NPC Natural Product Communications Pharmaceutical, Ethnopharmacological, Phytochemical and Synthetic Importance of Genus Aerva: A Review 2018 Vol. 13 No. 3 375 - 385 Sara Musaddiqa*, Kiran Mustafaa, Sajjad Ahmadb, Samina Aslama, Basharat Alic, Samia Khakwania, Naheed Riazb, Muhammad Saleemb and Abdul Jabbarb a Department of Chemistry, Kutchehry Campus, The Women University Multan, Multan 60000, Pakistan Department of Chemistry, Baghdad-ul-Jadeed Campus, The Islamia University of Bahawalpur, 63100, Bahawalpur, Pakistan c Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 63100, Pakistan b drsara.chem@wum.edu.pk Received: November 22nd, 2017; Accepted: January 23rd, 2018 Aerva plants are known widely for their exceptional medicinal uses. They have been employed conventionally for their medicinal properties by the common folk in several regions of the world. This indicates the efficacy of these remarkable herbs. They are also known for their multiple biological activities such as antioxidant, antibacterial, antilithiatic, hepatoprotective, antidiabetic, anticancer, antihyperlipidemic and nephroprotective potential. These pharmacological actions are associated with the presence of valuable nutrients and biochemical compounds such as sterols/terpenes, flavonoids, alkaloids, phenolics and sugars. The proper utilization of the substances obtained from these plants can enhance the finesse of the capabilities of these plants. These plants are not only medicinally important but are significantly serving several other scientific purposes. In the prospect of medicinal, scientific uses and the bioavailability of precious chemicals of Aerva species, a comprehensive review is compiled, which focuses on the detailed profile of biochemical compounds, pharmacological functions and biological activities of Aerva plants. The review also discusses the synthetic importance and the toxicity of these plants. The study aims to compile comprehensively what is already done and what more is needed to be done in the future investigations related to Aerva species. Keywords: Aerva plants, Biological activities, Antilithiatic, Hepatoprotective, Ecdysteroids, Flavonoid glycosides, Coumarins, Nanoparticles, Toxicity. Abbreviations: ABTS, 2, 2′-Azinobis-3-ethylbenzothiazoline-6-sulfonic acid; CTL, Cytotoxic T-lymphocyte; DLA, Dalton lymphoma ascites; DPPH, 2, 2Diphenyl-1-picrylhydrazyl;DW, Dry weight; EAC, Ehrlich ascites carcinoma; FRAP, Ferric reducing antioxidant power; GAE, Gallic acid equivalent; GAO, Glycolic acid oxidase; HPLC, High-performance liquid chromatography; HPTLC, High performance thin layer chromatography; LDH, Lactate dehydrogenase; MIC, Minimum inhibitory concentration; MSUM, Monosodium Urate Monohydrate; NIDDM, Non-insulin dependent diabetes mellitus; NK, Natural killer; OGTT, Oral glucose tolerance test; TEAC, Trolox equivalent antioxidant capacity. Introduction Aerva plants of the family Amaranthaceae are perennial herbs with salient morphological characters. They constitute prostrate to erect stem, alternate branches and leaves with entire margins, hermaphrodite flowers, oval or oblong perianth, membranous and margined sepals. Flowers usually bear five stamens which are shortly monadelphous at the base, single pendulous ovule containing ovary with slender and distinct short style. Two stigmas are present which are short to long and thread like. The seeds are compressed which are reniform, firm and black [1].The Aerva plants are distributed in temperate regions of Africa and Asia. Reported species are given in the (Table 1) [2]. Table 1: Reported specie of the Genus Aerva. Reported Species A. artemisioides A. japonica A. sanguinolenta A. cordata A. lanata A. timorensis A. congesta A. leucura A. triangularifolia A. coriacea A. madagassica A. scandens A. edulis A. microphylla A. sericea A. elegans A. monsonia A. tomentosa A. glabrata A. persica A. villosa A. humbertii A. radicans A. wightii A. javanica A. revoluta Traditional uses: The Aerva species are known to be used in folk medicine system against several diseases. For example; A. tomentosa finds its uses as a demulcent, diuretic and as purgative. Its seeds and flowers are used for the treatment of headache, rheumatism and swelling [3-4]. A. lanata is a medicinally very important member of the genus. It is also commonly known as “mountain knot grass” and is used as, astringent, suppurative and cough reducer by the villagers of Thoppampatti, Dindigul district, Tamilnadu, India [5]. This plant is known as “polpala” in Sri Lanka and is used for different medical purposes [6]. In Guimaras Island, Philippines, it is known as “Buti-buti” and is used to treat fatigue, child sleeplessness and malaise [7]. A decoction of the whole plant is used as a diuretic by the people of district Udhampur, J&K, India [8]. Paunsia is another name for A. lanata in Kalahandi district, Odisha. Its roots are traditionally used against cough, congestion of liver, painful urine discharge, jaundice and headache [9]. In the Southern part of Nigeria, leaves of this plant are used for the treatment of sickle cell diseases. The common name of the herb in the area is Bhadrm and cherula wherein some native areas it is also known as eweowo, furfurata and fatumi [10]. It is reported that the plant is also used to treat kidney stones [11], as an antiinflammatory agent, for burn wounds and skin ailments. It also possesses uterus clearing activity after the childbirth, besides, it also found effective in the treatment of nasal bleedings, fractures, scorpion stings and bronchitis [12]. Another important member of the genus is A. persica. The common people use the plant for its diuretic and demulcent capabilitie; its decoction is employed for the cure of swellings and urinary ailments. Different parts of the plant such as leaves, roots and seeds 376 Natural Product Communications Vol. 13 (3) 2018 Musaddiq et al. Table 2: Biological activities associated with different parts of Aerva plants. Parts Used A. javanica Flowers Leaves Fruits Activities References Enzyme inhibition Antidiabetic, Antibacterial Antiplasmodial Antiulcer 19 20 21 22 52 Antioxidant 24 Antihyperlipidimic Antimicrobial Anti lithiatic Antidiabetic Anti lithiatic Anti-oxidant Hepatoprotective Antihyperglycemic Anti-hyperlipidimic Anti lithiatic Antimicrobial 32 24 55 31 55, 56 27 43 33 34 56 37 A. lanata Aerial parts Roots Leaf Whole Plant Anti-oxidant Hepatoprotective Immunomodulatory Anti-tumor activity Nephroprotective activity Anti-diuretic Enzyme inhibition Antiplasmodial A. persica Roots A. sanguinolenta Aerial parts 25 41 45,46 49 40 60 61 Antiulcer 53 Antioxidant Antidiabetic 28 28 Antimicrobial Antioxidant 29 30 A. tomentosa Whole plant are used in the treatment of kidney stones [13]. The roots of the plant A. javanica, are chewed for cleaning of teeth; the seeds are used for relieving the headache and rheumatism. The roots paste is applied directly on the face to cure acne [14]. The decoction of its aerial parts is used as a laxative by the pastoralists of the area [15]. This plant is also found in the District Lakki Marwat of Pakistan where it is also used for stomach disorders and as anti- flatulent [16]. Juice, paste and decoction of this plant is used orally as a medicinal herb against diabetes, as a blood purifier and as a diuretic and it is used as topical medication against ringworm, scabies and skin diseases [17]. The plant is also known as Booh in Thar desert of Pakistan. Its decoction, powder, extract, and poultice is used for the treatment of several diseases such as piles, hemorrhoids, snakebites and jaundice. It is also given to cancer patients and to the pregnant women during childbirth [18]. Pharmacological Studies: Aerva species are widely studied because of their pharmacological abilities. A Literature review has shown that varying activities of the plant of this genus are associated with different extracts of these plants (Table 2). Antioxidant activity: Antioxidant substances are found in different natural sources like plants and micro-organisms [23]. Different species of Aerva are also reported to show antioxidant activities. Aqueous and metabolic extract of the aerial parts of A. lanata exhibited significant antioxidant activity[24]. According to another study aqueous extract of A. lanata inhibited 2,2-diphenyl-1picrylhydrazyl (DPPH) radical with an IC50 value of 110.74 µg/mL and showed metal chelating activity with IC50 of 758.17 µg/mL [25]. ABTS and FRAP assays also assessed antioxidant potential of same plant with the antioxidant activity of 2.43 mM TEAC/100 g DW and 0.88 µM/g DW in both assays respectively [26]. In a study conducted in Sri Lanka, the antioxidant capacity of this plant is determined in terms of mean standard deviation which came out to be 7.54 ± 0.17 per mg of ascorbic acid which is equivalent to per gram dry weight of leaves. The total carotene of the herb was also determined in terms of mean standard deviation which comes out to be 1.17 ± 0.04 per mg of ascorbic acid which is equivalent to per gram dry weight of leaves [27]. Not much work has been done on other Aerva species and in this regard only a few reports are available. According to a study antioxidant potential is associated with ethyl acetate and chloroform extracts of aerial parts of A. sanguinolenta [28] and ethanolic and methanolic extracts of whole plant of A. tomentosa where the potent antioxidant activity of this specie has been attributed to the total phenolics. The same report also explains the structure activity relationship of total phenolics and antioxidant activity in comparison to the other extracts having phenolics constituents [29-30]. Antidiabetic activity: Antidiabetic potential of partially purified alkaloid basified toluene fraction PPABTF of methanolic root extract of A. lanata was assessed in Type-II NIDDM diabetic rats which exhibited significant antihyperglycemic activity. This fraction showed improvement in parameters like body weight and lipid profile as well as regeneration of β-cells of the pancreas [31]. Further, A. lanata’s alcoholic extract is found to be useful in controlling the increased blood sugar levels in mice [32]. The extract of leaves of the same plant was studied on serum glucose and OGTT. The results showed anti-hyperglycemic activity at the dosage of 400mg/kg [33]. In addition to the above activities, the extracts of aerial parts of A. lanata in methanol and water could sufficiently reduce glucose level of blood in rats with streptozotocin induced diabetes. A reduction in the amount of lipids was also seen in the similar experiment indicating anti-hyperlipidemic activity of the extracts of A. lanata [34].In a comparative study, it was noticed that A. lanata polysaccharide has greater hypoglycemic activity as compared to that of A. javanica which may be attributed to the difference in complexity of their structures [35]. A. javanica leaves have shown activity against alloxan induced diabetes in rats [20], whereas, ethyl acetate and chloroform extracts of aerial parts of A. sanguinolenta also exhibited mild anti diabetic activity [28]. Antimicrobial activity: Various studies have been conducted on assessment of the antimicrobial potential of Aerva species e.g., aqueous and alcoholic extracts of different plant parts of A. persica were also found active against S. typhi and S. aureus [36]. Further, an investigation of methanolic extract of aerial parts of A. lanata showed inhibition zone of 13.2 ± 0.5, 28.8 ± 0.2,30.6 ±0.9mm against P. aeruginosa, B. subtilis and S. aureus, respectively [24]. In another study, the whole plant ethyl acetate extract of A. lanata showed better activities at 200µg/disc with zone of inhibitions 18, 16, 13 and 12 (mm) against S. dysenteriae, B. cereus, E. coli and S. shiga respectively [37]. The ethyl acetate extract of endophytic fungi isolated from the leaves of A. lanata also showed a zone of inhibition of 12 mm against P. aeruginosa [38].Another investigation carried out on different extracts of A. javanica revealed that methanolic extracts showed potential antibacterial activities e.g., the zone of inhibitions for methanolic extract of leaves against P. aeruginosa, K. penumoniae, E. coli, P. putida were found to be 16, 15, 14 and 13 mm respectively [21]. Other report revealed that the extract of A. javanica inhibited the growth of E. coli (NCTC 10418), K. pneumoniae (ATCC 700603), P. aeruginosa, S. aureus, S. typhi, S. epidermidis (NCTC 11047) and methicillin resistant S. aureus (MRSA) (NCTC 13143) [39]. Alcoholic extracts of A. tomentosa has also been evaluated for their antimicrobial potential [30]. Review on Aerva plants Hepatoprotective activity: Antihepatotoxicity or hepatoprotection is the capability of different chemical substances to protect the damage to the liver. Significant hepatoprotective activity in albino mice was observed due to alcoholic extracts of leaf and root of A. lanata at a dose of 600 mg/kg of body weight [40]. A. lanata extract was also studied at the dose of 50 and 100 mg/kg body weight against CCl4 induced liver damage in Sprague Dawley rats. Partially purified petroleum ether extractable fraction of the whole plant of A. lanata significantly reversed the histopathological changes and restored the elevated activities of liver marker enzymes. The extract also reduced hepatic lipid peroxidation and increased the serum total protein and albumin/globulin (A/G) ratio [41]. Oral administration of an aqueous alcoholic extract of A. lanata (600mg/kg) was found effective in protecting the liver against the injury induced by paracetamol (3 g/kg) in rats [42]. Considerable activity against paracetamol induced hepatic damage in rats was observed for a biherbal ethanolic extract of leaves of A. lanata and leaves of Achyranthes aspera at a dose level of 200 mg/kg and 400 mg/kg body weight [43]. Immunomodulatory and anti-tumor activity: Immunotherapy is referred to the disease treatment by increasing, suppressing or inducing the immune response of the body. This activity is mostly used for the tumor related disease where an antitumor substance is the one which reduces the effects of a tumor causing substance or the one which prevents the cancer development [44]. Administration of an ethanolic extract of A. lanata was found to stimulate cell mediated immunological responses in normal and tumor bearing BALB/c mice. A significant enhancement in NK cell activity in both normal and tumor bearing hosts was observed after administration of A. lanata. The stimulatory effect of A. lanata on cytotoxic T-lymphocyte (CTL) production was detected by Winn's neutralization assay using CTL-sensitive EL4 thymoma cells [45]. The aqueous extracts of the stem of A. lanata were also studied against human erythrocytes and found non-toxic towards the hemolytic assay [25]. The ethanolic extract of all parts of A. lanata was examined for antitumor and Immunomodulatory effects. It was also determined that it increases the total number of white blood cells along with the α-esterase positive cells. This extract was completely cytotoxic to DLA and EAC cells [46]. A significant cytotoxicity of A. lanata’s petroleum ether extract was seen towards the Ehrlich Ascites, Daltons Lymphoma Ascites and B16F10 cell lines in vitro [47]. 10-Methoxycanthin-6-one, an alkaloid from the medicinal plant A. lanata, was assessed for immunomodulatory activity in BALB/c mice. The compound at 0.5 mg/kg body weight was found to enhance the total WBC count (13,975.50 ± 324.27 cells/mm3), bone marrow cellularity (23.08 ± 0.86 × 106 cells/femur), and number of α-esterase-positive cells (1283.16 ± 21.10 cells/4000 cells) [48]. Nephroprotective Activity: The effect of ethanolic extract of A. lanata was studied on mercuric chloride induced renal damage in rats. The results suggest that this extract possesses significant potential as a nephroprotective agent at a dose level of 200mg/kg and 400 mg/kg [49].A notable reduction in serum creatinine and blood urea has been reported to be 75, 150 and 300 mg/kg respectively when an alcoholic extract of the complete plant of A. lanata was applied to albino mice with acute renal failure. The renal failure in these mice was induced by gentamicin and cisplatin [50]. Anti-ulcer activity: The breaking in the gastric lining is known as ulcer; it is named differently depending on the part of gastric system damaged [51]. A. javanica’s ethyl acetate fraction of methanolic extract has been reported to display medium level antiulcer activity at a concentration of 0.2 mg/mL [52]. The extract of the roots of A. Natural Product Communications Vol. 13 (3) 2018 377 persica in ethanol was examined for antiulcer activity in albino Wistar mice. For an alcohol-induced model of ulcer, the extract has shown 70.43% protection at a dosage of 200 mg/kg from ulcers. This activity was very close to the activity of ranitidine a standard drug for this purpose. In another analysis of pylorus ligationinduced model of ulcer, the extract has shown 36.88% protection effect at a dosage of 200 mg/kg where ranitidine has shown 62.95% protection effects against ulcers at a dosage of 50 mg/kg, when the comparison was made with control groups [53]. Anti lithiatic activity: Leaf extract of A. lanata in water has been reported to help in the uric acid excretion. A dosage of the leaf extract of 3.0 mg/kg of body weight is given for 28 days in order to achieve the enhanced calcium oxalate and uric acid excretion in hyperoxaluric mice [54]. Another study has reported a decrease of enzymes which synthesize oxalates such as and lactate dehydrogenase (LDH) in liver and kidney and glycolic acid oxidase (GAO) in liver, with the administration of extract of aerial parts of A. lanata in water at a dosage of 2g per kg of the body weight of mice with calcium oxalate urolithiasis for 28 days [55].The extract of aerial parts of A. lanata in water has been seen to regularize the level of lipid, triglycerides and cholesterol in rats with ethylene glycol induced calcium oxalate urolithiasis [56]. Diuretic activity: The extracts of A. lanata has shown significant diuretic activities e.g., dose of 1.6g/kg of aqueous alcoholic extract in albino rats markedly increased Na+ output in urine [40] and alcoholic extract at dose of 800mg/kg showed diuretic activity in albino rats [57]. In a comparative study diuretic potentials of ethanolic extracts of A. lanata and A. tomentosa in healthy albino rats were studied. The urine output and concentration of electrolytes in urine increased with concentrated ethanolic extract of A. lanata only. At dose level of 300 mg/kg of A. lanata, concentration of Na+, K+ and Cl-has been reported as 14.00±000,6.68±0.14 and 23.04±0.00 (µmol/L) respectively [58]. Other biological activities: A. javanica extract in ethanol has killed P. falciparum. The extract of leaf, stem and mature fruit extracts showed IC50 values of 100, 308 and 76 µmol/mL, respectively [17]. Extracts of A. javanica were tested for antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger and Fusarium solani but poor activity was observed [39]. A. javanica’s raw extract has shown weak acetylcholinestrase inhibitory activity with an IC50 value of 275.2 µg/mL [19]. According to a recent study based on the analysis of LC-MS/MS and other biological activities A. javanica can be used as functional food ingredients and as well as for the pharmaceutical purposes in the treatment of many oxidation based diseases such as aging, neural disorders and genetic mutations such as cancer [59]. A. lanata’s 1% extract in water has shown good inhibition activity to stop the growth of MSUM (monosodium Urate Monohydrate) which causes gout [60]. A. lanata has also displayed anti-inflammatory activities. These activities are shown by its benzene and alcoholic extracts at the dosage of 800 mg/kg in model of rat paw edema induced by carrageenan [57].Ethyl acetate and methanol extract of A. lanata has shown remarkable antiplasmodial activity against the strains P. falciparum and their toxicity on HeLa cell line [61]. There are several benefits of the Aerva plants, yet no studies are encouraging the domestication of these plants. The domestication of these plants can lead to the harvesting of several useful phytochemicals and drugs. Elemental Analysis and Nutrition Value: Elemental composition of A. lanata calculated by SEM_EDX method showed C (38.4), O 378 Natural Product Communications Vol. 13 (3) 2018 (15.1), Si (0.31), Mg (0.32), Cl (0.42), K (3.44), Ca (2.28) (mg/100g) [62]. The ash content of the leaves was found to be 13.1±5.4 g/100g while concentrations of protein, fat, fiber and carbohydrate were (g/100g) 11.3±5.2, 25.2±7.9, 26.2±3.3, 22.0±2.6 respectively [63]. In another report of nutrient and mineral composition studies on A. lanata leaves were found to contain carbohydrate (26.6 g/100g), crude protein (22.6 g/100g) and ash (31.2 g/100g). Observed minerals (mg/100g) were P (187), K (47.9), Na (39.4), Ca (51.7), Mg (41.5), Zn (44.7) and Fe (11.0). Heavy metals such as Cu, Pb, Cd and Cr were not detected in the leaves [64]. Pb accumulation in the roots of A. lanata was also determined by substituted rhodamine based probe [65]. Nutrient evaluation of A. javanica showed round about 70 % carbohydrate, 7.3 % moisture, 1.1 % fats, 319.5 Kcal/100g of energy and 29.1 % fiber content. Elemental analysis of A. Javanica has shown the presence of different elements. Some of them are Cu (2.13 ppm), Mn (0.64 ppm), Pb (0.38 ppm), Cd (0.06 ppm), Fe (2.77 ppm), Cr (3.65 ppm), Mg (29.93 ppm), Na (28.46 ppm) [66]. Other Studies: Tolerance index: Tolerance index of A. lanata was calculated against air pollutants. A. lanata was found to be resistant specie and considered as to serve as sink to air pollutants [67]. Biosorption: Leaves of A. lanata are reported to possess sorption potential for chromium (VI) from wastewater with maximum extractability of 96.0%, 92.0% and 84.0% [68, 69]. A. sanguinolenta was included in 36 species selected to find good bioaccumulators for Cd and Zn from the Padaeng zinc mine area, Thailand, A. sanguinoleta was a moderate accumulator showing bioaccumulation factor of 1.04 or Cd and 1.72 for Zn [70]. Biofuel production: A study was carried out on halophytes in 2011 to find Potential sources of lignocelluloses biomass for ethanol production. This research concluded that halophytes can compete favorably with other conventional sources for biofuel production. Although, the results for A. javanica were not as effective as for some other species under consideration yet they were considerable showing hemi-cellulose 13.33, cellulose 15.67 and lignin 6.33 % DW [71]. Metal reduction: Hexavalent chromium is reduced by using A. lanata by batch equilibrium technique. This biological reduction converts the toxic hexavalent chromium to less toxic trivalent chromium ion. A. lanata also assists in the precipitation of the chromium ion which can then be easily separated. The reduction was confirmed by the cyclic voltammetry and ICP-MS [72]. Nano synthesis: The leaf extract of A. lanata have been used for the microwave aided green synthesis of gold and silver nanocatalysts. The catalytic activity of the newly synthesized substances was noted against the reduction of 4-nitrophenol to 4-aminophenol by NaBH4. Both the particles have shown excellent reduction potential [73]. This study is a big advancement in the development of green products. The whole plant aqueous extract of A. lanata is employed in the phytofabrication of silver nanoparticles. The fabricated nanoparticles were tested against several wound associated bacteria and these particles showed remarkable anti-bacterial activity. It was also found that the nanoparticles have similar action as that of ciprofloxacin on E. coli, S. aureus and S. agalactiae [74]. Silver nanocolloids have been prepared from A. javanica. These nanocolloids are then incorporated in chitosan hydrogels. The action of these hydrogels was determined by applying them to the infections caused by partially thick burn wounds. The application of Musaddiq et al. these hydrogels on the burn wounds has shown a significant reduction in the infection and the healing time [75]. The enzyme inhibitory activity: has also been observed in the alcoholic extract of A. Javanica. It is reported that kaempferol-3-Oβ-D-(6-E-p-coumaroyl)-glycosides and chlorinated dibenzofuran glycoside; aervfuranosidethat are obtained from the alcoholic extract show the inhibitory effect against acetylcholinesterase and butyryl cholinesterase. Eserine was used as the positive control for the study[76]. Phyto-constituents Isolated fromAerva Plants Investigation on the profile of biochemicals in Aerva species suggested it to be a valuable source of different classes of biologically active compounds. The survey of previous phytochemical work on the species of the genus Aerva revealed that alkaloids, flavonoids, coumarins, terpenoids, steroids and various phenolics have been discovered in these plants. Steroids: A literature search revealed that Aerva plants are producing steroids of ecdysteroid sub-group. For example, aervecdysteroids A-D (1-4) along with β-ecdysone (5), 5-β-2deoxyintegristerone A (6) and 24-epi-makisterone A (7) have been reported from the methanolic extract of the flowers of A. javanica(Figure 1). HO OH R4 R HO O HO H HO H O 1-2 Comp. 3 4 5 6 7 R2 OH R3 1. R: CH3 2. R: =CH2 R1 OH OH H OH H OH R1 H H OH O 3-7 R2 H H OH H OH R3 OH OH OH OH OH R4 CH3 =CH2 H H CH3 Figure 1: Ecdysteroids Isolated from theAervaPlants All isolates were evaluated for their inhibitory potential against enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX) but no significant activity has been reported [77]. Quantitative identification revealed that 0.035% ecdysteroids are present in the roots of A. tomentosa [78], whereas, in seeds their amount is estimated to be 0.030% [79]. Ecdysones are also reported from A. lanata [80]. Chromatographic fingerprint analysis done by HPTLC technique for steroids in the methanolic extract of different parts of A. lanata showed the presence of 30 different types of steroids [81]. βsitosterol (8) along with its D-glucoside (9) were identified as constituents of A. lanata [82, 83]. β-sitosterol (8) is also reported in alcoholic extract of A. Javanica’s flower [76]. In another study compound 9, stigmasterol-3-glyceryl-2'-linoleate (10) and campesterol (11) were also isolated from the extract of aerial parts of A. lanata [84]. Compound 8 and 11 are also reported from A. javanica var. bovi [85] and from A. persica, in addition to the ikisolation of 7-ergostenol (12), 7-stigmastenol (13), campestanol (14), 22-stigmastenol (15), stigmasterol (16) and spinasterol (17) [86]. Another derivative of β-sitosterol i.e., β-sitosteryl acetate (18) has been isolated from whole plant ethanolic extract A. persica [13]. Compound 8 is also reported from the petroleum-ether extract of A. tomentosa [87] (Figure 2). Natural Product Communications Vol. 13 (3) 2018 379 Review on Aerva plants R1 OR1 R R3O H H H R2 H H HO 8 R1= CH2CH3 9 R1 = CH2CH3 11. R1 = CH3 18 R1 = CH2CH3 R2= OH R2=O-Glc R2=OH R2=OAc 10 R1 = CH2CH3 O R2 = O O H 10 H O OH HO O O O R5O R6O Comp. 30 31 32 33 34 R1 H H H H H R2 H H H H OMe R3 H H H H H R4 H p-coumaroyl H H H 17 16 Terpenoids: Ameroterpene, bakuchiol (19) has been isolated from the methanolic extract of the dried leaves of A. sanguinolenta, which inhibited the growth of Streptococcus mutans -MTCC 497, Actinomyces viscosus -ATCC 15987 and Streptococcus sanguis ATCC 10556 with an MIC value of 0.98 µg/mL for each strain [88]. Squalene (20),a precursor of triterpenoids biosynthesis has been isolated from A. javanica [89]. Ursolic acid (21), a pentacyclic triterpenic acid was isolated from whole plant hydro methanolic extract of A. javanica, which was studied for anti-urease activity where it showed 33.4 % inhibition of the enzyme [52]. α-Amyrin (22) and β-amyrin (23) [90], oleanolic acid (24) and betulinic acid (25) have been isolated from A. javanica [91-92]. Oleanolic acid (24) is also reported in alcoholic extract of A. Javanica’s flower [76]. Compound 22 is also known as the constituent of A. tomentosa [71] and A. lanata [ 82] with betulin (26) from A. lanata, A. persica produced lupeol (27) and lupeol acetate (28) [13], presence of lupeol is also reported in the alcoholic extract of the flower of A. Javanica [76]. A diterpenoid named; 2α,3α,15,16,19-pentahydroxy pimar-8(14)-ene (29) has been isolated from methanolic extract of whole plant of A. lanata [83] (Figure 3). H R HO 20 H HO 21 R = COOH 22 R = CH3 OH H OH R HO R2 23 R = CH3 24 R = COOH 25 R1 = OH 26 R1 = OH 27 R1 = OH 28 R1 = OAc HO HO R1 R2 = COOH R2 = CH2OH R2 = CH3 R2 = CH3 R5 H H p-coumaroyl H H R2 Figure 2: Steroids Isolated from the Aerva plants. 19 OR4 R6 p-coumaroyl p-coumaroyl p-coumaroyl H p-coumaroyl Figure4:Flavonoid rubinosides Isolated from the Aerva Plants HO HO 15 R2 HO 14 4 6 HO OH O H HO 12 R = CH3 13 R = CH2CH3 O OH 29 Figure 3: Terpenoids Isolated from the Aerva Plants Phenolics Aerva plants have been intensively investigated for their phenolics contents and as a result, several flavonoids, phenolics acids or their derivatives, coumarins and chromones etc. have been isolated so far. Flavonoids: Aerva species produce variety of flavonoids and/or their glycosides e.g., kaempferol-3-O-β-D-[4'''-E-p-coumaroyl-α-Lrhamnosyl-(1→6)]-galactoside (30), kaempferol-3-O-β-D-[4'''-E-pcoumaroyl-α-L-rhamnosyl-(1→6)]-(3''-E-p-coumaroyl) galactoside (31) and kaempferol-3-O-β-D-[4'''-E-p-coumaroyl-α-L-rhamnosyl(1→6)]-(4''-E-p-coumaroyl) galactoside (32) were found in the ethyl acetate fraction of flowers of A. javanica [93]. R1O OR3 O O OH O O OH R5O OR4 OH Compound 35 36 37 38 R1 H H H H R2 H H OMe OMe R3 H H H H R4 H p-coumaroyl H p-coumaroyl R5 p-coumaroyl p-coumaroyl p-coumaroyl p-coumaroyl Figure5:Flavonoid glucosides isolated from Aerva plants OH OR2 R1O O R3 OH O Compound 39 40 41 R1 Me Me Glc R2 H Glc H R3 OH H OH Figure 6: Flavanones isolated from Aerva plants. Compound 30 showed weak inhibitory activity against enzymes acetylcholinesterase, butyrylcholinesterase and lipoxygenase with IC50 values of 205.1, 304.1, and 212.3 µM, respectively [93]. Kaempferol-3-O-robinoside (33) [90, 94] and isorhamnetin-3-(pcoumaroyl)-rhamnogalactoside (34) have also been isolated from A. javanica [94] (Figure 4). Acylated flavone glucosides: that include kaempferol-3-O-β-D-(6''E-p-coumaroyl) glucopyranoside (35) and kaempferol-3-O-(4'',6''di-O-E-p-coumaroyl)-β-D-glucopyranoside (36) are isolated from A. lanata. Compound 36 is also extracted from the alcoholic extract of flowers of A. Javanica [76] along with isorhamnetin-3-O-β-D-(6p-coumaroyl) glucopyranoside (37) and isorhamnetin-3-O-(4'',6''di-O-E-p-coumaroyl)-β-D-glucopyranoside (38) [95] (Figure 5). Anti-oxidant flavanones; persinol (39), persinoside A (40) and persinoside B (41) with IC50 values of 24.2, 21.4 and 20.0 µM respectively in DPPH scavenging assay and IC50 values of 21.1, 18.8 and 19.1 µM respectively in cytochrome-c-reduction assay are known as the phytochemicals of A. persica [96] (Figure 6). A quantitative estimation of the total flavonoids in the A. lanata L. by differential spectrophotometry suggested total flavonoid contents in the range of 0.51 to 1.02% [97]. Total flavonoid contents in the same species were found to be 6.99 mg quercetin/100 g Equivalents) when calculated by the aluminum chloride colorimetric assay [98]. A high amount of total phenolic contents 380 Natural Product Communications Vol. 13 (3) 2018 Musaddiq et al. R1 R2 R3 R4 R8 R9 O O R7 R6 R5 Compound 42 43 R1 H H R2 O-Glc OH R3 H H R4 OH OH R5 H OH R6 H OH R7 OH OH R8 H OH R9 H H 44 H OH H OH H H H H H 45 H OH H OH OH H OH OH H 46 47 48 H H H O-Glucuronic acid OH OH H H H OH OH OH H O-Glc H H OH H OH OH OH H H OMe H H H 49 H OH H OH O-Gal H OH H H 50 H OH H OH O-Gal H OH OH H 51 H OH H OH O-Glc H OH OMe H 52 OMe OMe H OH H H H H H 53 H OH H OH H H OH H H 54 OMe OMe OMe OH H OMe OMe H H 55 H OMe OMe OH OMe H OH H H 56 H OMe OMe OH OMe H OMe H H 57 H O-Glc H OH H H OH H H 58 H O-Glc H OH OH OH OMe H H 59 H OMe OMe H OMe OMe H H OMe 60 H O-Glc H OH H H OH H H Figure 7:Flavonoids isolated from Aerva plants was determined by Folin-Ciocalteau reagent method and HPLC in the stem of A. lanata. Some of the phenolics were identified as apigenin-7-O-glucoside (apigetrin, 42) and myricetin (43) [25]. Chrysin (44) is also reported from alcoholic extract of A. lanata [99]. Alcoholic extract of roots of A. javanica contain 0.02196 % wt/wt quercetin (45) [100]. OMe HO OH O HO O OH O O O O Me O O HO OH OH OH O 61 O O O HO OH O HO OH OH O HO O HO OR OH O HO OH O OH OMe O OH O HO HO O O HO 62 R = H OH O O O 64 OH OH 63 R = Me Me O MeO HO O HO OH O O OH OH O HO OH HO O OH O O OH O OH O OH O 67 OH OH O O HO OH OH O HO O O OH O OH HO OH O OMe O OH O O HO HO 68 O HO HO OH O O OH OH 65; R1=4-hydroxy trans cinnamoyl; R2 = H 66; R1=R2 = 4-hydroxy trans cinnamoyl HO O HO HO O OR1 HO R2O OMe OH O trimethoxyflavone (55), 5-hydroxy-3,6,7,4-tetramethoxyflavone (56), apigenin-7-O-β-D-glucopyranoside (57), 3,3,5-trihydroxy-4methoxyflavone-7-O-β-D-glucopyranoside (58) 5-hydroxy2,3,5,6,7-pentamethoxyflavone (59) [13] and Chrysin-7-Ogalactoside (60) are isolated from A. persica [103] (Figure 7). The perianth lobes of A. tomentosa produce kaempferide-3-O-(6''O-acetyl-4'''-O-α-methylsinapyl)neohesperidoside (61) [104], whereas quercetin-3-O-rutinoside (62) [25], isorhamnetin-3rutinoside (63) and aervitrin (isorhametin 3-rhanmosylrutinoside) (64) [105] were purified from the extracts of A. lanata whereas whole plant methanolic extract of the specie afforded tribuloside (65) and 3-cinnamoyltribuloside (66) [83]. Compound 63 has also been isolated from A. javanica [85]. Quercetin-3-O-xylosyl-(1→2)rhamnoside (67) [91], Isorhamnetin-7-p-coumaroyl galactoside (68) [94], kaempferol-3-O-β-D-glucopyranosyl-(1→2)-α-Lrhamnopyranoside-7-O-α-rhamnopyranoside (69) [101], Aervanone (70) have been reported as the metabolites of A. persica [106] (Figure 8). Other Phenolics: Methanolic extract of flowers of A. javanica yielded p-coumaric acid (71), caffeic acid (72), eicosanyl-trans-pcoumarate (73), hexadecyl ferulate (74) and hexacosyl ferulate (75) [93]. Ferulic acid (76), which is an important phytochemical has been known as the metabolite of A. lanata [2], Methyl grevillate (77) has been reported from A. persica [13] (Figure 9). OH R1 O 70 HO O 69 R2 Figure 8: Flavonoids isolated from Aerva plants. Other flavonoids isolated from A. javanica whole plant extract are apigenin-7-O-glucuronide (46), isoquercetrin (47) [101] chrysoeriol (48) [90], kaempferol-3-galactoside (49), quercetin-3-galactoside (50) and isorhamnetin-3-galactoside (51) [94]. 5-hydroxy-7-8dimethoxyflavone (52), 4,5,7-trihydroxyflavone (53) 5-hydroxy3,4,6,7,8 pentamethoxyflavone (54) [102], 5,4-dihydroxy-3,6,7- O Compound 71 72 73 74 75 76 77 R3 R H H -(CH2)19CH3 -(CH2)15CH3 -(CH2)25CH3 H CH3 R R1 H H H H H H OH Figure9:Phenolics Isolated from Aerva plants. R2 OH OH OH OH OH OH H R3 H OH H OMe OMe OMe H Natural Product Communications Vol. 13 (3) 2018 381 Review on Aerva plants Total phenolics of the whole plant of A. lanata were determined by Folin-Ciocalteu assay and were found to be 22.7 mg GAE/100g where GAE represents gallic acid (78) [98]. It has been reported that A. lanata also produce syringic acid (79) and vanillic acid (80) [107]. In another report, 2.61 µg/mL of gallic acid was quantified by HPTLC in ethanolic root extract of A. lanata [108]. O R1 Compound 78 79 80 81 82 83 84 85 86 R OH OH OH H -CH2CH2OH OH H OH OH R R2 R3 R1 OH OMe OMe OH OMe H H H OH R2 OH OH OH OMe OH -OCH2CH3 OH OH H R3 OH OMe H H OMe H H H H known as the metabolites of A. javanica [112]. The presence of allantois (102) and indole acetic acid (103) is reported in methanolic extract of flowers of A. javanica [76] (Figure 12). Sphingolipids: 1-O-β-D-glucopyranosyl-(2S,3R,8E)-2-[(2'R)-2hydroxylpalmitoylamino]-8-octadecene-1,3-diol (104), 1-O-(β-Dglucopyranosyl)-(2S,3S,4R,8Z)-2-[(2'R)-2'-hydroxytetracosanoyl amino]-8(Z)-octadene-1,3,4-triol (105), (2S,3S,4R,10E)-2- [(2' R)2'-hydroxytetracosanoylamino]-10-octadecene-1,3,4-triol (106), have been isolated from whole plant methanolic extract of A. lanata [83]. An anti-inflammatory cerebroside ASE-1 (107) is discovered from ethanolic extract of leaves of A. sanguinolenta [113], whereas (2S,3S,4R,8Z)-2-[(2R)-2-hydroxypentacosanoyl-amino]-8-octadecene-1,3,4-triol-1-O-β-D-glucopyranoside (108) and (2S,3S,4R,14E)-2-[(2R)-2-hydroxy octadecanoyl]amino-tetraeicos14-ene-1,3,4-triol-1-O-β-D-glucopyranoside (109) are found in flowers of A. javanica [76] (Figure 13). Figure 10: Phenolics Isolated from Aerva plants. OMe O OH OMe MeO O O MeO O O OH 87 O O 88 O O 89 O O O O 11 92 Aerva plants also produce other phenolic derivatives like chromones e.g., 2H-1-benzopyran-2-one (87), 5,7-dimethoxy coumarin (88), 5, 8-dihydroxy coumarin (89) 5,6,7-trimethoxy coumarin (90) and coumaranochromones i.e., aervin A-D (91-94 )are isolated from A. persica [109], 5-methylmellein (95) has been isolated from A. javanica [101] (Figure 11). Alkaloids: These compounds are generally used by the organisms for their chemical defenses. Aerva species are producing variety of alkaloids, for example canthin-6-one (96), 10-hydroxycanthin-6one(97), 10-methoxycanthin-6-one (98), canthin-6-one 10-O-β-Dglucopyranoside (99), β-carboline-1-propionic acid (100) and 6methoxy-β-carboline-1-propionic acid (101) have been isolated from A. lanata [83, 110, 111]. Compounds 96 and 97 are also O O N N O 96 OH HO HO MeO N N N O 97 N 98 MeO O OH N N 99 N H O 100 N HN O N H N H COOH OH O NH H2 N O O 102 Figure 12:Alkaloids isolated from Aerva plants. N H 103 HO HO n OH O 101 N COOH O O HO HO O 7 OH OH 107 OH HN OH 17 OH 106 Gallic acid (78) was also found in the extract of A. javanica [93] along with 3-hydroxy-4 methoxybenzaldehyde (81) [52], while, A. persica was found to contain 3, 4ʹ dihydroxy-3ʹ, 5ʹ-dimethoxy propiophenone (82), 4-ethoxy benzoic acid (83), 4hydroxybenzaldehyde (84), 4-hydroxybenzoic acid (85) and 3hydroxybenzoic acid (86) [102] (Figure 10). HO HO 95 OH HN OH OH n2 OH 105 n1= 18, n2 = 6 108 n1 = 19, n2=7 O 17 n1 OH O OH OH HN OH O Figure11: Coumarins and chromones isolated from Aerva plants. 7 OH O O 94 93 CH3 OH O HO HO O OH O 104 CH3 O O O HO HO OH HN OH 9 91 O O O O O O OMe O MeO OMe O O 90 OMe MeO O O O MeO HN OH OMe O OH 11 OH O 7 OH OH 7 109 Figure 13: Sphingolipids isolated from Aerva plants. Betacyanins: Acylated and simple betacyanins i.e., amaranthine (110), isoamaranthine (111), celosianin I (112) and celosianin II (113) were identified and quantified in inflorescence of A. sanguinolenta [114] (Figure 14). OH OH HO HO HOOC HO HO HO HO HOOC O O O O COO N HO HO HO O O O O COOH N HO OR OR 110; R= H 112; R= p coumaroyl 113; R= feruloyl HOOC HOOC N H COOH N COOH 111 Figure 14:Betacyanins isolated from Aerva plants Miscellaneous Metabolites: Various studied conducted on A. lanata afforded sulfonoquinovosyldiacylglyceride (114) [83], feruloyltyramine (115), feruloylhomovanillyl amine (116) and shikimic acid (117) [2, 107]. Further, HPTLC profile of the methanolic extract of various parts of same species showed the presence of 21 different types of saponins [81, 115]. Presence of saponins is also confirmed by hemolysis test in both aqueous and alcoholic extract and by foam test in aqueous extract [116]. In another study, aerial parts of A.lanata showed presence of hemicellulose, starch, acid-soluble polysaccharide, and watersoluble polysaccharides [117]. Qualitative and quantitative analysis of individual carbohydrates in the aerial parts of A. javanica and A. lanata showed free arabinose, rhamnose, xylose, galactose, 382 Natural Product Communications Vol. 13 (3) 2018 O HO HO O OH O H N MeO OCO(CH2)14CH3 R O OH 115 R = H 116 R = OMe 114 OH HO HO HO OCO(CH2)14CH3 SO3Na Musaddiq et al. OH 117 N O O HO OH Me OH O N O O OH 120 119 118 O Figure 15: Miscellaneous Metabolites isolated from Aerva plants. O O OH O HO O HO HO HO O OH O O OH 121 OH 122 OH O OMe HO O OMe OH OH 126 OH OH O 8-23 Cl O 124 O 125 HO O HO 123 O O HO O 127 hydrocarbons OH 23-33 alcohols Figure 16:Miscellaneous metabolites isolated from the Aerva plants glucose, mannose and mannitol [35].Ascorbic acid (118) content in the shoots of A. persica was found to be 115.00 mg/100g DW [118]. whereas, glycinebetaine (119) and trigonelline (120) have been quantified in A. japonica (Figure 15) [119]. 2-hydroxy-3-O-βprimeveroside naphthalene-1,4-dione (121) and 7-(1ʹhydroxyethyl)-2-(2″-hydroxyethyl)-3,4-dihydrobenzopyran (122) are observed in the extracts of A. javanica [101]. Long chain hydrocarbons with carbon chain length ranging between 14-27 along with β-damascenone (123), trans-β-ionone (124), megastigmatrienone (125) and 6,10,14-trimethyl-2-pentadecanone (126) were identified from the leaves and stems of A. javanica [89]. From the same source, long chain alcohols (C26-C36) were identified along with 14 different fatty acids [90].Chlorinated dibenzofuran glycoside; aervfuranoside (127) have been reported in the methanolic extract of A. javinaca’s flowers [76] (Figure 16). Toxicity: The toxicity of aqueous extract of A. lanata is determined in albino mice. The acute toxicity was determined by the administration of 1-30 g/kg intraperitoneally in the albino mice. For the determination of sub-chronic, 40-1000 mg/kg of the extract was administered daily to the mice orally. The extract produced visible changes in the body weights of the mice (both male and female)[120]. Conclusion: To conclude; A. lanata, A. javanica and A. persica are the species of family Amaranthaceae that have extremely useful qualities and scientists have paid special attention to these medicinal plants for the purpose of identification, isolation and extraction of potential medicinal constituents. Presence of unique biologically active compounds justify the usage of these plant extracts as anti-inflammatory, hepatoprotective, anthelmintic, antibacterial and antilithiatic agents. Many reports of successful usage of these species have been mentioned and discussed above, but there are still some important issues that need to be addressed by researchers. It is a noteworthy fact that more reports are published about few species of Aerva genus. Productive studies on medicinal and other aspects of related species may add knowledge about uses, availability or miraculous healing properties, if they exist, like other members of the genus. Acknowledgement - Present review article is part of PhD thesis funded by Higher Education Commission of Pakistan (HECPakistan) under M.Phil leading to PhD Indigenous Fellowship Program, Batch IV. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Alwadie HM. (2005) Morphology and distribution of three genera of Amaranthaceae in the south western area of Saudi Arabia. Journal of King Saud University, 18, 51-62 . Chawla P, Chawla A, Vasudeva N, Sharma SK. (2012) A review of chemistry and biological activities of the genus Aerva, A desert plant. Acta Poloniae Pharmaceutica - Drug Research, 69, 171-177. Bakshi GDN, Sarma PS, Pal DC. (1999), In A lexicon of medicinal plants in India. Naya Prokash, Calcutta, 61-63. Kirtikar KR, Basu BD. (2001) Indian Medicinal Plants. Oriental Enterprises, Dehradun, 2066-2077. Sivasankari B, Anandharaj M, Gunasekaran P. (2014) An ethnobotanical study of indigenous knowledge on medicinal plants used by the village peoples of Thoppampatti, Dindigul district, Tamilnadu, India. Journal of Ethnopharmacology, 153,408–423. Kankanamalage T, Dharmadasa R, Abeysinghe D, Wijesekara R. (2014) A survey on medicinal materials used in traditional systems of medicine in Sri Lanka. Journal of Ethnopharmacology , 155, 679–691. Ong HG, Kim YD. (2014) Quantitative ethnobotanical study of the medicinal plants used by the Ati Negrito indigenous group in Guimaras island, Philippines. Journal of Ethnopharmacology, 157, 228-242. Bhatia H, Sharma Y, Manhas RK, Kumar K. (2014) Ethnomedicinal plants used by the villagers of district Udhampur, J&K, India. Journal of Ethnopharmacology, 151,1005–1018. Shasank S. Swain, Rabindra N. Padhy. (2015) In vitro antibacterial efficacy of plants used by an Indian aboriginal tribe against pathogenic bacteria isolated from clinical samples. Journal of Taibah University Medical Sciences, 10, 379-390. Amujoyegbe O, Idu M, Agbedahunsi JM, Erhabor JO. (2016) Ethnomedicinal Survey of medicinal plants used in the management of sickle cell disorder in Southern Nigeria. Journal of Ethnopharmacology, 185, 347-360. Mukerjee T, Bhalla N, Sing AG, Jain HC. (1984) Herbal drugs for urinary stones. Indian drugs.21, 224-228. Rajesh R, Chitra K, Padmaa MP. (2011) Aerva lanata (Linn.) Juss ex Shult- An Overview. Indian Journal of Natural Product Resources, 2, 5-9. Ahmad E, Malik A, Ahmad MM, Munawar MA, Nagra SA, Anwar J, Qazi MA, Sharif A, Afza N, Ashraf M. (2008) Investigation of Antimicrobial Constituents from Aerva persica. Journal of the Chemical Society of Pakistan, 30, 936-941. Perry LM, Metzger J. (1980) Medicinal Plants of East and Southeast Asia. MIT Press, Cambridge, London.9 Raza A, Younas M, Buerkert A, Schlecht E. (2014) Ethno-botanical remedies used by pastoralists for the treatment of livestock diseases in Cholistan desert, Pakistan. Journal of Ethnopharmacology, 151, 333–342. Muhammad S, Naseer RK, Shah A, Shah SA, Majid M, Farooq MA. (2014) Ethnomedicinal plant use value in the Lakki Marwat District of Pakistan. Journal of Enthopharmacology, 158, 412-422 Ahmed N, Mahmood A, Mahmood A, Sadeghi Z, Farman M. (2015) Ethnopharmacological importance of medicinal flora from the district of Vehari, Punjab province, Pakistan. Journal of Ethnopharmacology, 168, 66-78. Review on Aerva plants [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] Natural Product Communications Vol. 13 (3) 2018 383 Yaseen G, Ahmad M,Sultana S, Alharrasi AS, Hussain J, Zafar M. (2014) Ethnobotany of medicinal plants in the Thar desert (Sindh) of Pakistan. Journal of Ethnopharmacology, 163, 43-59. Murtaza S, Ghous T, Ahmed S, Ullah RS, Abbas A. (2013) On-line antiacetylcholine esterase activity of extracts of Oxystelma esculentum, Aerva javanica and Zanthoxylum armatum. Journal of Chemical Society Pakistan, 35, 801-804. Srinivas KR, Reddy VM. (2009) Antihyperglycaemic activity of ethanol extract of Aerva javanica leaves in alloxan- induced diabetic mice. Journal of Pharmacy Research, 2, 1259-1261 Srinivas P, Reddy SR. (2012) Screening for antibacterial principle and activity of Aerva javanica (Burm .f) Juss. ex Schult. Asian Pacific Journal of Tropical Biomedicine, S838-S845. Simonsen HT, Nordskjold JB, Smitt UW, Nyman U, Palpu P, Joshi P, Varughese G. (2001) In vitro screening of Indian medicinal plants for antiplasmodial activity. Journal of Ethnopharmacology, 74, 195-204. Herrero M, Cifuentes A, Ibañez E. (2006), Sub-and supercritical fluid extraction of functional ingredients from different natural sources: Plants, food-by-products, algae and microalgae: A review, Food Chemistry, 98, 136-148. Muthukumaran P, Shanmuganathan P, Malathi C. (2011) Antioxidative and antimicrobial study of Aerva lanata. Asian Journal of Biochemical and Pharmaceutical Research, 1, 265-271. Kumar G, Karthik L, Rao KVB. (2013) Phytochemical composition and in vitro antioxidant activity of aqueous extract of Aerva lanata (L.) Juss. ex Schult. Stem (Amaranthaceae). Asian Pacific Journal of Tropical Medicine, 6, 180-187. Surveswaran S, Cai YZ, Corke H, Sun M. (2007) Systematic evaluation of natural phenolic antioxidants from 133 Indian medicinal plants. Food Chemistry, 102, 938-953 Gunathilake KDPP, Ranaweera KKDS. (2016) Antioxidative properties of 34 green leafy vegetables. Journal of Functional Foods, 26, 176–186. Pal D. (2013) Comparative analysis of in vitro antioxidant activity of two selected plants with a reference to antidiabetic profile. Asian Journal of Chemistry, 25, 2165-2169 Yogananda RK, Jayaveera K N, Rubesh KS. (2011) Phytochemical, antioxidant and antimicrobial studies on ethanolic and methanolic extracts of Aerva tomentosa Linn. Journal of Pharmaceutical Chemistry, 5, 3-7. Sethi A, Sharma RA (2011) Antioxidant activity with total phenolic constituents from Aerva tomentosa forsk, International Journal of Pharma and Bio Sciences, 2, 596-603. Agrawal R, Sethiya NK, Mishra SH. (2013) Antidiabetic activity of alkaloids of Aerva lanata roots on streptozotocin-nicotinamide induced type-II diabetes in rats. Pharmaceutical biology,51, 635-642. Vetrichelvan T, Jegadeesan M. (2002) Antidiabetic activity of alcoholic extract of Aerva lanata (L.) juss. ex Schults in rats. Journal of Ethnopharmacology, 80, 103-107. Deshmukh TA, Bapuso VY, Sachin LB, Subash LB. (2008) Antihyperglycaemic activity of alcoholic extract of Aerva lanata (L.) juss. ex Schults leaves in alloxan induced diabetic mice. Journal of Applied Biomedicine, 6, 81-87. Rajesh R, Chitra K, Paarakh PM. (2012) Anti hyperglycemic and antihyperlipidemic activity of aerial parts of Aerva lanata Linn Juss in streptozotocin induced diabetic rats. Asian Pacific Journal of Tropical Biomedicine, S924-S929. Aboutabl EA, Wassel GM, Wahab SM, Ammar NM, Yassin N, Afifi M. (1998) Study of different carbohydrates in Aerva lanata Jussex Schult and A. javanica Burm. Fil. growing in Egypt and evaluation of hypoglycemic effect of their polysaccharides. Egyptian Journal of Pharmaceutical Sciences, 38, 33-42. Gehlot D, Bohra A. (1998) Antimicrobial activity of various plant extracts of Aerva persica. Advanced Plant Science, 11, 109-111. Chowdhury D, Sayeed A, Islam AMSAB, Khan GRAM. (2002) Antimicrobial activity and cytotoxicity of Aerva lanata. Fitoterapia, 73, 92-94. Sunkar S, Nachiyar CV. (2011) Isolation and characterization of antimicrobial compounds produced by endophytic fungus Aspergillus sp. isolated from Writhtia tintorica. Journal of Pharmacy Research, 4, 1136-1137. Mufti FD, Ullah H, Bangash A, Khan N, Hussain S, Ullah F, Jamil M, Jabeen M. (2012) Antimicrobial activities of Aerva javanica and Paeonia emodi plants. Pakistan Journal of Pharmaceutical Sciences, 25, 565-569. Majmudar FI, Shah MB, Patel KN, Shah BK. (1999) Aerva lanata- its diuretic and hepatoprotective activity. Indian Journal of Natural product, 15, 9-12. Nevin KG, Vijayammal PL. (2005) Effects of Aerva lanata against hepatoxicity of carbon tetrachloride in rats. Environmental Toxicology and Pharmacology, 20, 471-477. Manokaran S, Jaswanth A, Sangottuvelu S, Nandhakumar J, Duraisamy R, Karthikeyan D, Mallegaswari R. (2008) Hepatoprotective activity of Aerva lanata Linn. Against paracetamol induced hepatotoxicity in rats, Research Journal of Pharmacy and Technology, 1, 398-400. Anantha KCD, Siva RC, Manohar RA. (2012) Hepatoprotective effect of biherbal ethanolic extract against paracetamol-induced hepatic damage in albino rats,Journal of Ayurveda and Integrative Medicine, 3, 198-203. Baxter D. (2007). Active and passive immunity, vaccine types, excipients and licensing. Occupational Medicine,57, 552–556. Siveen KS, Kuttan G. (2012) Effect of Aerva lanata on cell-mediated immune responses and cytotoxic T-lymphocyte generation in normal and tumor-bearing mice. Journal of Immunotoxicology,9, 25-33 Siveen KS, Kuttan G. (2011) Immunomodulatory and antitumour activity of Aerva lanata ethanolic extract. Immunopharmacology and immunotoxicology, 33, 423-432. Nevin KG, Vijayammal PL. (2003) Effect of Aerva lanata on solid tumor induced by DLA cells in mice. Fitoterapia,74, 578-582 Siveen KS, Kuttan G. (2012) Modulation of humoral immune responses and inhibition of proinflammatory cytokines and nitric oxide production by 10-methoxycanthin-6-one. Immunopharmacology and Immunotoxicology,34, 116-125. Soumya PS, Poornima K, Ravikumar G, Kalaiselvi M, Gomathi D, Uma C. (2011) Nephroprotective effect of Aerva lanata against mercuric chloride induced renal injury in rats. Journal of Pharmacy Research, 4, 2474-2476. Shirwaikar A, Issac D, Malini S. (2004) Effect of Aerva lanata on cisplatin and gentamicin models of acute renal failure. Journal of Ethnopharmacology, 90, 81-86. Najm WI. (2011) Peptic ulcer disease. Primary care, 38, 383–394. Khan AW, Jan S, Parveen S, Khan RA, Saeed A, Tanveer A J, Shad AA. (2012) Phytochemical analysis and enzyme inhibition assay of Aerva javanica for ulcer. Chemistry Central Journal, 6, 76. Vasudeva N, Sethi P, Sharma SK, Kumar S, Sharma S. (2012) Antiulcer potential of the ethanolic extract of A. persica Merrill root in rats. Journal of Acupuncture and Meridian Studies, 5, 80-86. Selvam R, Kalaiselvi P, Govindaraj A, Murugan VB, Kumar ASS. (2001) Effect of Aerva lanata leaf extract and vediuppo chunnam on the urinary risk factors of calcium oxalate urolithiasis during experimental hyperoxaluria. Pharmacological Research, 43, 89-93. Soundararajan P, Mahesh R, Ramesh T, Beguum VH. (2006) Effect of Aerva lanata calcium oxalate urolithiases in rats. Indian Journal of Experimental Biology, 44, 981-986. Soundararajan P, Mahesh R, Ramesh T, Begum VH. (2007) Hypolipidimic activity of Aerva lanata on ethylene glycol induced calcium oxalate urolithiasis in rats. Pharmacology Online, 1, 557-563. 384 Natural Product Communications Vol. 13 (3) 2018 [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] Musaddiq et al. Vetrichelvan T, Jegadeesan M, Palaniappan MS, Murali NP, Sasikumar K (2000) Diuretic and anti-inflammatory activities of Aerva lanata in rats, Indian Journal of Pharmaceutical Sciences, 62, 300-302. Deepak K, Prasad DN, Bhatnagar SP. (2005) Comparision of diuretic activity of ethanolic extract of Aerva lanata(Linn.) Juss. Ex. Schult & Aerva tomentosa forsk. Family: amaranthaceae. Ancient Science of Life, 2, 66-68. Yasir M, Sultana B, Amicucc M. (2016) Biological activities of phenolic compounds extracted from Amaranthaceae plants and their LC/ESIMS/MS profiling. Journal of Functional Foods, 26, 645–656. Parekh BB, Vasant SR, Tank KP, Raut A, Vaidya ADB. (2009) In vitro growth and inhibition studies of monosodium urate monohydrate crystals by different herbal extracts. American Journal of Infectious Diseases, 5, 225-230. Kaushik NK, Bagavan A, Rahuman AA, Zahir AA, Kamaraj C, Elango G. (2015) Evalution of antiplasmodial activity of medicinal plants from North Indian Buchpora and South Indian Eastern Ghats. Malaria Journal, 14, 65. Ragavendran P, Arul RC, Sophia D, Starlin T, Gopalakrishnan VK. (2012) Elemental analysis of Aerva lanata (L.) by EDX method. International Research Journal of Pharmacy, 3, 218-220. Emmanuel FD, Oluwole MD, Emmanuel AI, Oyedele, O. (2010) Chemical composition and antibacterial activities of some selected traditional medicinal plants used in the treatment of gastrointestinal infections in Nigeria. International Journal of Pharmaceutical Sciences Review and Research, 5, 192-197. Omoyeni OA, Adeyeye EI. (2009) Chemical composition, calcium, zinc and phytate interrelationships in Aerva lanata (Linn) Juss. ex Schult leaves.Oriental Journal of Chemistry, 25, 485-488. Pal A, Bag B, Thirunavoukkarasu M, Pattanaik S, Mishra B K. (2013) Solvent mediated tuning of selectivity in a rhodamine based probe and bioimaging for Pb(ii) detection in plant tissues. RSC Advances, 3, 18263-18266. Hussain J, Khan FU, Ullah R, Muhammad Z, Rehman NU, Shinwari ZK, Khan IU, Zohaib M, Imad-ud-din, Hussain SM. (2011) Nutrient evaluation and elemental analysis of four selected medicinal plants of Khyber Pakhtoon khwa, Pakistan. Pakistan Journal of Botany, 43, 427-434. Prabakaran R, Bidyalaxmidevi A (2013) Air pollution tolerance index of selected plants of Salem-Bangalore- NH-7, near Salem, Tamil Nadu. Pollution Research, 32, 411-413. Poonkuzhali, K., Manivannan, M., and Palvannan, T. (2013) Assessing the chelating ability of Aerva lanata: adsorption of chromium from tannery effluent and its toxicity measurement, Khimiya i Tekhnologiya Vody, 35, 240-250. Sekhar KPC, Vishnu Babu RV, Rohini T, Ravindhranath K. (2012) New bio-sorbents in the control of Chromium (VI) pollution in waste waters. International Journal of Applied Biology and Pharmaceutical Technology, 3, 115-125. Phaenark C, Pokethitiyook P, Kruatrachue M, Ngernsansaruay C. (2009) Cd and Zn accumulation in plants from the Padaeng zinc mine area. International Journal of Phytoremediation, 11, 479-495. Abideen Z, Ansari R, Khan MA. (2011) Halophytes: Potential source of ligno-cellulosic biomass for ethanol production. Biomass and Bioenergy, 35, 1818-1822. Poonkuzhali K, Rajeswari V, Saravanakumar T. (2014) Reduction of hexavalent chromium using Aerva lanata L.: Elucidation of reduction mechanism and identification of active principles. Journal of Hazardous Materials, 272, 89–95. Joseph S, Mathew B. (2015) Microwave-assisted green synthesis of silver nanoparticles and the study on catalytic activity in the degradation of dyes. Journal of Molecular Liquids, 204, 184-191. Appapalam S, Panchamoorthy R. (2017) Aerva lanata mediated phytofabrication of silver nanoparticles and evaluation of their antibacterial activity against wound associated bacteria. Journal of the Taiwan Institute of Chemical Engineers, 78, 539-551. Hashmi MU, Khan F, Khalid N, Shahid AA, Javed A, Alam T, Jalal N, Hayat MQ, Abbas SR, Janjua HA. (2017) Hydrogels incorporated with silver nanocolloids prepared from antioxidant rich Aerva javanica as disruptive agents against burn wound infections. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 529, 475-486. Musaddiq S, Saeed S, Riaz N (2017) Aervfuranoside: A new chlorinated dibenzofuran glycoside and other metabolites from the flowers of Aerva javanica. Journal of Chemical Society of Pakistan, 39, 572-577. Saleem M, Mussadiq S, Riaz N, Zubair M, Ashraf M, Nasar R, Jabbar A. (2013) Ecdysteroids from the flowers of Aerva Javanica, Steroids,78, 1098-1102. Maher SMA, Valhari MU, Khatri LM. (1995) Identification and quantification of ecdysteroids from Aerva tomentosa and Pandiaka involucrate. Pakistan Journal of Scientific and Industrial Research, 38, 91-93. Hardman R, Mahar SMA. (1978) Isolation, identification and quantification of ecdysones from Aerva tomentosa and Pandiaka involucrata [drug plant] Planta Medica, 33, 278-279. Baltaev UA, Murdakhaev YM, Abubakirov NK. (1992) Phytoecdysteroids of Aerva lanata .Chemistry of Natural Compounds, 28, 123-124. Yamunadevi, M., Wesely, E. G., and Johnson, M. (2011) Chromatographic finger print analysis of steroids in Aerva lanata L by HPTLC technique, Asian Pacific Journal of tropical Biomedicine, 1, 428-433. Chandra S, Sastry MS. (1990) Chemical constituents of Aerva lanata. Fitoterapia, 61, 188. Yogesh PB, Hazra A, Poduri NSA, Ash A, Maulik PR, Mondal NB. (2015) Isolation, structural elucidation and cytotoxicity evaluation of a new pentahydroxy-pimarane diterpenoid along with other chemical constituents from Aerva lanata. Natural Product Research, 29, 253-261. Kamurthy H, Sumalatha C, Sunandan RN, Muvvla S. (2013) Antinociceptive activity of stigmosterol-3-glyceryl-2'-linoleiate, campesterol and daucosterol isolated from Aerva lanata Linn. aerial parts. Asian Journal of Pharmaceutical and Clinical Research, 6, 149-152. Radwan HM, Nazif NM, Hamdy AA. (2001) The lipid and flovonoidal constituents of Aerva javonicavar. bovi webb in hook. F. and their antimicrobial activity. Egyptian Journal of Pharmaceutical Sciences, 40, 167-178. Patterson GW, Sihua X, Salt TA. (1991) Sterols of caryophyllales with emphasis on amaranthaceae. Phytochemistry, 30, 523-526. Bishay DW, Ross SA, El-Saiad M. (1980) Phytochemical study of Aerva tomentosa Forsk. Egyptian Journal of Pharmaceutical Sciences, 18, 377386. Gottumukkala VR, Kandaswamy K, Gopalakrishnan M, Mukhopadhyay T. (2012) Isolation and characterization of a potent antimicrobial compound from Aerva sanguinolenta Blume: an alternative source of bakuchiol. Journal of Pharmaceutical Research, 5, 174-176. Samejo MQ, Memon S, Bhanger MI, Khan KM. (2012) Chemical compositions of the essential oil of Aerva javanica leaves and stems. Pakistan Journal of Analytical and Environmental Chemistry, 13, 48-52. Radwan HM, Nazif NM, Hamdy AA. (1999) The lipid and flavonoidal constituents of Aerva javonica var. bovi webb in hook. F. and their antimicrobial activity. Egyptian journal of Pharmaceutical Sciences, 40, 167-178. El-Seedi HR, Sobaih SAM. (1999) Triterpenes and flavonol glycosides from Aerva javanica. Revista Latinoamericana de Quimica, 27, 17-21. Usmanghani K, Nazir T, Ahmad VU. (1982) Sitosterol glucoside from Aerva javanica. Fitoterapia, 53, 75-77. Mussadiq S, Naheed R, Saleem M, Ashraf M, Ismail T, Jabbar A. (2013) New acylated flavonoid glycosides from flowers of Aerva javanica. Journal of Asian Natural Product Research, 15, 708-716. Saleh NAM, Mansjur RMA, Markham KR. (1990) An acylated isorhamnetin glycoside from Aerva javanica. Phytochemistry, 29, 1344-1345. Review on Aerva plants [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] Natural Product Communications Vol. 13 (3) 2018 385 Zadorozhnii AM, Zapesochnaya GG, Pervykh L N, Shchavlinskii AN, Kovtun LS, Svanidze NV. (1986) Investigation of the herb Aerva lanata. I-O-acylglycosides of flavonoids. Khimiko-Farmatsevticheskii Zhurnal, 20, 855 -858. Ahmed E, Imran M, Malik A, Ashraf M. (2006) Antioxidant activity with flavonoidal constituents from Aerva persica. Archives of Pharmacal Research, 29, 343-347. Kurkina AV, Osipova AA. (2010) New approaches to the standardization of Aerva lanata drugs. Khimiya Rastitel'nogo Syr'ya, 2, 117-121. Sulaiman CT, Balachandran I. (2012) Total phenolics and total flavonoids in selected Indian medicinal plants, Indian Journal of Pharmaceutical Sciences, 74, 258-260. Wassel GM, Ammar NM. (1987) Phytochemical study of A. lanata. Fitoterapia, 58, 367. Movaliya V, Zaveri MN. (2012) HPTLC method development and estimation of quercetin in the alcoholic extract of Aerva javanica root. Advance Research in Pharmaceuticals and Biologicals, 2, 222-228. Sharif A, Ahmed E, Malik A, Hassan M, Munawar MA, Farrukh A, Nagra SA, Anwar J, Ashraf M, Mahmood Z. (2011) Antimicrobial constituents from Aerva javanica. Journal of the Chemical Society of Pakistan, 33, 439-442. Imran M, Riaz N, Ibrahim M, Ahmad E, Rasool MA, Malik A, Moazzam M. (2009) Further phytochemical studies on Aerva persica. Journal of Chemical Society of Pakistan, 31, 126-130. Garg SP, Bhushan R, Kapoor RC. (1979) Chrysin-7-O-galactoside; a new flavonoid from Aerva persica. Indian Journal of Chemistry, 17, 416-417. Jaswant B, Ragunathan V, Sulochana N. (2003) A rare flavonol glycoside from Aerva tomentosa Forsk. as antimicrobial and hepatoprotective agent. Indian Journal of Chemistry, 42, 956-958. Pervykh, LN, Karasartov, BS, and Zapesochnaya GG. (1992) A study of the herb Aerva lanata. IV. Flavonoid glycosides. Chemistry of Natural Compound, 28, 509-510. Garg SP, Bhushan R, Kapoor RC. (1980) Aervanone, a new flavonoid from Aerva persica. Phytochemistry, 19, 1265-1267. Zapesochnaya GG, Kurkin VA, Pervykh LN. (1990) Constituents of the herb Aerva lanata. II. Feruloyl amides. Khimiya Prirodnykh Soedinenii, 5, 694-695. Vijayalakshmi R, Ravindhran R. (2012) HPTLC method for quantitative determination of gallic acid in ethanolic root extract of Diospyros ferrea (Willd.) Bakh and Aerva lanata (L.) Juss. Ex Schultes - a potent indian medicinal plants. Asian Journal of Pharmaceutical and Clinical Research, 5, 170-174. Imran M, Ibrahim M, Riaz N, Malik A. (2009) Structure determination of Aervins A-D, new coumaronochromone analogues from Aerva persica, by 1D and 2D NMR spectroscopy. Magnetic Resonance in Chemistry, 47, 532-536. Zapesochnaya G, Kurkin V, Okhanov V, Miroshnikov A. (1992) Canthin-6-one and β-carboline alkaloids from Aerva lanata. Planta Medica, 58, 192-196. Zapesochnaya GG, Pervykh LN, Kurkin VA. (1991) A study of the herb Aerva lanata. III. Alkaloids. Chemistry of Natural Compounds, 27, 336340. Ammar N, El-Sayed NH, Tabl ESA, Wahab SA, Wassel G, Afifi M. (1996) Study of the alkaloidal contents of Aerva species, family Amaranthaceae, growing in Egypt. Revista Latinoamericana de Quimica, 25, 1-3. Mandal A, Ojha D, Lalee A, Kaity S, Das M, Chattopadhyay D, Samanta A. (2015) Bioassay directed isolation of a novel anti-inflammatory cerebroside from the leaves of Aerva sanguinolenta. Medicinal Chemistry Research, 24, 1952-1963. Cai Y, Sun M, Corke H. (2001) Identification and Distribution of Simple and Acylated Betacyanins in the Amaranthaceae. Journal of Agriculture and Food Chemistry, 49, 1971−1978. Abdel Wahab SM, Wassel GM, Aboutabl EA, Ammar NM, Afifi MS. (1998) Investigation of saponin content and lipoidal matter in two Aerva species growing in Egypt. Egyptian Journal of Pharmaceutical Sciences, 38, 209-220. Zhao Y, Deepak K, Prasad DN. (2015) Morphoanatomic, physicochemical, and phytochemical standardization with HPTLC fingerprinting of aerial parts of Aerva lanata (Linn) Juss ex Schult. Journal of Traditional Chinese Medical Sciences, 2, 39-44. Mallabaev A, Rakhimov DA, Murdakhaev YM. (1989) Carbohydrates of Aerva lanata. Khimiya Prirodnykh Soedinenii, 3, 425-426. Harsh GR, Kapoor BBS. (2004) Ascorbic acid contents of some arid zone medicinal plants of Rajasthan, Oikoassay, 19, 49-50. Gerald B, Yang MH, Gabor J, Mathe I, Carabot-Cuervo A. (1998) Betaine distribution in the Amaranthaceae. Biochemical Systematics and Ecology, 27, 87-92 Omotoso S, Aigbe F, Olanrewaju A. (2017) Toxicological evaluation of the aqueous whole plant extract of Aerva lanata (l.) Juss. ex Schult (Amaranthaceae). Journal of Ethnopharmacology, 208, 174-184.