., Choudhury, S.N., Choudhury, R., Natung, T. and De, B. 2015. Medicinal plants in traditional use at Arunachal
Pradesh, India. 2015. Int. J. Phytopharm. 5(5): 86–98.
Pholphana, N., Rangkadilok, N., Thongnest, S., Ruchirawat, S., Ruchirawat, M. and Satayavivad, J. 2004. Determination
and variation of three active diterpenoids in Andrographis paniculata (Burm.f.) Nees. Phytochem. Anal. 15: 365–371.
Pietta, P.G. 2000. Flavonoids as antioxidants. J. Nat. Prod. 63: 1035–1042.
Porter, L.J. 1989. Tannins. pp. 389–419. In: Harborne, J.B. (ed.). Methods in Plant Biochemistry: Vol 1. Plant Phenolics.
London academic press.
Purwianingsih, W., Febri, S. and Kusdianti. 2015. Formation Flavonoid Secondary Metabolites in Callus Culture of
Chrysanthemum cinerariefolium as Alternative Provision Medicine. Proceedings of International Seminar on Mathematics,
Science, and Computer Science Education (MSCEIS 2015).
Puupponen Pimia, R., Nohynek, L., Meier, C., Kahkonen, M., Heinonen, M. and Hopia, A. 2001. Antimicrobial properties of
phenolic compounds from berries. J. Appl. Microbiol. 90: 494–507.
Qinh, N.B., Dai, D.N, Than, B.V., Dung, V.T., Hang, V.T.T. and Ogunwande, I.A. 2016. Volatile Constituents of Three Illicium
Plants. Rec. Nat. Prod. 10(6): 806–811.
Rethy, P., Singh, B., Kagyung, R. and Gajurel, P.R. 2010. Ethnobotanical studies of dehang-debang biosphere reserve of
Arunachal Pradesh with special reference to Memba tribe. Indian J. Trad. Knowl. 9(1): 61–67.
Ramashankar, R. and Rawat, M.S. 2008. Medicinal plants used in traditional medicine in Lohit and Dibang valley districts
of Arunachal Pradesh. Indian J. Trad. Knowl. 7(2): 288–295.
Samman, S., Lyons wall, P.M. and Cook, N.C. 1998. Flavonoids and coronary heart disease: Dietary perspectives. pp. 469–482.
In: Rice-Evans, C.A. and Packer, L. (eds.). Flavonoids in Health and Disease. Marcel Dekker, New York.
Sarmah, R. and Arunachalam, A. 2010. Contribution of Non Timber Forest Products (NTFPS) to the Livelihood Economy of the
People living in the Forest in Changlang district of Arunachal Pradesh, India. Indian J. Fund. Appl. Life Sci. 1(2): 157–169.
Secondary metabolites – Knowledge Encyclopedia” www. biology reference.com. Retrieved 2016-05-10.
Sen, P., Dollo, M., Dutta Choudhury, M. and Choudhury, D. 2008. Documentation of traditional herbal knowledge of Khamptis
of Arunachal Pradesh. Indian J. Trad. Knowl. 7(3): 438–442.
Shahidi, F. and Naczk, M. 1995. Food phenolics: Sources, Chemistry, effects application. PA:Technomic Pub. Co., Inc.,
Lancaster.
Shrivastava, K., Greeshma, A.G. and Srivastava, B. 2012. Biotechnology in Traditional – methods of starter preparation for
alcoholic beverages employed by different tribal communities of Arunachal Pradesh. Indian J. Trad. Knowl. 11(1):
194–201.
Singh, R.K. and Singh, A. 2013. Biodiversity and recipe contests: Innovative socioecological approaches to capture ecological
knowledge and conserve biodiversity in Arunachal Pradesh. Indian J. Trad. Knowl. 12(2): 240–251.
Srinivasan, G.V., Unnikrishnan, K.P., Remashree, A.B. and Balachandran, I. 2008. HPLC Estimation of berberine in Tinospora
cordifolia and Tinospora sinensis. India J. Pharm. Sci. 70(1): 96–99.
Srivastava, R.C. and Adi Community. 2009. Traditional knowledge of Adi tribe of Arunachal Pradesh on Plants. Indian J.
Trad. Knowl. 8(2): 146–153.
Shrivastava, R.C. and Nyishi Community. 2010. Traditional knowledge of Nyishi (Daffla) tribe of Arunachal Pradesh. Indian
J. Trad. Knowl. 9(1): 26–37.
Srivastava, R.C., Singh, R.K., Apatani Community and Mukherjee, T.K. 2010. Indigenous biodiversity of Apatani plateau:
Learning on bioculture knowledge of Apatani tribe of Arunachal Pradesh for sustainable livelihood. Indian J. Trad.
Knowl. 9(3): 432 – 442.
Tag, H. and Das, A.K. 2004. Ethnobotanical notes on the hill miri tribe of Arunachal Pradesh. Indian J. Trad. Knowl. 3(1): 80–85.
Tag, H., Das, A.K. and Kalita, P. 2005. Plants used by the hill miri tribe of Arunachal Pradesh in Ethnofisheries. Indian J.
Trad. Knowl. 4(1): 57–64.
Tag, H., Jambey, T., Pallabi, K.H., Baikuntha, J.G. and Vijay, V. 2014. Nutritional Potential and Traditional Uses of High
Altitude Wild Edible Plants in Eastern Himalayas, India. Int. J. Agr. Biosyst. Sci. Eng. 8(3): 395–400.
Taiz, L. and Zeiger, E. 2010. Augmentation of Dry Matter Production, Photosynthetic Enzymes, Yield Attributes and Quality
Parameters of Sunflower through Seed Priming Effect of Gibberellic Acid—A Multifaceted Hormone. Plant Physiology
[5th Edition]. Sinauer Associates Inc., Sunderland.
Taktajan. 1996. Indo-Myanmar phytogeographical rims of fareast Himalayan are considered as centre of diversity of flowering.
J. Ethnobiol. Ethnomed. 15(4): 43 – 57.
Thothathri, K. and Pal, G.D. 1987. Further contribution to the Ethnobotany of Tribals of Subansiri District of Arunachal
Pradesh. J. Econ. Taxon. Bot. 10: 149 – 157.
Tiwari, K.C., Majumdar, R. and Bhattacharjee, S. 1976. Folklore medicine from Assam and Arunachal Pradesh (District
Tirap). Pharm. Biol. 17(2): 61–67.
Tiwari, U.L., Kotia, A. and Rawat, G.S. 2009. Medico-ethnobotany of the Monpas in Tawang and West Kameng districts of
Arunachal Pradesh, India. Pleione 3(1): 1–8.
Tripathi, A.K., Limasenla and Shankar, R. 2017. Ethno-medicinal plants used by nyishi tribe of Arunachal pradesh, India.
World J. Pharm. Pharm. Sci. 6(5): 1246–1253.
Tsering, J. 2016. Ethnobotany and phytochemical analysis of selected Traditional wild food and medicinal plants of the Monpa
Community of Arunachal Pradesh (Thesis submitted for PhD). Dept. of Botany, Rajiv Gandhi University. Arunachal
Pradesh, India.
Tsering, J., Gogoi, B.J., Hui, P.K., Tam, N. and Tag, H. 2017. Ethnobotanical appraisal on wild edible plants used by the
Monpa community of Arunachal Pradesh. Indian J. Trad. Knowl. 16(4): 626–637.
Valsaraj, R., Pushpangadan, P., Smitt, U.W., Adsersen, A., Christensen, S.B., Sittie, A., Nyman, U., Nielsen, C. and Olsen, C.E.
1997. New Anti-HIV-1, Antimalarial, and Antifungal Compounds from Terminalia bellerica. J. Nat. Prod. 60(7): 739–742.
Wangpan, T., Chetry, L.B., Tsering, J., Taka, T. and Tangjang, S. 2016. Anti-Malarial Plants of Jonai, India: an ethnobotanical
approach. Not. Sci. Biol. 8(1): 27–32.
Wong, K.C. and Tan, G.L. 1994. Steam volatile constituents of the aerial parts of Paederia foetida L. Flavour Frag. J. 9: 25–28.
Xu, X., Lin, Q., He, X., Fu, F. and Chen, G. 2010. Determination of protoberberine alkaloids in medicinal plants based on
acidic potassium permanganate chemiluminescence system. Luminescence 25: 403–408.
Yakang, B., Gajurel, P.R., Potsangbam, S. and Bhuyan, L.R. 2013. Account of common and traditional non-timber forest
products used by Apatani of Arunachal Pradesh, India. Pleione 7(2): 514–530.
13
Characterization and Purification
of Antiurolithiatic Metabolites from
Medicinal Plants
Ankit S. Kale,1 Anita S. Patil,1,* Hariprasad Paikrao2 and
Surendra R. Patil3
Introduction
Urolithiasis is one of the common disorders in the global population; every 10th person of entire population
is suffering with these painful urological disorders (Edvardsson et al. 2013). It is an alarming situation
in developing as well as developed countries due to the absence of a permanent remedial solution. It is
reported that the percentage of urolithiasis is greater in males than females with a male:female ratio of
3:1 (Stamatelou et al. 2003).
In India, approximately 5–7 million patients suffer from stone disease and nearly 1/1000 of the Indian
population needs hospitalization due to kidney stone disease (Pearle et al. 2005). A huge number of patients
belong to the age group of almost twenty (Munver and Preminger 2001). The rate of recurrence is about
15% in one year and up to 50% within five years of the initial stone (Spirnak and Resnick 1987).
Urolithiasis is the disorder earlier seen in history back not only to 4000 B.C. in the tombs of Egyptian
mummies (4000 B.C.) but also in graves of North American Indians from 1500 to 1000 B.C. (Bahuguna
et al. 2009). It is also documented in the early Sanskrit documents during 3000 and 2000 B.C. Urolithiasis
is considered as a medical challenge due to its multifactorial etiology and high rate of recurrence. It was
reported earlier that super-saturation of urine with salt and minerals such as calcium oxalate (CaOx), struvite
(ammonium magnesium phosphate), uric acid and cysteine is actually causing renal calculi formation
(Kulaksizoglu et al. 2008, Martin and Nieto 2011, Macneil and Bariol 2011). These calculi are of different
sizes and shaped-small ‘gravel-like’ stones to large stag horn calculi. The crystals stay at their location or
move further down the urinary tract, producing symptoms along the way.
In spite of substantial progress in the biological and physical manifestation of urolithiasis, its
mechanism is still not clearly understood and there are no satisfactory safe drugs available for the treatment
and prevention of urolithiasis. The drugs which are used for prophylactic therapy are primarily aimed to
1
Lab # 106 Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati (M.S.), India.
2
Government Institute of Forensic Science, Aurangabad, 431004 (M.S.), India.
3
College of Horticulture, Dr. Panjabrao Deshmukh Agriculture University, Akola (M.S.), India.
* Corresponding author: anitapatil@sgbau.ac.in
correct the underlying metabolic disorders, but still results are not so convincing. The limited success of
chemical drugs in urolithiasis is that multiple factors are involved in its pathogenesis, and the treatment
demands multifactorial drug with various biological activities, such as an antispasmodic, antimicrobial,
antioxidant, anti-inflammatory, etc. (Khan et al. 2011).
Several medicines like Thiazide diuretics (e.g., Hydrochlorothiazide), alkali, (e.g., Potassium citrate),
Allopurinol, Sodium Cellulose Phosphate (SCP), Penicillamine (Cuprimine), Analgesic (Diclofenac
sodium), Bisphosphonates, Potassium phosphate, Oxalobacter formigenes and other probiotics are used
in urolithiasis, which act by decreasing the excretion of the stone forming agent such as oxalates, calcium,
phosphates, etc. (Choubey et al. 2010).
The medicinal plants contain multiple chemical constituents, which could offer synergistic or side-
effect neutralizing properties that are likely to offer a more effective and safer remedy. Therefore, there is
a need to look for an alternative therapy, especially herbal remedies, for the management and treatment
of urolithiasis (Butterweck and Khan 2009).
Now-a-days, herbal medicine has gained much popularity being more efficient, easily available, having
a low cost, with fewer side effects and the reducing recurrence rate of stone formation, hence search for
antilithiatic drug from natural sources has assumed greater importance. In Ayurveda, many plants having the
property of disintegrating and dissolving the stone are collectively referred to as “Pashanbheda” (Agarwal
and Varma 2014). Plant extracts contain phytochemicals that prevent stone formation by inhibiting synthesis
and agglomeration of crystals (Bhattacharjee et al. 2012).
Recently, significant progress has been made in identifying and quantifying physicochemical processes
responsible for urinary stone formation. It is evident that super-saturation of urine with calcium oxalate is
essential for urinary calcium oxalate crystallization (Kulaksizoglu et al. 2008). The best ways to prevent
and treat urolithiasis are to control the process of crystallization events and most important is controlling
the initial step, i.e., nucleation step. This is exceptionally achieved using herbal extracts since they have
been widely used in folk medicine to treat kidney stones. The idea to use herbal extracts in the first step is
that if nucleation itself is stopped or controlled, the next steps which lead to formation, aggregation and
retention of crystals do not occur at all. In present chapter, we propose methods based on confirmation
of antilithiatic plant bioactive metabolites including their purification and preliminary characterization.
Urolithiasis
Kidney stone remains one of the major painful problems of a human population worldwide. Formation of
stones in the urinary system, i.e., in the kidney, ureter and urinary bladder or in the urethra is Urolithiasis
(Chandrasoma and Taylor 1998). There are several factors responsible for formation of stones such as
climate, geographical distribution, food habits, changing lifestyle, genetic factors, etc. (Anderson 1979).
Urolithiasis, kidney stones, nephritic stones, and renal calculi are interchangeably used to refer to the
accretion of hard, solid, non-metallic minerals anywhere in the urinary system, including the kidneys,
urethra and the bladder. There are five different types of stones reported, including calcium oxalate stones,
calcium phosphate stone, magnesium ammonium phosphate, cysteine and uric acid stone (Free and Free
1975), and many are yet to be identified (Table 13.1). Common stones among all are types of renal stones
CaOx, which are of two types, i.e., monohydrate type (in the form of dump bell or oval) and dihydrate
type (in the form of the double pyramid) (Kannabiran and Selva 1997). Hydrated forms of CaOx are
reported as: whewellite (monohydrate, known from some coal beds), weddellite (dihydrate) and a very
rare trihydrate called caoxite. These crystals look like a six sided prism and often look like a pointed
picket from a wooden fence.
Calcium oxalate Stones

Calcium oxalate Stone (CaOx) is the most common type of stone found in different renal type of stones.
It was found that approximate 80% of stone patient cases in US were CaOx type; these CaOx may be
alone or may be in combination with calcium phosphate in the form of apatite or brushite (Coe et al.
2003). Hyperoxaluria, hyperparathyroidism and renal tubular acidosis are some factors that promote the
Characterization and Purification of Antiurolithiatic Metabolites from Medicinal Plants 219
Table 13.1 Types of kidney stones found in renal disorder.
Name of stone Approximate incidence Constituents

CaOx 70% of all stones Calcium, oxalate
Calcium phosphate 10% of all stones Calcium, phosphate
Uric acid 5–10% of all stones Uric acid
Struvite 10% of all stones Calcium, ammonia, phosphate
Cystine Less than 1% of all stones Cystine
Medication-induced stones Less than 1% of all stones Composition depends on medication or
herbal product (e.g., include indinavir,
ephedrine, guaifenesin, silica)
precipitation of CaOx and calcium phosphate stones (Hoppe and Langman 2003). Hyperoxaluria is seen
in patients who eat more oxalate containing food like vegetables and nuts. Many drugs are available in the
market for treatment of urolithiasis with significant results, which include allopurinol, tri-sodium citrate,
Cystone, thiazide diuretics, etc. Some surgical procedures are also used in routine practices to remove
stones, which include Ureteroscopy; Percutaneous nephrolithotomy (PCNL), Extracorporeal Shock Wave
Lithotripsy (ESWL) and open surgery are applied to remove kidney stones. These therapies are very costly,
painful, and recur along with a side effect (Fig. 13.1), which strongly calls for new treatment options. The
lowered side effects associated with herbal medicines have reignited interest in phytomedicine (Fig. 13.2).
The Ayurveda system of medicine, which is widely followed in India, provides a solid foundation to search
new herbal formulations having the ability to act on stones. All such factors make this area interesting for
the researcher’s aim of hunting new possible solutions for human welfare (Aeckart and Schroder 1989).
Fig. 13.1 Some effects of Urolithiasis.
Fig. 13.2 Benefits of Ayurvedic treatment.

Medicinal plants for treatment of urolithiasis

Medicinal plants are as old as mankind itself and connecting man and his search for drugs in nature from
the far past, as found in written documents, preserved monuments, and even original plant medicines of
ancient times. People living in the interiors and inaccessible remote rural areas have excellent knowledge
about medicinal utility of the local flora, and they have strong faith in their own folklore preparations or
crude formulations. The knowledge of medicinal plants is applied against illnesses due to which man learned
to pursue drugs in different plant parts. Based on scientific validation such plants have been included in
modern pharmacotherapy. Studies related to the usage of medicinal plants as well as awareness have been
increased which has enhanced the ability of medical professionals to respond to the challenges.
Modern science has taken advance steps in the field of medicine, but use for conventional medicine
is in the primary form available to the people in developing countries, including India. It is observed
that about 80% of the population of developing countries still believes in traditional medicine for basic
health issues (Ekor 2013). India has a rich heritage of traditional medicine, and the traditional health care
system has been flourishing in many countries. Still today such medicines are not incorporated in most
national health systems, and the potential of services provided by the traditional practitioners (Mukerjee
2002). During the last decade, the use of herbal medicine has increased worldwide, which has provided an
excellent opportunity in India to look for therapeutic lead compounds from an ancient system of therapy,
i.e., Ayurveda. Over 50% of all modern drugs are of natural product origin, which play an important role
in drug development programs of the pharmaceutical industry (Baker et al. 1995).
Recent studies are trying to find out the exact mechanism and effectiveness of such traditional drugs
against different stages of urolithiasis, such as: the diuretic action increases the quantity of fluid going pass
through the kidneys and as a result flush out the deposits (Gohel and Wong 2006). It has been reported that
crystal inhibitors in plants are supposed to decrease crystal nucleation, aggregation and growth (Patil et
al. 2017, Kale et al. 2017). Furthermore, they also inhibit crystallization by their adsorption to the crystal
surface which makes them unable for renal tubular attachment (crystallization inhibition activity). The
formation of stones in the urinary system leads to lipid peroxidation producing Reactive Oxygen Species
(ROS) followed by renal cell injury and inflammation. It also includes loss of membrane integrity, promotes
fibrosis and collagen formation, and facilitates CaOx retention and subsequent stone formation (Khan 2013).
Plant drugs are in the demand worldwide because of their higher potential to treat diseases, safety margin
and less cost (Banso and Ngbde 2006). The increasing interest in traditional phytomedicine may lead to
the discovery of novel therapeutic agents. Although herbs are supposed to be safe, many unsafe and fatal
side effects have recently been reported due to dose and unprescribed application (Ikegami et al. 2003, Izzo
2004). Remedial plants possess various medicinal properties, which includes antiviral, antilithiatic, anti-
inflammatory, antimicrobial, antioxidant, cytotoxic, hepatoprotective, antidiabetic, insecticidal, antilarval
and many more (Marino and Bersani 1999, Nickavar et al. 2005, Nolkemper et al. 2006, Szczepanik et al.
2012, Amiri 2012, Chang et al. 2017).
Antiurolithiatic drugs available from the medicinal plants are the easiest and well known alternative
sources, which are cost-effective and with the least side effects. Such herbal drugs are in great demand
in developing and developed countries because of their potential to treat diseases, safety margin and less
cost. A large number of Indian medicinal plants have been used in the treatment of urolithiasis, which is
reported to be effective with no side effects. Their extracts were prepared in different solvent by different
methods; different assays were used to analyze their potential, as shown in Table 13.2.
Extraction and purification of antilithiatic compounds

Medicinal plants are the important natural resource for novel therapeutic compounds. Although many
approaches are available for the discovery of pharmaceutical constituents, the plant remains major reservoirs
of new structural types. Plants are capable of synthesizing a diverse array of secondary metabolites, which
include tannins, terpenoids, coumarin, alkaloids and flavonoids (Perez and Anesini 1994). These metabolites
may be produced constitutively or in response to pathogen or herbivore attack or stress (phytoalexins)
(Wittstock and Gershenzon 2002). Out of the several hundred thousand plant species over the globe,
only a small proportion has been investigated both phytochemically and pharmacologically. The crucial
Table 13.2 A list of medicinal plants with antilithiatic property.
S. No. Botanical name Common names Plant part Solvent extract In vitro/in vivo Reference
assay
1. Boerhaavia diffusa L. Gadha-khand Whole plant Aqueous In vitro (Pareta et al. 2010)
2. Acalypha indica L. Indian nettle Whole plant Ethanol In vivo (Sathyaa et al. 2011)
3. Achyranthes indica L. Chirchira Roots Hydro alcoholic In vitro (Patera et al. 2010)
4. Achyranthes aspera L. Putkhanda, Prickly chaff Roots Aqueous In vitro (Aggarwal et al. 2010)
flower
5. Achyranthesindica L. Chirchira Roots Hydroalcoholic In vitro (Pareta et al. 2011)
6. Aerva lanata L. Sirupoolai, Chaya Whole plant Aqueous In vivo (Soundararajan et al. 2006)
7. Ageratum conzoides L. Chick weed Whole plant Hydro alcoholic In vivo (Khan et al. 2011)
8. Alismatis rhizome (Sam.) Juzepcz. Takusha Whole plant Aqueous In vitro (Suzuki et al. 1999)
9. Argemone mexicana L. Datturigida Leaves Aqueous In vitro (Chilivery et al. 2016)
10. Asparagus racemosus W. Shatavari Roots Ethanol In vivo (Jagannath et al. 2012)
11. Bergenia ligulata W. Paashaanbhed Rhizomes Methanol, Aqueous In vitro (Bashir and Gilani 2009)
12. Beta vulgaris L. Ullamgadda Roots Aqueous In vitro (Saranya and Geetha 2014)
13. Boerhaaviadiffusa L. Hogweed Whole plant Aqueous In vitro (Pareta et al. 2010)
14. Bryophyllum pinnatum (Lam.) Oken Patharchatta Leaves Aqueous In vitro (Patil et al. 2015)
15. Celosia argentea L. Silver Cockscomb Seed Ethanol In vivo (Joshi et al. 2012)
16. Ceropegia bulbosa Roxb. Hedulo Root Ethanol, Aqueous In vitro (Monika et al. 2012)
17. Citrus limon (L.) Osbeck Lemon Fruit Aqueous In vitro (Kulaksizoglu et al. 2008)
18. Citrus medica L. Bara nimbu Fruit Aqueous In vitro (Kalpeshsinh et al. 2012)
19. Coleus aromaticus Benth. Indian borage Leaves Hydro alcoholic In vivo (Venkatesh et al. 2010)
20. Convulvus arvensis L. Bindweed Leaf, flower Aqueous In vitro (Rajeshwari et al. 2013)
21. Costus arabicus L. Crepe Ginger Aerial part Aqueous In vitro (De Cagoin et al. 2015)
22. Cynodon dactylon Bermuda grass Root Hydro alcoholic In vivo (Ashok Kumar et al. 2013)
23. Glochidion veluntinum Tshangla Leaf Methanol In vivo (Vijaya et al. 2013)
24. Hygrospila spinosa Ikshura Leaf Aqueous In vivo (Satish et al. 2010)
Table 13.2 contd. …
S. No. Botanical name Common names Plant part Solvent extract In vitro/in vivo Reference
assay
25. Hyptis suaveolens Bilatti Aerial part Ethanol In vitro (Agarwal and Varma 2012)
26. Kalanchoe pinnata Stone breaker Leaf Aqueous In vitro (Pathak and Hendre 2015)
27. Lantana camara L. Spanish flag Leaves Aqueous In vitro (Reddy 2013)
28. Launaea procumbens Pathari Leaf Methanol In vivo (Makasan et al. 2014)
29. Lawsonia L. inermis Henna Leaves Aqueous In vivo (Kore et al. 2011)
30. Melia azadirachta Chinaberry tree Aerial part Aqueous In vivo (Tina et al. 2006)
31. Melia dubai C. Malabar Neem Leaves Aqueous In vitro (Venilla and Mariyal 2015)
32. Mimusops elengi L. Spanish cherry, Bullet wood Bark Ethanol, Aqueous In vivo (Ashok et al. 2010)
33. Moringa oleifera Drum stick tree Pods, bark Aqueous In vivo (Fahad et al. 2010)
34. Musa paradisica L. Banana plantain Stem Aqueous In vivo (Thirumala et al. 2013)
35. Ocimum gratissimum African basil Arial part Ethanol In vitro (Agarwal and Varma 2014)
36. Orthosiphon stamineus MisaiKucing Leaves Ethanol In vivo (Ramesh et al. 2014)
37. Pergularia daemia Forssk Dustapuchettu Whole plant Hydroalcohlic In vivo (Vyas et al. 2011)
38. Phyllanthus niruri L. Stone breaker Leaves Aqueous In vitro (Patil et al. 2015)
39. Pinus eldarica M. Goldwater pine Fruits Aqueous In vivo (Hosseinzadeh et al. 2010)
40. Portulaca oleracea Green Purslane Leaves Ethanol In vivo (Kishore et al. 2013)
41. Rotula aquatic L. Pashannabedha Roots Chloroform, Aqueous In vitro (Gilhotra et al. 2011
42. Solanum virginianum L. Bari kateli Whole plant Ethanol In vivo (Chinnala et al. 2013)
43. Tamarix gallica L. Aabda Leaves Diethyl ether In vitro (Bensatal and Quahrani 2008)
44. Tecoma stans Yellow bells Leaves Aqueous In vivo (Kameshwaran et al. 2013)
45. Tribulus terrestris L. Chhotagokhru Fruits Aqueous In vitro (Patil et al. 2015)
46. Withenia somnifera Winter cherry Fruits Methanol In vivo (Patel and Mandal 2014)
47. Zea mays L. Makki, Makka Styles Aqueous In vitro (Rathod et al. 2013)
48. Zingiber officinale R. Ginger, Sunthi Rhizomes Ethanol In vivo (Lakshmi and Divya 2014)
factor in investigation of bioactive plant metabolites is the selection of plant material or their parts for the
optimum amount of phytoconstituents.
The robust bioassays and targeted isolation of bioactive compounds are need for current pharmacological
research. The major problem in ethnopharmacology research is to isolate and characterize the molecules
from extracts and their purification. The extensive fractionation of extracts may lead to reduction or
loss of biological activity due to break down or loss of additive or synergistic effects between analogue
constituents. Some modern extraction techniques are also available, including solid-phase micro-extraction,
supercritical-fluid extraction, pressurized-liquid extraction, microwave-assisted extraction, solid-phase
extraction, and surfactant-mediated techniques, which possess advantages over the traditional methods.
All these methods save solvents, reduces the time, sample degradation, elimination of additional
sample. These methods reduced concentration steps before chromatographic analysis, improvement in
extraction efficiency, selectivity, and kinetics of extraction. This automation also favours their usage for the
extraction of plant’s materials (Huie 2002). Extraction is an important step in the analysis of medicinal plants;
it gives the opportunity to extract the desired chemical compounds for separation and characterization.
The basic operation include steps, such as pre-washing, drying of plant materials or freeze drying,
grinding to obtain a homogenous sample and often improving the kinetics of analytic extraction and also
increasing the contact of sample surface with the solvent system. Proper actions must be taken to ensure
that potential active constituents are not lost, distorted or destroyed during the preparation of the extract
from plant samples.
Purification of antilithiatic metabolites

Plants provide an excellent opportunity for new drug discovery because of the unmatched availability
of chemical diversity (Cos et al. 2006). It is clear that plant extracts usually occur as a combination with
various types of bioactive compounds or phytochemicals with different polarities. However, their isolation,
purification, separation still remains a challenging task in the process of identification and characterization
of bioactive compounds. Some common techniques used for isolation, and purification included Thin Layer
Chromatography, column chromatography, flash chromatography; Sephadex chromatography and HPLC
are useful in obtaining the pure compounds. The pure compounds can be used for determination of structure
and biological activity. TLC bioautography and column chromatography is becoming an important tool
in the isolation of bioactive metabolites of plant crude extract.
TLC bioautography
A novel Thin-Layer Chromatography (TLC)-direct bioautography method was also proposed to detect the
antilithiatic metabolites separates on TLC plate (Patil et al. 2017). The CaOx inhibitors or constituents of
plant extracts are separated on TLC and comes in contact with agar; these metabolites diffuse in gel beads
of agar to form a zone of inhibition. The clear zones formed against CaOx crystals in the gel confirms
the antilithiatic potential. Such separated bioactive band can be scrapped from TLC and identified by the
spectroscopic and chromatographic technique, as shown in Fig. 13.3 (Patil et al. 2017, Indian Patent no.
494/MUM/2013, Method for identification of metabolites possessing calcium oxalate stone inhibitory
properties in plant extract using TLC bioassay).
Column chromatography
Column chromatography is one of the powerful tools used in separation of pure compounds into a crude
drug. This drug can be purified by using a gradient of solvents of different polarity in different times. The
fraction of different polarity separates based upon their solubility in the solvent. These fractions can be
collected in distinct tubes, and vacuum dried. The entire fraction should be screened by antiurolithiatic
assays such as slide gel assay, agar gel assay or crystallization assay; the most potent antilithiatic fraction
compounds can be identified by spectroscopic and chromatographic technique such as HR-LCMS.
Fig. 13.3 TLC bioautography for detection of CaOx inhibition by tri-sodium citrate. (A) TLC plate under UV light 365 nm
(arrows showing bands of tri-sodium citrate). (B) TLC plate after over layered with calcium containing agar gel. (C) TLC
plate after ammonium oxalate treatment and staining with Alizarin red S for detection of CaOx inhibition (Circles showing
region of inhibition).
Secondary metabolites reported in various plants for antilithiatic purpose

There are several phytochemicals which could be accountable for the antilithiatic effect. According to Arafat
et al. (2008), flavonoids and triterpenes have a key role in preventing urolithiasis. It is also believed that
saponins and tannins act as antiurolithiatic phytoconstituents (Doddola et al. 2008). Soundararajan et al.
(2006), reported the dissolution of CaOx crystals due to effect of flavonoids (Kaemepferol-3-rhamnoside
and kaempferol-3-rhamnogalactoside), triterpenes (betulin) and tannins. It is also reported that saponin rich
fractions of other plants like, Herniaria hirsuta act as a great inhibitor of calcium stone formation under in
vitro and in vivo model studies (Fouada et al. 2006). Lupeol and betulin (triterpenes) have been found to
be efficient in reducing the risk of stone formation in animals by way of preventing crystal-induced tissue
damage and dilution of urinary stone-forming constituents (Malini et al. 2000). Patil et al. (2017) reported
the presence of antiurolithiatic plant metabolites including tuberonic acid, Methyl-8-(2-(2-formyl-vinyl)-3-
hydroxy-5-oxy-cyclopentyl) octanoate, 9-hexadecen-1-ol, 1-hexadecanoyl-sn-glycero-3-phosphocholine.
Screening methods
A large number of medicinal plants are reported with an antiurolithiatic activity. So it would an area of
interest to find the most potent antilithiatic potential of plants. There are some in vitro and in vivo rat
model methods reported to find and validate the activity. The studies are routinely employed for screening
medicinal plants with respect to their antilithiatic property in inhibiting/assessing the nucleation, aggregation
and growth inhibition of urinary stone constituents. The chemical analysis of kidney stones shows that
most of the urinary stones predominantly consists of CaOx and calcium phosphate. Hence, most of the
studies to assay or screen the antiurolithiatic property of medicinal plants were done by initial screening
of the crude drugs by standardized in vitro gel method of crystallization (Henisch et al. 1970, 1988) or by
in vitro method of Baumann and Wacker (1980) or by in vivo rat model experiments . The effect of Crataeva
nuruala bark decoction on CaOx urolithiasis induced by 3% glycolic acid has been studied in rats.
Many in vitro bioassays were performed including slide gel assay (Schneider et al. 1983), agar gel
overlay assay (Patil et al. 2014), dot blot assay (Kale et al. 2017), urine assay (Patil et al. 2015), and
microscopic crystallization assay (Patil et al. 2017) as shown in Fig. 13.4.
Slide gel assay
Modified Schneider slide gel method was used for the in vitro study of potential of antiurolithiatic medicinal
plants. The potential can be calculated by measuring the inhibitory area formed by the plant drug and the
negative control using the formula as below (Schneider et al. 1983).
Fig. 13.4 Some in vitro assays used for urolithiasis (A) slide gel assay (B) agar gel overlay assay (C) microscopic crystallization
assay.
Inhibitory indexes can be calculated by:

I = 1–As/Ac × 100
Where, As = area of calcium oxalate crystals in presence of sample tested and
Ac = area of calcium oxalate crystals formed for the corresponding blank.
Agar gel overlay assay
Agar gel overlay method is one of the most significant methods for qualitative and quantitative potential
of compounds and any plant extracts. The potential of the plant drug can be measured by calculating the
inhibitory area and percentage area of zones of inhibition using the formula as suggested by Patil et al.
(2014) in the Indian Patent No. 1501/MUM/2014; the method for in vitro qualitative and quantitative
detection of calcium oxalate inhibitory activity.
Percent Inhibition can be calculated by:
PI = 100–(1–(As/Ac)) × 100
Where
As = Area of diffused sample; Ac = Area of control region
Microscopic Crystallization Assay
Microscopic Crystallization Assay is one of potent methods, which screens out the plants antiurolithiatic
potential on the basis of change in crystal number, size and shape. The method shows visible change in
number, size and shape under the microscope and gives qualitative and quantitative data. Many in vivo
models have been developed to understand the mechanisms involved during the formation of urinary stones
and to ascertain the effects of various therapeutic agents on development and progression of the disease.
CaOx kidney stones in both humans and mildly hyperoxaluria rats are located on renal papillary
surfaces and consist of an organic matrix and crystals of CaOx. The rat is the most frequently used animal
to induce CaOx deposition into kidneys and mimic the etiology of the formation of stones in humans.
Stones formed in kidneys of humans, and rats are identical and exhibit similarities between human and
rats CaOx kidney stones in many aspects.
Hyperoxaluria, defined as excessive urinary oxalate, is the main risk factor for human idiopathic CaOx
stone formation and induction of hyperoxaluria is essential for the development of CaOx urolithiasis in
rats (Khan 1995). CaOx stone is the most prevalent component in urolithiasis, and many experimental
models have been used to demonstrate its formation in the animal kidney (Khan et al. 1982, Khan 1995).
Ethylene Glycol (EG), which is a precursor to oxalate formation, has generally been used in combination
with ammonium chloride (NH4Cl) or vitamin D3 in an attempt to form CaOx crystals in urine and CaOx
deposits in the kidney of rats (Yamaguchi et al. 2005). Urinary excretion of oxalate will be increased
during the chronic administration of ethylene glycol (EG) as a 0.75% aqueous solution in drinking water
to male Sprague-Dawley rats.
Future perspectives
In developing countries, most of the population uses medicinal plants as their home-based treatment. Herb
based antiurolithiatic drugs are available in medical stores; they are cost effective, easily available and
without side effects. The potential of such drugs is widely accepted by the people. Different companies are
selling these drugs in the market with variable content, different name and in a different form; some drugs
are Cystone of Himalaya, Gokru Kada of Baidyanath and many more. Recent technology with traditional
medicine has opened the new channels in the field of improving health; such treatment is especially useful
for people, who cannot afford costly western medicines. These researches also generate the opportunity
for the Indian farmers to produce medicinal plants having economic importance. This clearly opens door
for policy makers, researchers, industry and farmers to manage important medicinal plants.
Conclusion
The growing resurgence and revival of interest in indigenous systems of medicine and traditional herbal
remedies, especially for their use for urolithiasis are regarded as quite safe. The best way to prevent and
treat urolithiasis is to control the process of crystallization events from initial step, i.e., nucleation. Many
herbs themselves possess inhibitory activity against crystallization, and their antioxidant activity helps in
preventing the urolithiasis renal cell damage.
In the present chapter we have described quantitative/qualitative antiurolithiatic potential of medicinal
plants by using in vitro assays viz. slide gel assay, agar gel overlay assay and microscopic crystallization
assay. The proposed in vitro assays conclude that plants possess tremendous potential to stop the growth
of crystals; and shows special mechanism of reducing the size and number of the crystal which help
in removing them from the urinary system. Agar Gel Overlay Assay is supposed to be a more efficient
method compared to conventional methods, as it saves time and interprets very clear measurable results.
As the previously reported the slide gel method is sensitive, but time consuming, and also calculation
is very difficult and with chances of human error, which can be overcome by the proposed methods.
Furthermore, the plant extracts prepared by maceration method in water confirmed as the most potent
method for the crude drug extraction in terms of antilithiatic potential. Although the use of herbal medicines
are popular and promising, it is essential to carry out further research to understand the pathophysiology
of disease, and mechanism of action in order to develop an efficient and safe litholytic agent.
Acknowledgment
The authors would like to thank Rajiv Gandhi Science and Technology Commission, Mumbai, India for
research grant (RGSTC/File-2012/DPP-94/CR-12) under the major research project sanctioned to Prof.
Anita Patil and also to Department of Biotechnology, Sant Gadge Baba Amravati University, Amravati
(M.S.) India for providing the research facilities.
References
Aeckart, K.S.J. and Schroder, F.H. 1989. Effect of extra corporeal shock wave lithotripsy (ESWL) on renal tissue. Urol. Res.
17: 3–7.
Agarwal, K. and Varma, R. 2012. Inhibition of calcium oxalate crystallization in vitro by various extracts of Hyptis suaveolens
(L.) PIOT. Int. Res. J. Pharm. 3(3): 261–264.
Agarwal, K. and Varma, R. 2014. Ocimum gratissimum L.: A medicinal plant with promising antiurolithiatic activity. Int. J.
Pharm. Sci. Drug. Res. 6(1): 78–81.
Aggarwal, A., Tandon, S., Singla, S.K. and Tandon, C. 2010. Diminution of oxalate induced renal tubular epithelial cell
injury and inhibition of calcium oxalate crystallization in vitro by aqueous extract of Tribulus terrestris. Int. Braz. J.
Urol. 36(4): 480–489.
Amiri, H. 2012. Essential oils composition and antioxidant properties of three thymus species. Evid.-Based Compl. Alt.:
728065. doi:10.1155/2012/728065.
Anderson, C.K. 1979. The anatomical aetiology of renal lithiasis. pp. 40–68. In: Wickham, J.E.A. (ed.). Urinary Calculous
disease. Edinburgh: Churchill Livingstone.
Arafat, O.M., Tham, S.Y., Sadikun, A., Zhari, L, Haughton, P.J. and Asmawi, M.Z. 2008. Studies on diuretic and hypouricemic
effects of Orthosiphon stamineus methanol extracts in rats. J. Ethnopharmacol. 118(3): 354–360.
Ashok Kumar, K., Selvaraj, K. and Muthukrishnan, S.D. 2013. Cynodondactylon (L.) Pers.: An updated review of its
phytochemistry and pharmacology. J. Med. Plants Res. 7(48): 3477–83.
Ashok, P., Koti, B.C. and Vishwanathswami, A.H.M. 2010. Antiurolithiatic and antioxidant activity of Mimuspos elengi on
ethylene glycol-induced urolithiasis in rats. Ind. J. Pharmacol. 42(6): 380–386.
Bahuguna, Y.M., Rawat, M.S.M., Juya, V. and Gnanarajan, G. 2009. Antilithiatic effect of grains of Eleusine coracana. Saudi
Pharm. J. 17(2): 182–188.
Baker, J.T., Borris, R.P., Carte, B., Cordell, G.A. and Soejarto, D.D. 1995. Natural product drug discovery and development:
New perspective on international collaboration. J. Nat. Prod. 58: 1325–57.
Banso, A. and Ngbde, J.E. 2006. Phytochemical screening and in vitro antifungal properties of Fagara zanthoxyloides. J.
Food Agric. Environ. 4(3 and 4): 8–9.
Bashir, S. and Gilani, A.H. 2009. Antiurolithiatic effect of Bergenia ligulata rhizome: an explanation of the underlying
mechanisms. J. Ethnopharmacol. 122: 106–116.
Baumann, J.M. and Wacker, M. 1980. The direct measurement of inhibitory capacity to crystal growth of calcium oxalate in
undiluted urine and in other inhibitor containing solutions. Urol. Res. 8(3): 171–5.
Bensatal, A. and Ouahrani, M.R. 2008. Inhibition of crystallization of calcium oxalate by the extraction of Tamarix gallica
L. Urol. Res. 36: 283–287.
Bhattacharjee, A., Shashidhara, S.C. and Aswathanarayana. 2012. Phytochemical and ethno-pharmacological profile of
Cratraeva nurvala Buch-Hum (Varuna): A review Asian Pac. J. Trop. Biomed. 45: 1162.
Butterweck, V. and Khan, S.R. 2009. Herbal medicines in the management of urolithiasis: alternative or complementary? Planta
Med. 75: 1095–1103.
Chandrasoma, P. and Taylor, C.R. 1998. Concise Pathology. 3rd Edition. USA: Appleton & Lange; The ureter, urinary bladder
& urethra, pp. 738–739.
Chang, N., Luo, Z., Li, D. and Huiying Song. 2017. Indigenous Uses and Pharmacological Activity of Traditional Medicinal
Plants in Mount Taibai, China. Evid.-Based Compl. Alt. 1–11.
Chilivery, R.K., Alagar, S. and Darsini, T.P. 2016. In vitro Anti-Urolithiasis Potentials of Argemone mexicana L. Leaves. Curr.
Clin. Pharmacol. 11(4): 286–290.
Chinnala, K.M., Shanigarm, S. and Elsani, M.M. 2013. Antiurolithiatic activity of the plant extracts of Solanum virginianum
on ethylene glycol induced urolithiasis in rats. Int. J. Pharm. Biol. Sci. 3(4): 328–334.
Choubey, A., Parasar, A., Choubey, A., Iyer, D., Pawar, R.S. and Patil, U.K. 2010. Potential of medicinal plants in kidney, gall
and urinary Stones. Int. J. Drug Dev. Res. 2(2): 431–447.
Coe, F.L., Evan, A. and Worcester, E. 2003. Kidney stone disease. J. Clin. Invest. 115 (10): 2598–2608.
Cos, P., Vlietinck, A.J., Berghe, D.V. and Maes, L. 2006. Anti-infective potential of natural products: How to develop a stronger
in vitro ‘proof-of-concept’. J. Ethnopharmacol. 106: 290–302.
De Cagoin, M.R., Linnes, M.P., Lee, H.J., Krambeck, A.E., De Mendonca Uchoa, J.C., Kim, S.H. and Lieske, J.C. 2015.
Aqueous extract of Costus arabicus inhibits calcium oxalate crystals and adhesion to renal epithelial cells. Urolithiasis.
43: 119–124.
Doddola, S., Pasupulati, H., Koganti, B., Koganti, V.S.R. and Prasad, G. 2008. Evaluation of Sesbania grandiflora for
antiurolithiatic and antioxidant properties. J. Nat. Med. 62(3): 300–307.
Edvardsson, V.O., Goldfarb, D.S., Lieske, J.C., Beara-Lasic, L., Anglani, F., Milliner, D.S. and Palsson, R. 2013. Hereditary
causes of kidney stones and chronic kidney disease. Pedriat. Nephrol. 28(10): 1923–1942.
Ekor, M. 2013. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety.
Front. Pharmacol. 4(177): 1–10.
Fahad, J., Vijayalakshmi, M.C., Kumar Satish, Sanjeeva, Kodancha, G.P., Adarsh, B., Udupa, A.L. and Rathnakar, U.P. 2010.
Antiurolithiatic activity of aqueous extract of bark of Moringa oleifera (Lam.) in rats. Health. 2(4): 352–355.
Fouda, A., Yamina, S., Nait, M.A., Mohammed, B. and Abdlekrim, A. 2006. In vitro and in vivo antilithiatic effect of saponin
rich fraction isolated from Herniaria hirsute. J. Bras. Nefrol. 28, pp. 199–203.
Free, A.H. and Free, H.M. 1975. Renal Lithiasis. In Urinalysis in Clinical Laboratory Practice, CRC Press, pp. 229–243.
GilhotraUmesh, K.R. and Christina, A.J.M. 2011. Effect of Rotula aquatica Lour. on ethylene glycol induced urolithiasis in
rats. Int. J. Drug Deliv. Res. 3: 273–280.
Gohel, M.D. and Wong, S.P. 2006. Chinese herbal medicines and their efficacy in treating renal stones. Urol. Res. 34(6): 365–372.
Henisch, H.K. 1970. Crystal Growth in Gels, The Pennsylvania State University Press, USA, pp. 93.
Henisch, H.K. 1988. Crystals in Gels and Liesegang Rings, Cambridge University Press, Cambridge. pp. 15–22.
Hoppe, B. and Langman, C.B. 2003. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria.
Pediatr. Nephrol. 18(10): 986–91.
Hosseinzadeh, H., Khooei, A., Khashayarmanesh, Z. and Shariaty, V.M. 2010. Antiurolithiatic activity of Pinus eldarica
Medw. fruits aqueous extract in rats. Urol. J. 7(4): 232–237.
Huie, C.W. 2002. A review of modern sample-preparation techniques for the extraction and analysis of medicinal plants.
Anal. Bioanal. Chem. 373: 23–30.
Ikegami, F., Fujii, Y., Ishihara, K. and Satoh, T. 2003. Toxicological aspects of Kampo medicines in Clinical Use. Chem.
Biol. Interac. 145: 235–250.
Izzo, A.A. 2004. Drug interactions with St. John’s Wort (Hypericum perforatum): a review of the clinical evidence. Int. J.
Clin. Pharmacol. Ther. 42: 139–148.
Jagannath, N., Chikkannasetty, S.S., Govindadas, D. and Devasankaraiah, G. 2012. Study of antiurolithiatic activity of
Asparagus racemosus on albino rats. Indian J. Pharmacol. 44(5): 576–9.
Joshi, P.C., Patil, S.A. and Sambrekar, S.N. 2012. The antiurolithiatic activity of ethanolic extract of Celosia argentea (seeds)
in rats. Universal J. Pharm. 1(1): 52–60.
Kale, A.S., Patil A.S. and Paikrao, H.M. 2017. A modified TLC bioautographic technique for the detection of antilithiatic
potential of therapeutic plants from Indigenous Ayurvedic System. Pharm. Methods. 8(1): 209–212.
Kalpeshsinh, C.S., Kumar, F.N., Kirti, P.V., Kalpana, P.G. and Tejal, G.R. 2012. J. Drug Deliv. Ther. 2(4): 109.
Kameshwaran, S., Thenmozhi, S., Vasuki, K., Dhanalakshmi, M. and Dhanapal, C. 2013. Antiurolithiatic activity of aqueous
and methanolic extracts of Tecoma stans. Flowers in rats. Int. J. Pharm. Biol. Arch. 4(3): 446–450.
Kannabiran, K. and Selva, M.R. 1997. Induction of renal nukleus oxalate binding activity in experimental hyperoxaluric rats.
Nephron. 75: 219–223.
Khan, A., Bashir, S., Khan, S.R. and Gilani, A.H. 2011. Antiurolithic activity of Origanum vulgare is mediated through multiple
pathways. BMC Complem. Altern. M. 11: 96.
Khan, M.A. and Pradhan, D. 2011. Antiurolithic activity of Ageratum conzoides extract in rats. Pharmacol. Online. 3: 953–958.
Khan, S.R. 1995. Calcium-oxalate crystal interaction with renal tubular epithelium, mechanism of crystal adhesion and its
impact on stone development. Urol. Res. 23: 71–79.
Khan, S.R., Finlayson, B. and Hackett, R.L. 1982. Experimental calcium-oxalate nephrolithiasis in the rat - role of the renal
papilla. Am. J. Pathol. 107: 59–69.
Khan, S.R. 2013. Reactive oxygen species as the molecular modulators of CaOx kidney stone formation: evidence from
clinical and experimental investigations. J. Urology 189(3): 803–811.
Kishore, D.V., Moosavi, F. and Varma R.K. 2013. Effect of ethanolic extract of Portulaca oleracea Linn. on ethylene glycol
and ammonium chloride induced urolithiasis. Int. J. Pharm. Pharm. Sci. 5(2): 134–140.
Kore, K.J., Shete, R.V., Jadhav, P.J. and Kabra, M.P. 2011. Antiurolithiatic effects of hydroalcoholic extract of Lawsonia
inermis L. leaves. Int. J. Uni. Pharm. Life Sci. 1(2).
Kulaksızoglu, S., Sofikerim, M. and Cevik, C. 2008. In vitro effect of lemon and orange juices on calcium oxalate crystallization.
Int. Urol. Nephrol. 40: 589–594.
Lakshmi, B.V.S. and Divya, V. 2014. Antiurolithiatic and antioxidant activity of Zingiber officinale rhizomes on ethylene
glycol-induced urolithiasis in rats. Int. J. Adv. Pharm. Med. Bioal. Sci. 2(3): 148–153.
Macneil, F. and Bariol, S. 2011. Urinary stone disease - assessment and management. Aust. Fam. Physician. 40(10): 772–5.
Makasana, A., Ranpariya, V., Desai, D., Mendpara, J. and Parekh, V. 2014. Evaluation for the anti-urolithiatic activity of
Launaea procumbens against ethylene glycol-induced renal calculi in rats. Toxicol. Rep. 1: 46–52.
Malini, M.M., Lenin, M. and Varalakshmi, P. 2000. Protective effect of triterpenes on CaOx crystal-induced peroxidative
changes in experimental urolithiasis. Pharmacol. Res. 41: 413–418.
Marino, M. and Bersani, C. 1999. Antimicrobial activity of the essential oils of Thymus vulgaris L. measured using a
bioimpedometric method. J. Food Prot. 62: 1017–1023.
Martin, N. and Nieto, V. 2011. Hypouricemia and tubular transport of uric acid. Nefrologia 31(1): 44–50.
Monika, J., Anil, B., Aakanksha, B. and Priyanka, P. 2012. Isolation, characterization and in vitro antiurolithiatic activity of
cerpegin alkaloid from Ceropegia bulbosa Var. Lushii root. Int. J. Drug Dev. Res. 4(4): 154–160.
Mukerjee, P.K. 2002. Quality control of herbal drugs. 1st ed. New Delhi: Business Horizons Publication, pp. 2–24.
Munver, R. and Preminger, G. 2001. Urinary tract stones in comprehensive urology. St. Louis: Mosby.
Nickavar, B., Mojab, F. and Dolat-Abadi, R. 2005. Analysis of the essential oils of two thymus species from Iran. Food
Chem. 90: 609–611.
Nolkemper, S., Reichling, J., Stintzing, F.C., Carle, R. and Schnitzler, P. 2006. Antiviral effect of aqueous extracts from species
of the lamiaceae family against Herpes simplex virus type 1 and type 2 In vitro. Planta Med. 72: 378–1382.
Pareta, S.K. 2011. Establishing the principle of herbal therapy for antiurolithiatic activity: a review. J. Pharmacol. Toxicol.
6(3): 321–32.
Pareta, S.K., Patra, K.C., Mazumder, P.M. and Sasmal, D. 2010. Boerhaavia diffusa Linn. aqueous extract as curative agent
in ethylene glycol induced urolithiasis. Pharmacol. Online. 3: 112–12.
Patel, R.R. and Mandal, S.D. 2014. Activity of Withania somnifera in ethylene glycol induced urolithiasis in rats. Int. J.
Pharm. Arch. 3(3): 346–355.
Pathak, R.S. and Hendre, A.S. 2015. In vitro antiurolithiatic activity of Kalanchoe pinnata extract. Int. J. Pharmacog.
Phytochem. Res. 7: 275–279.
Patil, A.S., Kale, A.S. and Paikrao, H.M. 2014. Screening the in vitro calcium oxalate crystal inhibition potential of Abutilon
indicum L.: a common weed plant from the Indian medicine system. Austin. J. Biotech. Bioeng. 1(6): 4.
Patil, A.S., Paikrao, H.M., Kale, A.S. and Manik, S.R. 2015. Effect of aqueous extracts from therapeutic plants from indigenous
ayurvedic system on in vitro calcium oxalate crystallization in human urine. Curr. Trad. Med. 1(3): 193–202.
Patil, A.S., Paikrao, H.M., Kale, A.S. and Manik, S.R. 2017. A TLC-Direct bioautography method for detection of antiurolithiatic
metabolites. J. Chromatogr. Sci. 55(5): 578–585.
Pearle, M.S., Calhoun, E.A. and Curhan, G.C. 2005. Urologic diseases in America project: urolithiasis. J. Urology 173(3):
848–57.
Perez, C. and Anesini, C. 1994. Antibacterial activity of alimentary plants against Staphylococcus aureus growth. Am. J.
Chin. Med. 22: 169–174.
Rajeshwari, P., Rajeswari, G., Jabbirulla, S.K. and Vishnu vardhan, I. 2013. Evaluation of in vitro antiurolithiasis activity of
Convolvulus arvensis. Int. J. Pharm. Pharm. Sci. 5(3): 599–601.
Ramesh, M.S.K. and Shanmugam, R. 2014. Nephroprotective activity of Ethanolic Extract of Orthosiphon stamineus Leaves
on Ethylene Glycol induced Urolithiasis in Albino Rats. Int. J. Pharm. Tech. Res. 6(1): 403–408.
Rathod, V.D., Fitwe, P., Sarnaik, D. and Kshirsagar, S.N. 2013. In vitro Anti-urolithiatic activity of corn silk of Zea mays. Int.
J. Pharm. Sci. Rev. Res. 21(2): 16–19.
Reddy, N.M. 2013. Lantana camara Linn. Chemical constituents and medicinal properties: a review. Scholars Acad. J. Pharm.
2(6): 445–448.
Saranya, R. and Geetha, N. 2014. Inhibition of Calcium oxalate (CaOx) crystallization in vitro by the extract of Beet root
(Beta vulgais L.) Int. J. Pharm. Pharm. Sci. 6(2): 361–365.
Sathyaa, M., Kokilavani, R., Ananta Teepa, K.S. and Balakrishnan, A. 2011. Supplementation of ethanolic extract of Acalypha
indica Linn. prevents hyperoxaluria in experimental urolithic rats. J. Bloomers. Res. 4: 305–308.
Satish, H., Raman, D., Kshama, D., Shivananda, B.G. and Shridhar, K.A. 2009. Study the relative effect of spironolactone
and different solvent extract of Tribulus terrestris on urolithiatic rats. Phcog. Mag. 5: 83–9.
Schneider, H.J., Bothor, W., Berg, W., Börner, R.H. and Jakob, M. 1983. A gel model for measuring crystallization inhibitor
activities. Urol. Int. 38: 33–38.
Soundararajan, P., Mahesh, R., Ramesh, T. and Begum, V.H. 2006. Effect of Aerva lanata on Calcium Oxalate Urolithiasis
in Rats. Indian J. Exp. Biol. 44(12): 981–986.
Spirnak, J.P. and Resnick, M.I. 1987. Retrograde percutaneous stone removal using modified Lawson technique. Urology
30(6): 551–3.
Stamatelou, K.K., Francis, M.E., Jones, C.A., Nyberg, L.M. and Curhan, G.C. 2003. Time trends in reported prevalence of
kidney stones in the United States: 1976–1994. Kidney Int. 63: 1817–23.
Suzuki, K., Kawamura, K. and Tsugawa, R. 1999. Formation and growth inhibition of calcium oxalate crystals by Takusha
(Alismatis rhizoma). Scan. Microscopy 13(2-3): 183–189.
Szczepanik, M., Zawitowska, B. and Szumny, A. 2012. Insecticidal activities of Thymus vulgaris essential oil and its components
(Thymol and Carvacrol) against larvae of lesser mealworm, Alphitobius diaperinus Panzer (Coleoptera: Tenebrionidae).
Allelopath. J. 30: 129–142.
Thirumala, K., Janarthan, M. and Firasat, A.M. 2013. The aqueous extract of stem core of Musa paradisiaca against ethylene
glycol and ammonium chloride induced urolithiasis. Int. J. Res. Pharm. Biotech. 1(6): 866–868.
Tina, C., Najumadeen, N.A.H., Kumar, S.V., Mainikandan, N., Tobin, G.C., Venkataraman, S. and Murugesh N. 2006.
Antilithiatic effect of Melia azedarach on ethylene glycol induced nephrolithiasis in rats. Pharm. Bio. 44(6): 480–485.
Venilla, V. and Mariyal, A. 2015. In vitro analysis of phytochemical and antiurolithiatic activity of various extract of Melia
dubia leaves. World J. Pharm. Pharm. Sci. 4: 1277–1289.
Venkatesh, G., Baburao, K., Rajesh, B.M., Dhanalakshmi, S. and Indira, P.D.G. 2010. The Coleus aromaticus activity. Int.
J. Phytomed. 2: 284–291.
Vijaya, T., Rao, N.V.R., Narendra Babu, A., Kumar, S.M., Nirojini, P.S., Reddy, B.S. and Nadendla, R. 2013. Antiurolithiatic
activity of methanolic extract of dried leaves of Glochidionc velutinium using ethylene glycol induced rats. Int. J. Biol.
Pharm. Res. 4(12): 878–884.
Vyas, B., Vyas, R.B., Joshi, S. and Santani D. 2011. Antiurolithiatic Activity of Whole-Plant Hydroalcoholic Extract of
Pergularia daemia in Rats. J. Young Pharm. 3(1): 36–40.
Wittstock, U. and Gershenzon, J. 2002. Constitutive plant toxins and their role in defense against herbivores and pathogens.
Curr. Opin. Plant. Biol. 5(4): 300–7.
Yamaguchi, S., Wiessner, J.H., Hasegawa, A.T., Hung, L.Y., Mandel, G.S. and Mandel, N.S. 2005. Study of a rat model for
calcium oxalate crystal formation without severe renal damage in selected conditions. Int. J. Urol. 12: 290–298.
Section II
Ethnopharmacology
14
In Vitro Experimental Design and Data
Analysis in Ethnopharmacology
Raúl Vinet,1,2,* Marcela Knox,1 Marcos Lorca-Morales,1
Claudio Laurido3 and José Luis Martínez4
Introduction
Ethnopharmacology is an interdisciplinary field that seeks to understand the traditional therapeutic use
of natural bioactive products. This area was first defined as “the interdisciplinary scientific exploration of
active biological agents traditionally employed or observed by man” (Holmsted and Bruhn 1983). The term
“ethnopharmacology” is an amalgam of the Greek word ethnos (culture), pharmakos (drug or medicine),
and logia (the study of). On this basis, ethnopharmacology is considered as the study of drugs that have
been traditionally used to treat ailments.
Ethnopharmacology pursues to understand the pharmacological basis of culturally significant plants,
so that it may require preclinical and clinical pharmacological studies. It is common for a medicinal plant
to have more than one use in a culture and even between cultures, a situation that makes its study even
more challenging (Heinrich and Jäger 2015). Therefore, ethnopharmacology needs a multidisciplinary work
approach that integrates scientific data offered by a variety of disciplines such as cultural anthropology,
archeology, linguistics, history, botany, zoology, chemistry, pharmacology, toxicology, and medicine to
take up the challenge (de Smet and Rivier 1989).
According to the World Health Organization (WHO) definition, there are three kinds of herbal
medicines: raw plant material, processed plant material, and medicinal herbal products. Herbal drugs are
defined as finished labeled medicinal products that contain active ingredients such as aerial or underground
parts of plant or other plant material or combination thereof, whether in the crude state or as plant
preparations (Choudhary and Sekhon 2011).
Herbal and other traditional pharmacologic therapies are in widespread use throughout the world. A
WHO estimation indicates that about 80% of the world population still uses herbs and other traditional
medicine for their primary health care needs (Atmakuri and Dathi 2010). Such widespread use suggests
but does not assure, that traditional medicines have a favorable risk-benefit ratio. The actual benefits and
1
Laboratory of Pharmacology, Faculty of Pharmacy, Universidad de Valparaíso, Valparaíso 2360102, Chile.
2
Regional Centre for the Study in Foods and Health (CREAS), Valparaíso 2362696, Chile.
3
Faculty of Chemistry and Biology, Universidad de Santiago de Chile, Santiago 9170022, Chile.
4
Vice Rectory of Research, Development and Innovation, Universidad de Santiago de Chile, Santiago 9170022, Chile.
* Corresponding author: raul.vinet@uv.cl
risks remain to be evaluated by clinical trials involving four sets of issues: chemical-manufacturing-control
issues, non-clinical issues, clinical issues, and ethical issues. Two unique characteristics of herbal products
are that they are multi-component mixtures and that substantial prior human use precedes their formal
investigation (WHO 2005).
As a part of one of the fundamental disciplines of ethnopharmacology, this chapter focuses on
pharmacology of medicinal plants. A distinctive feature of pharmacology is that the effect of a drug is often
observed indirectly, which means that while a drug affects a biochemical process in a cell, the response
is a large-scale change in the state of the whole body (Kenakin 2017). Accordingly, if the response is
appropriately quantified it can be used to predict the effect of a drug at the pharmacological target in all
systems including the therapeutic system.
Evaluation of bioactivities
Evaluation of bioactivities of natural products, including plant material, is not an easy task, especially if
the research is in the field of ethnopharmacology. There are several mandatory steps to achieve consistent
results. As shown in Fig. 14.1, the first step is to obtain reliable ethnopharmacological evidence indicating
that a population use or has used a plant species for therapeutic purposes. Secondly, we must differentiate
two parallel paths with their respective components and associated restrictions: Plant material and biological
model.
Fig. 14.1 A general approach to evaluate bioactivity of plant material (see the text for description).
Plant material
The “Plant Material” path considers the following components (C1–C4):
C1. Population (Plant Material). A theoretical population of plant species associated with the therapeutic
effect.
C2. Certified Plant Material. A certified source of the “Population” (C1), namely the means and sources
of plant identification, the institutions holding the voucher specimens, and the experts that have
helped to identify the sample (Weckerle et al. 2017).
In Vitro Experimental Design and Data Analysis in Ethnopharmacology 235
C3. Sample. A sample of the “Certified Plant Material” (C2), namely a representative sampling of the
certified plan material (whole plant, roots, stem, leaf, flower, fruit, seed).
C4. Sample Processing. Typically, a dried and powdered plant material containing one or more plant
parts. This material is usually macerated in water or ethanol-water at room temperature for some
days. Then the material is filtered, evaporated in vacuo and lyophilized, obtaining the dry aqueous or
hydroalcoholic extract. This product is the “total or whole extract” and the first source for bioactivity
evaluation. Additional processes included fractionation and purification, finalizing with one or more
isolated compounds. Additionally, these sources require different techniques to identify and quantify
their components (Trease and Evans 1989, Lakshmana Prabu and Suriyaprakash 2012). In Fig. 14.1,
these sources of bioactive material are represented by “Dose (X)”.
Solution Preparation. A practical rule of thumb for preparing a drug stock solution is to weigh 10% of
the drug’s molecular weight and then dissolve it in 10 mL. For example, if a drug has a molecular weight
of 200 Da, we can weigh 20 mg (or less) and then dissolve it in a total volume of 10 mL (or the equivalent
volume depending on the mass weighed). Therefore, the final concentration will be 10–2 M (i.e., 10,000 μM).
In the following example, we will assume that we have a 10–2 M drug stock solution with the drug
dissolved in pure ethanol. We also suppose that the final experimental concentration is defined as 100
µM (the highest concentration). The experimental chamber is a cell culture dish of 1 mL (i.e., 1,000 µL).
Consequently, the experimenter adds 10 µL of stock solution into the dish and completes its volume to 1
mL with the experimental solution (e.g., saline solution or culture medium). Because of this procedure,
the cell culture dish has reached 1% of ethanol.
If the biological model is highly sensitive to ethanol and 1% may be harmful, it is possible to prepare
a more concentrated drug stock solution. This example is also valid for dimethylsulfoxide (DMSO), a
solvent widely used in pharmacological tests for its ability to dissolve water-insoluble drugs.
Another important consideration relates to the stability of compounds derived from natural sources.
Bioactive compounds present in plants are especially sensitive to temperature, pH, and light, so precautions
must be taken to avoid degradation.
Biological model
The “Biological Model” involves the following components (C5–C8):
C5. Population (Biological Model). A theoretical population of the biological model suitable to evaluate
the therapeutic effect associated with the plant species.
C6. Certified Biological Model. A certified source of the “Population” (C5), specifically a biological model
that have been proven to render the relevant pharmacological parameters that characterized a drug
(Peng and Zhao 2009, Kenakin 2017). Usually, the certified biological model included laboratory
animals and cell culture providers from universities and private organizations. At this point, we are
going to focus on two biological models widely used in vitro assays: rat aortic rings and Human
Umbilical Vein Endothelial Cells (HUVEC).
C7. Sample. A sample of “Certified Biological Model” (C2), namely a representative sample of the
certified biological model (laboratory animals, cell cultures).
C8. Sample Processing. In vitro (e.g., primary cultures, cell lines, isolated organs) and in vivo (laboratory
animals like mouse and rat) models play a significant role in preclinical pharmacological assays
(Peng and Zhao 2009). In this work, we described two in vitro models, rat aortic rings, and HUVEC:
Rat Aortic Ring Preparation. We will describe the modified methods for measuring rat aorta contractility
(Vinet et al. 1991, Illanes et al. 1993, Vinet et al. 2012). Rats weighing 250–290 g are sacrificed by an
overdose of CO2 inhalation. The thoracic aorta is carefully excised and placed in a Petri dish containing
modified Krebs-Henseleit buffer (KHB) (in mM: NaCl 122; KCl 4.7; NaHCO3 15.5; KH2PO4 1.2; MgCl2
1.2; CaCl2 2.0; D-glucose 11.5; EDTA 0.026; pH 7.4) at 37°C and oxygenated continuously with a 95%
O2 – 5% CO2 gas mixture. Aorta is dissected, cleaned of connective tissue and divided into 5 mm rings
segments. Rings are suspended between two L-shaped stainless-steel hooks and placed into a 20–30 mL
organ chambers containing modified KHB at 37°C and oxygenated continuously with a 95% O2 – 5%
CO2 gas mixture. Isometric tensions are measured using a force displacement transducer connected to
a polygraph. Rings are exposed to a basal tension of 1.5 g for 60 minutes. Then, rings are progressively
stretched at least three times with a depolarizing 70 mM KCl solution (in mM: NaCl 52; KCl 70.0; NaHCO3
15.5; KH2PO4 1.2; MgCl2 1.2; CaCl2 2.0; D-Glucose 11.5; EDTA 0.026; pH 7.4) until reaching a maximum
stable contraction (reference tension). Rings are repeatedly washed and equilibrated for 30 minutes. The
preparation is now ready to evaluate aorta contractility, i.e., relaxation or contraction activities. The analysis
of the effect of a drug on aortic reactivity included the maximal response and the concentration causing
50% of the maximal response (EC50). The integrity of endothelium is assessed by testing the relaxation
produced by the addition of 1 µM acetylcholine in 0.1 µM phenylephrine-precontracted rings.
To evaluate a drug with a vasoconstriction potential, the drug is added directly to the organ chamber
containing the aorta under a basal tension. On the other hand, if a drug is suspected to have a vasodilatory
potential, the vessel is previously contracted with phenylephrine, and when a stable contraction is reached,
the drug is added. In both cases, the drug is applied in increasing doses, usually between concentrations
from 10–9 to 10–4 M.
HUVEC Preparation. Primary culture of HUVEC are isolated and pooled from umbilical cords obtained
from normal vaginal deliveries according to Jaffe et al. (1973) and modified by Cortés et al. (2013). Cells
are cultured in gelatin-coated Petri dishes and grown in medium 199 supplemented with 2 mM glutamine,
20% heat-inactivated fetal bovine serum, and 25 mg/mL endothelial cell growth supplement. HUVEC
are incubated in 5% CO2–95% air-gas mixture. The medium is changed 24 hours after seeding and cells
subcultured on reaching confluence using 0.01% trypsin-EDTA. Usually, HUVEC of the first and second
passage is used for experiments. Cells are seeded at a density of (1.3 x 105 cell/mL) in gelatin-coated Petri
dishes and allowed to attach overnight. HUVEC are ready to be submitted to the experimental protocol.
Experimental design and data analysis

Statistical Analysis. The randomized and blinded controlled experiment was first established in the early
1900s by Fisher in agricultural research (Festing and Nevalainen 2014). The rationale is clear: if the test
compares an intervention in two or more groups, necessarily need to be contrasted with a non-intervention
group, i.e., the control group. If the researchers know the treatments, they can bias the results favoring one
group. In blinded, controlled experiment it is the statistical analysis that determines the probability that
differences among groups can be attributed to the effect of the intervention rather than chance.
Replicates are intended to evaluate and isolate sources of variation in measurements and to limit the
effect of false variation on parameter estimation. Distinguishing between biological and technical variation
is important. Biological variation can be detected by measurements of distinct samples while technical
variation can be detected by repeated measurements of the same sample. Taking additional biological
replicates is the best option for improving the efficiency of statistical testing (Blainey et al. 2014).
Our experience shows that by working with calibrated instruments, with triplicate samples, and with
six independent experiments (N = 6), it is possible to obtain consistent results allowing us to discriminate
small effects attributable to the intervention being evaluated.
Mathematical Models. The purpose of this section is to find a simple model to adjust the experimental
data and to obtain the parameters that characterized the system. A system is a pool of objects and processes
that interact to create a unified whole, such as a cell culture system, a rat, or a human (Bonate 2011). A
mathematical model is a caricature, a deliberate oversimplification of reality (Hannon and Ruth 2014).
Therefore, a mathematical model represents the system of interest and can be used to explore its structure
and behavior (Wastney et al. 1997).
The regression model is an equation that defines the Output, or dependent variable Y, as a function
of the Input, or independent variable X, and one or more model parameters (Motulsky and Christopoulos
2003). There are two types of regression models, empirical and mechanistic models. Empirical models
just describe the general form of data that is tried to fit. The parameters of the model do not necessarily
correspond to a natural process.
On the other hand, mechanistic models are explicitly formulated to represent a specific natural process
that is supposed to control the phenomenon under study. The parameters resulting from mechanical models
are quantitative estimates of real system properties. In general, the mechanistic models are more useful
because they are a quantitative representation of a hypothesis. However, if the wrong mechanistic model
is chosen to fit the data, the consequences are more negative than for the empirical models, since it is
very likely that erroneous conclusions are reached regarding the mechanism under study (Motulsky and
Christopoulos 2003).
Dose-Response Curves. Dose-response curves are used to plot the results of many types of biological
experiments mainly pharmacological. The X-axis represents the concentration of a bioactive compound
(e.g., drug, hormone). The Y axis represents the biological response (e.g., enzymatic activity, intracellular
messenger level, contraction, etc.). Figure 14.2 shows a representation of a dose-response curve as a cell
process.
The term “dose” is frequently used to refer to both in vivo and in vitro assays (dose-response curve).
However, to be fair, it should be clarified that the term dose is suitable for in vivo experiments (i.e., dose-
response curve), whereas for in vitro experiments it is more correct to use concentration (i.e., concentration-
response curve). It is important to consider that in in vivo experiments the concentration of drug at the site
of action is unknown so that only dose control is available. In contrast, in vitro experiments, it is generally
assumed that the concentration of drug at the site of action is equal to the concentration of drug reaching
the system and therefore is controlled by the investigator.
An agonist is a drug that binds to a receptor and alters the receptor state triggering a biological response.
If several concentrations of an agonist induce a sharp response, the dose-response curve will go uphill as
drug concentration increases. On the other hand, if the agonist produces an inhibitory response, the curve
will go downhill as drug concentration increases. A full agonist is a drug producing the maximum cellular
or tissue response. A partial agonist is a drug that provokes a response, but the maximum response is less
than the maximum response compared to a full agonist in the same cell or tissue. An inverse agonist is a
drug that decreases an established basal response.
An antagonist is a drug that decreases the action of another drug, generally an agonist. It is important
to note that the classification of drugs as full agonists, partial agonists, inverse agonists, and antagonists
is highly dependent on the biological system in which they are tested.
Choosing the Mathematical Model: To fit data obtained from pharmacological experiments we suggest
using the standard model known as the “Hill equation”, the “four-parameter logistic equation”, the “variable
slope sigmoid equation” or simply “4PL” (Motulsky and Christopoulos 2003). This model can be written
Fig. 14.2 Representation of a dose-response curve as a cell process. The figure shows a system symbolized by the sequence
INPUT-PROCESS-OUTPUT. The amount of liquid entry into the container (e.g., fuel) represents the INPUT (Dose), and
the level of liquid in the container (e.g., energy) represents the OUTPUT (Response). The Bottom level corresponds to the
basal level and the Top level the maximal effect. Note that the INPUT (Dose) is transformed into OUTPUT (Response) by a
PROCESS that can be represented by a mathematical model. A key task of pharmacology is to find the model and associated
parameters that allow characterizing a drug and inferring its action in other biological systems, particularly in human beings.
as an equation that defines the response (the dependent variable Y) as a function of dose (independent
variable, X) and the four parameters as shown in Fig. 14.2:
where,
Bottom = Y value for the minimal curve asymptote (theoretically, the response in the absence of drug)
Top = Y value maximal curve asymptote (theoretically, the response produced by an infinitely high
concentration of drug).
LogEC50 = the logarithm of drug dose (or concentration) that produces the response halfway between the
Bottom and Top (commonly used as a measure of a drug’s potency).
Hill Slope = indicates the steepness of the dose-response curve and usually associated with the system’s
sensitivity to the drug.
The next step is defining which of the parameters, if any, should be fixed to constant values. This
decision should be based on experimental controls, or on theoretical aspects. When the basal response of
the system is assumed to be zero, it is often to consider the Bottom value also as zero.
Nonlinear regression can be performed using GraphPad Prism (GraphPad, San Diego, CA, USA) and
SigmaPlot (Systat Software, Inc., San Jose, CA, USA). Both programs have a trial version.
Conclusion
Ethnopharmacology pursues to understand the traditional therapeutic use of natural bioactive products.
To reach this purpose ethnopharmacology needs a multidisciplinary work approach that integrates
scientific data offered by a variety of disciplines including pharmacology. In this work, we conclude that
to achieve reliable data that understand and validate the traditional use of bioactive compounds, a strict
experimental protocol aligned with the scientific method is necessary. To contribute to experimental
research in ethnopharmacology, in this chapter, we have proposed a general pharmacological approach to
obtain an acute estimation of plant material bioactivity using two in vitro models: isolated rat aorta and
endothelial cell cultures.
References
Atmakuri, L.R. and Dathi, S. 2010. Current trends in herbal medicines. J. Pharm. Res. 3: 109–13.
Blainey, P., Krzywinski, M. and Altman, N. 2014. Points of Significance: Replication. Nat. Methods 11: 879–s880.
Bonate, P.L. 2011. Pharmacokinetic-Pharmacodynamic Modeling and Simulation. 2nd ed. Springer, USA.
Choudhary, N. and Sekhon, B.S. 2011. An overview of advances in the standardization of herbal drugs. J. Pharm. Educ. Res.
2: 55–70.
Cortés, M.P., Becerra, J.P., Vinet, R., Alvarez, R. and Quintana, I. 2013. The inhibition of ATP-induced calcium influx by
homocysteine in human umbilical vein endothelial cells. Cell Biol. Int. 37: 600–607.
De Smet, P.A. and Rivier, L. 1989. A general outlook on ethnopharmacology. J. Ethnopharmacol. 25: 127–138.
Festing, M.F. and Nevalainen, T. 2014. The design and statistical analysis of animal experiments: introduction to this issue.
ILAR J. 55: 379–382.
Hannon, B. and Ruth, M. 2014. Modeling Dynamic Biological Systems. 2nd. ed. Springer, USA, pp. 3–10.
Heinrich, M. and Jäger, A.K. 2015. Ethnopharmacology. 1st ed. Wiley Blackwell, Oxford, UK, pp. 3–5.
Holmstedt, B. and Bruhn, J. 1983. Ethnopharmacology—a challenge. J. Ethnopharmacol. 8: 251–256.
Illanes, A.G., Penna, M. and Martinez, J.L. 1993. The vascular relaxing effect of a factor released by rat atria distension. Gen.
Pharmacol. 24: 315–319.
Jaffe, E.A., Nachman, R.L., Becker, C.G. and Minick, C.R. 1973. Culture of human endothelial cells derived from umbilical
veins. Identification by morphologic and immunologic criteria. J. Clin. Invest. 52: 2745–2756.
Kenakin, T.P. 2017. Pharmacology in drug discovery and development: understanding drug response. 2nd. ed. Amsterdam:
Elsevier/Academic Press, pp. 7–40.
Lakshmana Prabu, S. and Suriyaprakash, T.N.K. 2012. Extraction of drug from the biological matrix: a review. In: Ganesh R.
Naik (ed.). Applied Biological Engineering - Principles and Practice. ISBN: 978-953-51-0412-4, InTech.
Motulsky, H.J. and Christopoulos, A. 2003. Fitting models to biological data using linear and nonlinear regression. A practical
guide to curve fitting. GraphPad Software Inc., San Diego CA, USA, pp. 256–265.
Peng, S. and Zhao, M. 2009. Pharmaceutical Bioassays: Methods and Applications. John Wiley & Sons, Inc., Hoboken, New
Jersey, USA, pp. 1–443.
Trease, G.E. and Evans, W.C. 1989. Pharmacognosy. 13th ed. Bailliere Tindall, London, UK.
Vinet, R., Brieva, C., Pinardi, G. and Penna, M. 1991. Modulation of alpha-adrenergic-induced contractions by endothelium-
derived relaxing factor in rat aorta. Gen. Pharmacol. 22: 137–142.
Vinet, R., Knox, M., Mascher, D., Paredes-Carbajal, C. and Martinez, J.L. 2012. Isolated aorta model and its contribution to
phytopharmacology. Bol. Latinoam. Caribe Plant. Med. Aromat. 11: 35–45.
Wastney, M.E., Siva Subramanian, K.N., Broering, N. and Boston, R. 1997. Using models to explore whole-body metabolism
and accessing models through a model library. Metabolism 46: 330–332.
Weckerle, C.S., de Boer, H.J., Puri, R.K., van Andel, T., Bussmann, R.W. and Leonti, M. 2017. Recommended standards for
conducting and reporting ethnopharmacological field studies. J. Ethnopharmacol. 210: 125–132.
World Health Organization. 2005. Operational Guidance: Information Needed to Support Clinical Trials of Herbal Products.
(Document reference who/TDR/GEN/Guidance/051). http://apps.who.int/iris/bitstream/10665/69174/1/TDR_GEN_
Guidance_05.1_eng.pdf.

15
Insights into the Ethnopharmacological
Uses of Rutaceae
A Golden Source for Many Pharmaceutical
Preparations
Dalia I. Hamdan,1 Fadia S. Youssef,2 Mohamed L. Ashour2,* and
Assem M. El-Shazly3
Introduction
The family Rutaceae that is also named the Rue or Citrus family belongs to the order Sapindales. Most
species of the family Rutaceae are mainly herbs, trees as well as shrubs, having a particular glandular
punctuate in addition to possessing a strong scent. It includes almost 150 genera with 1,500 species that
are greatly spread worldwide with special occurrence in tropical as well as subtropical regions particularly
in southern Africa and Australia (Hume 1957, Reuther et al. 1967, Mabberley 2008).
In spite of the existence of numerous subfamilies within the family Rutaceae, all the members of genus
Citrus belong to the subfamily Aurantioideae, that comprises of two tribes namely, the Clauseneae and
Citreae, the former includes the very remote citroid fruit trees with five genera. While the latter comprises of
citroid fruit trees with three subtribes: the first is the Triphasiinae that is named by minor citroid fruit trees;
the second is the Balsamocitrinae that is also known by hard–shelled citroid fruit trees whereas the third is
Citrinae (Citrus fruit trees) (Ortiz 2002, Mabberley 2008). The above taxonomy is illustrated in Fig. 15.1.
The Citrus family is very popular by the presence of spines in addition to winged petioles. Additionally,
the leaves are characterized by being exstipulate, opposite or alternate in its phyllotaxis that are simple
or pinnately or palmately or compound. However in some cases it is characterized by being in the form
of sheath like or diminished to spines. Meanwhile, most flowers of the Rutaceae members possess a
characteristic sweet odor and are mostly bisexual, and actinomorphic and occasionally zygomorphic.
Basically, its calyx contains 3–5 sepals that are either discriminate or basally connate meanwhile its
corolla comprises of 3–5 petals that are mostly distinct and sometimes connate and scarcely the petals are
1
Department of Pharmacognosy, Faculty of Pharmacy, Menoufia University, 32511 Shebin El Koum, Egypt.
2
Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, 11566, Cairo, Egypt.
3
Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt.
* Corresponding author: mohamed_ashour@pharm.asu.edu.eg; ashour@pharma.asu.edu.eg
Insights into the Ethnopharmacological Uses of Rutaceae 241
Fig. 15.1 Phylogenetic tree of Rutaceae family.
absent. Besides, the fruit is extremely variable in its appearance as well as in its size. The former ranges
from round to sub-globose as well as oblate to obovoid and from broadly pyriform to cylindrical, ovoid,
elliptical and oblong. Furthermore, its rind is familiar by being very variable, rough, ribbed, wrinkled or
bumpy. The variation in the internal characters between the fruits of Citrus members mainly relied upon
the discriminate structure of hesperidium in addition to the fruit segments and inclusions, the rind, the
central axis or medulla, and the seeds (Ortiz 2002, Mabberley 2008). In the foregoing chapter we aim to
shed light on the traditional uses, phytochemistry and its correlation with the biological activity of some
important species of one of the popular genera in the Rutaceae that is the genus Citrus.
Genus Citrus
Citrus is among the most important genera of flowering plants within the Rutaceae, that is native to
tropical, semitropical as well as subtropical Southeast Asia. The term Citrus originates from the Ancient
Greek word that is kedros or from its Latin derivate which is called cedrus. It is noteworthy to mention,
that the names were applied by both the ancient Greeks as well as by the Romans describing various trees
that possess fragrant foliage or wood (Andrews 1961, Ortiz 2002).
The genus Citrus is characterized by a very complex taxonomy and the actual figure of the naturally
occurring species is still unclear in addition to the occurrence of many clonally-propagated hybrids with
genetic evidence that declares that even the wild, true–breeding species are of hybrid origin. True fruits
of Citrus comprise five genera and 29 species that are as follow: Fortunella that includes four species,
Eremocitrus with four species also, in addition to Poncirus that is of only one species whereas, Citrus
includes two subgenera and 16 species, Microcitrus, and Clymenia that possess four species.
Moreover, the two discriminate subgenera of the genus Citrus, Citrus and Papeda, are easily
differentiated by the characters of their leaf, flower, as well as the fruit. Most of the popular cultivated
members of Citrus exemplified by mandarin, sweet orange, lemon, lime and grapefruit are contained within
the subgenus Citrus (Fig. 15.2). These species are characteristic by the presence of pulp vesicles which are
filled with a pleasant acidic or sweet juice with the presence of an everlasting unifoliate or simple leaves
(Ortiz 2002, Mabberley 2008).
Citrus fruits are considered not only as a favorite food but also a medicinally active agent possessing
multiple phytoconstituents that are beneficial to human health. These constituents are mainly limonoids,
flavonoids, coumarins and acridone alkaloids in addition to the presence of a high level of vitamin C,
vitamin–B complex as folic acid, biotin, pantothenic acid, pyridoxine and β–carotene and lycopene type
carotenoids (Berhow et al. 2000, Ladaniya 2008). Notable improvement in blood circulation, anti-allergic,
antiviral and anti-carcinogenic activities has been attributed to Citrus juices in particular to that of grapefruit
and oranges owing to their richness by flavonoids. Furthermore, fresh Citrus fruits are also popular by
reducing the risk of heart attacks if taken in the diet on a daily basis owing to their high content of fiber and
pectin. The fragrance obtained from the flowers of grapefruits is effective in relieving insomnia and as a
stomachic and cardiac tonic. The pulp provides an effective therapy in the alleviation of urinary disorders
in addition to the antibiotic activity exhibited by leaf extracts (Filatova 1999).
Nowadays, Citrus is considered as the most widely spread and produced fruits in the form of as a
group of numerous species that is grown in more than 80 countries (Chang 1992, Berhow et al. 2000). The
production of Citrus in the globe elevated at the rate of 4.5% annually during the 1990s, that resulted in
the production of 98.35 million tons during the period between 2001 and 2002, and this number exceeded
the 100 million tons mark during 2003–2004 (FAO 2006).
Owing to the tremendous economic developments and rapid alteration in the lifestyle of people
with different cultures, fresh fruit utilization is highly elevating in the category of easy–peelers, such as
tangerines/mandarins. Being seedless and small, these fruits are more preferable and convenient in eating.
Fig. 15.2 Different fruits belonging to Citrus subgenus.

Moreover, consumption of fresh oranges rapidly increased by a rate of 2.9% from 1986–88 to 1996–98. In
regions that are characterized by their high population such as African regions and many Asian countries as
China and India, Citrus fruits are used in a fresh form and are supplied by local Citrus industries. In Central
and Latin America, a large category of the population still prefers and can withstand the consumption of
only fresh Citrus. The majority of the rise in the consumption of domestic production is mainly in China,
India, Mexico, Pakistan, and Brazil. In spite of the increase in the production of Citrus fruits with a rate
of 2–5% each year, the per capita annual consumption differs from 40 kg in European countries to 4 kg
in Asia and Africa countries (Ladaniya 2008).
Traditional uses of family Rutaceae and genus Citrus

In the folk medicine Citrus plants were believed to be an effective method to combat moths in clothes as
well as a mouthwash as written by Theophrastus owing to its insecticidal limonoids that were recently
discovered. Moreover, it was popular as an efficacious poison antidote and as a tonic keeping the vitality of
skin as mentioned by Abu Marwan in his ‘Treatise of foodstuff’. Regarding the pharmaceutical importance
of the Citrus plants, it was early recognized by Linnaeus. Additionally, sour orange was greatly adopted
in the Middle Ages in Europe both as a flavoring agent and to prevent worms. Besides, it gained a great
reputation in China to alleviate a wide array of disorders starting from mild skin ailments to influenza,
gout, cough, sore throat, liver and gall bladder problems, rheumatism and to reduce blood pressure (Arias
and Ramón-Laca 2005).
Additionally, in western medicine, the essential oil of Citrus plants were widely consumed as an
antiseptic against bacteria, fungi, protozoa and insects attributing to their high content of phenol. Citrus
hystrix that is familiar by the richness of its leaves with citronellal is recognized to be essential in cooking,
meanwhile the hesperidium is still consumed to wash hair and to propel leeches. Citrus plants were widely
utilized in the west to alleviate scurvy that is caused by significant reduction in vitamin C in addition to
common cold (Arias and Ramón-Laca 2005).
Moreover, some clinicians in the early last century postulated that lemon juice countered obesity
via the interaction that takes place between a compound existing in the fruit’s ‘membrane’ and the liver
to diminish cholesterol content and to control insulin. Additionally, it was reported that black women in
tropical America utilize a douche comprising of lemon juice as a mean of contraception through its action as
a potent spermicide in which the citric acid causes destruction of the proteins of the mitochondria resulting
in immobility. Also, the pips were used during pregnancy to combat nausea and stomach weakness whereas
lime pickle enhances the appetite. It is worth mentioning that control of HIV spread among the population
was believed to be achieved via the consumption of lemon juice (Mabberley 2004).
Biological activity of genus Citrus and its correlation with its predominant
classes of secondary metabolites
Biological activity of limonoids
Limonoids represent one of the major classes of active constituents in the Citrus, which is characterized
by the attachment of a furan ring to C17 position that effectively induced glutathione S-transferase in both
mice and rats. The effectiveness of a certain drug to enhance the activity of glutathione S-transferase has
been notably correlated with its efficacy to inhibit carcinogenesis. The limonoids existing in the Citrus
have been proved to inhibit the occurrence of the neoplasia that is induced by chemicals in the skin, fore-
stomach, small intestine, colon and the lungs of experimental, laboratory animals. Also, they prohibited
the proliferative spread of human breast cancer cell (Berhow et al. 2000). Besides, they enhance human
health acting as cholesterol–lowering as well as antiviral agents (Manners 2007).
Furthermore, limonoids exhibited a marked inhibition concerning the growth of estrogen receptor-
negative and positive human breast cancer cells culture. A mixture of limonoids consisting of limonin,
nomilinic acid 17-β-glucoside, nomilin, and obacunone 17β-glucoside has shown an obvious inhibition
in human breast cancer cell line (MCF-7). Additionally, a high concentration of 100 µg/ mL from the
previously mentioned mixture could effectively induce apoptosis in MCF-7 (Tian et al. 2001).
The effect of Citrus limonoids as an antifeedant against insects was first discussed in 1982. It has
been largely confirmed that limonoid aglycones showed an antifeedant activity towards a large number of
insects comprising corn earworm, Colorado potato beetle, spruce budworm, fall armyworm and tobacco
budworm. In addition, it was reported that previously mentioned limoniods showed insecticidal activity
against Culex quinquejasciatus larvae (Jayaprakasha et al. 1997). The efficacy of limonin as antifeedant
was found to be one tenth comparable to azadirachtin. Limonin as well as ichangensin exhibited significant
antifeedant against Colorado potato beetle. On the contrary, limonoid glucosides did not show any
antifeedant property against insects (Berhow et al. 2000, Ruberto et al. 2002).
Furthermore, it was proved that limonin showed hypoglycemic activity (Hasegawa et al. 1986) in
addition to antitumor activity towards benzo[α] pyrene and azoxymethane induced neoplasia in the fore
–stomach of mice and colon of rats, respectively (Lam and Hasegawa 1989, Tanaka et al. 2000, Tanaka
et al. 2001). Additionally, limonin exhibited anti-inflammatory property towards paw edema induced by
bradykinin and ear swelling produced by arachidonic acid (Matsuda et al. 1998).
Furthermore, a notable antifungal property was exhibited by limonin, nomilinic acid and limonol
against Puccinia arachidis. The activity of limonoids is mainly due to the presence of a highly reactive
epoxide group that is composed of three ring structures in addition to anoxirane ring that could effectively
bind to proteins via covalent bonds to the sulfhydryl (SH), NH groups and the amino group (NH2) of the
amino acid residue. Consequently, this will probably lead to a significant alteration in both the conformation
as well as the recognition processes of protein. Epoxides have long been known as powerful alkylating
agents that can alkylate DNA resulting in mutations and malformations that consequently lead to cancer if
not repaired by the naturally occurring repair enzymes (Govindachari et al. 2000, Wink 2008). Examples
of some limonoids isolated from some members of genus Citrus is represented in Table 15.1.
Biological activity of flavonoids
Flavonoids also constitute one of the major classes of secondary metabolites predominating in Citrus
that eventually showed a marked role in both human diet and health. In addition, flavonoids exhibited a
great diversity in functions and actually attracted many researchers in attributing many reasons including
ecological, biological and chemotaxonomic, functions and acting as discriminant markers assessing food
quality as well as potential industrial investments (Tusa et al. 2007). Flavonoids prevailing in this genus
are highly popular as anti-allergic, anticarcinogenic, antioxidant, antiviral and as a cardioprotective agent
(Cook and Samman 1996, Del Caro et al. 2004, Lee et al. 2004, Yu et al. 2005). Besides, they showed a
drastic effect in improving capillary fragility and inhibiting the aggregation of human platelet (Bocco et
al. 1998).
In spite of the comprehensive studying of the biological activity of a large number of popular Citrus
flavonoids (e.g., tangeretin, hesperidin, naringin and diosmin, and) both in vivo and in vitro, the potential
biological activities of others as the hydroxycinnamates and several minor flavonoids have not been fully
elucidated in Citrus. Meanwhile, hydroxycinnamates isolated from other food crops have been widely
investigated and was proved to exhibit marked beneficial roles, comprising their actions as antioxidants,
antimicrobial and anticancer agents (Manthey and Grohmann 2001).
In an attempt to assess the biological activities of Citrus flavonoids, naringin has showed a potential
antihypercholesterolemic activity, it reduced the total cholesterol and low-density lipoprotein cholesterol
levels in plasma (Jung et al. 2003), moreover, hesperetin and its related derivatives significantly lowered
the total cholesterol and triglyceride concentration in plasma (Kim et al. 2003).
On the other hand, many other flavonoids including hesperidin, diosmin, quercetin and rutin act as a
chemopreventive agent against colorectal carcinogenesis and neoplasia induced by azoxymethane (Tanaka
et al. 2000, Kawaii et al. 1999). The polymethoxylated flavones in Citrus have also been shown to exhibit
antiproliferative effects against many cell lines as well as anti-inflammatory actions (Manthey and Grohmann
2001). For instance, nobiletin down-regulated the production of pro-matrix metalloproteinase 3, 9 and to
interfere with the proliferation of synovial fibroblasts (Ishiwa et al. 2000). Also, it showed amelioration in
the hepatic parameters (lipid peroxides, reduced glutathione, and catalase enzyme) in mice (Wink 1999).
Tangeretin showed a relevant suppressive effect on malignant tumor invasion and metastasis. Besides,
treatment of ARPE-19 human retinal pigment epithelial cells with diosmin after being exposed to a high
Table 15.1 Examples of some limonoids isolated from some members of genus Citrus.
Compound Structure Formula, Source Reference

molecular
weight
O C26H30O8 C. medica (Cai et al. 1993)

M+ 470.3 C. reticulata (Breksa and Ibarra
O
Limonin O Calamondin* 2007)
O
(C. reticulata+ (Manners and
O Fortunella sp.) Breksa 2004)
O O
O C. limon (Vikram et al.
2007)
Nomilin O C28H34O9 C. medica (Cai et al. 1993)
M+ 515.3 C. reticulata (Vikram et al.
OAc O
2007)
Calamondin* (Manners and
O O
O
O Breksa 2004)
O (Vikram et al.
C. limon
2007)
Obacunone O C26H30O7 Calamondin* (Manners and
Breksa 2004)
M+ 454.4 C. reticulata (Khalil et al. 2003)
O
(Moodley et al.
O O C. limon
O 1995)
O
O
Ichangin C26H32O9 C. reticulata (Khalil et al. 2003)

O
M+ 488.53 Calamondin* (Manners and
O Breksa 2004)
O
O C. limon (Vikram et al.
2007)
HO O
O
HO O
Deoxylimonin C26H30O7 Calamondin* (Manners and

Breksa 2004)
O M+ 454.51 C. limon (Miller et al. 2004)
O
O
O
O
O
O
Isolimonic acid C26H32O9 C. reticulata (Vikram et al.

O 2007)
M+ 488.53 C. limon
OH O
HOOC
O
O O
O


molecular
weight
Isoobacunoic acid C26H32O8 C. reticulata (Vikram et al.
O
M+ 472.53 C. limon 2007)
COOH
O
O
O O
O
Deoxylimonol C26H32O7 Calamondin* (Manners and

O Breksa 2004)
M+ 456.53
O
O
O
O
O
OH
7 α-Limonol C26H32O8 Calamondin* (Manners and

O Breksa 2004)
M+ 472.53
O C. limon (Manners and
O Hasegawa 1999)
O
O
O O
OH
7α-Limonol acetate C28H34O9 Calamondin* (Manners and

O Breksa 2004)
M+ 514.56
O
O
O
O
O O
OAc
Deacetylnomilin C26H32O8 Calamondin* (Manners and

O
M+ 472.4 Breksa 2004)
C. reticulata (Bennett and
OH O Hasegawa 1981)
C. limon (Tian et al. 2003)
O O
O
O
O


molecular
weight
Methyl C27H36O9 Calamondin* (Manners and
deacetylnomilinate O Breksa 2004)
M+ 504.3
OH Hasegawa 1981)
O
MeOOC O
O
HO
O
Isolimonexic acid O C27H32O10 C. reticulata (Khalil et al. 2003)

methyl ether M+ 516.21
O
O OCH3
O O
O
O O
O
7 α-Obacunol C26H32O7 Calamondin* (Manners and

O Breksa 2004)
M+ 456.3
O O
O
O
OH
Limonoic acid C26H32O9 C. reticulata (Breksa et al.

A-ring lactone O 2005)
M+ 488.53
C. limon (Raman et al.
O
2005)
O
OH
COOH
O O
O
Nomilinoate A-ring C28H36O10 C. reticulata (Breksa and Ibarra

O
lactone M+ 532.58 2007)
C. limon (Raman et al.
OAc 2005)
OH
COOH
O
O
O
O


molecular
weight
Ichangin 4-β-glucoside C32H42O14 C. limon (Matsubara et al.
O 1990)
M+ 650.1
O O
O
O
O
OH O
OH
OH
O
O OH
HO
Nomilinic acid O
C34H46O15 C. limon (Matsubara et al.
4–β-glucoside M+ 692.1 1990)
OAc O
HOOC O
O
O
OH
O OH
OH
O
OH
Ichangensin C25H32O7 Calamondin* (Manners and

O
M+ 444.4 Breksa 2004)
C. limon (Miller et al. 2004)
OH O
O
O O
O
Methyl isoobacunoate C27H34O8 Calamondin* (Manners and

O Breksa 2004)
M+ 486.55
COOMe
O
O
O O
O
Methyl isoobacunoate C27H32O9 Calamondin* (Manners and

diosphenol O Breksa 2004)
M+ 502.2 C. reticulata (Bennett and
COOMe Hasegawa 1981)
O
O
O O
O
OH


molecular
weight
Calamin C27H36O10 Calamondin* (Manners and
O
M+ 520.57 Breksa 2004)
OH O Hasegawa 1981)
MeOOC O
O
HO OH
O
Cyclocalamin O
C27H34O9 Calamondin* (Manners and
M+ 502.2 Breksa 2004)
COOMe C. reticulata (Bennett and
O Hasegawa 1981)
O
O O
OH
O
Retrocalamin C24H30O9 Calamondin* (Manners and

O
M+ 462.3 Breksa 2004)
OH O Hasegawa 1981)
MeOOC O
O
OH
O
6-Keto-7β- C26H32O9 Calamondin* (Miyake et al.
O
deacetylnomilol M+ 488.1 1992)
OH O
O O
O
O
OH
O
Nomilinic acid C28H36O10 C. reticulata (Ozaki et al. 1991)

O
M+ 532.58 C. limon
Calamondin*
OAc O
O O
O
OH
HO O
Deacetyl nomilinic acid C26H34O9 C. reticulata (Ozaki et al. 1991)

O
C. limon
OH
M+ 490.54
O
O O
O
OH
HO O


molecular
weight
Limonin glucoside O C32H42O14 C. reticulata (Ozaki et al. 1991)
C. limon
O HO
H H M+ 650.67
O O
O
H OH
HHO H OH
O O O
O HO
Obacunone glucoside C32H42O13 C. reticulata (Ozaki et al. 1991)

O HO
M+ 634.67 C. limon
O
O
OH
COOHHO OH
O
O
O
O
Obacunoic acid C26H32O8 C. limon (Herman and

O
M+ 472.53 Hasegawa 1985)
O O
O
OH
HO O
Obacunoic acid C32H44O14 C. limon (Tian and Schwartz

O
glucoside HO M+ 652.53 2003)
O
O
OH
COOHHO OH
O
O
OH
HO O
Nomilin glucoside C34H46O15 C. reticulata (Ozaki et al. 1991)

O
M+ 694.72 C. limon
HO
OAc O
O
COOH OH
O OH
OH
O
O
O


molecular
weight
Deacetyl nomilin C32H44O14 C. reticulata (Ozaki et al. 1991)
O
glucoside M+ 652.68 C. limon
HO
OH O O
OH
O COOHHO OH
O
O
O
Nomilinic acid glucoside C34H48O16 C. reticulata (Ozaki et al. 1991)

O
HO M+ 712.74 C. limon
O O Calamondin*
OAc
OH
O COOHHO OH
O
OH
HO O
Deacetyl nomilinic acid C32H46O15 C. reticulata (Ozaki et al. 1991)

O
glucoside HO M+ 670.70 C. limon
O O
OH
OH
O COOHHO OH
O
OH
HO O
glucose concentration perfectly alleviates the oxidative damage triggered by hyperglycemia and thus could
offer a good candidate for the prohibition of the visual impairment sparked by diabetic retinopathy (Liu et
al. 2017a). Similarly, hesperidin may protect retinal ganglial cells from elevated glucose-induced damage
owing to its antioxidant properties and blockage of mitochondria-mediated apoptosis (Liu et al. 2017b).
Additionally, Apigenin is capable of diminishing glucose uptake by the cancer cells, preventing remodeling
of the extracellular matrix as well as the molecules that cause cell adhesion that in turn participate in the
dissemination of cancer in addition to prohibiting the development of blood vessels required for tumor
growths (Kowalczyk et al. 2017).
The flavonoids contain several phenolic groups, which dissociate under physiological conditions into
negatively charged phenolate ions. These phenolate ions bind with the positively charged amino groups in
proteins to form a stable ionic bond. Therefore proteins would become fixed and would lose their structural
flexibility. Also, phenylpropanoids are characterized by allylic side chain. They are lipophilic, uncharged
molecules and can cross biomembranes by free diffusion. Higher concentration of this metabolite can
influence membrane fluidity and disturb the interaction of membrane proteins with membrane lipids (Wink
1999, Wink 2008). Examples of some flavonoids and phenyl propanoids isolated from some members of
genus Citrus is represented in Table 15.2.
Table 15.2 Examples of some flavonoids and phenylpropanoids isolated from some members of genus Citrus.

molecular
weight
Polymethoxylated OMe C20H20O7 C. limon (Robards et al.
flavones- OMe 1997)
M+ 372.37 C. reticulata
Sinensetin MeO O
MeO
OMe O
Nobiletin OMe C21H22O8 C. limon (Robards et al.

OMe 1997)
OMe
MeO O
MeO
OMe O
5-Demethylnobiletin OMe C20H20O8 C. limon (Kawaii et al. 2000)

OMe M+ 388.37 C. reticulata
OMe
MeO O
MeO
OH O
Heptamethoxyflavone OMe C22H24O9 C. limon (Robards et al.

OMe M+ 432.21 C. reticulata 1997)
OMe
MeO O
MeO OMe
OMe O
Tangeretin OMe C20H20O7 C. limon (Robards et al.
MeO O
MeO
OMe O
Natsudaidain OMe C21H22O9 C. limon (Kawaii et al. 1999)
OMe M+ 418.39
OMe
MeO O
MeO OH
OMe O
Isosinensetin OMe C20H20O7 C. limon (Robards et al.
OMe
MeO O
OMe O


molecular
weight
Tetramethylscutellarein OMe C19H18O6 C. limon (Robards et al.
M+ 342.34 C. reticulata 1997)
MeO O
MeO
OMe O
Quercetogenin OMe C21H22O8 C. limon (Robards et al.

hexamethyl ether OMe M+ 402.39 C. reticulata 1997)
MeO O
MeO OMe
OMe O
Flavonoid Aglycones- OH C16H14O6 C. limon (Robards et al.
A-Flavanone OMe M+ 302.28 C. reticulata 1997)
Hesperitin
HO O
OH O
Eriodictyol OH C15H12O6 C. limon (Robards et al.
OH M+ 288.25 C. reticulata 1997)
HO O
OH O
Naringenin OH C15H12O5 C. limon (Robards et al.
HO O
OH O
Isosakuranetin OMe C16H14O5 C. limon (Robards et al.

HO O
OH O
Citflavanone OH C20H18O5 C. medica (ITO et al. 1988)
M+ 338.35
O O
OH O


molecular
weight
B-Flavone OH C15H10O6 C. limon (Kawaii et al. 1999)
OH M+ 286.24
Luteolin
HO O
OH O
Flavonols- OMe C17H14O8 C. limon (Baldi et al. 1995)
1-Limocitrin OH M+ 346.29
OMe
O
HO
OH
OH O
2-Limocitrol OMe C18H16O9 C. limon (Baldi et al. 1995)

OMe
OH M+ 376.31
HO O
MeO OH
OH O
Isolimocitrol OH C18H16O9 C. limon (Baldi et al. 1995)

OMe M+ 376.31
OMe
O
HO
MeO OH
OH O
Flavonoid glycosides- OH C28H34O15 C. limon (Robards et al.

HO
A-Flavanone glycosides- HO O OH M+ 610.56 C. reticulata 1997)
OMe
Hesperidin O
HO O O O
HO
OH
OH O
Neohesperidin OH OH C28H34O15 C. limon (Bocco et al. 1998)

O OMe M+ 610.56 C. reticulata
HO
HO O
O O
O
HO
HO OH OH O
Narirutin OH C27H32O14 C. limon (Robards et al.

HO 1997)
O M+ 580.53 C. reticulata
HO
OH
(Bocco et al. 1998)
O
HO O O O
HO
OH
OH O


molecular
weight
Naringin OH C27H32O14 C. limon (Bocco et al. 1998)
O OH M+ 580.53 C. reticulata
HO
HO O O O
O
HO
HO OH
OH O
Naringenin7-O-glucoside OH OH C21H22O10 C. limon (Baldi et al. 1995)

HO O O O M+ 434.39
HO OH
OH O
Eriocitrin OH C27H32O15 C. limon (Robards et al.

HO
M+ 596.53 1997)
HO O OH
O OH C. reticulata (Bocco et al. 1998)
HO O O
O
HO
OH
OH O
Neoeriocitrin OH OH C27H32O15 C. limon (Bocco et al. 1998)

HO O OH M+ 596.53 C. reticulata
HO
O O O
HO O
HO OH
OH O
Didymin (neoponcirin) OH C28H34O14 C. limon (Kawaii et al. 1999)

HO
HO O M+ 594.56 C. reticulata (Robards et al.
O OMe 1997)
HO OO O
HO OH
OH O
Homoeriodictyol C28H34O15 C. limon (Gil-Izquierdo et al.

7-O-rutinoside M+ 610.53 2004)
OMe
OH
HO OH
HO O
O O
HO O
O
HO
OH
OH O
B- Flavone glycosides- OH C27H30O14 C. limon (Nogata et al. 2006)

HO O OH M+ 578.52
Rhoifolin HO
O O O
HO O
HO OH
OH O
Isorhoifolin OH C27H30O14 C. limon (Kawaii et al. 1999)

HO OH
O M+ 578.52 C. reticulata
HO OO
O
HO O
HO OH O
OH


molecular
weight
Diosmin HO
HO C28H32O15 C. limon (Kawaii et al. 1999)
HO O M+ 608.54 C. reticulata
O OMe
HO O O O
HO OH
OH
OH O
Neodiosmin OH
OH C28H32O15 C. reticulata (Nogata et al. 2006)
OMe
HO
HO
O M+ 608.54
O O O
HO O
HO OH
OH O
Vicenin OH C27H30O15 C. limon (Tusa et al. 2007)

HO
M+ 594.52
OH OH
HO O
HO O
OH
HO O
HO
OH OH O
Narirutin 4´-glucoside OH C33H42O19 C. limon (Manthey and

HO HO Grohmann 2001)
OO
OH M+ 842.1 C. reticulata
HO O OH
OO O HO
HO O
HO
OH
OH O
Apigenin 7-glucoside C21H20O10 C. limon (Dugo et al. 2005)

OH M+ 432.38
OH O O
HO O
HO
OH
OH O
Diosmetin 6,8-di-C- C28H32O16 C. limon (Dugo et al. 2005)

OH
glucoside OH M+ 624.54 C. reticulata
OH
HO O OMe
HO
OH O
O OH
HO
HO
OH OH O
Luteolin 6,8-di-C- OH
OH C27H30O16 C. limon (Baldi et al. 1995)
glucoside OH
OH M+ 610.52
OH
HO O
HO O
OH
O
HO
HO OH
OH O


molecular
weight
Apigenin 6,8-di-C- HO
OH
C27H30O15 C. limon (Dugo et al. 2005)
glucoside M+ 594.52 C. reticulata
OH
HO O OH
HO O
OH
O
HO
HO OH OH O
Chrysoeriol 6,8-di-C- C28H32O16 C. limon (Gil-Izquierdo et al.

glucoside M+ 624.54 2004)
HO
OH OMe
OH OH
HO O
OH HO O
O
HO
HO OH OH O
C-Flavonol glycosides- OH C27H30O16 C. limon (Baldi et al. 1995)

Rutin OH M+ 610.52 (Nogata et al. 2006)
HO O C. reticulata
HO
OH
O
O OH
OH O O
O OH
OH
OH
Quercetin-3-O rutinoside- C33H40O21 C. limon (Gil-Izquierdo et al.

7-O glucoside OH M+ 772.66 2004)
OH OH
HO O OH
HO OH
OHO O
O OH
O
OH O O O OH
HO OH
Limocitrol 3-β C24H26O14 C. limon (Dugo et al. 2005)

D-glucoside OMe M+ 538.45
OMe OH
HO O
HO
MeO O OH
OH O O OH
HO
Isolimocitrol 3-β OH C24H26O14 C. limon (Dugo et al. 2005)

D-glucoside OMe M+ 538.45
OMe
HO O
HO
O OH
MeO O OH
HO
OH O


molecular
weight
Limocitrin 3-β OMe C23H24O13 C. limon (Dugo et al. 2005)
D-glucoside OH M+ 508.43
OMe
O
HO
HO
O OH
O OH
OH O HO
Phenolic acids- COOH C9H8O4 C. limon (Bocco et al. 1998)

Caffeic acid M+ 180.16 C. reticulata
HO
OH
P-coumaric acid COOH C9H8O3 C. limon (Bocco et al. 1998)

HO
Ferulic acid COOH C10H10O4 C. limon (Bocco et al. 1998)

HO
OMe
Sinapic acid MeO COOH C11H12O5 C. limon (Bocco et al. 1998)

HO
OMe
Valencic acid C12H14O3 C. medica (ITO et al. 1988)

M+ 206.24
O
COOH
Phenolic alcohol- C13H18O2 C. medica (ITO et al. 1988)

Etrogol M+ 206.24
O
CH2CH2OH
Biological activity of coumarins
The genus Citrus constitutes one of the highly popular genera that are very rich in oxyprenylated coumarins
(Genovese et al. 2018). Most of the isolated coumarins from genus Citrus plants were found to possess
antioxidant (Yu et al. 2005), antibacterial (Damu et al. 2005), antifungal (Ju-Ichi et al. 1988), cardiovascular
(Takeuti et al. 1991), antiplatelet (Teng et al. 1992), and antitumor effects (Berhow et al. 1994). Nordentatin
revealed a promising antibacterial activity against many microbes such as Bacillus subtilis, Bordetella
brochiseptica, Pseudomonas aeruginosa, Staphylococcus aureus, and S. lutea (Wu and Furukawa 1982).
Moreover, seselin and xanthyletin increased heart rate and slightly decreased blood pressure, moreover
seselin showed calcium blocking activity (Takeuti et al. 1991). Other biological activities such as anticancer,
antiproliferative, anti-inflammatory were also reported for some isolated coumarins (Gunatilaka et al.
1994, Garcia-Argaez et al. 2000, Kawaii et al. 2001, Murakami et al. 2005). Coumarins contain phenolic
hydroxyl group which dissociate into negatively charged ions. This ion binds to positively charged amino
acid residue in protein, the proteins would be become fixed and that might lead to loss of function. Moreover,
furanocoumarins are intercalating secondary metabolites (Wink 2008). Some coumarins isolated from a
few members of genus Citrus representatives are represented in Table 15.3.
Biological activity of sterols
The plant sterols are known to reduce the total and Low-Density Lipoprotein (LDL) (Normen et al. 1999) and
a high dietary intake might therefore improve health. Several investigators stated those sterols as β-sitosterol,
campesterol, and stigmasterol exhibited numerous biological effects, e.g., hypocholestermic, anticancer
activity against colon, breast and prostate malignant tumors, immunostimulant activity, antibacterial and
antifungal effects (Potter 1995, Awad and Fink 2000, Matvienko et al. 2002, Ju et al. 2004).
Sterols are lipophilic secondary metabolites, which can intercalate between DNA bases that lead to a
stabilization of the DNA double helix. This stabilization disturbs the activity of DNA polymerase and this
leads to frame shift mutations in the corresponding protein. In addition, sterols are lipophilic and uncharged
molecules that can cross biomembranes by free diffusion. Therefore, at higher concentrations, sterol can
influence membrane fluidity and disturb the interaction of membrane proteins with membrane lipids (Wink
2008). Most of the relevant isolated sterols from some members of genus Citrus are found in Table 15.4.
Biological activity of acridone alkaloids
Several authors reported the acridone alkaloids isolated from Citrus species exhibited antiviral, antimicrobial,
antifungal, mutagenic, antineoplastic, anti-herpes and antimalarial effects (Wolters and Eilert 1981, Yang et
al. 1987, Paulini et al. 1991). Acridone alkaloids are reported to have mutagenic and carcinogenic properties
through intercalation of DNA and related target of the organism (Wink 2008). Examples of some acridone
alkaloids isolated from some members of genus Citrus is represented in Table 15.5.
Biological activity of essential oils
Citrus essential oils are a major source for many natural flavoring materials of commercial importance.
They are widely used in beverages, candy, frozen, desserts, confectionary, pharmaceuticals, cosmetics and
perfumery industry. As a result, extensive research efforts have been directed towards analysis of these oils.
Limonene was the main constituent in mandarin peel oils (67.0%) while γ-terpinene (53.0%) and linalool
(16.1%) were the chief constituents of leaf oil (Njoroge et al. 2005, Karioti et al. 2007).
Singh et al. (1999) analyzed the chemical constituents of leaf and peel essential oil of C. medica by
HPLC, GLC and GLC-MS. Twenty four components (99.7%) of the leaf oil were identified and the main
constituents were citronellal (63.3%), citronellol (15.1%), limonene (8.0%), citronellyl acetate (5.2%),
isopulegol (1.6%), and linalool (1.3%). While thirty five components of the peel oil, which amounting
99.1% of the total identified components, and the major constituents are limonene (32.0%), citronellal
(27.5%), citronellol (13.0%), p-cymene (6.5%), geranial (2.3%), γ-terpinene (2.0%), citronellic acid (1.8%),
α-terpineol (1.2%), and linalool (1.2%) (Lota et al. 1999).
The leaf and peel essential oil of C. medica was studied and their components were investigated.
Three chemotypes- limonene, limonene/γ-terpinene and limonene/geranial/neral were observed for the
peel oil while leaf oil exhibited the limonene/geranial/neral composition. On the other hand, the peel and
leaf oils of C. limon L. were analyzed where 42 and 27 components were identified. The main constituents
of the lemon peel were limonene (70.4%), while the leaf oil consisted mainly of limonene (40.8%), and
β-pinene (18.5%) (Singh et al. 1999).
A comparative study between the volatile components of C. junos with those of C. limon have been
studied. The two oils were distinctively different. In the C. junos oil, alcohols were the second major
components (2.05%), while in the C. limon aldehydes (2.10%) and esters (0.63%) were more dominant
(Njoroge et al. 1994).
Table 15.3 Examples of some coumarins isolated from some members of genus Citrus.
Compound Structure Formula, Source References

molecular
weight
Heraclenol C16H16O6 C. limon oil (Ziegler and
M+ 304.29 Spiteller 1992)
O O O
OH
O
OH
Oxypeucedanin hydrate OH C16H16O6 C. limon oil (Ziegler and

O
OH
O O O
Byakangelicin OMe C17H18O7 C. limon oil (Ziegler and

O O O
OH
O
OH
Heraclenin C16H14O5 C. limon oil (Ziegler and

O O O
O
O
Pabulenol C16H14O5 C. limon oil (Ziegler and

OH M+ 286.28 Spiteller 1992)
O
O O O
Neobyakangelicol OMe C17H16O6 C. limon oil (Ziegler and

O O OH O
O
Oxypeucedanin C16H14O5 C. limon oil (Ziegler and

O M+ 286.28 Spiteller 1992)
O
O O O


molecular
weight
Byakangelicol OMe C17H16O6 C. limon oil (Ziegler and
O O O
O O
5-(3’-Methylbut-2’- C21H24O7 C. limon oil (Ziegler and

enyloxy)-8-(2’,3’-dihydroxy- O M+ 388.29 Spiteller 1992)
3’-methylbutyloxy)
psoralen
O O O
OH
O
OH
Imperatorin C16H14O4 C. limon oil (Ziegler and

O O O
O
8-(7’,8’-Epoxygeranyloxy) C21H22O5 C. limon oil (Ziegler and

psoralin M+ 354.12 Spiteller 1992)
O O O
O O
Phellopterin OMe C17H16O56 C. limon oil, (Ziegler and

M+ 300.31 leaves Spiteller 1992)
O O O
O
Isoimperatorin C16H14O4 C. limon oil (Ziegler and

O O O

enyloxy)-8-(2’,3’-epoxy3’- O M+ 370.12 Spiteller 1992)
methylbutyloxy)psoralen
O O O
O O


molecular
weight
Cnidicin C21H22O5 C. limon oil (Ziegler and
O O O
O C
8-Geranyloxypsoralen C21H22O4 C. limon oil (Ziegler and

O O O
O
5-Methoxy-8- OMe C22H24O5 C. limon oil (Ziegler and

geranyloxypsoralen M+ 368.40 Spiteller 1992)
O O O
O
Bergamottin C21H22O4 C. limon oil (Ziegler and

O
O O O
Aurapten C19H22O3 C. limon oil (Ziegler and

O O O
5-Geranyloxy-7- C20H24O4 C. limon oil (Ziegler and

methoxycoumarin M+ 328.40 Spiteller 1992)
O
MeO O O

enyloxy)-7- O M+ 260.29 Spiteller 1992)
methoxycoumarin
MeO O O


molecular
weight
7-(3’-Methylbut-2’-enyloxy) C14H14O3 C. limon oil (Ziegler and
coumarin M+ 230.29 Spiteller 1992)
O O O
5-(2’,3’-Epoxy-3’- O C15H16O5 C. limon oil (Ziegler and

methylbutyloxy)-7- O M+ 276.29 Spiteller 1992)
methoxycoumarin
MeO O O
5-(2’,3’-Dihydroxy- OH C15H18O6 C. limon oil (Ziegler and

3’-methylbutyloxy)-7- O M+ 294.21 Spiteller 1992)
methoxycoumarin OH
MeO O O
Citropten OMe
C11H10O4 C. limon oil (Nordby and
M+ 206.19 C. reticulata Nagy 1981,
Ziegler and
Spiteller 1992)
MeO O O
Scopoletin MeO C10H8O4 C. limon (Zobel et al.

M+ 192.17 1991)
HO O O
Osthol C15H16O3 C. limon (Nordby and

M+ 244.29 C. reticulata Nagy 1981)
MeO O O
Seselin C14H12O3 C. limon (Zobel et al.

M+ 228.24 1991)
O O C. reticulata (Nordby and
O
Nagy 1981)
Bergaptol OH C11H6O4 C. limon oil (Ziegler and

O O O
Limettin a C15H16O4 C. limon oil (Ziegler and

O
H3CO O O


molecular
weight
Limettin b C20H24O4 C. limon oil (Ziegler and
MeO O O
Xanthyletin C14H12O3 C. limon (Nordby and

Me
O O O
Me
Xanthoxyletin OMe C15H14O4 C. limon (Nordby and

Me
O O O
Me
Alloxanthoxyletin C15H14O4 C. limon (Nordby and

O M+ 258.27 C. reticulata Nagy 1981)
O O
Suberosin C15H16O3 C. limon (Nordby and

MeO O O
Braylin MeO C15H14O4 C. limon (Nordby and

O O
O
Me Me
Luvangetin C15H14O4 C. limon (Nordby and

Me
O O O
Me
OMe
Bergapten OMe C12H8O4 C. limon oil (Chouchi and
M+ 216.19 Barth 1994)
O O O


molecular
weight
Umbelliferone C9H6O3 C. limon juice (Feldman and
M+ 162.14 Hanks 1965)
HO O O
Esculetin HO C9H6O4 C. limon root, (Feldman and

M+ 178.14 leaves Hanks 1965)
HO O O
Herniarin C10H8O3 C. limon oil (Chouchi and
Barth 1994)
M+ 176.17
MeO O O
Table 15.4 Examples of some sterols isolated from some members of genus Citrus.
Compound Structure Formula, M. Wt Source References

Campesterol C28H48O C. limon (Jiménez-Escrig et al. 2006)
M+ 400.69 C. reticulata (Douglas and Sykes 1985)
HO
Stigmasterol C29H48O C. limon (Jiménez-Escrig et al. 2006)

HO
β-Sitosterol C29H50O C. limon (Jiménez-Escrig et al. 2006)

HO
Cholesterol C27H46O C. reticulata (Douglas and Sykes 1985)
M+ 386.66
HO
Table 15.5 Examples of some acridone alkaloid isolated from some members of genus Citrus.
Compound Structure Formula, molecular Source References

weight
Citracridone I Me C20H19NO5 C. limon (Chang 1990)
OMe Me
Me M+ 353
HO N O
O OH
Citrusinine I OMe Me OH C16H15NO5 C. limon (Chang 1990)

MeO N M+ 301
OH O
5-Hydroxynoracronycine Me C19H17NO4 C. limon (Chang 1990)

OH Me
Me M+ 323
N O
O OH
9(10H)-Acridinone O C13H9NO C. reticulata (Sun et al. 2007)

M+ 195
N
H
It was reported that C. reticulata and C. medica essential oils were found to exhibit a promising
fungitoxic activity with growth inhibition of 45% and 30%, respectively. C. limon and C. medica essential
oils were screened on both MCF-7 and HeLa. IC50 for HeLa cell line was 17 µg/mL and 1 μg/mL for
C. limon and C. medica, respectively. In addition, they found that C. limon had a greater cytotoxic effect
on MCF-7 than that on HeLa cells (Tripathi et al. 2008, Monajemi et al. 2010).
The antifungal efficacy, antiviral and the higher significant reduction of DPPH radicals (antioxidant)
of the mandarin oils and the activity might be related to the presence of N-methylanthranilate (Schnitzler
et al. 2008). Recently, the essential oil of Citrus lumia Risso had shown a pronounced antioxidant, anti-
cholinesterase, and neuroactive with a potent acetylcholinesterase inhibitory activity as well as anti-
cholinesterase using both cell-free in addition to cell-based assays (Smeriglio et al. 2017). Moreover,
the essential oil of Citrus aurantium L. presented a potent anxiolytic activity in cocaine users who were
subjected to Simulated Public Speaking (Chaves Neto et al. 2017).
Essential oil contains lipophilic terpenoids which can enter into the membrane of the cell and
form hydrophobic interaction with the lipophilic side chains of phospholipids or cholesterol. Higher
concentrations can influence membrane fluidity and disturb the interaction of membrane proteins with the
membrane lipids, which are important for proteins correct three dimensional conformation. Any change
in protein will modulate its activity (Wink 2008).
Conclusions
The family Rutaceae in general and genus Citrus in particular act as a natural everlasting source of
medicinally effective phytoconstituents that could be of high relevance in curing a wide array of ailments.
Undoubtedly this is attributed to their richness by several classes of active constituents comprising
limonoids, flavonoids, coumarins and essential oils. Nevertheless, more thorough phytochemical and
biological studies should be done on many of its species to discover more of its biological importance and
secondary metabolites guided by its earlier traditional popularity.
References
Andrews, A.C. 1961. Acclimatization of Citrus fruits in the Mediterranean region. Agr. Hist. 35: 35–46.
Arias, B.A. and Ramón-Laca, L. 2005. Pharmacological properties of citrus and their ancient and medieval uses in the
Mediterranean region. J. Ethnopharmacol. 97: 89–95.
Awad, A.B. and Fink, C.S. 2000. Phytosterols as anticancer dietary components: evidence and mechanism of action. J. Nutr.
130: 2127–2130.
Baldi, A., Rosen, R.T., Fukuda, E.K. and Ho, C.-T. 1995. Identification of nonvolatile components in lemon peel by high-
performance liquid chromatography with confirmation by mass spectrometry and diode-array detection. J. Chromatogr.
A. 718: 89–97.
Bennett, R. and Hasegawa, S. 1981. Limonoids of calamondin seeds. Tetrahedron. 37: 17–24.
Berhow, M.A., Bennett, R.D., Poling, S.M., Vannier, S., Hidaka, T. and Omura, M. 1994. Acylated flavonoids in callus cultures
of Citrus aurantifolia. Phytochemistry 36: 1225–1227.
Berhow, M.A., Hasegawa, S. and Manners, G.D. 2000. Citrus Limonoids: Functional Chemicals in Agriculture and Food,
ACS Publications.
Bocco, A., Cuvelier, M.-E., Richard, H. and Berset, C. 1998. Antioxidant activity and phenolic composition of citrus peel and
seed extracts. J. Agr. Food Chem. 46: 2123–2129.
Bracke, M., Bruyneel, E., Vermeulen, S.J., Vennekens, K.l., Vanmarck, V. and Mareel, M. 1994. Citrus flavonoid effect on
tumor invasion and metastasis. Food Technol. 48: 121–124.
Breksa, A.P. and Ibarra, P. 2007. Colorimetric method for the estimation of total limonoid aglycones and glucoside contents
in Citrus juices. J. Agr. Food Chem. 55: 5013–5017.
Breksa, A.P., Zukas, A.A. and Manners, G.D. 2005. Determination of limonoate and nomilinoate A-ring lactones in Citrus
juices by liquid chromatography–electrospray ionization mass spectrometry. J. Chromatograph. A 1064: 187–191.
Cai, H., Kharel, G.P. and Hashinaga, F. 1993. Changes in the limonoid content during development of citron fruit (Citrus
medica L.). J. JPN Soc. Hortic. Sci. 62: 215–220.
Chang, K. 1992. The evaluation of citrus demand and supply. Proceeding of International Society Citric. Italy 3: 1153–1155.
Chang, S.-H. 1990. Flavonoids, coumarins and acridone alkaloids from the root bark of Citrus limonia. Phytochemistry 29:
351–353.
Chaves Neto, G., Braga, J.E.F., Alves, M.F., de Morais Pordeus, L.C., Dos Santos, S.G., Scotti, M.T., Almeida, R.N.
and Diniz, M.F.F.M. 2017. Anxiolytic effect of Citrus aurantium L. in crack users. Evid.-Based Compl. Alt. 2017,
doi:10.1155/2017/7217619.
Chouchi, D. and Barth, D. 1994. Rapid identification of some coumarin derivatives in deterpenated citrus peel oil by gas
chromatography. J. Chromatogr. A 672: 177–183.
Cook, N. and Samman, S. 1996. Flavonoids—chemistry, metabolism, cardioprotective effects, and dietary sources. J. Nutr.
Biochem. 7: 66–76.
Damu, A. G., Kuo, P.-C., Shi, L.-S., Li, C.-Y., Kuoh, C.-S., Wu, P.-L. and Wu, T.-S. 2005. Phenanthroindolizidine alkaloids
from the stems of Ficus septica. J. Nat. Prod. 68: 1071–1075.
Del Caro, A., Piga, A., Vacca, V. and Agabbio, M. 2004. Changes of flavonoids, vitamin C and antioxidant capacity in minimally
processed citrus segments and juices during storage. Food Chem. 84: 99–105.
Douglas, T. and Sykes, S. 1985. Phospholipid, galactolipid and free sterol composition of fibrous roots from citrus genotypes
differing in chloride exclusion ability. Plant. Cell Environ. 8: 693–699.
Dugo, P., Lo Presti, M., Öhman, M., Fazio, A., Dugo, G. and Mondello, L. 2005. Determination of flavonoids in citrus juices
by micro-HPLC-ESI/MS. J. Sep. Sci. 28: 1149–1156.
FAO. 2006. Citrus fruit–fresh and processed, annual statistics, 2003. Commodities and Trade Division. FAO of the UN, Rome.
Feldman, A. and Hanks, R. 1965. Phenolic compounds in roots and leaves of four citrus cultivars. Nature. 207: 985–986.
Filatova, L.A.K., Y. . 1999. The significance of flavonoids from citrus juices in disease prevention. Pishchev. Promyshlen.
8: 62–63.
Garcia-Argaez, A.N., Apan, T.O.R., Delgado, H.P., Velázquez, G. and Martínez-Vázquez, M. 2000. Anti-inflammatory activity
of coumarins from Decatropis bicolor on TPA ear mice model. Planta Med. 66: 279–281.
Genovese, S., Taddeo, V.A, Epifano, F. and Fiorito, S. 2018. Prenylated coumarins of the genus Citrus: An overview of the
2006–2016 literature data. Curr. Med. Chem., doi:10.2174/0929867325666180104154443.
Gil-Izquierdo, A., Riquelme, M.T., Porras, I. and Ferreres, F. 2004. Effect of the rootstock and interstock grafted in lemon tree
(Citrus limon (L.) Burm.) on the flavonoid content of lemon juice. J. Agr. Food Chem. 52: 324–331.
Govindachari, T., Suresh, G., Gopalakrishnan, G., Masilamani, S. and Banumathi, B. 2000. Antifungal activity of some
tetranortriterpenoids. Fitoterapia. 71: 317–320.
Gunatilaka, A.L., Kingston, D.G., Wijeratne, E.K., Bandara, B.R., Hofmann, G.A. and Johnson, R.K. 1994. Biological activity
of some coumarins from Sri Lankan Rutaceae. J. Nat. Prod. 57: 518–520.
Hasegawa, S., Bennett, R.D. and Herman, Z. 1986. A limonoid from young calamondin seedlings. Phytochemistry 25:
1984–1985.
Herman, Z. and Hasegawa, S. 1985. Limonin biosynthesis from obacunone via obacunoate in Citrus limon. Phytochemistry
24: 2911–2913.
Hume, H.H. 1957. Citrus fruits. Citrus fruits. The Macmilian Company, New York, 1957.
Ishiwa, J., Sato, T., Mimaki, Y., Sashida, Y., Yano, M. and Ito, A. 2000. A citrus flavonoid, nobiletin, suppresses production
and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts. J. Rheumatol. 27: 20–25.
Ito, C., Mizuno, T., Matsuoka, M.M., Kimura, Y., Sato, K., Kajiura, I., Omura, Mitsuo, Juichi, M. and Furukawa, H. 1988.
Constituents of domestic Citrus plants. A new flavonoid and other new components from Citrus plants. Chem. Pharm.
Bull. 36: 3292–3295.
Jayaprakasha, G., Singh, R., Pereira, J. and Sakariah, K. 1997. Limonoids from Citrus reticulata and their moult inhibiting
activity in mosquito Culex quinquefasciatus larvae. Phytochemistry 44: 843–846.
Jiménez-Escrig, A., Santos-Hidalgo, A. B. and Saura-Calixto, F. 2006. Common sources and estimated intake of plant sterols
in the Spanish diet. J. Agr. Food Chem. 54: 3462–3471.
Ju-Ichi, M., Inoue, M., Ikegami, M., Kajiura, I., Omura, M. and Furukawa, H. 1988. New coumarins from Citrus funadoko.
Heterocycles 27: 1451–1454.
Ju, Y.H., Clausen, L.M., Allred, K.F., Almada, A.L. and Helferich, W.G. 2004. β-sitosterol, β-sitosterol glucoside, and a mixture
of β-sitosterol and β-sitosterol glucoside modulate the growth of estrogen-responsive breast cancer cells in vitro and in
ovariectomized athymic mice. J. Nutr. 134: 1145–1151.
Jung, U., Kim, H., Lee, J., Lee, M., Kim, H., Park, E., Kim, H., Jeong, T. and Choi, M. 2003. Naringin supplementation
lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin.
Nutr. 22: 561–568.
Karioti, A., Skaltsa, H. and Gbolade, A.A. 2007. Constituents of the distilled essential oils of Citrus reticulata and C. paradisi
from Nigeria. J. Essent. Oil Res. 19: 520–522.
Kawaii, S., Tomono, Y., Katase, E., Ogawa, K. and Yano, M. 1999. HL-60 differentiating activity and flavonoid content of
the readily extractable fraction prepared from Citrus juices. J. Agr. Food Chem. 47: 128–135.
Kawaii, S., Tomono, Y., Katase, E., Ogawa, K., Yano, M., Koizumi, M., Ito, C. and Furukawa, H. 2000. Quantitative study
of flavonoids in leaves of Citrus plants. J. Agr. Food Chem. 48: 3865–3871.
Kawaii, S., Tomono, Y., Ogawa, K., Sugiura, M., Yano, M., Yoshizawa, Y., Ito, C. and Furukawa, H. 2001. Antiproliferative
effect of isopentenylated coumarins on several cancer cell lines. Anticancer Res. 21: 1905–1911.
Khalil, A.T., Maatooq, G.T. and El Sayed, K.A. 2003. Limonoids from Citrus reticulata. Z. Naturforsch. C. 58: 165–170.
Kim, H.K., Jeong, T.-S., Lee, M.-K., Park, Y.B. and Choi, M.-S. 2003. Lipid-lowering efficacy of hesperetin metabolites in
high-cholesterol fed rats. Clin. Chim. Acta. 327: 129–137.
Kowalczyk, A., Bodalska, A., Miranowicz, M. and Karłowicz-Bodalska, K. 2017. Insights into novel anticancer applications
for apigenin. Adv. Clin. Exp. Med. 26: 1143–1146.
Ladaniya, M. 2008. Citrus fruit: biology, technology and evaluation San Diego: Academic.(p. 198).
Lam, L. K. and Hasegawa, S. 1989. Inhibition of Benzo [a] pyrene-Induced Forestomach Neoplasia in Mice by Citrus Limonoids.
Lee, L.-T., Huang, Y.-T., Hwang, J.-J., Lee, A. Y.-L., Ke, F.-C., Huang, C.-J., Kandaswami, C., Lee, P.-P. H. and Lee, M.-T.
2004. Transinactivation of the epidermal growth factor receptor tyrosine kinase and focal adhesion kinase phosphorylation
by dietary flavonoids: effect on invasive potential of human carcinoma cells. Biochem. Pharmacol. 67: 2103–2114.
Liu, W.Y., Liou, S.S. Hong, T.Y. and Liu, I.M. 2017a. The benefits of the Citrus flavonoid diosmin on human retinal pigment
epithelial cells under high-glucose conditions. Molecules, 22: doi: 10.3390/molecules22122251.
Liu, W.Y., Liou, S.S., Hong, T.Y. and Liu, I.M. 2017b. Protective effects of hesperidin (Citrus Flavonone) on high glucose
induced oxidative stress and apoptosis in a cellular model for diabetic retinopathy. Nutrients, 9: doi: 10.3390/nu9121312.
Lota, M.L., de Rocca Serra, D., Tomi, F., Bessiere, J.M. and Casanova, J. 1999. Chemical composition of peel and leaf essential
oils of Citrus medica L. and C. limonimedica Lush. Flavour Frag. J. 14: 161–166.
Mabberley, D. 2004. Citrus (Rutaceae): a review of recent advances in etymology, systematics and medical applications.
Blumea-Biodiv. Evol. Biogeogr. Plants 49: 481–498.
Mabberley, D.J. 2008. Mabberley’s plant-book: a portable dictionary of plants, their classifications, and uses, Cambridge
University Press.
Manners, G.D. 2007. Citrus limonoids: analysis, bioactivity, and biomedical prospects. J. Agr. Food Chem. 55: 8285–8294.
Manners, G.D. and Breksa, A.P. 2004. Identifying citrus limonoid aglycones by HPLC-EI/MS and HPLC-APCI/MS techniques.
Phytochem. Anal. 15: 372–381.
Manners, G.D. and Hasegawa, S. 1999. A new normal phase liquid chromatographic method for the analysis of limonoids in
citrus. Phytochem. Anal. 10: 76–81.
Manthey, J.A. and Grohmann, K. 2001. Phenols in citrus peel byproducts. Concentrations of hydroxycinnamates and
polymethoxylated flavones in citrus peel molasses. J. Agr. Food Chem. 49: 3268–3273.
Matsubara, Y., Sawabe, A. and Iizuka, Y. 1990. Structures of new limonoid glycosides in lemon (Citrus limon Burm. f.)
peelings. Agr. Biol. Chem. 54: 1143–1148.
Matsuda, H., Yoshikawa, M. and Kubo, M. 1998. Antinociceptive and anti-inflammatory activities of limonin isolated from
the fruits of Evodia rutaecarpa var. bodinieri. Planta Med. 64: 339–342.
Matvienko, O.A., Lewis, D. S., Swanson, M., Arndt, B., Rainwater, D. L., Stewart, J. and Alekel, D. L. 2002. A single daily
dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly
hypercholesterolemic men. Am. J. Clin. Nutr. 76: 57–64.
Miller, E.G., Porter, J.L., Binnie, W.H., Guo, I.Y. and Hasegawa, S. 2004. Further studies on the anticancer activity of Citrus
limonoids. J. Agr. Food Chem. 52: 4908–4912.
Miyake, M., Ozaki, Y., Ayano, S., Bennett, R.D., Herman, Z. and Hasegawa, S. 1992. Limonoid glucosides in calamondin
seeds. Phytochemistry 31: 1044–1046.
Monajemi, R., Oryan, S., Haeri-Roohani, A., Ghannadi, A. and Jafarian, A. 2010. Cytotoxic effects of essential oils of some
Iranian Citrus peels. Iran. J. Pharm. Res. 183–187.
Moodley, V.E., Mulholland, D.A. and Raynor, M.W. 1995. Micellar electrokinetic capillary chromatography of limonoid
glucosides from Citrus seeds. J. Chromatogr. A. 718: 187–193.
Murakami, A., Shigemori, T. and Ohigashi, H. 2005. Zingiberaceous and citrus constituents, 1′-acetoxychavicol acetate,
zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.
7 murine macrophages through different modes of action. J. Nutr. 135: 2987S–2992S.
Njoroge, S., Ukeda, H., Kusunose, H. and Sawamura, M. 1994. Volatile components of Japanese yuzu and lemon oils. Flavour
Frag. J. 9: 159–166.
Njoroge, S.M., Koaze, H., Mwaniki, M., Minh Tu, N. and Sawamura, M. 2005. Essential oils of Kenyan Citrus fruits: volatile
components of two varieties of mandarins (Citrus reticulata) and a tangelo (C. paradisi × C. tangerina). Flavour Frag.
J. 20: 74-79.
Nogata, Y., Sakamoto, K., Shiratsuchi, H., Ishii, T., Yano, M. and Ohta, H. 2006. Flavonoid composition of fruit tissues of
citrus species. Biosci. Biotechnol Biochem. 70: 178–192.
Nordby, H.E. and Nagy, S. 1981. Chemotaxonomic study of neutral coumarins in roots of Citrus and Poncirus by thin-layer,
gas-liquid and high-performance liquid chromatographic analyses. J. Chromatogr. A. 207: 21–28.
Normen, L., Johnsson, M., Andersson, H., Van Gameren, Y. and Dutta, P. 1999. Plant sterols in vegetables and fruits commonly
consumed in Sweden. Eur. J. Nutr. 38: 84-89.
Ortiz, J.M. 2002. Botany: taxonomy, morphology and physiology of fruits, leaves and flowers. Citrus. 16–35.
Ozaki, Y., Fong, C.H., Herman, Z., Maeda, H., Miyake, M., Ifuku, Y. and Hasegawa, S. 1991. Limonoid glucosides in citrus
seeds. Agr. Biol Chem. 55: 137–141.
Paulini, H., Popp, R., Schimmer, O., Ratka, O. and Röder, E. 1991. Isogravacridonchlorine: a potent and direct acting frameshift
mutagen from the roots of Ruta graveolens. Planta Med. 57: 59-61.
Potter, S.M. 1995. Overview of proposed mechanisms for the hypocholesterolemic. J. Nutr. 125: 606S.
Raman, G., Cho, M., Brodbelt, J.S. and Patil, B.S. 2005. Isolation and purification of closely related Citrus limonoid glucosides
by flash chromatography. Phytochem. Anal. 16: 155–160.
Reuther, W., Webber, H.J. and Batchelor, L.D. 1967. History, World Distribution, Botany, and Varieties, University of California,
Division of Agricultural Sciences.
Robards, K., Li, X., Antolovich, M. and Boyd, S. 1997. Characterisation of citrus by chromatographic analysis of flavonoids.
J. Sci. Food Agr. 75: 87–101.
Ruberto, G., Renda, A., Tringali, C., Napoli, E.M. and Simmonds, M.S. 2002. Citrus limonoids and their semisynthetic
derivatives as antifeedant agents against Spodoptera frugiperda Larvae. A structure−activity relationship study. J. Agr.
Food Chem. 50: 6766–6774.
Schnitzler, P., Schuhmacher, A., Astani, A. and Reichling, J. 2008. Melissa officinalis oil affects infectivity of enveloped
herpesviruses. Phytomedicine. 15: 734–740.
Smeriglio, A., Alloisio, S., Raimondo, F.M., Denaro, M., Xiao, J., Cornara, L. and Trombetta, D. 2017. Essential oil of Citrus
lumia Risso: Phytochemical profile, antioxidant properties and activity on the central nervous system. Food. Chem.
Toxicol. 17: 30801–30803.
Singh, G., Kapoor, I., Singh, O., Leclercq, P. and Klinkby, N. 1999. Chemical constituents of peel and leaf essential oils of
Citrus medica L. J. Essent. Oil Bear. Pl. 2: 119–125.
Sun, C., Li, X., Xu, C., Zhang, S., Chen, K., Chen, Q. and Liu, C. 2007. Determination of 9 (10 H)-Acridone by HPLC with
Fluorescence Detection. J. Liq. Chromatogr. Rel. Technol. 30: 245–254.
Takeuti, N., Kasma, T., Aida, Y., Oki, J., Maruyama, I., Watanabe, K. and T obinaga, S. 1991. Pharmacological activities
of the prenylcoumarins, developed from folk usage as a medicine of Peucedanum japonicum THUNB. Chem. Pharm.
Bull. 39: 1415–1421.
Tanaka, T., Kohno, H., Tsukio, Y., Honjo, S., Tanino, M., Miyake, M. and Wada, K. 2000. Citrus limonoids obacunone and
limonin inhibit azoxymethane-induced colon carcinogenesis in rats. Biofactors. 13: 213–218.
Tanaka, T., Maeda, M., Kohno, H., Murakami, M., Kagami, S., Miyake, M. and Wada, K. 2001. Inhibition of azoxymethane-
induced colon carcinogenesis in male F344 rats by the citrus limonoids obacunone and limonin. Carcinogenesis. 22:
193–198.
Teng, C.-M., Li, H.-L., Wu, T.-S., Huang, S.-C. and Huang, T.-F. 1992. Antiplatelet actions of some coumarin compounds
isolated from plant sources. Thromb. Res. 66: 549–557.
Tian, Q., Li, D., Barbacci, D., Schwartz, S. J. and Patil, B. S. 2003. Electron ionization mass spectrometry of citrus limonoids.
Rapid Commun. Mass Sp. 17: 2517–2522.
Tian, Q., Miller, E. G., Ahmad, H., Tang, L. and Patil, B. S. 2001. Differential inhibition of human cancer cell proliferation
by citrus limonoids. Nutr. Cancer. 40: 180–184.
Tian, Q. and Schwartz, S. J. 2003. Mass spectrometry and tandem mass spectrometry of citrus limonoids. Anal. Chem. 75:
5451–5460.
Tripathi, P., Dubey, N. and Shukla, A. 2008. Use of some essential oils as post-harvest botanical fungicides in the management
of grey mould of grapes caused by Botrytis cinerea. World J. Microbiol Biotechnol. 24: 39–46.
Tusa, N., Abbate, L., Renda, A. and Ruberto, G. 2007. Polyphenols distribution in juices from Citrus allotetraploid somatic
hybrids and their sexual hybrids. J. Agr. Food Chem. 55: 9089–9094.
Vikram, A., Jayaprakasha, G. and Patil, B.S. 2007. Simultaneous determination of citrus limonoid aglycones and glucosides
by high performance liquid chromatography. Anal. Chim. Acta 590: 180–186.
Wink, M. 1999. Functions of plant secondary metabolites and their exploitation in biotechnology, Taylor & Francis.
Wink, M. 2008. Evolutionary advantage and molecular modes of action of multi-component mixtures used in phytomedicine.
Curr. Drug Metab. 9: 996–1009.
Wolters, B. and Eilert, U. 1981. Antimicrobial substances in callus cultures of Ruta graveolens. Planta Med. 43: 166–174.
Wu, T.-S. and Furukawa, H. 1982. Biological and phytochemical investigation of Clausena excavata. J. Nat. Prod. 45: 718–720.
Yang, M.-S., Wu, T.-S. and Wang, C.-H. 1987. Citracridone-I: A new antispasmodic from root barks of Citrus depressa.
Planta Med. 53: 143–147.
Yu, J., Wang, L., Walzem, R.L., Miller, E.G., Pike, L.M. and Patil, B.S. 2005. Antioxidant activity of citrus limonoids,
flavonoids, and coumarins. J. Agr. Food Chem. 53: 2009–2014.
Ziegler, H. and Spiteller, G. 1992. Coumarins and psoralens from Sicilian lemon oil (Citrus limon (L.) Burm. f.). Flavour
Frag. J. 7: 129–139.
Zobel, A.M., Wang, J., March, R.E. and Brown, S.A. 1991. Identification of eight coumarins occurring with psoralen,
xanthotoxin, and bergapten on leaf surfaces. J. Chem. Ecol. 17: 1859–1870.
16
Pharmacological Properties of
Extracts and Compounds Isolated from
Platonia insignis Mart.—A Perspective
for Developing Phytomedicines
Antonio do Nascimento Cavalcante,1,2 Chistiane Mendes Feitosa,1,3,*
Layana Karine Farias Lima,3 Ronaldo dos Santos Sousa Júnior1 and
Ana Gabriela Sousa Alencar1
Introduction
The increasing use of plants and herbal extracts with therapeutic purposes curing or preventing several
diseases has made these plants’ extractivism an indispensable choice in national agriculture and popular or
traditional medicine. The medicines represent the support of small and medium national pharmaceuticals
industries.
Among the cultivated medicinal plants, there is a very good amount of exotic species; however, many
of the native plant species are used by the population based on chemical and pharmacological researches,
or on empirical or traditional knowledge.
Since the civilization’s earliest days, plant species have been a main source of resources enabling
accumulation and learning based on the information experience about the environment through the constant
observation of natural phenomena in order to improve the conditions of feeding and, mainly, the search
for a cure of many diseases, thus demonstrating a close relation between medicinal plants’ use and their
own evolution. There are reports existing of the use of vegetal extracts as medicines between 4500 and
1600 B.C. (Miguel and Miguel 2000, Rokaya et al. 2010, Allabi et al. 2011). Miraculous powers were
attributed to sorcerers, shamans, magicians, healers, among others who had the known—wisdom of the
power of drugs and/or poisons. Through this empirical (non-scientific) method it became possible to
accumulate knowledge about the use of medicinal plants with the purpose of prevention, treatment, and
1
Department of Chemistry, Federal University of Piauí, Ininga, 64049-550, Teresina, PI, Brazil.
2
Institute of Education, Science and Technology of Maranhão, 65760-000, Presidente Dutra, MA, Brazil.
3
Department of Pharmacy, Federal University of Piauí, 64049-550 Teresina, PI, Brazil.
* Corresponding author: chistiane@ufpi.edu.br
cure of several diseases; being a referential and inexhaustible source of new compounds in the search for
phytomedicines (Corrêa et al. 2003, Leonti et al. 2010).
Until the 19th century, therapeutic resources were constituted predominantly by plants and their
extracts. These last ones represented homemade medicine used at that time. The use of these extracts for
therapeutic purposes were anchored in popular and scientific knowledge. In this context, medicinal plants
were used in many ways and in different forms such as: isolated active substances suppliers, such as total
extracts, purified or selected extracts, as a drug in the preparation of infusions or decoctions (Simões
et al. 2000).
In this matter, Brazil stands out as a country with great research potential on plant species, since it has
the largest and richest biodiversity on the planet (Nascimento 2013). One medicinal plant family that has
aroused a great interest of the scientific community due to the promising chemical and biological properties
is the family Clusiaceae (Noldin et al. 2006, Nualkaew et al. 2012). This family comprises approximately
1000 subordinated species to 47 genera, distributed in tropical and subtropical climate regions of the planet
and a genus that reaches temperate regions. Of these genera, nine have about 90 species that are edible
(Barroso et al. 2002, Costa Júnior 2011a). Furthermore, many of these species are widely used in popular
medicine for pain treatment, infection, inflammation, and ulcer control (Noldin et al. 2006).
Regarding chemosystematics, plants belonging to this family are mainly composed by the following
secondary metabolites: coumarins, xanthones, steroids, triterpenes and flavonoids; these natural metabolites
have led to great interest from several researchers, especially from the medical field, since many of these
substances are endowed with important biological activities. Many of these natural metabolites have
shown some activities such as antidepressant, antioxidant, antifungal, cytotoxic, anti-HIV and antibacterial
(Monache et al. 1988, Gustafson et al. 1992, Noldin et al. 2006, Costa Júnior 2011a).
Studies about the chemical composition of the family Clusiaceae’s plants have shown that they are
also rich in polyisoprenylated benzophenones (Costa Júnior 2011a).
This chapter describes Platonia insignis Mart. including its economic importance. In addition, it
makes a general overview on the biological-pharmacological properties as well as the main constituents
found in this plant.
Platonia insignis Mart. (bacurizeiro)

The bacurizeiro is a plant species that belongs to the family Clusiaceae, subfamily Clusioideae and Platonia
genus. It is a monotypic species, classified as Platonia insignis Mart. (Braga 1976). It is composed of 1000
species and 47 genera distributed in tropical and subtropical regions of the world. The term Platonic is an
Platan’s attribute, a Greek philosopher, and insignis, means notable, significant, important, great, in other
words, something that draws much attention, in reference to the physical structure and utility of the plant,
as well as its size, flavor, and fruit aroma (Barroso et al. 2002, Moura et al. 2007).
The bacurizeiro is a large fruit tree, with a height from 15 to 25 meters and a diameter up to 100 cm
(Cavalcante 1988). This tree is native to the Amazon region of Brazil and Guyana, but is also found in
Colombia and Paraguay, always occurring in open undergrowth areas, clearings and, mainly, secondary
vegetation, rarely found in dense primary forest (Cavalcante 1988, Mourão and Beltrati 1995, Chitarra
and Chitarra 2005, Fontenele et al. 2010). In Brazil, the dissemination center is the state of Pará, where a
wide range of fruit shape, size, pulp yield and quality is found, besides other characteristics of economic
interest; it can also be find in the states of Maranhão, Mato Grosso, Piauí and Goiás (Ferreira et al. 1987,
Silva and Donato 1993, Villachica et al. 1996, Aguiar et al. 2008). In the state of Piauí, the bacurizeiro
is found in limited lands to the north in the cities of Murici dos Portelas, Amarante and Palmeirais. It is
commonly known as “bacuri”, “bacuri-açu”, “pakoori”, and “wild mamme aple” in Guyana, “pakoelie” and
“geelhart” in Suriname, “parcori” in French Guiana and “matazona” in Ecuador (Mourão and Beltrati 1995).
The bacuri is a large fruit bacurizeiro, round, with a thick rind and it has a yellowish color as it can
be observed in Fig. 16.1, inside the bark there is pulp, which has a whitish color, being viscous with very
pleasant odors and flavors (Fontenele et al. 2010). The fruit shows great potential, not only from the point
of view of its industrial processing, in ice cream preparation, creams, soft drinks, jams and jellies; but also
for in nature consumption (Silva et al. 2010). When it is in the process of ripening, it exudes a soft and
fragrant odor and is rich in terpenes (Calvazara 1970, Alves and Jennings 1979).
Pharmacological Properties of Extracts and Compounds Isolated from Platonia insignis Mart. 273
Fig. 16.1 Fruits and seeds of P. insignis Mart. Source: Adapted by Costa Júnior 2011a.
In general, the number of seeds per fruit is from one to five, with predominance from two to four
seeds (Villachica et al. 1996). In abnormal cases, fruits containing up six seeds can be find (Mourão 1992)
or, in other cases without seeds (Calzavara 1970). According to Teixeira et al. (2005), bacuri is a non-
climacteric fruit, which means that it only ripens when bound to the plant and in most trees, the fruits fall
when ripe, so that harvesting fruits consists of collecting them from the soil (Fao 1987). The expression
“bacuri” is from Tupi origin which means: “to fall” and curi: “soon”, in other words, it only falls when
it matures, indicating that it has ripened completely. After this phase, they do not improve their sensorial
and nutritional characteristics, although a slight softening and loss of green color can be noticed (Nagy
et al. 1990, Souza et al. 2001).
In Brazil the pulp has a very pleasant odor and taste, which is popularly accepted, both in the “in
nature” way and in the preparation of sweetmeats, pies, jams, juices, jellies, and ice creams. The shell can
also be used to make sweetmeats, creams, and ice creams, increasing fruit yield, and consequently adding
values. This process must occur after the separation of the existing resin from this part of the fruit (Aguiar
2006). The growing demand for the fruit has stimulated producers to establish growing areas. The seeds of
bacuri fruit have no utility in food, however, they can be used in the production of soap or the production
of bacuri grease. The oil extracting process occurs with great difficulty once the seeds are soaked in water
for more than a year and then boiled, the oil being removed from the surface of the boiling water. The
bacuri butter makes the skin look golden, within a few minutes after its application, it is absorbed and the
skin is left with a velvety touch, besides removing spots, and diminishing scars (Ferreira 2008, Moraes
and Gutjahr 2009, Costa Júnior 2011a).
Pharmacological activities of Platonia insignis Mart.

Species from the family Clusiaceae such as P. insignis Mart. (bacurizeiro) are important medicinal plants
used in Brazilian popular medicine, mainly for eczema, herpes, gastrointestinal diseases, dermatitis,
schistosomiasis, leishmaniasis and malaria treatments. Studies involving the biological-pharmacological
properties of this species can be seen in literature and most of these studies are especially focused on the
seeds vegetal extracts of P. insignis Mart. Vegetal extracts or fats have shown important pharmacological
activities such as: anti-inflammatory, antimalarial, antihypertensive, antidiabetic, immunomodulatory-
respiratory, antiviral, antitumor, antidepressant, anti-allergic, anti-mutagenic and anti-oxidant effects
(Bilanda et al. 2010, Costa Júnior et al. 2013a). In addition, these extracts are widely used in popular
medicine for the treatment of various diseases such as: diarrhea, skin problems, earaches, spider and
snakes’ bites, rheumatism, arthritis and even as healing (Moraes and Gutjahr 2009, Costa Júnior et al.
2013a, Costa Júnior et al. 2013b).
The “bacuri grease” obtained from the seeds oil is commonly used in popular medicine as healing for
burns and in the treatment of dermatological diseases (Agra et al. 2007). In vivo assays demonstrated its
potential to accelerate the healing of rats’ skin wounds (Santos et al. 2013, Feitosa et al. 2016). Popularly,
the seeds’ decoction is used for diarrhea treatment, while the seed`s oil is used both against spider and
snakes’ bites and in the treatment of skin problems, otitis, rheumatism, and arthritis (Agra et al. 2008,
Mendes et al. 2014).
Pharmacological studies demonstrated that the ethyl acetate fraction from the P. insignis Mart. seeds
have anticonvulsant activity potential in rats induced by pilocarpine (Costa Júnior et al. 2011b).
Through the leishmanicide property of the P. insignis Mart. seeds’ extracts a patent order was requested
(Citó et al. 2011), based on hexane activities, dichloromethane and ethyl acetate, and especially in isolated
tautomerics substances, garcinielliptona FC (GFC) (Fig. 16.2), which presented a potential leishmanicidal
activity against the Leishmania amazonensis promastigotes forms (Costa Júnior et al. 2013a, 2013b).
Studies analyzing the toxicological profile of GFC in animals, after the administration of Swiss mice
treated by oral and intraperitoneal ways, showed that it did not produce toxic effects as evidenced by the
absence of toxicity or mortality signs in the animals during the experimental period. However, a study by
Prado et al. (2017) investigating the cytotoxic, genotoxic, and mutagenic effects of GFC, showed that GFC
concentrations above 50 μg mL–1 were cytotoxic during the experimental time. No GFC concentration was
mutagenic or genotoxic in the salmonella/microsome and comet assays.
The in vitro anti-oxidant property of bacuri has been commonly reported through the loss of
free radicals. This exhibits a possible protective action against the appearance and/or development of
degenerative processes associated with several types of diseases (Rufino et al. 2010, Vieira et al. 2011,
Costa Júnior et al. 2013a).
The research conducted by Santos Júnior et al. (2010) allows us to suggest a potential healing activity
for the P. insignis Mart. seeds oil in their experiments using “bacuri grease” to heal cutaneous wounds
in the dorsal region of rats. The results showed that the lard was efficient in the treatment and the treated
animals showed considerable re-epithelialization.
Mendes (2013) tested the healing activity of a pasty pharmaceutical formulation containing the
compound 1,3-distearyl-2-oleyl glycerol (TG1) (Fig. 16.3), a triglyceride isolated from the hexanic extract
of P. insignis Mart. seeds in Wistar rats. Macroscopic and histological analysis of the mice’s wounds treated
with the cream containing TG1 demonstrates a possible healing activity of the compound.
In studies performed by Mendes et al. (2014), the ethyl acetate fraction of the ethanolic extract from
the bark of bacuri promoted a powerful hypotensive effect, related to α-adrenergic receptors.
Evaluating the in vitro anti-oxidant potential of P. insignis Mart. hexanic extract and its β-cyclodextrin
inclusion complex against lipid peroxidation (2-thiobarbituric acid–TBARS formation inhibition); removing
hydroxyl radical, and nitrite radical production in vivo inhibition, both extract and inclusion complex could
inhibit lipid peroxidation by reducing the amount of TBARS, of hydroxyl radical and nitrite production
(Nascimento et al. 2015).
Results reported by Costa Júnior et al. (2013b) indicated that the ethyl acetate and dichloromethane
fractions of P. insignis ethanolic extract showed antioxidant activities in vitro, measured by 2,2’-azino-
bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vivo
Fig. 16.2 Chemical structure of the garcinielliptona tautomerics (1/1a). Molecular structures were drawn with ChemDraw13
(Perkin Elmer).
Fig. 16.3 Chemical structure of 1,3-distearyl-2-oleoyl glycerol molecular structures were drawn with ChemDraw13. (Perkin
Elmer).
assays, measured by protective effects against H2O2-induced cytotoxicity in Saccharomyces cerevisiae

stranins; leishmanicidal effect and genotoxicity in V79 cells where the compounds α-mangostin and γ-
mangostine are responsible for these actions.
Other biological activities of P. insignis Mart. seeds reported in the literature are antimicrobial, against
Saccharomyces cerevisiae strains; cytotoxicity in Artemia salina; genotoxic effect on Chinese hamster
lung fibroblasts (V79); pilocarpine-induced anticonvulsive effect; healing; anti-inflammatory activity and
stimulatory effect on mice’s Central Nervous System (CNS) (Costa Júnior et al. 2010, Santos Júnior et
al. 2010, Costa Júnior et al. 2011a, 2011b, 2011c, Costa Júnior et al. 2013a, 2013b). Table 16.1 lists the
biological activities described in the literature for all parts of the bacuri fruit.
Table 16.1 Biological activities of the bacuri fruit parts.
Part Biological activities References

Seeds Diarrhea, skin problem, Moraes and Gutjahr 2009, Costa Junior et
Earaches; Spider, snakes and insect bites; al. 2010, Santos Júnior et al. 2010, Costa
Rheumatism and arthritis; Healing; leishmanicidal Júnior et al. 2013a, 2013b, Costa Júnior et
activity; Antioxidant; Anti-inflammatory; al. 2011a, 2011b
cytotoxicity in Artemia salina; genotoxic effect on
Chinese hamster lung fibroblasts; Anticonvulsive
effect induced by pilocarpine; Protective effect,
reducing lipid peroxidation; Anticonvulsive
activity; CNS stimulatory effect in mice
Pulp Antioxidant activity Rufino et al. 2010
Trunk bark Eczema treatment, herpes virus and dermatitis Shanley and Medina 2005
treatment
Fruit peel Hypotensive activity Mendes et al. 2014
Source: Adapted from Klenicy et al. 2014
Chemical composition of Platonia insignis Mart.

The P. insignis Mart. is a vegetal species composed mostly of terpenes, xanthones and phenols. Thus, the
interest of this species has aroused the food industry due the potential of its biological activities found
(Yamaguchi et al. 2014). The Platonia genus is quite abundant in several natural substances (metabolites)
such as xanthones (euxanthones), fatty acids, and triacylglycerols (Hilditch and Pathak 1949, Roberts
1961, Bentes et al. 1986).
Research on P. insignis fruit pulp detected the ascorbic acid (1) of Fig. 16.4 and the presence of
polyphenols as the main bioactive compounds (Clerici and Carvalho-Silva 2011). The xanthones class
is responsible for several pharmacological properties of great importance, such as: antitumor, anti-
HO
OH
O
O OH (2)
OH
(1)
OH
O O O O OH
OH O
OH O
(4)
(3)
OH
OH O OH
OH
HO
O
(6)
(5)
O O
OH OH
(7) (8)
O O
OH
OH
(9) (10)
O
O
O
OH O
O
(11)
O O
(12)
HO O
(13)
O
OH
(14)
Fig. 16.4 contd.…
…Fig. 16.4 contd.
O
O O OH O O O
HO O OH O OH
OH
(16)
(15)
O OH
H3CO
HO O OH
(17)
Fig. 16.4 Shows some of the P. insignis Mart. (Bacurizeiro) constituents chemical structures.
inflammatory, antithrombotic, antimicrobial and neuropharmacological effects, thus inducing the formation
of neurites in nervous tissue (Mak et al. 2000, Ha et al. 2006).
The search for components with active biological activities of the family Clusiaceae, Costa Júnior
et al. (2011b) investigated bioactive components of P.insignis seeds and isolated tautomerics compounds
from a polyisoprenylated benzophenone, garcinielliptona (1/1a) (Fig. 16.2). These substances have been
identified by spectroscopic methods. Another isolated compound from the same P. insignis seed extract
was the triacylglyceride, 1,3-distearyl-2-oleyl glycerol (Fig. 16.3). The fruit of this species is also rich in
β-carotene (2) (Rodriguez-Amaya et al. 2008).
Phytochemical studies of pericarp hexanic extracts and bacupari seeds, Garcinia brasiliensis (species
from the same bacuri family), methanolic extract showed, respectively, the presence of prenylated
benzophenones, 7-epiclusianonae (3) and guttiferone-A (4). Both vegetal extracts and isolated compounds
were pointed out as potential herbal remedies for diseases caused by gram negative microorganisms
(Naldoni et al. 2009). The acylphloroglucinol substance, which is a polyclenyl polycyclic isolated from
the Clusiaceae family, has aroused the interest of many researchers, because this substance presents an
important range of pharmacological properties: antimicrobial (Oliveira et al. 1999), leishmanicide (Pereira
et al. 2010), antidepressant (Cuesta-Rubio et al. 2002), antioxidant (Cuesta-Rubio et al. 2002, Ciochina and
Grossman 2006, Chen et al. 2010), cytotoxic (Baggett et al. 2005), antiretroviral (Piccinelle et al. 2005),
anti-inflammatory (Weng et al. 2004) and antitumoral (Zeisser-Labauébe et al. 2006, Henry et al. 2009).
Studies on the bacuri pulp identified the presence of chemical constituents with antioxidant proprieties
such as vitamins C (ascorbic acid), vitamin E (tocopherols), flavonoids, anthocyanins, and polyphenols,
also, the presence of glutamine and glutamic acid (as major aminoacids). Saccharides (glucose, fructose and
sucrose) and metals (Na, K, Ca, Mg, Fe, Zn and Cu) were observed in higher amounts than those found in
Amazon region fruits, such as araçá-boi and cupuaçu (Rogez et al. 2004, Rufino et al. 2010). The analysis
of volatile compounds studies of P. insignis Mart. showed the presence of terpene alcohols, linalool being
the the most abundant (5) (Alves and Jennings 1979, Boulanger et al. 1999, Rogez et al. 2004, Franco
and Janzantti 2005). P. insignis shells showed a high euxanthone content (6) (1.3%), a yellow crystalline
substance with melting point 240°C that undergoes sublimation easily (Roberts 1961).
In phytochemical studies of seeds lipid fractions of P. insignis Mart. confirmed the presence of fatty
acids such as palmitic acid (7) (44.2%), palmitoleic (8) (13.2%), stearic (9) (2.3%), oleic (10) (37,8%) and
linoleic (11) (2.5%), besides 10% tripalmitin (12), indicating it is a good alternative for the oil industry
(Bentes et al. 1986).
In the P. insignis Mart. low polarity fraction detected the presence of cauran and labdane diterpenes
skeletons, caura-16-ene (13) and E-labda-8 (20), 13-diene-15,19-dioic acid (14), respectively. These
diterpene skeletons are normally associated with pharmacological activities, since there are antibacterial
and anti-inflammatory activities reports for some diterpenes, such as those found in copaiba (Copaifera
sp.) and Eperua species fixed oils and resins (Leandro et al. 2012). In the medium polar fraction, analyzed
by Gas Chromatography coupled to Mass Spectrometer (GC-MS), detected the presence of the xanthones:
1,3,5,6-tetrahydroxy-2,2-(2-methylbut-3-en-2-yl)-7-(3-methylbut-2-enyl)-xanthen-9-one (15) (Gamma-
mangostin), associated with 1-hydroxy-3,5,6-trimethoxyxanthen-9-one (16) and 1,3,6-trihydroxy-7-
methoxy-2,8-bis- (3-methylbut-2-enyl)-xanthen-9-one (17) (Costa Júnior et al. 2012).
The volatile substances present in P. insignis are basically concentrated on the shell. Through the shell
supercritical fluid extraction, the following compounds were detected: fatty acids: palmitic, oleic, linoleic,
linolenic, stearic, caprylic and myristic; the alcohols found were: linalool, 3,7-dimethyl-oct-1-ene-3,7-
diol and terpineol; in addition to linalool oxide; eugenol ether; the following hydrocarbons: bisabolene,
2-methylheptane and nonacosane, as well as trimethyl citrate (Monteiro et al. 1997).
Table 16.2 shows the pharmacological properties of P. insignis Mart. main bioactive compounds.
Figure 16.4 shows some of the P. insignis Mart. (Bacurizeiro) constituents chemical structures.
Table 16.2 Pharmacological properties of P. insignis mart. Main bioactive compounds.
Bioactive compounds Pharmacological Properties References

Xanthones Antitumoral Roberts 1961
Anti-inflammatory Mak et al. 2000
Antithrombotic Ha et al. 2006
Antimicrobial
Neuropharmacological
Fatty acids Accelerates healing Calder 2003
Cardoso et al. 2004
Hatanaka and Curi 2007
Costa Júnior et al. 2011a
Acylphloroglucinol Antimicrobial Oliveira et al. 1999, Cuesta-Rubio et al.
Polycyclic Leishmanicide 2002, Baggett et al. 2005
polyprenylated Antidepressant Pereira et al. 2010
Antioxidant Ciochina and Grossman 2006
Cytotoxic Chen et al. 2010
Euxantone Antiretroviral Piccinelli et al. 2005
Anti-inflammatory Weng et al. 2004
Antitumoral Zeisser-Labouebe et al. 2006
Pro-oxidant effect on DNA Henry et al. 2009
Wu et al. 2008
Garcinielliptona FC Anti-inflammatory Harborne et al. 1999
Vasodilator Fang et al. 2006
Neurrite promoter Ha et al. 2006
In vitro antioxidant action by TBARS Naidu et al. 2007
methods, hydroxyl radicals (OH) Costa Júnior et al. 2013a, Costa Júnior et
sequestration and nitric oxide (NO) al. 2011a
Cytotoxic activity
Leishmanicide
TG1 Acetylcholinesterase enzyme inhibitory Santos 2012, Feitosa et al. 2016, Mendes
action 2013
Healing
Source: Adapted from Santos et al. 2013

Anticholinesterase activity test

The inhibition of the acetylcholinesterase enzyme, AChE, a key enzyme in the acetylcholine degradation,
serve as a strategy for various neurodegenerative diseases treatment such as Alzheimer’s Disease (AD).
There are some synthetic and natural rivastigmine-based medicine for the cognitive dysfunction and memory
loss associated with AD treatment. These compounds have been known for an adverse effect, including
gastrointestinal problems and disorders, associated with their bioavailability, which requires in finding
more efficient acetylcholinesterase enzyme (AChE) inhibitors from natural resources (Mukherjee et al.
2007). AD is related to cognitive deficit and memory retention due to the cholinergic neurotransmission
disjunction, another efficient treatment for this disease is based on the acetylcholine levels increase from
the acetylcholinesterase (AChE) enzyme inhibition, that is the cholinergic hypothesis.
In the same context, the search for new AChE inhibitors present in natural products, such as P. insignis
Mart. extracts, which may have fewer side effects to be used as phytotherapies in the future, has increased.
One of the frequently used assays to detect the anticholinesterase activity is the Ellman assay. Ellman
et al. (1961) developed an assay through a photometric method which is able to measure the AChE activity
in natural products, tissues extract, homogenates, cell suspensions, among others. The AChE use stands
out as one of the fastest and most sensitive bioassays to select samples with anticholinesterase action.
The enzyme qualitative inhibition test is performed on silica gel chromatoplate. Caffeine and isolated
substances or extracts in five concentrations are applied on the plate (positive standard) (image A of
Fig. 16.5). The eluents used are: chloroform-methanol (9:1) (image B of Fig. 16.5). The plates are
sprayed with a solution formed by mixing a 10 mL Tris (hydroxymethyl methane) buffer pH 8, 2,9 mg of
acetylcholine iodide and 4 mg of 5,5’-dithiobis (2-nitrobenzoic acid) (image D of Fig. 16.5). After drying
the plate, the AChE enzyme with concentration of 5 U mL–1 is sprayed. A positive result for the AChE
(anticholinesterase activity) inhibition is obtained from the yellow chromatoplate with white halos (image E of
Fig. 16.5), and it was necessary to proceed with this enzyme quantitative inhibition test.
Fig. 16.5 Ellman assays for TLC (A) sample application and positive pattern, (B) sample sowing, (C) sample eluted, (D)
sample spray, (E) positive result of cholinesterase activity.
The AChE activity measurement can be performed according to the Ellman Method (1961) modified
by Ingkaninan et al. (2001) for Thin Layer Chromatography (TLC). The principle of this method is the
thiocholine production ratio measurement when the acetylthiocholine iodide substrate is hydrolyzed
by the AChE. When thiocholine reacts with 5,5’-Dithiobis-2-nitrobenzoic acid (DTNB) produces the
yellowish anion 5-thio-2-nitrobenzoate (Fig. 16.6). The yellow color production ratio is measured in a
spectrophotometer (405 nm) or visualized in thin TLC by white spots on a yellow field. Alzheimer’s disease
is related to neurotransmitter acetylcholine decrease.
Fig. 16.6 Formation of the 5-thio-2-nitrobenzoate yellow anion resulting from the reaction between a thiocholine and the
5,5’-dithiobis-2-nitrobenzoate ion.
Conclusion
In the extract and isolated substances of Platonia insignis Mart. (bacurizeiro) phytochemical and
pharmacological studies demonstrated that this species is a potential promising source for elaboration
of possible drugs. Some of the pharmacological properties that were found in this plant’s extract and
isolated compounds were anti-inflammatory, antioxidant, anticonvulsive, healing and anticholinesterase.
These characteristics are important for the preparation of drugs from this medicinal plant. In its chemical
composition, bacuri presents classes of terpenes, xanthones and phenolic compounds as major constituents.
Some of these classes of compounds present biological activities related to the ethnopharmacological use
and activities found.
Thus, interest is aroused in the food industry for bacuri due to the potential biological-pharmacological
activities found.
References
Agra, M.F., Freitas, P.F. and Barbosa-Filho, J.M. 2007. Synopsis of the plants known as medicinal and poisonous in Northeast
of Brazil. Braz. J. Pharmacogn. 17: 114–40.
Agra, M.D.F., Silva, K.N., Basílio, I.J.L.D., Freitas, P.F.D. and Barbosa-Filho, J.M. 2008. Survey of medicinal plants used in
the region Northeast of Brazil. Braz. J. Pharmacogn. 18(3): 472–508.
Aguiar, L.P., Figueiredo, R.W., Alves, R.E., Maia, G.A. and Souza, V.A.B.D. 2008. Physical and physico-chemical
characterization of fruits from different genotypes of bacuri (Platonia insignis Mart.). Food Sci. Technol. 28: 2.
Aguiar, L.P. 2006. Quality and potential use of bacurís (Platonia insignis Mart.) From the Mid-North region. 122 p. Masters
dissertation. Fortaleza-CE, Brazil.
Alves, S.M. and Jennings, W.G. 1979. Volatiles composition of certain Amazonian fruits. Food Chem. 4: 149–159.
Allabi, A.C., Busia, K., Ekanman, V. and Bakiono, F. 2011. The use of medicinal plants in self-care in the Agonlin region of
Benin. J. Ethnopharmacol. 133: 234–243.
Barroso, G.M., Peixoto, A.L., Ichaso, C.L.F., Costa, C.G., Guimarães, E.F. and Lima, H.C. 2002. Sistemática de Angiospermas
do Brasil Minas Gerais: Viçosa, p. 309.
Baggett, S., Protiva, P., Mazzola, E.P., Yang, H., Ressler, E.T., Basile, M.J., Weinstein, I.B. and Kennelly, E.J. 2005. Bioactive
Benzophenones from Garcinia xanthochymus Fruits. J. Nat. Prod. 68: 354–360.
Bentes, M.H.S., Serruya, H., Rocha Filho, G.N., Godoy, R.L.O., Silva Cabral, J.A. and Soares Maia, J.G. 1986. Chemical
study of bacuri seeds. Acta Amazon. 16: 363–368.
Bilanda, D.C., Dimo, T., Dzeufiet Djomeni, P.D., Bella, N.M.T., Aboubakar, O.B.F., Nguelefack, T.B., Tan, P.V. and
Kamtchouing, P. 2010. Antihypertensive and antioxidant effects of Allanblackia floribunda Oliv. (Clusiaceae) aqueous.
Boulanger, R., Chassagne, D. and Crouzet, J. 1999. Free and bound components of Amazonian fruits.1: Bacuri. Flavour Frag.
J. 14: 303–311.
Braga, R. 1976. Plantas medicinais do Nordeste, especialmente do Ceará: Mossoró: ESAM.
Calder, P.C. 2003. Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients. Braz.
J. Med. Biol. Res. 36: 433–446.
Calzavara, B.B.G. 1970. Fruteiras: abieiro, abricozeiro, bacurizeiro, biribazeiro, cupuaçuzeiro. IPEAN, Séries Culturas da
Amazônia, Belém. 63–68.
Cardoso, C.R.B., Souza, M.A., Ferro, E.A.V., Favoreto, J.R. and Pena, J.D.O. 2004. Influence of topical administration of n-3
and n-6 essential and n-9 nonessential fatty acids on the healing of cutaneous wounds. Wound Repair Regen. 12: 235–243.
Carvalho, J.E.U., Nascimento, W.M.O. and Muller, C.H. 1998. Características físicas e de germinação de sementes de espécies
frutíferas nativas da Amazônia. Belém: Embrapa-CPATU, (Boletim de Pesquisa, 203), p. 18.
Cavalcante, P.B. 1988. Frutas comestíveis da Amazônia. 4. ed. Belém: Museu Paraense Emílio Goeldi. 48–50.
Chitarra A.B. and Chitarra, M.I.F. 2005. Pós-colheita de frutos e hortaliças: Glossário. Lavras, UFLA, p. 256.
Chen, X.Q., LI, Y., Cheng, X., Wang, K., He, J., Pan, Z.H., Li, M.M., Peng, L.Y., Xu, G. and Zhao, Q.S. 2010. Polycyclic
polyprenylated acylphloroglucinols and chromone O-glucosides from Hypericum henryi subsp. Uraloides. Chem.
Biodivers. 7: 196–204.
Clereci, M.T.P.S. and Silva, L.B.C. 2011. Nutritional bioactive compounds and technological aspects of minor fruits grown
in Brazil. Food Res. Int. 44: 1658–1670.
Ciochina, R. and Grossman, R.B. 2006. Polycyclic polyprenylated acylphloroglucinols. Chem. Rev. 106: 3963–86.
Citó, A.M.G., Costa Junior, J.S., Santana, L.C.L.R., Freitas, R.M., Carvalho, F.A.A., Ferraz, A.B.F. and Saffi, J. 2011. Seeds oil
activity of Platonia insignis Mart. as leishmanicide. Brasil. Patent: Industrial model. Registration number: PI1101608-6,
deposit date: 04/15/2011.
Corrêa, A.D., Batista, R.S. and Quintas, L.E. 2003. Plantas Medicinais: do cultivo à terapêutica-contém formulação e modo
de preparo de cosméticos. Petrópolis: Vozes. 6. Petrópolis-RJ, p. 103.
Costa Júnior, J.S., Feitosa, C.M., Citó, A.M.G.L., Freitas, R.M., Henriques, J.A.P. and Saffi, J. 2010. Evaluation of effects of
ethanolic extract (EE) from Platonia insignis Mart. on pilocarpine-induced seizures. J. Biol. Sci. 10: 747–753.
Costa Junior, J.S., Ferraz, A.B.F., Filho, B.A.B., Feitosa, C.M., Citó, A.M.G.L., Freitas, R.M. et al. 2011a. Evaluation of
in vitro antioxidant effects of garcinielliptona fc (GFC) isolated from platonia insignis Mart. J. Med. Plants Res. 5: 293–299.
Costa Júnior, J.S., Almeida, A.A.C., Tomé, A.R., Citó, A.M.G.L., Saffi, J. and Freitas, R.M. 2011b. Evaluation of possible
anticonvulsant effects of ethyl acetate fraction from Platonia insignis Mart. on epilepsy models. Epilepsy Behav. 22:
678–684.
Costa Júnior, J.S., Ferraz, A., Feitosa, C.M., Citó, A.M.G.L., Saffi, J. and Freitas, R.M. 2011c. Evaluation of effects of
dichloromethane fraction from Platonia insignis Mart. on pilocarpine-induced seizures. Braz. J. Pharmacogn. 21:
1104–1110.
Costa Júnior, J.S., Ferraz, A.B.F., Sousa, T.O., Silva, R.A.C., Lima, S.G., Feitosa, C.M., Citó, A.M.G.L., Freitas, R.M., Sperotto,
A.R.M., Peres, V.F., Moura, D.J. and SAFFI, J. 2012. Investigation of biological activities of dichloromethane and ethyl
acetate fractions of Platonia insignis Mart. seed. Basic Clin. Pharmacol.
Costa Junior, J.S., Almeida, A.A.C., Ferraz, A.B.F., Rossato, R.R., Silva, T.G., Silva, P.B.N., Militão, G.C.G., Citó, A.M.G.L.,
Santana, L.C.L.R., Carvalho, F.A.A. and Freitas, R.M. 2013a. Citotoxic and leishmanicidal properties of garcinielliptone
FC, a prenylated benzophenone from Platonia insignis. Nat. Prod. Res. 27: 470–474.
Costa Júnior, J.S., Ferraz, A.B.F., Sousa, T.O., Silva, R.A.C., Lima, S.G., Feitosa, C.M., Citó, A.M.G.L., Cavalcante, A.A.C.M.,
Freitas, R.M., Speroto, A.R.M., Peres, V.F., Moura, D.J. and Saffi, J. 2013b. Investigation of biological activities of
dichloromethane and ethyl acetate fractions of Platonia insignis Mart. seed. Basic Clin. Pharmacol. 112: 34–41.
Cuesta-Rubio. O., Frontana-Uribe, B.A., Ramirez-Apan, T. and Cardenas, J. 2002. Polyisoprenylated benzophenones in cuban
propolis; biological activity of nemorosone. Z. Naturforsch. C 57: 372–378.
Ellman, G.L., Courtney, D.K. and Andres, V. Jr. 1961. Featherstone, R.M. A new and rapid colorimetric determination of
acetylcholinesterase activity. Biochem. Pharmacol. 7: 88–95.
Fao. 1987. Especies forestales productoras de frutas y otros alimentos. Ejemplos de América Latina. Roma: SIDA. 167–170.
Fang, L.H., Um, Y.M., Lin, L.L., Xiao, P.G. and Du, G.H. 2006. Vasorelaxant effect of eu-xanthone in the rat thoracic aorta.
Vasc. Pharmacol. 45: 96–101.
Feitosa, C.M., Cavalcante, A.N., Chaves, S.K.M. and Araújo, L.S. 2016. Medicinal plants of Brazil and Alzheimer’s disease:
Evolution in traditional use and pre-clinical studies. Asian J. Biomed. Pharm. Sci. 6: 01–13.
Ferreira, F.R., Ferreira, S.A.N. and Carvalho, J.D.U. 1987. Espécies frutíferas pouco exploradas, com potencial econômico
e social para o Brasil.
Ferreira, M.S.G. 2008. Manejo da espécie Platonia insignis Mart – Bacurizeiro, em florestas secundárias da Amazônia
Oriental: proposta para uma produção sustentável. doctoral thesis, Centro de Desenvolvimento Sustentável, University
of Brasília, Brasília, DF. Brazil, p. 246.
Fontenele, M.A., Figueiredo, R.W., Maia, G.A., Alves, R.E., Sousa, P.H.M.D. and Souza, V.A.B.D. 2010. Conservação pós-
colheita de bacuri (Platonia insignis Mart.) sob refrigeração e embalado em PVC. Rev. Ceres, Viçosa. 57: 292–296.
Franco, M.R.B. and Janzantti, N.S. 2005. Aroma of minor tropical fruits. Flavour Frag. J. 20: 358–371.
Gustafson, K.R., Blunt, J.W., Munro, M.H.G., Fuller, R.W., Mckee, T.C., Cardellina II, J.H., Mcmahon, J.B., Cragg, G.M. and
Boyd, M.R. 1992. Theguttiferones, HIV-inhibitory benzophenones from Symphonia globulifera, Garcinia livingstonei,
Garcinia ovalifolia, and Clusia rosea. Tetrahedron 48: 10093–10102.
Ha, W.Y., Wu, P.K., Kok, T.W., Leung, K.W., Mak, N.K., Yue, P.Y.K., Ngai, S.M., Tsai, S.N. and Wong, R.N.S. 2006.
Involvement of protein kinase C and E2F-5 in euxanthone-induced neurite differentiation of neuroblastoma. Int. J.
Biochem. Cell B. 38: 1393–1401.
Harbone, J.B., Baxter, H. and Moss, G.P. 1999. Phytochemical dictionary: a handbook of bioactive compounds from plants.
2. ed. London: Taylor & Francis, p. 893.
Hatanaka, E. and Curi, R. 2007. Ácidos graxos e cicatrização: uma revisão. Braz. J. Pharm. Sci. 88: 53–58.
Henry, G.E., Campbell, M.S., Zelinsky, A.A., Liu, Y., Bowen-Forbes, C.S., Li L., Nair, M.G., Rowley, D.C. and Seeram, N.P.,
2009. Bioactive acylphloroglucinols from Hypericum densiflorum. Phytother. Res.: PTR. 23: 1759–1762.
Hilditch, T.P. and Pathak, S.P.S. 1949. The component glyceride of Bacury (Platonia Insignis Mart.) seed fat. J. Chem. Soc.
1949: 87–90.
Inghaninan, K., Bes, C.M., Van Der Heijden, R., Hofte, A.J.P., Karabatak, B., Irth, H., Rhee, I.K., Van De Meent, M., Ingnaninan,
K. and Verpootte, R. 2001. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer
chromatography in combination with bioactivity staining. J. Chromatogr. A 915: 217–223.
Klenicy, K.L., Yamaguchi, C.V.L.P., Lima, E.S. and Veiga Júnior, V.F. 2014. Química e farmacologia do bacuri (Platonia
insignis). Sci. Amazon. 3: 39–46.
Leandro, L.M. and Veiga Júnior, V.F. 2012. O gênero Eperua Aublet: uma revisão. Sci. Amazon. 1: 14–22.
Leonti, M., Cabras, S., Weckerlec, C.S., Solinas, M.N. and Casu, L. 2011. The causal dependence of present plant knowledge
on herbals—Contemporary medicinal plant use in Campania (Italy) compared to Matthioli (1568). J. Ethnopharmacol.
130: 379–391.
Mak, N.K., Li, W.K., Zhang, M., Wong, R.N.S., Tai, L.S., and Yung, K.K.L. 2000. Effects of euxanthone on neuronal
differentiation. Life Sci. 66: 347–354.
Mendes, C.S.M. 2013. Delineamento de um fitomedicamento a partir de 1,3-diestearil-2-oleil-glicerol isolado de Platonia
insignis Mart: avaliação da atividade cicatrizante. Masters dissertation-Pharmaceutical Sciences. Federal University of
Piaui-. Teresina-Brazil, 80 p.
Mendes, M.B., Silva Filho, J.C., Sabino, C.K.B., Arcanjo, D.D.R., Sousa, C.M.M., Costa, I.C.G., Chaves, M.H., Oliveira,
R.C.M. and Oliveira, A.P. 2014. Pharmacological evidence of α2-adrenergic receptors in the hypotensive effect of
Platonia insignis Mart. J. Med. Food 17: 1079–1085.
Miguel, M.D. and Miguel, O.G. 2000. Desenvolvimento de Fitoterápicos. 1ª Ed. Robe editorial.
Monache, F.D., Monache, G.D., Moura Pinheiro, R. and Radics, L. 1988. Nemorosonol, a derivative of tricyclo-[4.3.1.03,7]-
Decane-7-hydroxy-2,9-dione from Clusia nemorosa. Phytochemistry 27: 2305–2308.
Monteiro, A.R., Meireles, M.A., Marques, M.O.M. and Petenate, A.J. 1997. Extraction of the soluble material from the shells
of the bacuri fruit (Platonia insignis Mart) with pressurized CO2 and other solventes. J. Supercrit. Fluid. 11: 91–102.
Moraes, R.L.B. and Gutjahr, E. 2009. Química de Oleogenosas - Valorização da Biodiversidade Amazônica. German Technical
Cooperation Agency.
Moura, M.C.C.L., Homma, A.K.O., Menezes, A.J.E.A., Carvalho, A.C.P.P., Ferreira, A., Benbadis, A.K., Muller, C.H.,
Ferreira, C.A.P., Cruz, C.D., Araujo, E.C.E., Matos, G.B., Almeida, H.J., Carvalho, J.E.U., Costa, J.T.A., Araújo, J.R.G.,
Macarenas, K.M., Vasconcelos, L.F.L., Aloufa, M.A.I., Martins, M.R., Innveco, R. and Souza, V.A.B. 2007. Bacuri:
Agrobiodiversidade. São Luís: Interamerican Institute for Cooperation on Agriculture. 210 p.
Mourão, K.S.M. and Beltrati, C.M. 1995. Morfologia dos frutos, sementes e plântulas de Platonia insignis Mart. (Clusiaceae).
I. Aspectos anatômicos dos frutos e sementes em desenvolvimento. Acta Amazon. 25: 11–32.
Mourão, K.S.M. 1992. Morfologia e desenvolvimento dos frutos, sementes e plântulas de Platonia insignis Mart. (Clusiaceae)
Platonia insignis Mart. (Guttiferae). Master’s dissertation – Institute of Biology, Universidade Estadual Paulista, Rio
Claro-Brazil.
Nagy, S., Shaw, P.E. and Wardowski, W.F. 1990. Fruits of tropical and subtropical origin. Composition, properties and uses.
Florida Science Source, Inc. ISBN 0944961002.
Naidu, M., Kuan, C.Y.K., Lo, W.L., Raza, M., Tolkovsky, A., Mak, N.K., Wong, R.N.S. and Keynes, R. 2007. Analysis of
the action of euxanthone, a plant-derived compound that stimulates neurite outgrowth. Neuroscience 148: 915–924.
Naldoni, F.J., Claudino, A.L.R., Cruz Jr, J.W., Chavasco, J.K., Faria e Silva, P.M., Veloso, M.P. and Santos, M.H. 2009.
Antimicrobial Activity of Benzophenones and Extracts from the Fruits of Garcinia brasiliensis. J. Med. Food 12: 403–407.
Nascimento, J.N. 2013. Complexo de inclusão do extrato hexânico de Platonia insignis Mart e β-ciclodextrina: caracterização
e avaliação das atividades gastroprotetora e antioxidante in vitro. 137 p. Masters dissertation – Centro de Ciências da
Saúde, Federal University of Piaui, Teresina, Brazil.
Noldin, V.F., Isaias, D.B. and Cechinel Filho, V. 2006. Gênero Calophyllum: importância química e farmacológica. Quim.
Nova 29: 549–554.
Nualkaew, N., Morita, H., Shimokawa, Y., Kinjo, K., Kushiro, T., Deeknamkul, W., Ebizuka, Y. and Abe, I. 2012. Benzophenone
Synthase from Garcinia Mangostana L. Pericarps. Phytochemistry 77: 60–69.
Oliveira, C.M.A., Porto, A.L.M., Bittrich, V. and Marsaioli, A.J. 1999. Two polyisoprenylated benzophenones from the floral
resins of three Clusia species. Phytochemistry 50: 1073–1079.
Pereira, I.O., Marques, M.J., Pavan, A.L.R., Codonho, B.S., Barbiéric, L., Beijo, L.A., Doriguetto, A.C., D’martín, E.C. and
Santos, M.H. 2010. Leishmanicidal activity of benzophenones and extracts from Garcinia brasiliensis Mart. fruits.
Phytomedicine 17: 339–345.
Pccinelli, A.L., Cuesta-Rubio, O., Chica, M.B., Mahmood, N., Pagano, B., Pavone, M., Barone, V. and Rastrelli, L. 2005.
Structural revision of clusianone and 7-epi-clusianone and anti-HIV activity of polyisoprenylated benzophenones.
Tetrahedron 61: 8206–8211.
Roberts, J.C. 1961. Naturally occurring xanthones. Chem. Rev. 61: 591–605.
Rodriguez-Amaya, D.B., Kimura, M., Godoy, H.T. and Amaya-Farfan, J. 2008. Updated Brazilian database on food carotenoids:
Factors affecting carotenoid composition. J. Food Compos. Anal. 21: 445–463.
Rogez, H., Buxant, R., Mignolet, E., Souza, J.N.S., Silva, E.M. and Larondelle, Y., 2004. Chemical composition of the pulp
of three typical Amazonian fruits: araça-boi (Eugenia stipitata), bacuri (Platonia insignis) and cupuaçu (Theobroma
grandiflorum). Eur. Food Res. Technol. 218: 380–384.
Rokaya, M.B., Munzbergová, Z. and Timsina, B. 2010. Ethnobotanical study of medicinal plants from the Humla district of
western Nepal. J. Ethnopharmacol. 130: 485–504.
Rufino, M.S.M., Alves, R.E., Brito, E.S., Pérez-Jimenez, J., Saura-Calixto, F. and Mancini-Filho, J. 2010. Bioactive compounds
and antioxidant capacities of 18 non-traditional tropical fruits from Brazil. Food Chem. 121: 996–1002.
Santos, P.R.P. 2012. Estudos farmacológicos e ensaios pré-clínicos com 1,3-diestearil-2-oleil-glicerol (TG1) derivado de
Platonia insignis Mart. 95 p. Master’s dissertation – Centro de Ciências da Saúde, Federal University of Piaui, Teresina-
Brazil.
Santos, P.R.P., Carvalho, R.B.F., Costa Junior, J.S., Freitas, R.M. and Feitosa, C.M. 2013. Survey of physicochemical and
pharmacological properties of extracts and compounds isolated from Platonia insignis Mart. a perspective for developing
phytomedicines. Braz. J. Pharm. 94: 161–168.
Shanley, P., Medina, G. 2005. Frutíferas e Plantas Úteis na Vida da Amazônica. Belém: CIFOR, Imazon.
Santos Júnior, R.Q., Soares, L.C., Maia Filho, A.L.M., Araújo, K.S., Santos, I.M.S.P., Costa Júnior, J.S. and Saffi, J. 2010.
Histologic study of skin of wounds healing using the cream of bacuri (Platonia insignis Mart.). Conscient. Saude
9: 575–581.
Silva, S. and Donato, H. 1993. Frutas do Brasil. São Paulo, Imprensa de Arte e Projetos e Edições Artísticas, p. 50.
Silva, V.K.L., Figueiredo, R.W., Brito, E.S., Maia, G.A., Sousa, P.H. and Figueiredo, E.A.T. 2010. Stability of the bacuri pulp
(Platonia insignis Mart.) frozen for 12 months. Sci. Agrotechnol. 34.
Simões, C.M.O., Schenkel, E.P., Gosmann, G., Mello, J.C.P., Mentz, L.A. and Petrovick, P.R. 2000. Farmacognosia: Da planta
ao medicamento. 2ed. Porto Alegre/Florianópolis. 221–320.
Souza, V.A.B.D., Araújo, E.C.E., Vasconcelos, L.F.L. and Lima, P.S.D.C. 2001. Variability of physical and chemical fruit
characteristics of bacury germplasm from mid-north region of Brazil. Braz. Mag. Fruit Cult. 23: 677–683.
Teixeira, G.H.A. 2000. Frutos do bacurizeiro (Platonia insignis Mart.): caracterização, qualidade e conservação. 106 p. Master
dissertation - Faculdade de Ciências Agrárias e Veterinárias de Jaboticabal, Universidade Estadual Paulista, Jaboticabal.
Vieira, L.M., Sousa, M.S.B., Mancini-Filho, J. and Lima, A. 2011. Total phenolics and antioxidant capacity “in vitro” of
tropical fruit pulps. Braz. Mag. Fruit Cult. 33: 888–897.
Villachica, H., Carvalho, J.E.U., Muller, C.H., Diaz, S.C. and Almanza, M. 1996. Frutales y hortaliças promossoras de la
Amazônia. Lima, Tratado de Cooperación Amazônica. Secretaria Pró-Tempore. 152–156.
Yamaguichi, K.K.L., Pereira, C.V.L., Lima, E.S. and Veiga Júnior, V.F. 2014. Chemistry and pharmacology of Bacuri (Platonia
insignis). Sci. Amazon. 3: 39–46.
Weng, J.R., Tsao, L.T., Wang, J.P., W, R.R. and Lin, C.N. 2004. Antiinflammatory phloroglucinols and terpenoids from
Garcinia subelliptica. J. Nat. Prod. 67: 1796–1799.
Wu, C.C., Lu, Y.H., Wei, B.L., Yang, S.C., Won, S.J. and Lin, C.N. 2008. Phloroglucinols with prooxidant activity from
Garcinia subelliptica. J. Nat. Prod. 71: 246–250.
Zeisser-Labouebe, M., Lange, N., Gurny, R. and Delie, F. 2006. Hypericin-loaded nanoparticles for the photodynamic treatment
of ovarian cancer. Int. J. Pharm. 326: 174–181.
Index
A Experimental design 233, 236

Extractive practices 69, 73, 83, 84
Action mechanism 52
Adesmia boronioides 89, 91, 98 G
Adverse effects 78
Africa 105, 106, 123 Genetic diversity 73, 74
Agro-technology Research 213
Alkaloids 204, 205, 210, 211 H
Anthelmintic 37, 38, 41, 43
Herbal drugs 233
Anticancer/antitumor properties 4, 5, 8, 25–27
herbal medicine 38, 43, 179–182, 185, 186, 189, 191, 192,
Anti-inflammatory and antioxidant effects 280
195
antilithiatic herbal drug 220
Hypericaceae family 105, 106
Arunachal Himalayas 204, 208
Hypertension 47–52
B
I
Bangladesh 156–158
in vitro models 235, 238
bilharzias 35, 38
Indians 56, 59–63
bioactivity evaluation 235
bioassay 223, 224
K
Biological activity 241, 243, 244, 258, 259
biological model 234, 235 Khyang 156–160, 167, 169, 173
biological properties 105 kidney stone 217–219, 224, 226
Biomedical applications 136
Brazil 56, 58, 59, 61, 67 M
C mathematical model 236, 237

Medicinal applications 75
calcium oxalate crystal 218, 225 Medicinal plants 47–49, 51, 52, 156, 157, 159, 160, 169,
Cancer 3–9, 12–16, 18–23, 25–29 173, 233, 234
Cardiovascular diseases 177, 178 Medicinal/aromatic plants 4
Central America 106 Molecular Markers 72–74
Central Nervous System 56, 57, 60, 61, 63, 65, 66
chemical composition 105 N
chemical diversity 100
Chromosomes 72, 73 neglected tropical disease 35
Citrus 240–245, 251, 252, 258–260, 265, 266
P
cultural context 57, 58
Curcuma longa 136–138, 141, 142, 145, 149 Patagonia 89–91, 94, 96, 99, 100, 101
Curcumin 136–149 Patents 79–81, 83, 84
Cytogenetic 72 Pharmacological activity 273, 278, 280
pharmacology 58, 64
D Phenolic Compounds 206, 207
Dose-response curves 237 phytochemicals 157, 169–172
Phytochemistry 241
E Pigment 78, 79, 82, 83
Plant extracts 271
essential oils 89, 90, 93–101 Plant material 233–235, 238
Ethnobotanical uses 4, 8, 9, 14, 15, 29 Platonia insignis Mart 271–273, 275, 280
Ethnomedicinal 136, 189–200 praziquantel 37, 38
Ethnopharmacology 56–58, 231, 233, 234, 238 primary health care 189, 191, 198, 200
propagation 90, 100, 101 T

purification 217, 218, 220, 223
Terpenoids 204–206, 210
R Toxicity 78, 82, 83
traditional medicine 178–183, 186, 233
rat aorta 235, 238 Turmeric 136–138, 142, 143, 145, 149
Rural Livelihood Security 213
Rutaceae 240, 241, 243, 266 U
S Urolithiasis 217–220, 224–226
Schistosoma 35, 36, 41–43 V

schistosomiasis 35–39, 41, 43
Scientific validation 5, 8, 15, 29 Venezuela 105, 107, 108, 126–128, 130
Secondary Metabolites 202–205, 207–210, 212, 213 Vismia genus 105, 106, 109, 111, 113–122, 125, 131, 132
shamanism 58–60, 62, 63
W
South America 105, 106
spices 177, 179, 181, 183, 186 Wood exploitation 79
sub-Saharan Africa 35
Z
Zimbabwe 35–38, 43
Editors’ Biography
Professor José L. Martinez

Professor José Luis Martinez is a chemical biologist and did his MSc from the Pontifical
Catholic University of Chile. He works at the Vice-Rectory for Research, Development
and Innovation of the University of Santiago, Chile. He is the author and co-author of
scientific articles in pharmacology and ethnobotany and has a hundred presentations in
conferences at national and international scientific events. He is the editor and founder of
the Latin American and Caribbean Bulletin of Medicinal and Aromatic Plants (BLACPMA)
and is also the Editor of other journals and scientific research books.
Professor Amner Muñoz-Acevedo

Professor Amner is PhD in Chemistry and teaches in the Department of Chemistry and
Biology at Universidad of the North Colombia, with wide experience in studies of natural
products (plants/microorganisms—volatile/non-volatile secondary metabolites) based
on ethnomedicine, organic synthesis, in vitro biological assays (antioxidant capacity,
cito-toxicity/anticancer, antimicrobial, repellency/insecticidal, antiviral activities),
functionalized beverages and food, sustainable uses of agroindustrial wastes, sample
preparation techniques (HD, SPME, S-HS, SDE, SFE, SPE, Soxhlet, US, LLE) and
instrumental methods of chemical analysis (TLC, GC, LC, MS, NMR, IR, UV/Vis). He
has authored/co-authored several papers and delivered lectures at national/international
scientific events.
Professor Mahendra Rai

Professor Rai is a senior professor and Basic Science Research Faculty (UGC) at the
Department of Biotechnology, Sant Gadge Baba Amravati University, Maharashtra,
India. He has been Visiting Scientist in the University of Geneva, Debrecen University,
Hungary; University of Campinas, Brazil; Nicolaus Copernicus University, Poland.
VSB Technical University of Ostrava, Czech Republic, and National University of
Rosario, Argentina. He has published more than 380 research papers in national and
international journals. In addition, he has edited/authored more than 45 books and 6
patents.

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Section I: Applications of Ethnomedicinal Plants

Section II: Ethnopharmacology

Cancer: general aspects

600 521 522 522

Text mining about cancer, medicinal plants and scientific validation

Traditional drugs used as therapeutical agents against cancer

Scientific validation of medicinal plants ethnobotanically recognized by

Benth. BDF1 mice.

Another interesting species is R. mucosa (Annonaceae, common name: anonillo or cherimoya),

Development of anticancer/antitumor drugs from chemical constituents of

Medicinal plant Patent code Title IPC classifications Asignees Date

Table 1.2 contd. ...

Medicinal plant Patent code Title IPC classifications Asignees Date

Table 2.1 Schistosomiasis control in Zimbabwe.

Control model Relevant notes

Potential of herbal medicines in treating and managing schistosomiasis in

Table 2.2 contd. ...

Terminalia brachystemma Welw. Combretaceae Shrub Roots Ndamba et al. 1994

Table 2.3 contd. ...

Future research and conclusion

Ethnobotanical studies and hypertension

Blood pressure control by medicinal plants

Ethnopharmacology: approaches and cultural context

Indigenous people and shamanism

Plants used in Central Nervous System disorders by Brazilian Indians

Tonics and/or adaptogens 40

...Table 4.1 contd.

Plants used by indigenous communities cited in the literature and

Number of Species with possible action on the Central Nervous System

Table 4.2 contd. ...

Number of Species with possible action on the Central Nervous System

ISA - Instituto Socioambiental. Povos Indígenas no Brasil. Available at: https://pib.socioambiental.org/pt/c/0/1/2/populacao-

Taxonomy and morphological features of G. americana L.

Origin and geographical distribution of G. americana

Phylogenetic studies on Genipa and G. americana

Folk medicinal applications

Ethnobotanical indication Plant part used Form of use Category1 Reference(s)

Adverse effects and toxicity analyses

Genipap fruit as food and source of raw material

Genipap as a source of pigments

Patents associated to G. americana

Table 5.2 Non-medicinal uses of G. americana reported in the literature.

Sector Plant part Uses and applications Source

Patent # Title Description Inventor Deposited in

Table 5.3 contd.…

Patent # Title Description Inventor Deposited in

Conservation, cultivation and extractive practices

Conclusions and future perspectives

Botanical and ecological information of the species

Generalities of the Adesmia genus

Fig. 6.3 A. boronioides distribution map. Neri, A. and Gastaldi, B.

Popular uses of paramela

Other local uses

Essential oil composition of A. boronioides

Fig. 6.5 Biosynthesis of Esquelenone (González 2002).

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