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A Review of the Genus Actaea L.: Ethnomedical Uses, Phytochemical and Pharmacological Properties
Abstract
Introduction: The genus Actaea L., comprising of 32 species, has recently emerged as a source of potential phytochemicals with promising pharmacological properties. However, there is no review available integrating the scattered scientific studies on this genus. To fill this knowledge gap, an extensive review of the genus Actaea is presented with focus on its ethnomedical uses, phytochemistry, and pharmacology.
Methods: For this review, 162 publications including 152 research papers, 7 books, 2 dictionaries and one glossary published from 1896 to April, 2020 A.D. were critically reviewed and relevant data extracted. The chemical structures and formulae of compounds have been sourced and validated using PubChem database; and drawn using Chem Draw Ultra 6.0. The scientific nomenclature follows The Plant List.
Results & Discussion: For over more than a century, the ethnomedical uses of 8 species of this genus in treating 29 types of human diseases under different traditional medical systems have been reported. Over the last two decades, the phytochemical studies so far conducted on 16 species of Actaea have led to the isolation of more than 400 different compounds, notably cycloartane triterpenoids, flavonoids, phenylpropanoids, and nitrogenous compounds. Based on these phytochemical studies on Actaea species, the recent resurgence on pharmacological research conducted on 16 species has led to novel leads with potential applications.
Conclusions: We highlight the current knowledge gaps and discuss future research prospects on genus Actaea, which can guide its bio-prospection and sustainable use in near future.
For the first time, hydroethanolic extracts from Actaea cimicifuga and Actaea erythrocarpa were analyzed using LC-HRMS, HPLC, and spectrometry in this study. Extracts from the above-ground parts of Actaea species exhibited higher concentrations of saponins (up to 248 mg/g of DE), coumarins (up to 162 mg/g of DE), flavonols (up to 32 mg/g of DE), and catechins (up to 11 mg/g of DE) compared to extracts from the underground parts. The concentrations of phenolic acids (up to 112 mg/g of DE) and tannins (up to 202 mg/g of DE) in the underground parts were comparable to or even higher than those in the above-ground parts of the two analyzed species. The concentration of the main metabolites detected was higher in the extract of A. erythrocarpa than that of A. cimicifuga. The metabolite profile of the extracts from both species showed 66 compounds, including chromones, coumarins, phenolic and nitrogenous compounds, fatty acids, and triterpenes. The HPLC analysis of the four extracts revealed that the concentration of caffeic acid (0.74 mg/g of the dry extract [DE]) was the highest in the extract from the underground part of A. erythrocarpa, whereas the extract from the above-ground part of this species showed the highest levels of ferulic (1.16 mg/g of DE) and isoferulic acids (1.49 mg/g of DE) and of hyperoside (13.05 mg/g of DE). The study of biological activity showed that A. erythrocarpa is most promising for further research, with the highest antioxidant activity found in the underground parts of this species (IC50 = 79.7 μg/mL) compared to the above-ground parts (IC50 = 85.8 μg/mL). In addition, the extract from the above-ground part of A. erythrocarpa was found to exhibit the greatest cytotoxic activity among the studied specimens against 3T3-L1, HepG2, and MDA-MB-231 cells.
To enrich the bioactive cycloartane triterpenoid glycoside named actein and find out more cytotoxic cycloartane triterpenes, a phytochemical study of Cimicifuga foetida was conducted. 113 g (0.17%) actein was purified by recrystallization while eight cycloartane-type triterpenes (1–8) were isolated from the mother liquid. The chemical structures of new compounds (1–4) were elucidated by 1D and 2D NMR and HRESIMS spectroscopic analyses. Moreover, new compounds showed moderate and broad-spectrum cytotoxicity against 5 human cancer cell lines with IC50 values ranging from 4.02 to 15.80 μM.
Graphic Abstract
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Background
The roots and rhizomes of Cimicifuga yunnanensis Hsiao are commonly used as anti-inflammatory, antipyretic, and analgesic remedies and detoxification agents in traditional Chinese medicine (TCM). Although C. yunnanensis has been considered as supplementary medicine for several disorders, the antitumor effect of this herb and its key components has not been explored.
Materials and methods
The rhizomes of C. yunnanensis were isolated by chromatographic techniques. Structures of isolated compounds were identified based on spectroscopic methods and comparison with published data. The in vitro anticancer activities of purified components were also performed by MTT experiments. The in vivo anticancer activities were examined by subcutaneous tumor model or a breast cancer liver metastasis model.
Results
In this study, we aimed to identify and characterize the effective antitumor components from the rhizomes of C. yunnanensis. By bioassay-guided fractionation techniques and chemical characterization, 12 cycloartane triterpenes and four chromones were isolated, among them, 11 compounds were identified in this genus at first. The identified two compounds showed dramatic inhibitory activities against breast cancer cells: compound 4 (23-epi-26-deoxyactein) and compound 13 (cimigenol). Then, we examined the antitumor effect of these two selective candidate chemicals on triple-negative breast cancer (TNBC) cells in vivo and found that they could reduce tumor growth in subcutaneous tumor model or breast cancer liver metastasis model.
Conclusion
These results suggested that the selective compounds isolated from C. yunnanensis Hsiao could be the promising new agents for TNBC treatment.
To achieve the challenging goals of minimizing loss of species and achieving sustainable use of biodiversity, conservation prioritization merits urgent research attention. The present study identifies the priority of conservation for the medicinal flora of the Jammu and Kashmir (J&K) region, a Himalayan biodiversity hotspot. A total of 881 medicinal plant species were scored based on key ecological (endemism, threat status) and socioeconomic (use value, mode of harvesting) criteria, and 50 of these are prioritized for conservation; most of these are narrow endemics. Worryingly, all of the 50 prioritized species are currently recognized under different International Union for Conservation of Nature and Natural Resources threat categories, are highly prized for their use in traditional medicine in the region and are precious sustainable bioresources for the herbal industry. Most of these prioritized species are being harvested illegally. This integrated ecological and socioeconomic study has immediate implications for evidence-based and target-orientated conservation policy and practice in this Himalayan region.
Cholinesterases (ChEs) are enzymes that break down neurotransmitters associated with cognitive function and memory. We isolated cinnamic acids (1 and 2), indolinones (3 and 4), and cycloartane triterpenoid derivatives (5–19) from the roots of Cimicifuga dahurica (Turcz.) Maxim. by chromatography. These compounds were evaluated for their inhibitory activity toward ChEs. Compound 1 was determined to have an IC50 value of 16.7 ± 1.9 μM, and to act as a competitive inhibitor of acetylcholinesterase (AChE). Compounds 3, 4 and 14 were found to be noncompetitive with IC50 values of 13.8 ± 1.5 and 6.5 ± 2.5 μM, and competitive with an IC50 value of 22.6 ± 0.4 μM, respectively, against butyrylcholinesterase (BuChE). Our molecular simulation suggested each key amino acid, Tyr337 of AChE and Asn228 of BuChE, which were corresponded with potential inhibitors 1, and 3 and 4, respectively. Compounds 1 and 4 were revealed to be promising compounds for inhibition of AChEs and BuChEs, respectively.
This study was designed to search for novel anti-cancer compounds from natural plants. The 70% ethanolic extract from the rizhomes of Cimicifuga dahurica (Turcz.) Maxim. (Ranunculaceae) was found to possess significant in vitro anti-proliferative effects on MCF-7 breast cancer cells. A phytochemical investigation using assay-guided fractionation of the ethanolic extract of C. dahurica resulted in the isolation of one new phenolic amide glycoside 3, two new lignan glycosides 4 and 7, one new 9,19-cycloartane triterpenoid glycoside 6, and thirteen known constituents 1, 2, 5, and 8–17. The structures of 3, 4, 6, and 7 were established using contemporary NMR methods and from their HRESIMS data. The anti-proliferative effects of isolated compounds were evaluated using the BrdU-proliferation kit. Five among the 17 isolated compounds showed significant anti-proliferative effects (p ≤ 0.05), wherein compound 7 showed the most significant anti-proliferative and cell cycle arresting effect (p ≤ 0.05) which followed a dose dependent manner. Western blot protein expression analysis showed a down expression of c-Myc and cyclin D1 which further elucidated the anti-proliferation mechanism of compound 7 while apoptotic effects were found in association with Bcl-2 family protein expression variations. Conclusively this study reports the isolation and identification of 17 compounds from C. dahurica, including four novel molecules, in addition to the fact that compound 7 possesses significant anti-proliferative and apoptotic effects in vitro that may require further exploration.
A new cycloartane triterpene, yunnanterpene G (1), containing an oxaspiro[5.4]decane moiety, was purified from the roots of Cimicifuga foetida. The new structure was determined from spectroscopic data and the X-ray diffraction method. Biological evaluations revealed that compound 1 significantly inhibited the mRNA expression of the atherosclerosis-related adhesion molecule CD147 (extracellular matrix metalloproteinase inducer, EMMPRIN), and proteolytic enzymes matrix metalloproteinase 2 (MMP-2), MMP-9 and MMP-14, in a dose-dependent manner in phorbol-12-myristate-13-acetate-induced human monocytic THP-1 cells by quantitative real-time PCR method. At the same time, the migration ability of the induced THP-1 cells was potently inhibited. Furthermore, western blot experiments showed that compound 1 at 25 μM strongly suppressed phosphorylation of NF-κB p65 and p38 MAPK in the differentiated THP-1 cells.
Two new cycloartane triterpenes, cimyunnin E (1), containing a unique oxaspiro[4.4]nonanedione moiety based on rings D and E, together with cimicifine B (2), a 25,26,27-trinortriterpene featuring a pyridine ring E, were purified from the fruits of Cimicifuga yunnanensis. Their structures were elucidated by spectroscopic methods and ECD (electronic circular dichroism calculations). Compounds 1 and 2 showed significant acetylcholinesterase (AChE) inhibition with IC50 values of 1.58 and 3.87 μM, respectively. In addition, they noticeably enhanced the neurite outgrowth of nerve growth factor (NGF) mediated PC12 cells at a concentration of 10 μM.
A new cycloartane triterpenoid bisdesmoside, soulieoside S (1), was isolated from the ethanolic extract of rhizomes of Actaea vaginata. The structure was determined by extensive spectroscopic analysis including 1D- and 2D NMR and HRESIMS, as well as chemical methods. Compound 1 was evaluated for its cytotoxic activities against HepG2, MDA-MB231 and A549 cancer cell lines.
A new cycloartane triterpenoid glycoside, named soulieoside R, was isolated from the rhizomes of Souliea vaginata. Its structure was characterized by comprehensive analyses of 1H, 13C NMR, COSY, HSQC, HMBC, NOESY spectroscopic, and HRESIMS mass spectrometric data, as well as chemical methods. The new compound showed weak inhibitory activity against three human cancer cell lines.
Seven new dahurinol-type triterpene derivatives, including three aglycones, cimifrigines A–C (1–3), and four glycosides, cimifrigines D–G (4–7), were purified from the flowers of Cimicifuga frigida. These triterpenoids are characterized by an oxime group at C-15. Spectroscopic analyses and X-ray crystallography were used to determine the new structures. In the in vitro cytotoxicity screening, glycosides (4–7) exhibited more noticeable activities than the aglycones (1–3) against human HL-60, SMMC-7721, A549, MCF-7, and SW-480 cell lines. Interestingly, compounds 5 and 7, bearing a 2′-O-acetyl moiety on the sugar unit, showed comparable cytotoxicities to the positive control, cisplatin (IC50: 0.5 to 5.4 μM). Whereas, analogues 4 and 6, without the 2′-O-acetyl group, indicated weaker activities with IC50 values ranging from 8.9 to 14.3 μM.
Two dimeric prenylindole alkaloids with a unique indole‐benzoindolequinone skeleton, cimicifoetones A (1) and B (2), were isolated as black pigments from the rhizomes of Cimicifuga foetida. The structures were elucidated by spectroscopic methods including HRMS and 2D NMR, as well as single‐crystal X‐ray diffraction and computational chemical modeling techniques. Cimicifoetones A and B represented the first examples of dimeric indole alkaloids generated through [4+2] Diels–Alder cycloaddition between the prenyl side chain in one 3‐prenylindole and the aromatic ring in another. The two compounds showed promising anti‐proliferative activity on seven tumor cell lines with IC50 values in the range of 1.36–21.09 μm. Flow cytometric and western blot analysis revealed that compound 2 induced cell apoptosis via death receptor‐mediated extrinsic and mitochondrial‐mediated intrinsic pathways.
A new cyclolanostane triterpenoid xyloside, soulieoside P (1), and a known oleanane-type saponin, hederasaponin B (2), were isolated from the rhizomes of Souliea vaginata. Their structures were established by extensive spectroscopic and HRESIMS analysis, as well as chemical methods. Compound 1 showed significant inhibitory effects with IC 50 values of 7.6−11.2 μM against three human cancer cell lines, while compound 2 exhibited no hepatoprotective effect on CCl 4-induced injury of human HepG2 cells, in the tested range of 0.1−100 μM.
The extract from Cimicifuga, a genus of flowering plants, has been demonstrated to have mainly therapeutic effects on menstrual and menopausal symptoms and also exhibits immunomodulatory, anti-inflammatory and antimicrobial activity. Moreover, the anticancer effects of Cimicifuga have been reported, but the underlying mechanism causing cancer cell death has been poorly described. The present study was designed to investigate the antitumor effects and underlying molecular mechanisms of cimigenol (KY17), a novel cycloartane triterpenoid from Cimicifuga. KY17-induced autophagy and apoptotic cell death in human colon cancer cells (HT-29) was investigated. KY17 treatment induced growth inhibition and apoptotic cell death in a concentration-dependent manner. The induction of apoptosis was confirmed by a change in cell morphology, and an increase in the G2/M phase, as well as increased protein levels of cleaved-caspase-8 and -3; cleavage of poly(ADP-ribose) polymerase (PARP) in the HT-29 cells following KY17 treatment. In addition, autophagy was evaluated by the accumulation of acridine orange, the appearance of green fluorescent protein-light-chain 3 (LC3) punctate structures and increased levels of LC3-II protein expression. Furthermore, combination treatment with the autophagy inhibitor bafilomycin A1 enhanced the induction of apoptosis by KY17. Taken together, the present study provides new insight into the role of KY17 as a potential antitumor compound. Combination of KY17 with an autophagy inhibitor may be a valuable strategy for the chemoprevention or treatment of colon cancer.
Rhizoma Cimicifugae (Sheng ma) is a Ranunculaceae herb belonging to a composite family and well known in China. has been widely used in traditional Chinese medicine. The Pharmacopoeia of the People׳s Republic of China contains three varieties (Cimicifuga dahurica (Turcz.), Cimicifuga foetida L. and Cimicifuga heracleifolia Kom.) which have been used clinically as “Sheng-ma”. However, the chemical constituents of three components of “Sheng-ma” have never been documented. In this study, a rapid method for the analysis of the main components of “Sheng-ma” was developed using ultra-high performance liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The present study reveals the major common and distinct chemical constituents of C. dahurica, C. foetida and C. heracleifolia and also reports principal component and statistical analyses of these results. The components were identified by comparing the retention time, accurate mass, mass spectrometric fragmentation characteristic ions and matching empirical molecular formula with that of the published compounds. A total of 32 common components and 8 markers for different “Sheng-ma” components were identified. These findings provide an important basis for the further study and clinical utilities of the three “Sheng-ma” varieties.
Purpose / Objective . To investigate the effect of Actaea racemosa (AR) extract on in vitro osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) via the ER/NO/cGMP signaling pathway. Methods / Materials . Rat BMSCs were treated with osteogenic differentiation-inducing medium containing AR; estrogen receptor antagonist, ICI 182,780 (10 ⁻⁶ mol/L); and nitric oxide synthase inhibitor, L-nitro arginine methyl ester (L-NAME, 6 × 10 ⁻³ mol/L). Markers of osteogenic differentiation (alkaline phosphatase [ALP] activity, osteocalcin secretion, and calcium ion deposit levels) and the levels of key signaling molecules (nitric oxide synthase [NOS], nitric oxide [NO], and cyclic guanosine monophosphate [cGMP]) were assessed. Results . AR (10 ⁻¹ –10 ⁻⁶ g/L) increased ALP activity in a dose-dependent manner, and the highest ALP, osteocalcin, and osteoprotegerin activities were achieved at an AR concentration of 10 ⁻⁴ g/L. Therefore, the concentration of 10 ⁻⁴ g/L was used for promoting osteogenic differentiation of BMSCs in subsequent analyses. At this concentration, AR increased the levels of NO and cGMP, and such effects could be blocked by the estrogen receptor antagonist (ICI 182,780) and nitric oxide synthase inhibitor (L-NAME). Conclusion . AR induced osteogenic differentiation of rat BMSCs through the ER/NO/cGMP signaling pathway. This finding provides the theoretical foundation for the mechanism of AR in the treatment of postmenopausal osteoporosis.
Actaea spicata Linn. (Ranunculaceae) has been traditionally used for the treatment of various ailments such as rheumatism, inflammation, nerve diseases, lumbago, scrofula and chorea. Despite a long tradition of use, no systematic phytochemical and pharmacological work has been carried out on this potential plant. Thus, A. spicata was subjected to preliminary anti-anxiety screening studies, with a view to ascertain the verity of its traditional use as an anxiolytic. In the present investigation, roots of the plant were extracted using solvents in order of increasing polarity viz., petroleum ether (60-80C), chloroform, methanol and distilled water. All the crude extracts were evaluated for anti-anxiety activity in mice using elevated plus maze apparatus. Among all these extracts, only methanol extract exhibited significant anti-anxiety activity at a dose of 100 mg/kg in mice with respect to control as well as standard (diazepam, 2 mg/kg). Phytochemical screening showed presence of alkaloids and polyphenols in methanol extract of A. spicata. Thus, Specific methods were adopted to extract total alkaloidal and polyphenol fractions from the plant material and methanol extract of plant, respectively. Polyphenol fraction exhibited significant anxiolytic activity at the dose of 50 mg/kg, while alkaloidal fraction was found to be devoid of any activity.
Aims: This work aims to study the in vitro and in vivo antitumor activities of tetracyclic triterpenoids compounds actein and 26-deoxyactein. Further, the mechanism is investigated. Methods: In vitro, a modified MTT method was used to assay the cytotoxicities of actein and 26-deoxyactein in 12 human tumor cell lines. In vivo, mouse sarcoma S180 and human lung cancer A549 cells were respectively implanted subcutaneously in ICR mice and nude mice to establish implanted tumor models. Flow cytometry (FCM) was used to assay the cycle distribution of the tumor cells. Immunohistochemistry was used to measure CD31-positive expression in the xenogrft tumor by analyzing microvessel density (MVD). In addition, acute toxicities of actein and 26-deoxyactein were also evaluated. Results: Actein and 26-deoxyactein inhibited the proliferation of the 12 human cancer cell lines tested with the values of 50% inhibitory concentrations (IC50) between 12.29 and 88.39 μg/mL. In vivo, both actein (3–27 mg/kg) and 26-deoxyactein (3–27 mg/kg) significantly inhibited the growth of the implanted sarcoma S180 in a dose-dependent manner. Actein (10, 30 mg/kg) and 26-deoxyactein (10, 30 mg/kg) markedly inhibited the xenograft growth with T/C (%) values of 38%, 55% for actein, and 35%, 49% for 26-deoxyactein. Compared with the vehicle control, actein (10, 30 mg/kg) and 26-deoxyactein (10, 30 mg/kg) significantly reduced the MVD in the xenograft tumor. The FCM result showed that human leukemia HL-60 cells were arrested at G1 phase after treated with either actein (6.25–25 μg/mL) or 26-deoxyactein (6.25–25 μg/mL) for 48 h. A limited trial in mice showed that both of the minimal lethal doses (MLDs) of actein and 26-deoxyactein were over 5 g/kg. Conclusions: Both actein and 26-deoxyactein have low toxicities. Importantly, both these two tetracyclic triterpenoids compounds isolated from rhizome of Cimicifuga foetida L. have significant antitumor activities in vitro and in vivo, which is associated with cell cycle arrest and angiogenesis inhibition.
In prioritising conservation and sustainable use of medicinal plants, endemic species merit immediate research priority. Towards this endeavour, understanding the basic reproductive biology of endemic medicinal plant species is crucial to their successful conservation and sustainable utilisation. In this study, the reproductive biology of Actaea kashmiriana, an endemic medicinal plant species from the Himalaya has been investigated for the first time. The results reveal that species is herkogamous and protoandrous in nature. The pollen grains are prolate spheroidal, and pollen viability ranges from 79.4 to 80%. Under in vitro pollen germination, sucrose, boric acid and calcium nitrate were found to be the key nutrients. Stigma receptivity was maximum on 5th – 7th days of anthesis. Higher pollen-ovule ratio and outcrossing index reflects that Actaea kashmiriana is predominantly outbreeder. The results of pollination experiment show that the species is self-compatible and cross-fertile. Higher fruit set in xenogamous and open pollination treatments under natural conditions suggests cross-pollination as primary mechanism in the species. Presence of sweet nectar, aroma, floral display, and copious amount of pollen serve as main attraction and reward in the species and thereby attracting diverse pollinators, which include: 13 insect visitors belonging to 7 families and 10 genera. Based on insect visitation efficiency and the pollen load, Bombus tunicatus, Bombus simillimus, Calliphora vomitoria and Eristalis sp. were found to be dominant pollinators. Overall, the findings of present study have immediate implications in informing the conservation and sustainable utilisation of this medicinally prized endemic species, and also guide strategies for its habitat restoration in high-altitude Himalaya.
Lack of sufficient studies on seed ecology of endemic species poses practical hurdles in their habitat restoration programs. Here, we studied the seed ecology traits and regeneration potential of Actaea kashmiriana – an endemic plant species to Kashmir Himalaya. We conducted population sampling of the species at four different sites in Kashmir Himalaya. The seeds showed profuse covering with brownish membranous wings, indicating wind dispersal in the species. The percentage of seed set varied from 67(±0.7) to 72(±0.6) and seed viability from 76 (±2.4) to 86(±2.4), with highest being at low-altitude site. We observed a gradual reduction in viability of the seeds over time, and 4 ◦C temperature optimum for maintaining long-term viability. Gibberellic acid (GA3) treatment (3 mM) showed highest percentage of seed germination and seedling survival. The treatments involving GA3 (2 mM), GA3 (2.5 mM), and GA3 (3 mM) showed highest number of seeds germinated per day as well as seedling vigour index. Mean germination time was significantly reduced to 45 ± 0.92 days under GA3 (3 mM) as compared to the other treatments. For breaking the epicotyl dormancy, 24–25 ◦C temperature was effective for the emergence of cotyledon. Faster seed germination initiated within 38 and40 days under treatments with GA3 (3 mM) and GA3 in combination with Thiourea respectively. Our results indicate non-deep morpho-physiological dormancy in the species and GA3 likely serves as a substitute for cold stratification. Based on our findings, we outline a protocol for production of quality seedlings in A. kashmiriana, which can steer restoration of the species in this Himalayan biodiversity hotspot and enlighten the restoration of endemic biodiversity elsewhere.
Thirteen Tabebuia species (family Bignoniaceae) have been reported in the literature to have pharmacological activity, or there have been reports of secondary active metabolites. The literature was collected from 1967 to 2018. This genus has great phytochemical diversity since it has over 163 natural compounds that have been extracted including; iridoids (36), phenolic acids & their derivatives (32), phenyl propanoids & phenyl ethanoids (7), lignans & neolignans (14), isocoumarins (7), flavonoids (14), quinones & naphthoquinones (50), sterols (2) and triterpene (1). Tabebuia avellanedae is currently the most investigated species. Quinones and naphthoquinones were the most frequently isolated compounds (49 compounds) from Tabebuia genus and they showed various pharmacological activities for example cytotoxic, antioxidant, fungicidal, analgesic effects. Therefore, they are a good source of new compounds with significant biological activities.
Phytochemical study on rhizomes of Cimicifuga dahurica resulted in the isolation of nine new neolignan and phenylpropanoid glycosides, cimicifugasides A-E (1, 2, 7–9), cimicifugamides B-D (3–5), shomaside G (6) along with four known compounds (10−13). Their structures were identified by extensive spectroscopic analyses (1D-, 2D-NMR, MS, CD, IR, UV) and chemical methods. Their anti-inflammatory potentials were evaluated by measuring their effects on PGE2 production of LPS-stimulated RAW264.7 cells, and compounds 12 and 13 showed moderate anti-inflammatory activities.
The plant genus Polyscias (family Araliaceae) comprises about 116 species that are widely used for ornamental purposes and some, bear potential medicinal value. Polyscias species are represented as perennial shrubs and are commonly cultivated in southeastern Asia and the Pacific region. Studies on species of this genus have provided essential data regarding the chemical composition and pharmacological activities of Polyscias extracts and isolated secondary metabolites. Phytochemical investigations of Polyscias species revealed the isolation of about 97 chemical compounds from various chemical classes, including saponins as major constituents. Biological studies demonstrated that Polyscias extracts and their bioactive compounds possess antibacterial, antifungal, cytotoxic, immuno-stimulant, wound healing and anti-asthmatic activities. Bearing potential value for drug discovery, regardless of the presented data, further studies are required to investigate other Polyscias species, to assess the biological activities of their extracts as well as the isolated chemical compounds and to identify the suggested underlying mechanisms of action for their pharmacological activities.
Cimicifuga dahurica has traditionally been used as an antipyretic, analgesic, and anti-inflammatory agent and as a treatment for uterine and anal prolapse. This study has investigated the potential beneficial effects of this medicinal plant and its components on Alzheimer's disease (AD) with a focus on amyloid beta (Aβ) production and scopolamine-induced memory impairment in mice. An ethanol extract from C. dahurica roots decreased Aβ production in APP-CHO cells [Chinese hamster ovarian (CHO) cells stably expressing amyloid precursor protein (APP)], as determined by an enzyme-linked immunosorbent assay and Western blot analysis. Then, the compounds isolated from C. dahurica were tested for their antiamyloidogenic activities. Four compounds (1-4) efficiently interrupted Aβ generation by suppressing the level of β-secretase in APP-CHO cells. Moreover, the in vivo experimental results demonstrated that compound 4 improved the cognitive performances of mice with scopolamine-induced disruption on behavioral tests and the expression of memory-related proteins. Taken together, these results suggest that C. dahurica and its constituents are potential agents for preventing or alleviating the symptoms of AD.
Ten cycloart-7-ene triterpenoid glycosides, including three new compounds (1–3), were isolated from the roots of Cimicifuga dahurica. Their structures were elucidated on the basis of extensive spectroscopic analyses, chemical methods and comparison with literatures. In addition, the isolates were evaluated for their inhibitory effects on the production of NO, as well as the expressions of iNOS and COX-2 in LPS-stimulated RAW 264.7 macrophages. The results showed that compounds 3, 5, 6, 7 and 8 can reduce the release of NO in a dose-dependent manner. Mechanistically, Western blot analysis indicated that the NO inhibitory effects relied on down-regulating the expression of iNOS, and partially associated with lowering the expression of COX-2.
A new cycloartane triterpene bisdesmoside, soulieoside T (1), and one known compound, oleanolic acid (2), were isolated from the ethanolic extract of the rhizomes of Actaea vaginata. Their structures were elucidated by spectroscopic methods and by comparison with data reported in the literature. Compound 1 was evaluated for cytotoxic activities against three human cancer cell lines.
One new triterpene glycoside, asiaticoside I (1), along with seven known ones (2–8), were isolated from the aerial parts of Cimicifuga dahurica (Turcz.) Maxim. The structure of 1 was elucidated on the basis of extensive spectroscopic methods including 1D-NMR, 2D-NMR and MS data. The structures of known compounds were determined by comparison with the literature data. Compound 1 exhibited moderate cell growth inhibitory activities in vitro against HELF, non-small cell lung cancer A549, and pancreatic cancer PANC-1 cell lines, with IC50 values of 62.97, 43.19, and 60.40 μM, respectively.
Eight undescribed 9,19-cycloartane type triterpenoid glycosides (cimdalglnoside A-H) and ten known analogues were obtained from the phytochemical research on the roots of Actaea dahurica (syn. Cimicifuga dahurica). All compounds were characterised by spectroscopic experiments, and chemical method. All the compounds isolated were assayed for cytotoxicity to five human cancer cell lines. Cimdalglnoside G showed promising cytotoxicities against Hela, and MCF-7 cell lines with IC50 values at 7.7 and 12.2 μM.
Five new phenylpropanoid allopyranosides (1–5), along with five known compounds (6–10) were isolated from the rhizomes of Cimicifuga dahurica. Their structures were established by means of spectroscopic analyses and chemical methods, as well as comparison with literatures. The anti-inflammatory activities of all isolates were evaluated. Compounds 6, 9 and 10 exhibited inhibitory effects on PGE 2 production in LPS stimulated RAW 264.7 macrophages with IC 50 values of 19.72, 6.33 and 39.90 µM, respectively.
The Indian Himalayan state of Jammu and Kashmir (J&K) harbours rich biodiversity, including diverse medicinal flora. The scientific documentation of diversity, distribution and traditional uses of medicinal flora can prove pivotal in the conservation and sustainable use of these precious plant resources in this Himalayan state. The present study, based on extensive ethno-medicinal surveys carried out during the last decade and supplemented with verified records from a systematic literature review, has developed a biodiversity database on medicinal plants of J&K state. The comprehensive database includes a total of 1123 plant species with practised ethno-medicinal uses in the state. The majority of the species (78%) are native to the Himalayan region. In most cases, whole plants are used, followed by leaves and underground parts. In total, these medicinal plant species are traditionally used to alleviate 266 types of disease. The present study has identified 20 important medicinal species, each used to cure more than 25 diseases. Based on the relative frequency citation (RFC) value, Taraxacum officinale and Aconitum heterophyllum are the most frequently used medicinal plant species in J&K. The present study, by adopting a scientifically sound taxonomic approach, reports one of the most comprehensive and updated syntheses of the medicinal flora of J&K state. This baseline information on the diversity, distribution and traditional uses of medicinal flora has immense applications, as it can provide insightful leads towards the discovery, development and designing of future drugs.
Ten undescribed 9,19-cycloartane type triterpenoid glycosides (cimdahxynoside A-J) and five known analogues were obtained from the phytochemical research on the roots of Actaea dahurica (syn. Cimicifuga dahurica). All compounds were characterised by spectroscopic experiments, chemical method and X-ray Single-crystal diffraction analysis. Cimdahxynoside A represented the first X-ray crystallography of 9,19-cycloartane type triterpenoid diglycoside. The cytotoxicity of all compounds were tested against five human cancer cell lines. Cimdahxynoside F showed significant cytotoxicity, with IC50 values between 6.6 and 9.9 μM.
Five undescribed cycloartane triterpenoids, including two cycloartane trinor-triterpenoids, were isolated from a 70% ethanol extract of the whole plant of Actaea vaginata (Ranunculaceae), together with thirteen known cycloartane triterpenoids. Their structures were determined by spectroscopic techniques and quantum chemical calculations for intramolecular noncovalent interactions with reduced density gradient method. All compounds were evaluated for their anti-inflammatory effects by a lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production model in RAW264.7 macrophage cells, and some showed potent inhibitory effects with IC50 values ranging from 5.0 to 24.4 μM. Further mechanism studies showed that one compound dose-dependently suppressed LPS-induced NO production and pro-inflammatory cytokines secretion, and decreased the expression of iNOS, through inhibiting NF-κB activation.
A new alkaloid, (E)-3-(3-methyl-1-oxo-2-butenyl)-6-methoxy-1
H
-indole (1), along with two known ones, was isolated from the aerial parts of Cimicifuga heracleifolia. The structure of 1 was elucidated on the basis of extensive spectroscopic data analysis. The structures of known compounds were determined by comparison with the literature data.
This study aimed to compare the influence between Cimicifuga foetida extract and different hormone therapies on breast pain in early postmenopausal women. A prospective, randomized, controlled clinical trial was conducted among 96 early postmenopausal women. Participants were randomly assigned to three groups: group A received 1 mg/day estradiol valerate plus 4 mg/day medroxyprogesterone acetate on days 19–30; group B received 1 mg/day estradiol valerate plus 100 mg/day micronized progesterone on days 19–30; group C received C. foetida extract, 1talet (contains 33.3 mg extract), t.i.d. Breast pain diary and numerical rating scale was used to access the breast pain. For 6 months’ treatment, the total incidence of breast pain in group A and B was significantly higher than that in group C (p < .05). The duration (day) of breast pain in each month decreased over time in group A and B while it was continuously low and without significant change in group C (p > .05). The intensity of breast pain was mild in most participants and did not differ among three groups (p > .05). During treatment of early postmenopausal women with C. foetida extract for 6 months, the incidence and duration of breast pain were lower than upon treatment with E2 plus cyclic MPA or m-P and did not change over time.
Inflammation is a biological response caused by overactivation of the immune system and is controlled by immune cells via a variety of cytokines. The overproduction of pro-inflammatory cytokines enhances abnormal host immunity, resulting in diseases such as rheumatoid arthritis, cardiovascular disease, Alzheimer’s disease, and cancer. Inhibiting the production of pro-inflammatory cytokines such as interleukin (IL)-12p40, IL-6, and tumor necrosis factor (TNF)-α might be one way to treat these conditions. Here, we investigated the anti-inflammatory activity of compounds isolated from Cimicifuga dahurica (Turcz.) Maxim., which is traditionally used as an antipyretic and analgesic in Korea. In primary cell culture assays, 12 compounds were found to inhibit the production of pro-inflammatory cytokines (IL-12p40, IL-6, and TNF-α) in vitro in bone marrow-derived dendritic cells stimulated with LPS.
One new 15,16-seco-cycloartane triterpene (1), three new cycloartane triterpene glycosides (2–4), and five known compounds (5–9) were isolated from the aerial parts of Actaea heracleifolia. The chemical structures of these compounds were determined on the basis of NMR analysis, HRTOF-ESIMS data, and other spectroscopic methods. Selected compounds were evaluated for their cytotoxicity against human tumor cell lines (HL-60, SMMC-7721, A549, MCF-7, and SW480) in vitro. Compounds 3 and 4 showed weak activity against the HL-60, A-549, and MCF-7 cell lines with IC50 values ranging from 21.34 to 36.98 µM.
Human enterovirus 71 (EV-A71) infections cause a wide array of diseases ranging from diarrhoea and rashes to hand-foot-and-mouth disease and, in rare cases, severe neurological disorders. No specific antiviral drug therapy is currently available. Extracts from seventy-five Chinese medicinal plants selected for antiviral activity based on the Chinese pharmacopeia and advice from traditional Chinese medicine clinicians were tested for activity against EV-A71. The aqueous extract of the rhizome of Cimicifuga heracleifolia (Sheng Ma) and Arnebia euchroma (Zi Cao) showed potent antiviral activity. The active fractions were isolated by bioassay-guided purification, and identified by a combination of high-resolution mass spectrometry and NMR. Fukinolic acid and cimicifugic acid A and J, were identified as active anti-EV-A71 compounds for Cimicifuga heracleifolia, whereas for Arnebia euchroma, two caffeic acid derivatives were tentatively deduced. Commercially available fukinolic acid analogues like L-chicoric acid and D-chicoric also showed in vitro micromolar activity against EV-A71 lab-strain and clinical isolates.
Objective: The aim of this study was to evaluate the efficacy and safety of long-term treatment with Cimicifuga foetida extract in menopausal women.
Methods: A prospective, randomized, controlled clinical trial was conducted. A total of 96 early postmenopausal women were randomly assigned to three groups: group A received 1 mg estradiol valerate daily plus 4 mg medroxyprogesterone acetate on days 19–30; group B received 1 mg estradiol valerate daily plus 100 mg micronized progesterone on days 19–30; group C received 100 mg C. foetida extract daily. The efficacy was evaluated. Safety parameters were recorded.
Results: A total of 81 patients completed the treatment and follow-up visit. The modified Kupperman Menopausal Index scores decreased after 3 months in all groups. No significant changes were observed in the liver, renal function and components of metabolic syndrome in group C (p > 0.05). There were no significant differences in the incidences of metabolic syndrome among the three groups (p > 0.05). After 24 months, the endometrial thickness increased significantly in group B (p = 0.014), but not in the C. foetida extract group (p > 0.05).
Conclusions: C. foetida extract is safe and effective for the treatment of menopausal symptoms in postmenopausal women.
Ethnopharmacological relevance:
Plants of the genus Cimicifuga have long been used as an ethnomedicine in China, Europe, and North America for its high medicinal value and health benefits. Their dried rhizomes are widely used for treating wind-heat headache, toothache, aphtha, sore throat, measles, spot poison, archoptosis, and uterine prolapse. In addition, it is used as a dietary supplement for preventing women menopausal symptoms and osteoporosis.
Aim of the review:
This paper aims to provide up-to-date information on the genus Cimicifuga, including botanical characterization, medicinal resources, traditional medicinal uses, phytochemistry, quality control, pharmacological research as well as the toxicology. The possible structural-activity relationships and molecular mechanisms of the bioactive constituents are discussed in ways that contribute to the structural optimization and preclinical safety assessment for further drug design.
Materials and methods:
The relevant information on Cimicifuga was collected from scientific databases (such as Google Scholar, PubMed, SciFinder Scholar, Science Direct, CNKI, Baidu Scholar, Web of Science, China Knowledge Resource Integrated Database), Chinese herbal classics, ethnobotanical books, PhD and MSc dissertations, Chinese Pharmacopoeia, published articles in peer-reviewed journals, local magazines, and unpublished materials. In addition, the Plant List (TPL, www.theplantlist.org) was also used to validate the scientific names and synonyms of this plant. The literature cited in this review dated from 1953 to 2017.
Results:
The majority of chemical constituents of this plant include triterpenoid glycosides, phenylpropanoids, nitrogenous compounds, chromones, flavonoids and 4α-methyl steroid. Among them, the primary bioactive constituents are believed to be present in the triterpene glycoside fraction. To date, investigation of seven Cimicifuga spp. plants led to the identification of more than 457 compounds. Years of pharma- cological research proved that the crude extracts and certain pure compounds obtained from Cimicifuga exhibited menopausal syndrome-treatment, anti-osteoporosis, antiviral, antitumor, antioxidant and antiangiogenic activities. On the other hand, Cimicifuga plant-induced toxicities of liver, cardiovascular, central and peripheral nervous systems have also been reported. Therefore, safety consideration should be placed into a high priority for herbal medicine Cimicifuga therapy in the early stages of development and clinical trials.
Conclusions:
This review presents information on botany, medicinal resources, and traditional medicinal history of some Cimicifuga plants. Modern pharmacology researchers have validated many traditional uses of Cimicifuga species. As the quality control and safety assessment of Cimicifuga plants is still incomplete, only a small part of the plant is permitted to be used as medicines. Expansion of medicinal resources in Cimicifuga is urgently needed to enable its full use. Currently research primarily focuses on the triterpenoid glycosides but there are many other types of compounds which may possess new biological activities however the systematic studies of these compounds are lacking. Extensive study is required on Cimicifuga plant before it can be fully used in clinics as a potent drug candidate.
Background:
Cimicifuga racemosa products are widely used in the treatment of climacteric symptoms. Aim was to evaluate Cimicifuga racemosa extract Ze 450 according Biopharmaceutics classification system (BCS).
Methods:
Triterpene glycosides served as analytical marker and were evaluated for solubility and absorption properties. pH-dependent thermodynamic solubility was tested via shake-flask method according to Yalkowsky (1) and dissolution performance of an herbal medicinal product containing Cimicifuga racemosa extract Ze 450 was assessed. Absorption was estimated by in vitro permeation through Caco-2 monolayers. Furthermore, different intestinal segments were screened for absorption performance using an in situ rat model.
Results:
Over a physiological pH range, triterpene glycosides exhibited pH-dependent solubility with highest concentration at pH 7.5. Dissolution profiles showed rapid dissolution of actein and 23-epi-26-deoxyactein. Furthermore, 23-epi-26-deoxyactein as surrogate for contained triterpene glycosides showed a high permeability through Caco-2 monolayers. Results of in situ rat model showed absorption capacity for 23-epi-26-deoxyactein in duodenum, jejunum, ileum as well as in colon.
Conclusions:
The results indicate high bioavailability of triterpene glycosides from Cimicifuga racemosa extract Ze 450. With regard to BCS, triterpene glycosides can be classified into BCS class I (high solubility, high permeability).
A phytochemical assay-guided fractionation of the 95% ethanol extract of Cimicifuga dahurica roots afforded 29 9,19-cycloartane triterpenoid glycosides, including the new cimiricasides A–F (1–6). The structures of 1–6 were established using contemporary NMR methods and from the HRESIMS data, and the sugar moiety in each case was confirmed by acid hydrolysis and subsequent GC/MS analysis. Compounds 2, 4, 5, 7–9, 18, 25, and 29 showed soluble epoxide hydrolase inhibitory effects with IC50 values of 0.4 ± 0.1 to 24.0 ± 0.2 μM. The compounds were analyzed by enzyme kinetic studies to explore the binding mode between the ligand and receptor. Compounds 4 (mixed type), 8, 18, and 29 (noncompetitive type) bound to a preferred allosteric site, while compounds 2, 5, 7, 9, and 25 had competitive interactions at the active site. The binding mechanism of selected inhibitors was investigated using molecular docking and dynamics simulations.
A new cyclolanostane triterpenoid glycoside, soulieoside O (1), together with 25-O-acetylcimigenol-3-O-?-d-xylopyranoside (2) and cimigenol-3-O-?-d-xylopyranoside (3), was isolated from the rhizomes of Souliea vaginata. Their structures were characterized by spectroscopic analysis and chemical methods. The new compound showed moderate inhibitory activity against three human cancer cell lines with IC50 values of 9.3-22.5??M.
The aim of this study was to search for potential therapeutic agents by identifying novel inhibitors of soluble epoxide hydrolase (sEH) from natural plants using an in silico approach. We found that an ethanolic extract from the roots of Cimicifuga dahurica (Turcz.) Maxim. significantly inhibited sEH in vitro. In a phytochemical investigation using assay-guided fractionation of the dichloromethane extract of C. dahurica, we isolated two new indolinone alkaloids (5 and 6) and five related constituents (1-4, and 7) and established their structures based on an extensive analysis using 1D and 2D NMR, and MS methods. All of the isolated compounds inhibited sEH enzymatic activity in a dose-dependent manner, with IC50 values ranging from 0.8±0.0 to 2.8±0.4μM. A kinetic analysis of compounds 1-7 revealed that compound 2 was non-competitive; 1, 3, and 7 were mixed-type; and 4-6 were competitive inhibitors. Molecular docking was employed to further elucidate their receptor-ligand binding characteristics. These results demonstrated that compounds from C. dahurica are potential sEH inhibitors.
In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that an ethanolic extract of the roots of Cimicifuga dahurica significantly inhibits sEH in vitro. A phytochemical study on the dichloromethane fraction of C. dahurica resulted in the isolation of two new cycloartane triterpenoids (1 and 6), together with 13 known cycloartane analogues (2–5 and 7–15). The structures of compounds were determined by spectroscopic methods. All of the triterpenoid derivatives inhibited sEH enzymatic activity in a concentration-dependent manner, and 13 of the tested compounds showed significant activity. Among them, compounds 1, 3, 5, 7, 9, and 12 showed the highest levels of inhibitory activity, with IC50 values of about 5 μM or less. Kinetic analysis of compounds 1, 3, 5–9, 11, 12, and 14 revealed that compounds 3, 6, 7, 11, and 14 were non-competitive; 1, 5, 9, and 12 were mixed-type; and 8 was a competitive inhibitor. Furthermore, in silico molecular docking indicated that compounds 3, 6–9, 11, 12, and 14 bound to sEH in a similar manner and had stable binding energies, as calculated by AutoDock 4.2 and processed in a 10,000-ps molecular dynamics simulation to assess the binding stability of compounds 5, 7, and 9.
Introduction:
The medicinal plant Actaea racemosa L. (Ranunculaceae, aka black cohosh) is widely used to treat climacteric complaints as an alternative to hormone substitution. Recent trials prove efficacy and safety of the approved herbal medicinal products from extracts of pharmaceutical quality. This led to worldwide increasing sales. A higher demand for the plant material results in problems with economically motivated adulteration. Thus, reliable tools for herbal drug authentication are necessary.
Objective:
To develop an economical, plain, and rapid method to distinguish between closely related American and Asian Actaea species, using securely established and resilient analytical methods coupled to a chemometric evaluation of the resulting data.
Methodology:
We developed and validated a RP-PDA-HPLC method including an extraction by ultra-sonication to determine the genuine contents of partly hydrolysis-sensitive polyphenols in Actaea racemosa roots and rhizomes, and applied it to a large number of 203 Actaea samples consisting of seven species.
Results:
We were able to generate reliable data with regards to the polyphenolic esters in the samples. The evaluation of this data by principle component analysis (PCA) made a discrimination between Asian Actaea species (sheng ma), one American Actaea species (Appalachian bugbane), and A. racemosa possible.
Conclusion:
The developed RP-PDA-HPLC method coupled to PCA is an excellent tool for authentication of the Actaea racemosa herbal drug, and can be a powerful addition to the TLC methods used in the dedicated pharmacopoeias, and is a promising alternative to expensive and lots of expertise requiring methods. Copyright © 2016 John Wiley & Sons, Ltd.
Eight new cycloartane triterpenoids (1–8), along with eight known analogues (9–16), were isolated from the roots of Cimicifuga foetida L. Their structures were elucidated by spectroscopic analysis and acidic hydrolysis. All of the new compounds were evaluated for their in vitro cytotoxicity against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480), and compound 2 showed inhibitory activities with IC50 values raging from 2.61 to 3.32 μM.
Actaea muliensis (Ranunculaceae), a new species from Muli County, Sichuan Province, China, is described and illustrated. Morphologically, it is somewhat similar to A. mairei, but is most readily distinguishable from that species and others within A. sect. Cimicifuga by, among other characters, the dark purple (vs yellow) staminodes. Actaea muliensis is revealed to be a diploid (2n = 16) species with 3-colpate pollen.