Overview of Pharmacological Research on Adonis L.

Wenhui YANG，Xiaowei ZHANG，Wenjin XU，Haiyan HUANG，Yarong MA，Han BAl，Jiang GONG，Shifeng Nl.The College of Life Sciences，Northwest University，Xi’an 70069，China；.Physics Department of Medicine，Northwest University，Xi’an 70069，China；3.Tibet Nationality College，Xianyang 708，China

Overview of Pharmacological Research on Adonis L.

Wenhui YANG1，Xiaowei ZHANG2，Wenjin XU1，Haiyan HUANG1，Yarong MA1，Han BAl1，Jiang GONG3*，Shifeng Nl2
1.The College of Life Sciences，Northwest University，Xi’an 710069，China；
2.Physics Department of Medicine，Northwest University，Xi’an 710069，China；
3.Tibet Nationality College，Xianyang 712082，China

On the basis of extensive literature retrieval，the species，composition，pharmacology，clinical application，contraindication of Adonis L.were reviewed in this paper，to provide data for the its further development and utilization.

Adonis L.；Composition；Pharmacology；Clinical applications；Contraindication

l ntroduction to Adonis L.Plants

Species generalization

Adonis L.，also known as Adonis amurensis Regel et Radde，derived from the Greek word Adonis，meaning the flower that developed from the death of the god of beauty and love Venus’s husband［1］.It is a species of the Ranunculaceae family，which has about 30 species，4 subspecies，11 varieties and2forms around the world，mainly distributed in Asia and Europe［2-4］.Most annual or perennial herbs，Adonis L.have leaves alternate，yellow or red flowers and aggregate achenes，making it an important nectar sources in spring［5-6］.

Currently，there are about 10 species in China，namely Adonis aestivatis L.，A.aestivates var.parviflora M.Bieb，A.amurensis Regal et Radde，A.bobroviasvi Sirm，A.brevistyla Franch.， A.chrysocyatha Hook.f.et Thoms，A.coerulea Maxim.，A.peudoamnremsis W.T.Wang，A.sibirioa Patr.ex Ledeb.，A.satchueasis Franch. （commonly known as Corydalis saxicola Bunting）and A.tiamschanica（Adolf）Lipsch.

ldentification method

Generally speaking，Adonis L. can be directly identified through the proper characters［7］.Paraffin section method could fulfill the microscopic identification of A.peudoamnremsis W.T.Wang in northeast China［8］. A.satchueasis Franch.can be identified by its proper characters，microscopic structure as well as the physico-chemical properties of related compositions［9］.

Resources distribution

Most species of Adonis L.genus mainly grow in moist soil with plenty of humus like the hillside bushes in northern，northwestern and southwestern areas［3-6］.Northeast China and Xinjiang area are rich in Adonis L.resources，while northwest Yunnan is abundant with A.brevestyla Franch［3］.

Compositions

Kubo［10］reported that chemical investigation of the seeds of Adonis aestivalis had led to the isolation of a new cardenolide（3β，5α，14β，17β-tetrahydroxycard-20，22-enolide） （1），two new glycosides （2，3）of 1，and a new strophanthidin hexaglycoside（4），together with a known compound，strophanthidin3-O-β-D glucopyranoside（5）.

Maoka［11］reported that carotenoids and their fatty acid esters were investigated in the petals of Adnois aestivalis by UV-VIS，（1）H-NMR，FABMS，and CD spectromety.（3S，3’S）-astaxanthin （diester:72.2% ，monoester:13.8%，free:1.4%）and（3S）-adonirubin （monoester:13.8%，free: 0.3%）were identified as the major components.

DAI［12］reported that eight compounds were isolated from Adonis coerulea Maxim and their structures were identified by the spectra evidences as 1-hentriacon tanol，p-formyl cinnamic acid，apigeni，luteolin，orientin， luteoloside， isorientin， and adonitol.

Kuroda［13］reported that five new pregnane tetraglycosides，amurensiosides A-E 91-5），two new pregnane hexaglycosides，amurensiosides F（6）and I（9），two new 18-norpregnane hexaglycosides，amurensiosides G（7）and H （8），and two new pregnane octaglycosides，amurensiosides J（10）and K （11），were isolated from the MeOH extract of the roots of Adnois amurensis.

The main active ingredient of Adonis L.is cardenolide.It has reported that the plants of this genus almost all contain cardenolide （such as strophanthin，digitoxin）.Moreover，there are also non-cardiac glycosides（such as li-neolone，isolineolone，Adonilide，coumarins， K-Strophanthin-βand adonitoxin etc.）［3，7］.

LIU［14］reported that the content of convallatoxin was the highest during the flowering phase of Adonis L.，and there were significant differences in the varieties and contents of the active ingredients of various varieties in different areas.

You［15］reported that antiangiogenic activity-guided fractionation and isolation carried out on the methanol extract of Adonis amurensis led to the identification of three compounds，namely cymarin，cymarol and cymarilic acid.

Pauli［16］reported that two kinds of oligoglycosidic cardenolides were deduced from Adonis aleppica with the structures of strophanthin-3-O-β-glucopyranosyl-（1-＞4）-O-β-diginopyranosyl-（1-＞4）-O-β-oleandropyranosyl-（1-＞4）-O-β-digitoxopyranosyl-（1-＞4）-O-β-digitoxopyranoside and strophanthin-3-O-β-glucopyranosyl-（1-＞4）-O-β-oleandropyranosyl-（1-＞4）-O-β-digitoxopyranosyl-（1-＞4）-O-β-digitoxopyranoside.

Kopp［17］reported that two new cardenolides were structurally elucidated from the aerial parts of Adonis aestivalis，namely strophanthidin-3-O-β-D-digitoxosido-α-L-cymarosido-β-D-glucoside and strophanthin-3-O-β-D-digitoxosido-β-D-diginosido-β-D-glucoside.

ZHANG［18］studied the chemical constituents of Adonis coerulea Maxim a Tebetan medicinal herb and isolated eight compounds，namely，stigmast-4-ene-3，6-dione，stigmast-4-ene-3-one，6β-hydroxy，orientin，β-D-glucopyranoside， apigenin，palmitic acid，adonitol and β-sitosterol.

GU［19］studied the Adonis amurensis and isolated 6 cardiac glyeosides from it，namely，somalin，strophanthidin，cymarin，convallatoxin glycosides，aglycone A and cymarinol，as well as extracted two cardiac glycosides with the molecular weight of 404 and 396 respectively.

GU［20］separated and discovered K-strophanthoside，k-strophanthin-β and Somalin from Adonis Pseudoamurensis.

ZHANG［21］determined twenty-eight inorganic elements in the roots，stems and leaves from Adonis amurensis Regel et Radd by means of fluorescence，among which the contents of Ca，K，Mg，P and Na were comparatively higher；among the essential trace elements，contents of Fe，Sr，Mn，Zn，Cu，Li，Ni，Cr，V，Mo，Co and Se，the first four were the highest；the harmful trace elements Pb，Cd，Hg and Be were less than their toxic doses（leaves ere the sensitive part rich in these elements）.Environmental Geological Research Group，Institute of Geochemistry Chinese Academy of Sciences［22］reported that Adonis L. could gather lithium that the lithium content in water extract was 28，28 μg/g in alcohol extract，40 μg/g in whole plant ashing（both dry weight）.

Pharmacological Research

Cardiotonic effect

QIN［23］reported that throught studies on the influence of ethanol extract，internal fat liquor of Adonis amurensis Regel et Radde，ketone liqour on the rabbi’s movement of Atrial muscle in virto，it had been found that the liquor of leaf，stem and root had the cardiotonic function.CHI［24］reported that the total glycoside of Adonis pseudoamurensis W.T.Wang（APAW）could enhance myocardial contractility，but the effect on diastolic function dysfuncion was weak，which might be affected by the heart contraction level before drugs application；with rapid onset，it could slowly decrease the normal heart rate under therapeutic doses，and with relatively larger therapeutic index and safety margin，it could be regarded as a better cardiotonic drug with positive inotropic action and larger treatment range.SHEN［25］reported that only using the total glucosides of Adonis L.lacked antiarrhythmic effects，while combining with disopyramide could achieve synergistic effect，which could also enhance the efficacy of other antiarrhythmic drugs.

Central sedation

The study of GU［26］showed that the total glycosides of Adonis L.had inhibitory effect on the cerebral cortex and the respiratory center.After intravenous injection of the total glycosides of Adonis L.to the rabbits，the cerebral cortex appeared high amplitude slow wave，and the response to acoustic stimuli weakened.

Diuretic action

WANG［27］reported that the total glycosides of Adonis L.showed secondary diuretic effect on the edema with insufficiency cardiac function.It also had a diuretic effect on anesthetized dogs，of which the urine had higher content of chlorine，sodium and potassium than the control，and the study also suggested that the mechanism of the diuretic effect may be achieved by inhibiting the reabsorption of renal tubular to chlorine，sodium，potassium ions.

Killing epizoa

SHANG［28］reported that the ethyl acetate extract of A.coerulea Maxim showed good activity of killing rabbit mites.

Clinical Application

Circulation system

The medicinal materials are usually used in the treatment of congestive heart failure，Keshan disease，coronary heart disease，pulmonary heart disease and a variety of other heart diseases［29-30］.It has especially good effects on the heart failure with rapid atrial fibrillation，and the intravenous injection has fast acting.Oral administration also shows fast acting，long duration and small accumulation［30］.JIANG［31］reported that the oral administration of Adonis L.medicinal liquor could activate blood circulation to dissipate blood stasis and blood Qi.

Nervous system

The combined application of this medicinal material and sodium bromide could strengthen the treatment of epilepsy［29］.

Cytotoxicity

Kubo［10］reported that strophanthidin hexaglycoside and strophanthidin 3-O-β-D-glucopyranoside，which were found in the seeds of Adonis aestivalis，displayed selective cytotoxicity toward malignant tumor cell lines，which could trigger caspase-3-independent apototic cell death in HL-60 and HSC-2 cells.Kuroda［13］reported that five new pregnane tetraglycosides，amurensiosides A-E，two new pregnane hexaglycosides，amurensiosides F and I，two new 18-norpregnane hexaglycosides，amurensiosides G and H，and two new pregnane octaglycosides，amurensiosides J and K were isolated from the MeOH extract of the roots of Adonis amurensis，all of which showed cytotoxic activity against HSC-2 human oral squamous cell carcinoma cells.You［15］reported that the cymarilic acid，which was isolated from the methaol extract of Adonis amurensis，showed no significant cytotoxicity against tumor cell lines but was found to be strongly inhibitory toward tube formation induced by human umbilical venous endothelial（HUVE）cells；moreover，cymarin and cymarol exhibited potent cytotoxicity against a human solid tumor cell line A549（human lung carcinoma），while being inactive on murine leukemic cells（L1210）.

Precautions for Use

Woods［32］reported the toxicity of Adonis aestivalis （adonis）in sheep that first，high-dose toxicity study:adult Suffollk ewes were administered 1 percent bodyweight adonis via surgically placed rumen cannulas in an acute；second，low-dose toxicity study: 0.2 percent bodyweigth daily in a twoweek.The ewes received cardiac examinations before dosing，24 and 48 h after dosing with 1 percent bodyweight adonis，and after continuous low-dose administration:all ewes administered adonis had transient sinus arrhytmias after receiving 1 percent bodyweight adonis.Two thirds of the ewes had transient reduced fractional shortening after administered with1percent bodyweigh adonis.The same two ewes had reduced fractional shortening after the low-dose treatment regimen.However，no gross and microscopic lesions were seen when the ewes were examined postmortern at the end of the study.

Woods［33］reported that toxicosis of Adonis aestivalis was well documented in horses，but little was known of its toxicity in cattle.A.aestivalis was collected over multiple years，under different growing conditions，and at various stages of maturity，dried and administered to calves to evaluate the toxicity of A.aestivalis in cattle.Holstein and preruminating Jersey calves were administered 1%body weight of ground A.aestivalis 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%body weight A.aestivalis daily for 4-5 weeks.The test found that the Holstein calves had transient，mild cardiac abnormalities during the feeding trial，while mild，transietn gastrointestinal and cardiac signs were noted in the preruminating calves.No gross or microscopic lesions were seen on necropsies performed at the end of the study.

Large dosage of adoniside to people could cause toxic reactions，mainly performances included arrhythmia，gastrointestinal disorders，abnormal hyperfunction in nervous system， and therefore， attention should be paid to controlling the dose which should be calculated in crude drug，and people should take no more than 1 g each time［34-35］.

Summary and Prospect

With wild distribution and large amount of resources in China，Adonis amurensis plants have cardiac glycosides and many other kinds of active ingredients，and it mainly used for the treatment of congestive heart failure and other cardiac diseases in clinical application （with certain toxicity and therefore attention should be paid to the dosage）.Currently，there is not sufficient research on the pharmacology of other active ingredients and clinical application，and therefore，analysis on its active ingredients and clinical application should be further analyzed to the further reasonable development of this drug and for the indepth research of related studies so as to let the Adonis L.plants provide new choices for human health.

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Responsible editor:Na LI

Responsible proofreader:Xiaoyan WU

侧金盏属植物药学研究新进展

杨文慧1，张小伟2，徐文进1，黄海艳1，马亚荣1，白晗1，巩江3，倪士峰1（1.西北大学生命科学学院，陕西西安 710069；2.西北大学物理学院，陕西西安 710069；3.西藏民族学院医学院，陕西咸阳 712082）

侧金盏属植物在我国分布较广，资源量较大，具强心苷等多种活性成分，临床主要用于治疗充血性心力衰竭等心脏病。目前对其他活性成分的药理和临床应用研究较不充分，在广泛文献检索基础上，对侧金盏属的种类、成分、药理、临床应用和禁忌等进行了综述，为进一步开发利用提供资料。

侧金盏属；成分；药理；临床应用；禁忌

西部资源生物与现代生物技术教育部重点实验室基金（KH09030）；西藏自治区科技厅重大科技专项基金（20091012）；陕西省教育厅科学研究项目计划（2010JK862）资助。

杨文慧（1991-），女，宁夏固原人硕士研究生，药物配体分析检测方向。*通讯作者，男，江苏沛县人，副研究员，博士，硕士研究生导师；研究方向：中药化学与资源学，E-mail：nsfstone@126.com；**共同通讯作者，女，甘肃人，高级实验师，硕士；研究方向：民族药化学与资源学，E-mail：flysnow002001@163.com。

2014-12-20

2015-03-03

Supported by Opening Foundation of Key Laboratory of Resource Biology and Biotechnology in Western China （Northwest University），Ministry of Education（KH09030）；the Major Scientific and Technological Project of the Department of Science and Technology，Tibet Autonomous Region （20091012）；the Scientific Research Plan Projects of Shaanxi Education Department（2010JK862）.

.E-mail:nsfstone@126.com；flysnow002001@163.com

December 20，2014Accepted:March 3，2015