CimicifugaCimicifugae RhizomaIt was first published in Shennong materia medica classic and has a long history of medicinal use in China. The resources of Cimicifuga are widely distributed and various, and domestic and foreign scholars focus on the black CimicifugaCimicifuga racemose (Linne) Nuttall.、 Single spike CimicifugaC. simplex Wormskarl.、 CohoshC. acerina (Sieb.et Zucc.) Tanaka.、 Cimicifuga yunnanensisC. yunnanensis [1]。
Which comes from the Ranunculaceae plant Cimicifuga TrifoliumC. heracleifolia Kom.、 Xing'an CimicifugaC. dahurica (turcz.) maxim. or CimicifugaC. foetida 50. The dried rhizome of Cimicifuga is the authentic medicinal product of Cimicifuga contained in the 2020 edition of Chinese Pharmacopoeia (hereinafter referred to as Chinese Pharmacopoeia)[2]At present, it is the main raw material of Cimicifuga for clinical use in traditional Chinese medicine. Big clover Cimicifuga, commonly known as Guan Cimicifuga, is mainly produced in Liaoning, Jilin and Heilongjiang; Xing'an Cimicifuga, commonly known as northern Cimicifuga, is mainly produced in Shanxi, Hebei and Inner Mongolia; Cimicifuga, commonly known as Western Cimicifuga and green Cimicifuga, is mainly produced in Sichuan, Yunnan, Gansu and other places[3]。
Ups and downs is an important part of the theory of traditional Chinese medicine. However, due to the ambiguity of its concept and the limitations of its research ideas, the scientific connotation of the rising and falling properties is still unclear. Traditional Chinese medicine believes that Cimicifuga is a representative drug with both floating and sedimentation properties. It tastes pungent, slightly sweet, and slightly cold, and belongs to the lung, spleen, stomach, and large intestine. .
In order to carry out in-depth research on the material basis and mechanism of action of the rising and falling properties of Cimicifuga, according to the clinical medication tradition of traditional Chinese medicine, this paper takes the original varieties of Cimicifuga collected in Chinese Pharmacopoeia as the research object, and takes "Cimicifuga"“Cimicifuga heracleifolia”“Cimicifuga dahurica”“Cimicifuga foetida”To search the relevant research literatures in CNKI and PubMed databases from 1990 to 2021, a total of 1075 literatures at home and abroad were retrieved. After screening the original variety research literatures in the Pharmacopoeia, 156 effective literatures were included. The research progress of chemical components and pharmacological effects of the original variety of Cimicifuga in the pharmacopoeia in the past 30 years was summarized and summarized, providing a literature basis for further elucidating the scientific connotation of the rising and falling properties of Cimicifuga.
1 chemical composition
Like Cimicifuga plants, Cimicifuga Trifolium, Cimicifuga Xingan and Cimicifuga contain rich chemical substances. In addition to triterpenoids and their glycosides, which are characteristic components of Cimicifuga plants, they also contain phenolic acids, chromones, lignans, indolones, alkaloids, amides, sterols, sugars, volatile oils and other compounds. .
1.1 triterpenoids and their glycosides
From 1990 to 2021, 380 triterpenoids and their glycosides were isolated from Cimicifuga trifoliata, Cimicifuga Hinggan and Cimicifuga, accounting for 70.11% of the total number of compounds. The main representative components are27 deoxycimicifugin, cimicifugin, cimicifugol-3-o - α - l-arabinoside, cimicifugol-3-o - α - l-arabinoside, cimicifugol-3-o - β - D-xyloside, etcSee Table 1 for the name, molecular formula and plant source of the compound.
1.2 phenolic acids
From 1990 to 2021, 77 kinds of phenolic acids were isolated from Cimicifuga Trifolium, Cimicifuga Xingan and Cimicifuga, accounting for 14.21% of the total compounds. See Table 2 for the compound name, molecular formula and plant source.
1.3 chromones
From 1990 to 2021, 12 kinds of chromones were isolated from Cimicifuga Trifolium, Cimicifuga Xingan and Cimicifuga, accounting for 2.21% of the total compounds. See Table 3 for the compound name, molecular formula and plant source.
1.4 other categories
From 1990 to 2021, 73 kinds of lignans, indolones, alkaloids, amides, sterols, sugars, volatile oils and other components were isolated from Cimicifuga trifoliata, Cimicifuga khingana and Cimicifuga, accounting for 13.47% of the total number of compounds. See Table 4 for the compound name, molecular formula and plant source.
2 pharmacological study of Cimicifuga
In the past 30 years, domestic and foreign scholars have carried out a large number of in vivo and in vitro pharmacological activity screening studies on Cimicifuga Trifolium, Cimicifuga Hinggan and Cimicifuga. The results show that Cimicifuga has anti-tumor, anti-inflammatory, anti viral, anti osteoporosis, hypoglycemic and lipid regulation, anti-oxidation, gastrointestinal regulation, nerve protection, excitation of smooth muscle, anti complement activity, anti mutation, anti hypoxia, anti depression, anti pigmentation, immunosuppression, anti climacteric syndrome, anti cholinesterase and other pharmacological activities. By constructing the network analysis framework of effective components of Cimicifuga - pharmacological effects - traditional Chinese medicine efficacy indications - rising and falling properties, the material basis and effects of rising and falling properties of Cimicifuga can be clearly revealed.The internal link between mechanisms. . See Figure 3 for the schematic diagram of the rising and falling drug substances and action mechanism of Cimicifuga.
2.1 anti tumor
Studies have shown that the ethyl acetate extract, water extract, total triterpenoid saponins, triterpenoids and their glycoside monomers of Cimicifuga are the main active components of the anti-tumor effect of Cimicifuga, which have broad-spectrum and effective cytotoxic activity, which is consistent with the "main detoxification" effect of Cimicifuga recorded in Shennong materia medica classic. The pharmacodynamic mechanism is mainly related to the proliferation of anticancer cells, the induction of cancer cell cycle arrest and apoptosis, and the regulation of cancer-related signaling pathways. . Cimigenol glycosides have broad-spectrum and moderate cytotoxicity against human acute promyelocytic leukemia HL-60 cells, liver cancer cmcc-7721 cells, rectal cancer SW-480 cells, etc., with IC50 values ranging from 4.2 to 14.5 μ mol / L. Cimigenol type aglycones exhibit a broad spectrum and weak cytotoxicity, with an IC50 value of about 20 μ mol/l[59]. .
. It inhibits the proliferation and migration of breast cancer cells by mediating mitochondrial apoptosis and epithelial mesenchymal transition through the γ - secretase /notch axis. The mechanism of action includes inhibiting the activation of γ - secretase catalytic subunit psen-1 and mediating the involvement of psen-1 in Notch protein cleavage [76].
The ethyl acetate and n-butanol extracts of Cimicifuga could inhibit the proliferation, migration and invasion of human breast cancer cell lines; The effect of ethyl acetate was better than that of n-butanol; Triterpenoid saponins are antitumor active components in ethyl acetate fraction. . Acteosin, a triterpenoid compound, has inhibitory effects on a variety of tumor cells and can promote trail induced apoptosis in gastric cancer by activating p53/caspase-3signaling pathway [96]; Inhibit the proliferation of oral squamous cell carcinoma cells, induce G1 phase cell arrest, induce apoptosis, and antagonize the proliferation of oral squamous cell carcinoma cells by activating akt/foxo1signaling pathway [97]; Antagonizing the pi3k/aktsignaling pathway by downregulating Inosine-5-Monophosphate dehydrogenase 2 levels inhibits the proliferation of human colon cancer cells [98].
2.2 anti inflammatory
Studies have shown that the water extract, phenolic acids, triterpenoids and their glycosides of Cimicifuga are the main active components of the anti-inflammatory effect of Cimicifuga. In particular, phenolic acids such as ferulic acid and isoferulic acid have strong anti-inflammatory activity, and are the main effective substances of Cimicifuga to exert heat clearing and detoxification effects. The pharmacodynamic mechanism is mainly related to inhibiting the release of inflammatory mediators, regulating the expression of inflammation related proteins, and regulating the number and function of neutrophils.
Cimigenoside, a triterpenoid compound, can inhibit the production of cxcl2 and CXCL10 and the expression of P-selectin and vascular cell adhesion molecule 1 to prevent neutrophil infiltration in the lung. Inhibit the production of inflammatory cytokines and chemokines by human airway epithelial cell line BEAS-2B cells induced by poly (I ∶ C) [12]. Phenolic compounds cimicifugic acid e, trans-N-Feruloyl tyramine and cimicifugal acid D can inhibit the production of prostaglandin E2 in lipopolysaccharide (LPS) - stimulated raw 264.7 macrophages, and down regulate the expression of COX-2, thereby exerting anti-inflammatory activity [88-89]. The chromogen ketone compound cimicifugin exerts anti-inflammatory and anti atherosclerotic effects by inhibiting the expression of inflammatory factors interleukin-6 (IL-6), tumor necrosis factor - α (tnf- α), increasing the expression of adenosine triphosphate binding cassette transporter A1 protein, and promoting cholesterol efflux [99].
2.3 antiviral
. The mechanism of efficacy is mainly related to inhibiting the production and activity of virus and stimulating the secretion of interferon - β by epithelial cells. Cimicifuga water extract and cimicifugin can dose dependently inhibit human respiratory syncytial virus (HRSV) - induced plaque formation in human laryngeal cancer epithelial Hep2 cells and human lung adenocarcinoma A549 cells, stimulate epithelial cells to secrete interferon beta to resist viral infection, inhibit viral adsorption and enhance the effect of hepcidin on viral adsorption [100-101].
The 75% ethanol extract of Cimicifuga, total saponins, and total phenolic acids showed significant anti hepatitis virus activity in vitro, and the half toxic concentration (tc50) values were 0.503 g / ml, 0.455 g / g, and 0.315 g / g, respectively, which exerted antiviral effect by inhibiting the secretion of HBsAg; In vivo studies have found that Cimicifuga extract from each group can significantly reduce the content of HBeAg, HBsAg and HBV-DNA in the serum of hepatitis virus transgenic mice, and has obvious anti hepatitis virus activity and liver protection [102-103]. The aqueous extract of Cimicifuga has strong inhibitory activity and low cytotoxicity against human enterovirus a71 (ev-a71). The half effective concentration (EC50) and ec90 were 1.6 μ g/ml and 5.7 μ g/ml, respectively [104].
2.4 anti osteoporosis
Studies have shown that the water extract, ethanol extract, triterpenoids and their mixtures of Cimicifuga are the main active components of the anti osteoporosis effect of Cimicifuga. The pharmacodynamic mechanism is mainly related to inhibiting osteoclast resorption, promoting osteoblast proliferation, increasing bone mineral density, etc. Cimicifuga Trifolium, ethyl acetate fraction of Cimicifuga, triterpenoid monomers and their mixtures can dose dependently inhibit the increase of serum ca2+ level and inhibit bone resorption in rats fed a low calcium diet. Increases bone mineral density in ovariectomized rats.
. The 50 mg/kg aqueous extract of Cimicifuga by intraperitoneal injection for 6 weeks can prevent the weight gain of mice induced by ovariectomy, reduce the level of serum alkaline phosphatase, and inhibit the absorption of osteoclasts. The bone mass, trabecular number, trabecular thickness, structural model index and bone mineral density of proximal tibial metaphysis or distal femoral metaphysis were significantly preserved. Prevent ovariectomy induced bone loss in mice [106]. The ethanol extracts of cohosh and black cohosh both showed anti osteoporosis and anti hyperlipidemia effects on menopausal syndrome. Cimicifuga Trifolium has similar effects with black Cimicifuga in relieving menopausal symptoms, and can be used as a substitute for black Cimicifuga [107].
Triterpenoid cimiciol-3-O-β-D-Xyloside, cimicifugol-3-O-β-D-Xyloside, alcotol-3-O-β-D-Xyloside can inhibit the bone resorption of osteoclasts in ovariectomized mice, and has a significant protective effect on bone mineral density, and there is a synergistic effect between the compounds. .
2.5 lowering blood glucose and lipid
Studies have shown that Cimicifuga extract, Cimicifuga triterpenoids, phenolic acids monomer compounds are the main active components of Cimicifuga hypoglycemic and lipid-lowering effects. The pharmacodynamic mechanism is mainly related to regulating the release of insulin and leptin, resisting the glycosylation of high-density lipoprotein, and promoting lipolysis of fat. Cimicifuga and ethyl acetate extracts can promote lipolysis of adipose tissue in mice fed a high-fat diet, improve lipid utilization, and improve obesity and metabolic disorders induced by a high-fat diet in mice by promoting browning and lipidation of white adipose tissue and increasing energy consumption. The triterpenoids cimicifugin H-2, cimicifugin H3, (16S,20S,24R）-12 β - acetoxy-16,23-epoxy-24,25-dihydroxy-3 β - (β-D-Xylopyranose) - 9,19-cycloartenol-22 (23) - ene and 23-epi-26-deoxyacterol at the concentration of 10 μ mol/l can significantly reduce the fat accumulation in 3T3-L1 adipocytes, showing a strong lipid-lowering effect, and the inhibition rate is 8.35% - 12.07% [75].
; Acteosin and 23-epi-26-deoxyacteosin significantly inhibit the activity of 3T3-L1 preadipocyte steatosis, can activate AMPK and sirt1-foxo1signaling pathway in adipose tissue, and promote adipose tissue lipolysis in mice on a high-fat diet [110].
Cimicifuga extract can inhibit the formation of glutamate and the activity of glutamate dehydrogenase in cultured rat islet cells, and play an anti glycemic role by inhibiting the activity of glutamate dehydrogenase and regulating insulin release [111]; Isoferulic acid can significantly reduce blood glucose in spontaneous diabetic rats [112]; Isoferulic acid can prevent the binding of aldehydes and free amino groups on human plasma high-density lipoprotein, and inhibit the free radical induced oxidation of high-density lipoprotein during glycation. Concentration dependent prevention of high-density lipoprotein glycosylation leads to changes in structural and functional properties and plays an anti glycosylation role [113].
2.6 oxidation resistance
Studies have shown that Cimicifuga polysaccharide and Cimicifuga phenolic acid monomers are the main active components of the antioxidant effect of Cimicifuga. The pharmacodynamic mechanism is mainly related to scavenging free radicals. . ABTS method was used to detect the antioxidant capacity of Cimicifuga polysaccharide. When the mass concentration was 1.66 mg / ml, its total antioxidant capacity was 0.64 mmol / L, and the DPPH free radical scavenging rate was 67.94% [114]; In addition, Cimicifuga polysaccharide has obvious scavenging effect on hydroxyl radicals, and the maximum scavenging rate is more than 90%. The scavenging ability has an obvious dose-response relationship with polysaccharide concentration, and has good antioxidant activity [115].
The combination of isoferulic acid and calycosin at a dose ratio of 1 ∶ 1 has a significant synergistic effect in the DPPH free radical scavenging assay, indicating that the combination of Astragalus membranaceus and Cimicifuga has a better antioxidant effect than the single use [116]; Isoferulic acid can inhibit the production of hydroxyl and superoxide anion radicals during the reaction of methylglyoxal and lysine, and prevent mg induced protein glycosylation and DNA damage through free radical scavenging [117], thus playing an antioxidant role.
2.7 regulation of gastrointestinal
Studies have shown that the water extract and chloroform extract of Cimicifuga, Cimicifuga saponins monomer compounds are the main active components of Cimicifuga for regulating gastrointestinal effects. The pharmacodynamic mechanism is mainly related to the regulation of gastrointestinal motility and gastrointestinal hormone disorders. Raw Cimicifuga, honey Cimicifuga and water extract of honey bran Cimicifuga can significantly reduce the gastric residual rate, increase the intestinal propulsion rate and promote the recovery of gastrointestinal function in mice with spleen deficiency. It significantly increased the contents of serum gastrin and plasma motilin in spleen deficiency rats, and regulated gastrointestinal hormone disorders [118]. ; In addition, the water extract of Cimicifuga and its chloroform extract could inhibit the total number of stools, the number of loose stools, the rate of loose stools and the diarrhea index of the diarrhea mouse model caused by Senna. It has no effect on gastric emptying and intestinal propulsion rate in normal mice. It was suggested that the aqueous extract of Cimicifuga could alleviate the degree of diarrhea in mice caused by Senna [120].
2.8 bacteriostasis
The results showed that the ethanol extract of Cimicifuga, Cimicifuga chromones and phenolic acid monomers were the main active components of the antibacterial effect of Cimicifuga. Ethanol extract, ferulic acid and caffeic acid can effectively inhibit the propagation of Helicobacter pylori and protect gastric injury. Ferulic acid and caffeic acid have strong DPPH free radical scavenging activity, with IC50 values of 5.68 and 2.63 μ mol/l, respectively [102]. The ethanol extract of Cimicifuga has antibacterial effect on Streptococcus mutans, Streptococcus sanguis, Streptococcus salivarius and Streptococcus haemolyticus B, which are the main components of dental plaque, and its minimum inhibitory concentration is 0.21 ~ 1.67 mg / ml[121]. Cimicifugin has inhibitory effect on 11 fungi, such as Candida albicans and Trichophyton gypseum. The minimum inhibitory concentration of 7 other fungi is 100 μ g/ml, which is equivalent to clotrimazole, except for curculiosporium ferrugosum, which is 300 μ g/ml. It has a good therapeutic effect on tinea corporis of guinea pigs infected with Trichophyton gypseum, and has no irritation on intact and damaged skin of rats [122].
2.9 cerebral neuroprotection
Studies have shown that the phenolic acids and saponins of Cimicifuga are the main active ingredients of the neuroprotective effect of Cimicifuga. ; Moreover, 4 '- methoxy-3' - hydroxy carboxybenzoyl isoferulic anhydride also has obvious neuroprotective activity against H2O2 induced neurotoxicity PC12 cell model, and the cell survival rate is 87.65% at the concentration of 10 μ mol/l [85].
Cimicifugin H-1 can inhibit the excessive release of excitatory amino acids glutamate and aspartate, and increase the concentration of inhibitory amino acids glycine and γ - aminobutyric acid in focal cerebral ischemia model rats. . Aurodone alcohol, 24-table-24-O--O-β-D-Triterpenoid saponins such as xylopyranoside can inhibit β - secretase in app-cho cells and effectively interrupt the production of β - amyloid; .
2.10 others
In addition, the total saponins of Cimicifuga and the aqueous extract of Cimicifuga still have other pharmacological activities, such as anti complement activity [6,32], anti hypoxia [9], anti cholinesterase activity [15], immunosuppression [45], excitation of uterine smooth muscle [125], antimutation [126-127], anti pigmentation [128], anti depression [129], anti menopausal syndrome [130]. In terms of pharmacokinetics, studies have reported that PO or single IV administration of four cimicifugin in rats[131], Beagle Dog Po 5 kinds of cimicifugin[132], and cimicifugin[133], caffeic acid, isoferulic acid and ferulic acid[134]Advances in pharmacokinetic studies in rats.
3 conclusion
The medicinal plants of Cimicifuga are rich in resources, and the research on the chemical constituents and pharmacological effects of Cimicifuga has been a research hotspot of scholars at home and abroad. Combined with the application of Cimicifuga in the field of traditional Chinese medicine, the following problems still exist in the research of Cimicifuga at present:
(1) In terms of drug base: to black cohosh, racemose cohosh,the main ingredient of the drug is the drug base.The main ingredient of the drug.The drug is the drug base..the drug of the black cohosh..the black cohosh.The black cohosh，Single spike Cimicifuga，There are many studies on non Chinese Pharmacopoeia based original Cimicifuga plants, such as Cimicifuga minor and Cimicifuga yunnanensis, while there are insufficient reports on Cimicifuga major, Cimicifuga Xing'an or Cimicifuga collected in Chinese Pharmacopoeia. Whether other cohosh can replace Chinese pharmacopoeia in the theoretical research of traditional Chinese medicine and clinical research of traditional Chinese medicine, its efficacy and safety need further research and research. Under the guidance of traditional Chinese medicine theory, we should select the original varieties of Cimicifuga contained in Chinese Pharmacopoeia, and closely combine the traditional Chinese medicine efficacy of Cimicifuga to study the material basis and mechanism of action of traditional Chinese medicine.
(2) In terms of chemical composition, there are many reports on the triterpenoids and saponins of Cimicifuga, while there are few reports on the phenolic acids, chromones, volatile oils, alkaloids and polysaccharides of Cimicifuga.
(3) In terms of pharmacological research: there are many studies on the anti-tumor effect of Cimicifuga, while there are few reports on the pharmacological effects of anti-inflammatory, bacteriostatic, antiviral, antioxidant, regulating gastrointestinal function and other aspects closely related to the efficacy of Cimicifuga and the main symptoms and signs. .
Therefore, according to the three original varieties of Cimicifuga collected in the 2020 edition of Chinese Pharmacopoeia, combined with the publication of penetration of rash, clearing heat and detoxification, raising Yang Qi, the main treatment of wind heat and cold, fever and headache, measles impervious, toothache, aphthous ulcer, sore throat, Yang toxin spots, Qi deficiency depression, organ prolapse and other traditional Chinese medicine efficacy indications, a systematic and in-depth study of the material basis and mechanism of action of the property is of great value for carrying forward the characteristics of traditional Chinese medicine and further revealing the scientific connotation of the rising and falling property of Cimicifuga.
Conflict of interest All authors declare no conflict of interest
References (omitted)
Source: chenliyi, Lijiaxin, zhangmeiqing, Yao tie, dingliqin, Qiufeng, zhangdeqin. Research progress on chemical constituents and pharmacological effects of Cimicifuga officinalis [j]. Chinese herbal medicine, 2023, 54 (5): 1685-1704