Abstract

Introduction

The genus Adonis L. (Ranunculaceae), native to Europe and Asia, comprises 32 annual or perennial herbaceous species and grows in temperate regions of the northern hemisphere (Ghorbani et al., 2008; Orhan et al., 2017). The genus was named after the Greek mythological character, and Adonis spp. have long been used in European and Chinese folk medicine for their cardiac-enhancing effects (Abduchamidov et al., 1971; Felter and Lloyd, 2006). Due to the marked effects on heart disease, researchers began focusing attention on the genus Adonis (Shikov et al., 2014). With advancements in phytochemistry research, greater numbers of compounds were isolated from the plants of this genus (Heyl et al., 1918); the compounds exhibiting significant cardiovascular activity were primarily classified as cardiac glycosides (Katz and Reichstein, 1947; Deng et al., 1963; Chi et al., 1985). These reports further substantiated the traditional uses of these plants for cardiac enhancement (Shikov et al., 2014). Moreover, flavones, carotenoids, coumarins and other structural classes were identified, and additional pharmacological activities were found, including antiangiogenic, antibacterial, antioxidant and anti-inflammatory activities, as well as effects on the central nervous system, a diuretic effect and acaricidal activity (May and Willuhn, 1978; Gu et al., 1980; Wang et al., 1981; You et al., 2003; Das et al., 2007; Shang et al., 2012, 2013, 2017; Mohadjerani et al., 2014). These newly discovered compounds and their previously unknown bioactivities advanced and promoted the development of the genus Adonis (Yang et al., 2015).

In the late 19th century, the cardiovascular activity of Adonis vernalis L. distributed in the Eurasian region was observed. And since the early 20th century, extracts of this plant enriched in cardiac glycosides were prepared to treat chronic heart failure in the former Soviet Union and Germany. In China and other East Asian countries including Korea, and Japan, A. amurensis Regel & Radde was studied and used to treat heart diseases in the mid-20th century due to a shortage of cardiotonic agents (Deng et al., 1963). Additionally, the toxicity of these plants became apparent, and Adonis-induced poisoning cases in both humans and animals were observed (Hurst, 1942; Galey et al., 1996; Woods et al., 2004).

Until recently, researchers have made great advances in studying the phytochemical and pharmacological activities of genus Adonis. However, no review article discussing these achievements is available in the literature. This review strives for a complete overview of the existing botanical knowledge, traditional uses, phytochemistry and pharmacological research of species belonging to the genus Adonis. Available information on these species enables us to explore their therapeutic potential, to highlight the gaps in our knowledge and to provide the scientific basis for future research.

Methods

As well as two reviews published by Kooti et al. (2016, 2018), in this review we searched the information on this genus from databases (using Elsevier, ACS, Springer, Wiley, Nature, RSC, Medline Plus, Bentham Science, Hindawi Science, CNKI, VIP, Web of Science, Google Scholar and Baidu Scholar) and libraries, and the search languages were set to English and Chinese. We didn’t set the time period for searching more literatures. The keywords were searched as Adonis for English literatures, Cejinzhan () and/or Fushoucao () for Chinese literatures. Three experts collected the literatures.

Botany

The generic name Adonis refers to the mythic character Adonis, a lover of the goddess Aphrodite or Venus. Plants belonging to the Adonis genus are native to Europe and Asia and have been introduced to North America. It includes approximately 32 annual or perennial herbaceous species of flowering plants of Ranunculaceae. In “The Plant List,” 143 scientific plant names of species rank for the genus Adonis are included, and of these 32 are accepted species names (The plant list, 2013). Basal and lower stem leaves are usually scaly and upper stem leaves alternate and are palmately or pinnately divided. One-flowered inflorescences terminate on branches or branchlets with absent bracts. The flowers are radially symmetric, bisexual and usually red, orange, or yellowish, having 5 to 30 petals. The plants possess numerous stamens and spirally arranged pistils, linear filaments, and one-ovuled ovaries with persistent styles and small stigma. The plants have achenes, usually with raised veins, and the leaves and roots are poisonous to humans and livestock (Heyn and Pazy, 1989; Gostin, 2011; Flora of China, 2018). Due to the beauty of the flower, the plants of this genus were used historically for ornamental purposes in some countries. Only in Germany, the former Soviet Union and some East Asian countries some species and their extracts were used as cardiac agents, especially A. vernalis and A. amurensis (Table 1 and Figure 1).

Table 1

The accepted plant names by The Plant List.

Name	Distribution	Traditional uses	Others	Reference
Adonis aestivalis L.	Native to Europe and Asia, was introduced into North America	Medicinal and ornamental plant	Stems 10–20 cm tall. Sepals narrowly rhombic to narrowly ovate, membranous. Petals orange.	Burrows and Tyrl, 2001
Adonis amurensis Regel & Radde	Native to Japan, Russia, Korea, and China	Medicinal plant	Stems 5–15 cm tall in flower, to 30 cm tall in fruit. Flowers 2.8–3.5 cm in diameter, sepals pale grayish purple, Petals yellow.	Shimizu et al., 1967; Flora of China, 2018.
Adonis annua L.	Native to North Africa, Western Asia, the Mediterranean, Europe	–	It is endangered and listed as a priority species in United Kingdom	Egger, 1965
Adonis bobroviana Simonov.	Native to China	–	Stems to 30 cm tall. Flowers 2–4 cm in diameter Sepals pale green tinged with purple, Petals yellow, abaxially tinged with purple.	Flora of China, 2018
Adonis chrysocyathus Hook.f. & Thomson	Native to Greek, and cultivated in the botanical gardens of Copenhagen or Gothenburg	–	Heights from 203 to 381 mm. Orange or yellow flowers. Flower color is variable within the species and changes with drying.	Heyn and Pazy, 1989
Adonis coerulea Maxim.	Native to China	Treating mange	Stems 3–15 cm tall. Flowers 1–1.8 cm in diameter Sepals obovate-elliptic to ovate, apex rounded. Petals ca. 8, pale purple to pale blue.	Shang et al., 2013; Flora of China, 2018
Adonis davidii Franch.	Native to China and Bhutan	–	Stems 10–58 cm tall. Stem leaves with petiole to 7 cm basally on stem, shortly petiolate or sessile toward stem apex; flowers 1.5–2.8 cm in diameter Sepals glabrous, rarely ciliate. Petals white, sometimes tinged with purple.	Flora of China, 2018.
Adonis flammea Jacq.	Distributes in the Anatolia, the Levant Central and Southern Europe	–	It is similar to A. annua but is more robust with large flowers with narrow and oblong petals, dark scarlet sepals that are attached to the petals.	Catalogue of Life, 2017
Adonis microcarpa DC.	Native to western Asia and southern Europe and is introduced in Australia	–	50 cm tall, has finely divided foliage and red flowers with black centers.	Kloot, 1976
Adonis multiflora Nishikawa & Koji Ito	Native to Korea, Japan, and Manchuria	Ornamental plant	20–25 cm tall at flowering with up to four yellow flowers per stem.	Lee et al., 2003
Adonis ramosa Franch.	Native to Japan, Russia, Korea, and China	–	Stems 4–20 cm tall, 1.2–2 mm in diameter Flowers 2.5–4 cm in diameter Sepals gray-purple. Petals yellow.	Flora of China, 2018
Adonis shikokuensis Nishikawa & Koji Ito. Or Adonis sibirica (Patrin ex DC.) Ledeb.	Native to Mongolia, Russia; Europe and China	Medicinal uses	Stems ca. 40 cm tall, 3–5 mm in diameter Sepals yellowish green, rounded-ovate. Petals yellow, narrowly obovate.	Flora of China, 2018
Adonis sutchuenensis Franch.	Native to China	–	Stems 15–40 cm tall, Flowers 2–4.8 cm in diameter Sepals pale green, usually oblanceolat. Petals yellow,	Flora of China, 2018
Adonis tianschanica (Adolf) Lipsch.	Native to Russia and China	–	Stems ca. 30 cm tall. Flowers 3.5–5 cm in diameter Sepals pale purple, slightly shorter than petals.	Flora of China, 2018
Adonis vernalis L.	Natively in central Europe and in Asia	Cardiac stimulant and ornamental plant	The flowers appear in springtime, and are up to 80 mm in diameter, with up to 20 bright yellow petals	Heyl et al., 1918

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The general description of following species hasn’t been done, including Adonis aleppica Boiss, Adonis apennina L., Adonis cyllenea Boiss., Heldr. & Orph., Adonis dentata Delile, Adonis distorta Ten., Adonis eriocalycina Boiss., Adonis globosa C.H.Steinb. ex Rech.f., Adonis × hybrida C.F.Wolff ex Nyman., Adonis leiosepala Butkov., Adonis mongolica Simonov., Adonis nepalensis Simonov., Adonis nepalensis Simonov., Adonis palaestina Boiss., Adonis pyrenaica DC., Adonis turkestanica (Korsh.) Adolf., Adonis villosa Ledeb., Adonis volgensis Steven ex DC., Adonis wolgensis Steven.

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FIGURE 1

The pictures of five plants grown in China.

Traditional Uses

Adonis vernalis, known as the Bird’s eye, Pheasant’s eye or False Hellebore, is a perennial, dry grassland plant species distributed in the Eurasian region along a 4698-km longitudinal transect from Russia to Spain (Hirsch et al., 2015). This species prefers calcium-rich chernozem soils of various types but also grows in meadow chernozems and gray forest soils (Poluyanova and Lyubarskii, 2008). It is listed in the German Homoeopathic Pharmacopoeia (Shikov et al., 2014). Historically, it was used to treat edema by local people of the former Soviet Union. Extracts of the plant were first introduced into medicine as a cardiac stimulant in 1879 by the Russian medical doctor, N. O. Buhnow, and A. vernalis has attracted the interest of many people ever since. In 1898, a mixture of this medicine with sodium bromide (or potassium bromide) or codeine was suggested to treat light forms of epilepsy and heart diseases (Bekhterev, 1898; Shikov et al., 2014). Over the intervening years, an ethanolic extract of the aerial parts of A. vernalis was prepared as an alternative cardiac agent in the former Soviet Union. The biological activity of this extract was defined as 50–66 frog units or 6.3–8.0 cat units (Chiang and Mi, 1958; Wagler, 2001). Now, in Russia, the aerial part as a cardiotonic, was applied in the clinics for internal use at the dose of 1 tablespoon of the infusion (7:200) 3–5 times per day (Sokolov et al., 2000; Shikov et al., 2014).

Ten species are distributed in China. One thousand years ago, plants belonging to the Adonis genus in China (Chinese name: Binglianghua or Fushoucao) were recorded in the ancient book “Gui Hai Yu Heng Zhi” written by Fan Chengda, a notable historical figure from the Song dynasty. The well-known classical book of Chinese materia medica, “Ben Cao Gang Mu,” also noted the effect (Keshan Research Group of Jilin Medical University, First Clinical College, Second Clinical College, Third Clinical College of Jilin Medical University, 1977), and raw materials have been used in folk medicine for the treatment of heart diseases and edema (Bae, 2000). During the 1950s, due to the shortage of cardiac agents, Adonis sp. distributed throughout China were widely studied and developed. These efforts resulted in the isolation and further study of the cardenolide-enriched extracts of A. amurensis. After comprehensive pharmacological tests, the extracts were prepared and developed in a new preparation that was used to clinically treat human heart failure (Coronary Disease Control Group of Liaoning TCM College’s Hospital, 1971). In 1975, the raw material of this plant was listed in the Pharmacopeia of the People’s Republic of China (Committee for the Pharmacopoeia of P. R. China, 1975). In Siberia, the aqueous extract of the aerial parts was used to treat malaria, kidney disease and other heart-related diseases (Utkin, 1931; Nosal and Nosal, 1960).

Phytochemistry

Since the first compound was isolated from Adonis plants in the early 19th century, more than 120 compounds have been isolated and identified to date. Fifty-four cardiac glycoside compounds were identified as active components. Additionally, flavones, carotenoids, coumarins and other compounds were also isolated and reported (Table 2). The chemical structures of active compounds isolated from the genus Adonis were listed in Figure 2.

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FIGURE 2

The chemical structure of some active compounds from the genus Adonis.

Analysis of Active Constituents and Quality Control

Due to the marked cardiac-enhancing effects, Adonis spp. have long been used in European and Chinese folk medicine, and some species, such as A. amurensis, have been historically applied in the clinic to treat heart diseases. To examine the active compound content in different parts of the plants and in different species, high-performance liquid chromatography (HPLC) and other chromatographic methods were utilized. Wang et al. (1991) reported that the highest content of total cardenolide glycosides was found in the roots of A. amurensis during the germination period with the lowest content levels isolated during the mature fruit phase. Chromatography of cardiac glycosides in A. amurensis used CH₃OH: H₂O (65:35) as the mobile phase with an ODS column (150 mm × 6.0 mm) at a flow rate of 0.80 mL/min monitored at 218 nm. The contents of convallatoxin, strophanthidin, cymarin, and aglycones A and B found in cardenolide-enriched extract were 6.58, 2.09, 2.54, 4.49, and 2.11%, respectively, in a chloroform-ethanol (1:1) fraction of an ethanolic extract (Gu et al., 1990). Liu and Cui (2007) studied the content of convallatoxin of A. amurensis obtained from various habitats throughout China. The results quantified the contents of the aerial parts and roots harvested from Liaoning province (0.0022 and 0.1400%), Jilin province (0.0019 and 0.1300%) and Heilongjiang province (0.0014 and 0.0790%). The amounts of somalin, k-strophanthoside and k-strophanthin-β in A. pseudoamurensis were determined to be 0.024, 0.13, and 0.071%, respectively (Gu et al., 1989).

Pharmacology

Toxicity

Animals consuming plants containing cardiac glycosides typically develop fatal digestive and cardiac disturbances (Galey et al., 1996), and many acute animal poisonings have been attributed to the Adonis spp. cardiac glycosides since 1912. These species include but are not limited to, A. aestivalis, A. annua, A. amurensis, A. autumnalis, and A. microcarpa (Maiden, 1912). The first experimental feeding trial was performed in 1929, and the results demonstrated that A. annua was lethal to sheep when fed 1.0 lb of fresh plant, the seed-bearing mature stage of the plant and extracts of the partially dried plant. However, feeding cattle 2 to 6 lb daily for 36 days failed to elicit clinical signs and death (Hurst, 1942). In 1932, toxicosis in horses was reported based on natural exposure to Adonis sp. (Degen, 1932; Kummer, 1952).

Woods et al. (2004) first reported Adonis toxicosis in North America. After eating grass hay containing A. aestivalis, three horses died. The signs of colic first appeared 24–48 h after initial exposure to the hay, and gastrointestinal stasis and myocardial degeneration of the horses were noted in subsequent clinical examinations. In 2007, the toxicity of A. aestivalis in calves was studied. Four Holstein and preruminating Jersey calves were administered 1% bodyweight of A. aestivalis (containing 11–98 mg/g of strophanthidin) via a stomach tube and monitored for clinical signs for 2 weeks and 1 week, respectively. The Holstein calves were then fed 0.2–1% bodyweight daily for 4–5 weeks. They had transient, mild cardiac abnormalities during the feeding trial, and mild transient gastrointestinal and cardiac signs were also noted in the preruminating calves. The above results showed that cattle are less susceptible than horses to cardiotoxic effects and sudden death after ingestion of relatively small quantities of A. aestivalis (Woods et al., 2007). Finally, the toxicity of A. aestivalis in sheep (ewes) was investigated in 2010. Results showed that after administrating 1% bodyweight to ewes for 24 and 48 h, the ewes all exhibited transient sinus arrhythmias, and two of the three ewes exhibited transient reduced fractional shortening. Moreover, after administering 0.2% bodyweight daily for 2 weeks, two ewes had reduced fractional shortening after the low-dose treatment regimen. No gross or microscopic lesions were seen when the ewes were examined postmortem at the end of the study (Woods et al., 2011).

In 1962, the toxicity of A. amurensis was first studied. After perfusing the cardenolide-enriched extract intravenously, the minimum lethal doses against cats and pigeons were 46.2 and 78.6 mg/kg, respectively (Kuo et al., 1962). In 1973, the toxicity to cats of the total glycoside preparation of A. amurensis was studied by observing the electrocardiogram, with results indicating that the minimum lethal dose in cats was 0.75 mg/kg (i.v.), while the minimum lethal doses of cedilanid and k-strophanthin were 0.77 and 0.49 mg/kg, respectively. The accumulative rates in body at 24 and 48 h were 74.2 and 23.8%, respectively, and at 74 h, the accumulative rate was less than 5%. The above results indicated the accumulative toxicity of the extract was lower than that of digitoxin and convallatoxin, higher than that of k-strophanthin (Shuguang Medical Team of Anshan City et al., 1973). The minimum lethal dose in pigeons was 1.469 ± 0.201 mg/kg (i.v.) (Shi et al., 1979). Acute toxicosis in mice and cats was also observed after intravenous administration of Adonis-like glycosides and the strophanthidin aglycone in the laboratory (Chen et al., 1951; Greeff and Kasperat, 1961).

Davies and Whyte (1989) found that feeding the seed of A. microcarpa (5.6 g/kg) induced total feed refusal within 3 days in growing and mature pigs, causing vomiting, rapid and shallow breathing, and even one pig died. These effects were probably caused by the cardiac glycosides and subsided within 2 weeks of removal of the seed. The toxicities of active compounds also were studied. The LD₅₀ of cymarin after intravenous injection in rats and cats were 24.8 and 95.4 mg/g, respectively (Chen et al., 1942; Vogel and Kluge, 1961); and the LD₅₀ for adonitoxin was 191.3 μg/kg (Chen and Anderson, 1947). Meanwhile, the average minimum dose producing a permanent systole (M.S.D.) values for above two compounds were 0.621 and 0.88 g/g frog, respectively (Chen and Anderson, 1947). After continuous intravenous infusion in dogs, the minimal lethal doses of adonidoside and adonivernoside at 30 min were found to be 0.7 and 1.75 mg/kg, respectively, and when they were used together, the LD₅₀ was 1.14 mg/kg (Lenel-Pekelis, 1949). Kovaříková and Chen (1965) studied the activities of 16-hydroxy-strophanthidin, 16-formyloxy-strophanthidin, acetyladonitoxin, and tetracetyladonitoxin, and results showed that the LD₅₀ in cats were 1.121, 0.1518, 0.3881, and 4.397 mg/kg, respectively.

In China, cases of A. amurensis poisoning in humans who misused or overdosed the plant have been noted. In most cases, the patient heart rate was seriously abnormal (Wang and Feng, 1982; Sun, 1988; Zhang, 1999).

Conclusion and Remarks

Because of the marked effects as a cardiotonic agent in treating heart diseases, some species of the genus Adonis L. and their extracts have been widely used clinically in some countries, including the use of A. vernalis and A. amurensis in Russia and China. To provide a comprehensive review, the information on this genus was gathered via the internet and libraries, and the search languages were set to English and Chinese. The native languages of some articles (written in Bulgarian, Russian and German) as well as other factors including older publication dates and the absence of an English abstract made it impossible for us to cite and understand some articles. Although the pharmacological effects of this plant were widely studied in Russia before 1950s, much of the relevant literature is hard to access (Shikov et al., 2014). As a result, some older studies published in various languages were not included in this review and should be examined and reviewed further. Recently, the review of botany, traditional use, phytomedicine, pharmacology and toxicity of A. vernalis provides comprehensively information for this plant used in Europe (Latté, 2018).

According to the website www.theplantlist.org, 32 species from the genus were accepted as native to Europe and Asia. However, with the exception of A. vernalis, A. aestivalis, and A. amurensis, the phytochemistry and the modern pharmacology of most of the species have not been investigated comprehensively and clinically validated. Although A. vernalis has been become a well-known herbal medicine for cardioprotection, especially in Russia, Bulgaria, etc. (Popiliev et al., 1973; Sorokina, 1989; Wichtl, 1990), only small numbers of in vitro and in vivo studies on their cardioprotective effects are available (Popiliev et al., 1973). Considering that some clinical studies assayed about 50 years old are not valid anymore, the development of this genus should be paid more attention.

To date, more than 120 chemical components have been isolated and identified from the genus Adonis. With the exception of the cardiac glycosides, some well-known flavones in the genus also were isolated and identified with the wide pharmacological activities, including antioxidant, anti-microbial, anti-inflammatory, cardioprotective, neuroprotective, and anti-allergic properties, and these compounds should be paid more attention (George et al., 2017; Aziz et al., 2018; Guo et al., 2018; Kim et al., 2018).

Additionally, A. vernalis is a medicinal plant whose above-ground parts at the flowering or fruiting stages are harvested from the wild as a raw material for the pharmaceutical industry in China. In the past century, with the abundant use of A. vernalis as well as a lack of xerothermic habitats and slow plant growth among others, this resource has rapidly decreased and is close to extinction (Lange, 2000; Baier and Tischew, 2004; Denisow et al., 2014). Meanwhile, owing to the weak germination of the seeds and the slow growth intensity of the plants, the cultivation is unsuccessful (Galambosi, 1980a,b). Since 1982, it has been protected in several countries and the trade of this plant was banned in many East European countries (Lange, 2000). Therefore, investigation of sustainable usage practices is still necessary. This introduces the urgent problem of cultivation on a commercial scale, which would be useful for its conservation (Poluyanova and Lyubarskii, 2008).

In short, the phytochemical and pharmacological studies of the genus Adonis L. have received much interest. Extracts enriched in cardiac glycosides have been developed, and active compounds have been isolated and proven to provide cardioprotective activity. However, plants of this genus should be studied and developed further, with particular attention paid to conservation of resources and clinical testing.

Author Contributions

XS and JZ conceived the review. XS, XG, XM, YZ, and BL wrote the manuscript. FY, HP, WW, and CW collected the literatures. YZ and CW edited the manuscript. All authors read and approved the final version of the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

References