Chinese Journal of Natural Chinese Journal of Natural Medicines 2013, 11(4): 03210329 Medicines

doi: 10.3724/SP.J.1009.2013.00321

Chemical constituents and pharmacologic actions of

MENG Hao-Cong, WANG Shuo, LI Ying, KUANG Yuan-Yuan, MA Chao-Mei*

College of Life Sciences, Inner Mongolia University, Huhhot, Inner Mongolia 010021, China Available online 20 July 2013

[ABSTRACT] The stem of Cynomorium songaricum is a traditional Chinese medicine reputed to have tonic effects. C. coccineum growing in northern Africa and the Mediterranean region is regarded in Arabian medical practice as the "treasure of drugs". The major constituents of Cynomorium plants have been revealed to be phenolic compounds, steroids, triterpenes, etc. Pharmacologic studies showed that the Cynomorium plants had antioxidant, immunity-improving, anti-diabetic, neuroprotective, and other bioactivities. Some chemical constituents in Cynomorium plants are unstable, implying that the chemical components of the herbal medicines produced under different conditions may be variable. This review covers the literature published until December, 2011 and describes the pharmacologic effects and secondary metabolites of Cynomorium species. [KEY WORDS] Cynomorium; Triterpenes; Phenolics; Antioxidant; Anti-diabetes [CLC Number] R284, R965 [Document code] A [Article ID] 1672-3651(2013)04-0321-009

 Extensive research has been carried out to inves- 1 Introduction tigate the bioactive constituents and pharmacological effects Cynomorium songaricum Rupr. and C. coccineum L., of Cynomorium plants. Some reviews published four years [8-11] belong to genus Cynomorium, which is the sole genus within ago , summarized the chemical constituents or pharmaco- the Cynomoriaceae family. Cynomorium plants are fleshy, logic effects of C. songaricum. In recent years, more original holoparasitic plants with no leaves. Without chlorophyll they research papers about Cynomorium plants covering broader cannot produce energy by themselves, instead, they parasitize research areas have been published. This review describes the the roots of other plants, such as those in the Nitrariaceae in pharmacologic effects and secondary metabolites reported for China [1-4]. Cynomorium species until December, 2011. The species C. songaricum is native to western Asia. The stem of this , “Suo Yang” in Chinese, is an important 2 Pharmacologic Activities herbal medicine for “nourishing kidney” and “strengthening Cynomorium plants have traditionally been used to [1] the yang” . Eaten raw or cooked with meat or flour, the support the male reproductive function, and there is some plant is considered to be a longevity food by the local evidence for this effect in animal studies and molecular Chinese people. Its local name, “Bu Lao Yao”, means “keeps pharmacologic studies. In addition, biological studies have people from becoming old”. revealed that these plants have anti-oxidative, anti-diabetic, C. coccineum is found in northern Africa and the Mediter- HIV-1-protease inhibitory, and immunity improving effects. ranean region [2], where it has long been known to the Muslim 2.1 Effects on factors related to reproductive function world as "tarthuth", and to Europeans as the "Maltese mush- The aqueous extract of C. coccineum could significantly room" [6]. The Arab medical system regarded it as the "treasure increase the sperm count, the percentage of live sperm and of drugs" for treatment of apoplexy, venereal disease, high [7] their motility, and decrease the number of abnormal sperm. blood pressure, irregular menstrual periods, etc . The serum interstitial cell stimulating hormone levels was

higher, whereas testosterone and follicle stimulating hormone  [Received on] 10-May-2012 levels were lower in treated animals. It was concluded that [Research funding] This project was supported by the Science and the aqueous extract of C. coccineum induced testicular Technology Department of Inner Mongolia, China (No. 20100507) development and spermatogenesis in immature Wistar rats [*Corresponding author] MA Chao-Mei: Prof., Tel: 86-471-4992435; through direct spermatogenic influence on the seminiferous E-mail: [email protected] [12-13] These authors have no conflict of interest to declare. tubules presumably by exerting a testosterone-like effect .

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After administration of C. songaricum to 8-week-old male antioxidant activities, suggesting that traditional medicines Wistar rats for 56 consecutive days (1.0 g·kg−1·day−1, p.o.), based on these plants might be beneficial to people with insu- the treated animals showed significant increases in lin-resistance disorders. epididymal sperm count and absolute testes weights 2.3 Inhibition of virus replication enzymes compared to the control group. C. songaricum also increased Human immunodeficiency virus protease (HIV-PR) and the expression of GDNF (Glial cell-derived neurotrophic hepatitis C virus protease (HCV-PR) are essential enzymes factor, which induces the proliferation of undifferentiated for the replication HIV and HCV. These enzymes are attract- spermatogonia) at both the mRNA and protein levels. The tive targets for developing therapeutic drugs for AIDS and results suggest that C. songaricum may improve male fertility type C hepatitis [23-24]. It was found that the extracts of C. by enhancing spermatogenesis and GDNF expression [14]. songaricum potently inhibited HIV protease. Bio-activity- The effects of C. coccineum on ovarian follicular guided fractionation and isolation led to the identification of development and serum levels of FSH and LH were triterpenes and flavan-3-ol polymers as the bioactive investigated. Water extract of C. coccineum was given to the components. Among the triterpene compounds, ursolic acid animals per os in a dose of 47 mg/100 g body weight for 6 malonylhemiester was more active than ursolic acid. As for days in 25-day-old rats. The extract elicited significant the activity of flavan-3-ols, the inhibition increased as the changes in gonadotrophin levels, and a significant increase in molecular weight increased [25-26]. In addition to the inhibition ovarian weight and profound folliculogenesis. Numerous on HIV-PR, the water extract of C. coccinneum was found to primary, secondary, tertiary and antral follicles were found, be inhibitory on HCV PR upon screening of 71 plants while distinct zona pellucida was not seen, and the oocyte commonly used as Sudanese traditional medicines [27]. The was often detached. The results indicated that the extract of C. triterpene constituents, ursolic acid, acetyl ursolic acid, and coccineum can modulate the activity of the pituitary malonyl ursolic acid hemiester, were found to be the active gonadotrophs [15]. components. Similar to the case for HIV PR, malonyl ursolic Cynomorium plants have traditionally been used as acid hemiester was the most potent against HCV PR [28]. The supportive herbs for male infertility, and the above research inhibitory activity of Cynomorium triterpenes on HIV PR and results provided some evidence for this effect in animal HCV PR suggested that these compounds are worthy of studies and molecular pharmacologic studies. Animal studies further study for their potential as leads to develop anti-viral have also shown that Cynomorium plants can significantly agents. increase ovarian weight and folliculogenesis in young rats, 2.4 Anti-diabetes activity and the inhibition of diabetes suggesting that Cynomorium plants may have beneficial related enzymes effects on both male and female fertility. α-Glucosidase is an essential enzyme for the digestion 2.2 Anti-oxidant activity and related functions and absorption of food polysaccharides. Inhibitors of The tannin-rich fractions and flavan-3-ol oligomers from α-glucosidase could effectively slow down the increased the stems of C. songaricum showed potent antioxidant glucose level in blood after meal. Thus, α-glucosidase is activity [16]. C. songaricum could enhance the endurance and regarded as an effective target for developing anti-diabetes antioxidative status of skeletal muscle in trained mice [17]. drugs. Some inhibitors of this enzyme have been successfully Flavonoids from C. songaricum could reduce free radical developed as clinic drugs, such as acarbose and voglibose formation, scavenge free radicals, reduce muscle fatigue and [29-31]. The extract of C. songaricum was found to be enhance swimming endurance of rats upon measuring inhibitory on α-glucosidase. Upon fractionation, the tannin- changes of free radical scavenging enzymes and body weight. rich fraction was found to be the most active fraction, from The CuZn-SOD and GSH-px activities in swimming rats which flavan-3-ol monomers and oligomers were isolated. increased, while the levels of malondialdehyde decreased The α-glucosidase inhibitory activity increased as the dose-dependently and significantly after treatment with the molecular weights of the flavan-3-ol oligomers increased [16]. flavonoid extract. Furthermore, significant increases in the A water-soluble polysaccharide from C. songaricum, average body weight and the total swimming time were namely CSPA, was purified and investigated for its anti- observed [18]. The above anti-oxidative activity of the diabetes potential. Oral administration of CSPA significantly flavonoids in Cynomorium plants agreed with the reported decreased blood glucose levels, glutamic oxaloacetic data that most phenolic compounds are strong antioxidants transaminase, glutamic pyruvic transaminase, blood urea [19-20]. In addition to the phenolic compounds, a nitrogen, and creatinine activities. In addition, CSPA polysaccharide from C. songaricum was found to show effectively increased serum insulin level and the content strong effects of scavenging free radicals [21]. of liver glycogen in streptozotocin-induced diabetic rats. Antioxidant therapy might be a useful strategy in Histopathology studies showed that CSPA could restore the insulin-resistant states, such as type 2 diabetes, cancer, obe- reduced islet cells to near normal level [32]. sity, and metabolic syndrome [22]. The constituents of struc- These results suggested the potential usefulness of C. turally different types of Cynomorium plants have potent songaricum in diabetes patients.

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2.5 Effects on the central nervous system and on the aging tory, and anti-diabetic activities of Cynomorium plants process suggest the beneficial effects of this plant medicine for C. songaricum displayed a multi-spectrum activity diabetes patients. Reported improvements in immunity, during a high-throughput screening of herb materials for diminished fatigue, improved physical endurance, neuro- modulating actions on neurotransmitter transporters. The protection, anti-aging, and anti-stress effects may be some chloroform extract showed a strong effect on of the reasons why these plant medicines are traditionally up-regulating dopamine/norepinephrine uptake, while the used as tonics. n-butanol extract potently inhibited γ-aminobutyric acid/serotoin uptake. The n-butanol extract of C. 3 Chemical Constituents songaricum would likely possess antidepressant, Triterpenes, steroids, lignans, flavonoids and other [33] antiepileptic, and anxiolytic actions . phenolics, n-butyl-fructoside, and other constituents have C. songaricum was also reported to show strong been isolated from Cynomorium plants. [34] anti-anoxia and notable antiepilepsy effects . A fraction of 3.1 Triterpenoids and steroids the water extract could reduce the damage of cerebral and Four triterpene and six steroid compounds were isolated cardiac muscle tissue induced by altitude low-pressured from C. songaricum. They were identified as ursolic acid (1), hypoxia. The mechanism of action was deduced to be related acetyl ursolic acid (2), ursolic acid malonyl hemiester (3), to the increase of SOD activity and inhibition of membrane oleanolic acid malonyl hemiester (4), β-sitosterol (5), lipid peroxidation, and to the decrease of the accumulation of β-sitosteryl oleate (6), β-sitosteryl glucoside (7), β-sitosteryl lactic acid in brain tissue and the increase of the protein glucoside 6-O-aliphatates (8), 5α-stigmast-9(11)-en-3β-ol (9), contents in cardiac muscle tissue [35]. and 5α-stigmast-9(11)-en-3β-ol tetracosatrienoic acid ester Studies revealed that C. songaricum exhibits anti-aging (10) (Fig. 1) [26, 43-46]. Ursolic acid and its malonate derivative effects. Both natural and cultivated C. songaricum promoted showed potent inhibition on HIV PR with IC values of 8 the serum SOD activity and extended the life span of 50 and 6 μmol·L−1, respectively. Other dicarboxilic acid drosophila [36]. Another study on Kunming mice in an aging hemiesters of ursolic acid, oleanolic acid and betulinic acid model revealed that C. songaricum polysaccharide exerted were synthesized and their activities on HIV PR were anti-aging effects by increasing telomere length of investigated. It was found that the glutaryl hemiesters showed senescence mice [37]. C. songaricum has also been found to the most potent activity with IC values of 6 μmol·L−1 [26]. have significant protective effect against progressive memory 50 deficits in models of Alzheimer’s disease [38]. 3.2 Lignans and alkaloid The methanolic extract of C. songaricum demonstrated Jiang et al isolated eight phenolic compounds including the capability to protect human neuroblastoma cell death two interesting new lignans, (−)-isolariciresinol 4-O-β-D- induced by amyloidbetapeptide or by superoxide anions. The glucopyranoside (11), and (7S, 8R) dehydrodiconiferyl ethyl acetate soluble part showed significant protective alcohol 9'-β-glucopyranoside (12), as well as an alkaloid, effects at a concentration as low as 0.1 g·mL−1 [39]. The nicoloside (13), from the stems of C. songaricum (Fig. 2). protective effects of different extracts of C. songaricum on The structures of the new compounds were determined by staurosporine-induced apoptotic cell death in SK-N-SH spectroscopic methods. The stereo-chemistry was determined [47] neuroblastoma cells were evaluated. The ethyl acetate soluble by analysis of the CD spectrum . part of C. songaricum significantly attenuated 3.3 Flavonoids staurosporine-induced cell death at concentrations of 100 and Cynomorium plants contain large amount of flavonoids 10 μg·mL−1 [40]. The observation that C. songaricum extracts with flavan-3-ols being the major ones. Other sub-flavonoid showed neuroprotective activity supported the traditional use types in Cynomorium plants are flavones, flavonols, and of this herbal medicine for alleviating the symptoms of aging. flavanones. 2.6 Other pharmacologic activities From the aqueous extract of the stems of C. songaricum, C. coccineum from Iran was found to possess significant catechin (14), procyanidin B-1 (15), procyanidin B-6 (16), blood pressure lowering activity in dogs. Further study flavan-3-ol trimers, flavan-3-ol tetramers, flavan-3-ol pen- revealed that the active components for lowering blood tamers, and flavan-3-ol polymers (condensed tannins) were pressure were mainly in the fresh juice of the plant. The fresh obtained. Thiolytic degradation of the flavan-3-ol polymers juice, as well as the water soluble fractions of the fresh juice, yielded benzylthioepicatechin, indicating that the extender exhibited strong activity, while the extract of the dried flavan unit of the condensed tannin is mainly epicatechin (Fig. powdered plant lacked significant activity [41]. 3). The flavan-3-ol polymers showed inhibitory activity A fraction from C. songaricum was found to have a against HIV PR with the activity increased as the molecular protective effect on immunosuppressed mice. The effect was weight increased [26]. Using capillary electrophoresis with deduced to be related to an increase in the humoral amperometric detection, epicatechin and catechin were de- immunity and non-specific immunity [42]. tected in all of the seven Cynomorium samples collected in In summary, the antioxidative, α-glucosidase inhibi- different areas [48].

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Fig. 1 Triterpenes and sterols isolated from Cynomorium songaricum

Fig. 2 Lignans and alkaloid from Cynomorium songaricum

Fig. 3 Flavan-3-ols from Cynomorium songaricum

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Two anthocyanin pigments (18, 19) were isolated from the flowering tops of C. coccineum (Fig. 4). Cyanidin 3-O-glucoside (18) was identified to be the major pigment (92%), while cyanidin 3-O-rhamnosylglucoside (19) was identified to be the minor one (8%) [49]. Besides the above mentioned flavan-3-ols and anthocyanins, compounds 20-27 (Fig. 5) of other flavonoid sub-types were isolated or detected in C. songaricum [26, 47, 50-51]. 3.4 Saccharides Fig. 4 Anthocyanins isolated from the flowering tops of Two polysaccharides, SYP-A and SYP-B, were purified Cynomorium coccineum

Fig. 5 Other flavonoid compounds from Cynomorium plants from C. songaricum by Sephadex G-100 and G-150 gel into three fractions (CSG-F1, CSG-F1, and CSG-F3). The column chromatography. The molecular weights of the average molecular weight of CSG-F1 (yield 21%) was es- isolated polysaccharides were estimated to be 3.1 × 105 and timated to be 2.4 × 105, composed mainly of galactose, 2.8 × 105, respectively. The polysaccharides were composed glucose, arabinose, and rhamnose. CSG-F2 (yield 14%) was of galactose, glucose, arabinose, rhamnose, mannose, and composed of galactose, glucose, arabinose, rhamnose, and ribose, with the molar ratio being 5.1 : 4.1 : 1.6 : 1.0 : 0.5 : ribose, and has an average molecular weight of 1.3 × 105. 0.3 and 5.2 : 4.2 : 1.5 : 1.0 : 0.5 : 0.2, respectively. The uronic With an average molecular weight of 1.9 × 105, CSG-F3 acid contents in the two polysaccharides were 10.7% and (yield 37%) was composed of galactose, glucose, arabinose, 10.5%, respectively [52]. rhamnose, ribose, and mannose. The C. songaricum glycan A water-soluble polysaccharide from C. songaricum exhibited dose-dependent scavenging activity of superoxide named CSPA was reported to have hypoglycemic effects on anion radical while did not significantly delay HepG2 cells STZ-induced rats. CSPA was identified to be a heteropolysac- growth [53]. charide consisting of Ara, Glu, and Gal, with a molecular 3.5 Miscellaneous weight of 1.394 × 105. It contained the following unit: Three n-butyl-fructosides were isolated from the stems →3)-α-araf –(1 →3)-α-D-glcp-(1→4)-α-D-GalpA6Me-(1→, of C. songaricum. Their structures were determined by spec- and held a conformation of a compact chain of a sphere-like troscopic methods to be n-butyl-β-D-fructofuranoside (28), structure in aqueous solution [32]. n-butyl-α-D-fructofuranoside (29) and n-butyl-β-D- fruc- A glycan isolated from C. songaricum was fractionated topyranoside (30) (Fig. 6) [54].

Fig. 6 Butyl-fructosides isolated from the stems of Cynomorium songaricum

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Compounds of other structural types isolated from this plant pounds 35-39, amino acid (40), nucleoside (41), glucose (42), [26, 47, 50-56] include stilbene (31), phenylpropanoids 32-34, phenolic com- succinic acid (43), and capilliplactone (44) (Fig. 7) .

Fig. 7 Compounds of other structural types isolated from Cynomorium plants

Using high-performance capillary electrophoresis with and harmala [57]. amperometric detection (CE-AD), phloridzin, epicatechin, In summary, Cynomorium plants have been reported to catechin, naringenin, rutin, luteolin, quercetin, gallic acid, contain condensed tannins, steroids, triterpenes, acidic heter- and protocatechuic acid were well separated under optimized opolysaccharides, butyl fructosides, flavanoids, lignan gly- conditions. Using the established conditions, seven cosides, alkaloids, and other compounds. The bioactive Cynomorium samples collected in different areas were components responsible for the antioxidant activity have analyzed. Phoridzin, epicatechin, catechin, rutin, and gallic been revealed to be phenolic compounds and heteropolysac- acid was detected in all of the seven samples. The assay charides. Those compounds responsible for the inhibition of results showed that C. songaricum samples contained viral essential enzymes have been reported to be triterpenes abundant amount of polyphenols and flavonoids, especially and tannins. of catechin and rutin. The author recommended that catechin and rutin could be used as index constituents for the quality 4 Changes in the Content of Bioactive Components control of C. songaricum. The electromigration profiles or The dynamic trends of the catechin content of wild and “electrochemical chromatograms” can be used for the cultivated C. songaricum in different growth stages and comparison of component diversity of medicinal different areas were studied by HPLC. The catechin level Cynomorium plants planted in different places [48]. from highest to lowest was found out to be in the following Through GC-MS analysis, Zhou et al found that the li- order: stage just before the plant grows out of the earth, posoluble constituents of C. songaricum were influenced by unearthed stage, flowering stage, and fruit developing stage. the geographic origin more than the host. The stems of C. If catechin is used as a marker component for quality control, songaricum collected from three different geographic regions the quality of Herba Cynomorii that is harvested just before and four different hosts were analyzed by GC–MS for their the plant grows out of the earth would be the best, which liposoluble constituents. Cluster analysis of the percentage agrees with the local custom that Herba Cynomorii was composition of 80 compounds showed that there were dif- usually collected in the beginning of May [58]. On the other ferences in chemical composition among the different geo- hand, the content of ursolic acid in C. songaricum at different graphic origins, while there was little composition difference growth stages changed irregularly. Thus ursolic acid can be among different host plants. Hexadecanoic acid was found to used as a marker component for quality evaluation of the be the most abundant compound in the essential oils of C. plant medicine, but cannot be used to determine the songaricum from hosts sibirica and N. tanguticum. appropriate collecting time [59]. Whereas (Z)-9-octadecenoic acid was found to accumulate in Cynomorium plants contain some constituents that are the oils of C. songaricum from Zygophyllum xanthoxylum liable to decompose or condense. One of the triterpene con-

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MENG Hao-Cong, et al. / Chinese Journal of Natural Medicines 2013, 11(4): 321329 stituent, ursolic acid malonyl hemiester (3), is unstable, with Such investigations may provide information on the struc- its content decreasing quickly under heating. When the dry ture-activity relationships of these compounds and identify powder of compound 3 was heated, it predominately decom- candidates for the development of new drugs. posed to acetyl ursolic acid. When its aqueous solution was heated, compound 3 decomposed to acetyl ursolic acid and References ursolic acid, which may be caused by spontaneous hydrolysis [1] State Administration of Traditional Chinese Medicine. [16] of compound 3 . C. songaricum contains a large amount of Zhonghuabencao [M]. Vol. 5. 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锁阳属植物的化学成分及药理作用

蒙昊聪, 王 硕, 李 颖, 况园园, 马超美*

内蒙古大学生命科学学院，呼和浩特 010021

【摘 要】 锁阳是锁阳科植物 Cynomorium songaricum 的根茎，是以具有强壮作用而著名的中药材。生长在北非及地中海 地区的同属植物 C. coccineum 被阿拉伯人看作是"宝药"。研究表明锁阳属植物的主要成分为酚类、甾体和三萜类化合物等。锁 阳属植物的药理作用包括抗氧化、提高免疫力、抗糖尿病及神经保护等。锁阳的一些化学成分结构容易发生变化，因此不同生 产条件得到的锁阳类药物成分会有所不同。该文综述锁阳属植物的药理作用及化学成分，检索的文献截至 2011 年底。 【关键词】 锁阳属; 三萜; 酚类; 抗氧化; 抗糖尿病

【基金项目】 内蒙古自治区科技厅草原英才人才引进项目“天然药物的基础研究与开发研究”(No. 20100507)资助

2013 年 7 月 第 11 卷 第 4 期 Chin J Nat Med Jul. 2013 Vol. 11 No. 4 329