Traditional uses, phytochemistry, pharmacology, quality control and clinical studies of Cimicifugae Rhizoma: a comprehensive review.

Cimicifugae Rhizoma, generally known as "Sheng Ma" in China, has great medicinal and dietary values. Cimicifugae Rhizoma is the dried rhizome of Cimicifuga foetida L., Cimicifuga dahurica (Turcz.) Maxim. and Cimicifuga heracleifolia Kom., which has been used to treat wind-heat headache, tooth pain, aphtha, sore throat, prolapse of anus and uterine prolapse in traditional Chinese medicine. This review systematically presents the traditional uses, phytochemistry, pharmacology, clinical studies, quality control and toxicity of Cimicifugae Rhizoma in order to propose scientific evidence for its rational utilization and product development. Herein, 348 compounds isolated or identified from the herb are summarized in this review, mainly including triterpenoid saponins, phenylpropanoids, chromones, alkaloids, terpenoids and flavonoids. The crude extracts and its constituents had various pharmacological properties such as anti-inflammatory, antitumor, antiviral, antioxidant, neuroprotective, anti-osteoporosis and relieving menopausal symptoms. The recent research progress of Cimicifugae Rhizoma in ethnopharmacology, phytochemistry and pharmacological effects demonstrates the effectiveness of its utilization and supplies valuable guidance for further research. This review will provide a basis for the future development and utilization of Cimicifugae Rhizoma.

Prescription Data Mining and Network Pharmacology Study of 1152 Patients with Rectal Prolapse Using Traditional Chinese Medicine.

BACKGROUND: In recent years, the incidence of rectal prolapse has increased significantly due to the sedentary lifestyle and irregular eating habits of modern life. However, there is a lack of clinical studies on the treatment of rectal prolapse with traditional Chinese medicine (TCM) with a large sample size. Therefore, this study investigated the characteristics of rectal prolapse treatment formulas and then studied the network pharmacology of their core therapeutic drugs, which can help to provide a reference for the treatment and postoperative care of rectal prolapse patients. OBJECTIVE: This study aimed to explore the prescription characteristics and the mechanism of action of core drugs in the treatment of rectal prolapse in Chinese medicine through data mining and bioinformatics techniques. METHODS: We collected the diagnosis and treatment information of patients with rectal prolapse from January 2014 to September 2021 in the electronic case database of Nanjing Hospital of TCM, mined the patient information and prescription features using R, screened the active ingredients of the core pairs of drugs and disease drug intersection targets using TCMSP and GnenCard databases, and constructed a Protein-protein interaction (PPI) network using STRING and Cytoscape, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the intersecting targets were performed using Metascape and R. RESULTS: We found that prolapse is easy to occur in people over 50 years old, preferably in autumn and winter. Commonly used therapeutic Chinese medicines include Glycyrrhiza glabra, Radix angelicae sinensis, Radix astragali, Atractylodes macrocephala, and Pericarpium citri reticulatae, which are mostly deficiency tonic medicines, warm in nature, and belong to spleen meridian. The core therapeutic medicinal pair was "Bupleuri radix-Cimicifugae rhizoma". There were 190 common targets of Bupleuri radix and Cimicifugae rhizoma, and 71 intersection targets of the drug pair and prolapse. The main components of the core drugs for the treatment of prolapse may be quercetin, kaempferol, Stigmasterol, etc, and the core targets may be CASP3, AKT1, HIF1A, etc. The total number of GO entries for the intersection targets of "Bupleuri radix-Cimicifugae rhizoma" and diseases was 3495, among which the molecular functions accounted for the largest proportion, mainly Pathways in cancer, IL-18 signaling pathway, etc. KEGG enriched pathway analysis yielded 168 results, and the major pathways were pathways in cancer, lipid and atherosclerosis, IL-17 signaling pathway, etc. Conclusion: This study adopted real-world research methodology and used data mining and bioinformatics technology to mine the medication law of rectal prolapse and its core drug action mechanism from the clinical information of Chinese medicine.

Unraveling the anti-breast cancer activity of Cimicifugae rhizoma using biological network pathways and molecular dynamics simulation.

Cimicifugae is a commonly used treatment for breast cancer, but the specific molecular mechanisms underlying its effectiveness remain unclear. In this research, we employ a combination of network pharmacology, molecular docking, and molecular dynamics simulations to uncover the most potent phytochemical within Cimicifugae rhizoma in order to delve into its interaction with the target protein in breast cancer treatment. We identified 18 active compounds and 89 associated targets, primarily associated to various biological processes such as lipid metabolism, the signaling pathway in diabetes, viral infections, and cancer-related pathways. Molecular docking analysis revealed that the two most active compounds, Formononetin and Cimigenol, exhibit strong binding to the target protein AKT1. Through molecular dynamics simulations, we found that the Cimigenol-AKT1 complex exhibits greater structural stability and lower interaction energy compared to the stigmasterol-AKT1 complex. Our study demonstrates that Cimicifugae rhizoma exerts its effects in breast cancer treatment through a multi-component, multi-target synergistic approach. Furthermore, we propose that Cimigenol, targeting AKT-1, represents the most effective compound, offering valuable insights into the molecular mechanisms underpinning its role in breast cancer therapy.

Combining network pharmacology, RNA-seq, and metabolomics strategies to reveal the mechanism of Cimicifugae Rhizoma - Smilax glabra Roxb herb pair for the treatment of psoriasis.

BACKGROUND: Psoriasis is a prevalent chronic inflammatory skin condition marked by immune cell infiltration and keratinocyte abnormal proliferation. Cimicifugae Rhizoma - Smilax glabra Roxb (CS) herb pair, the main component of Shengma Detoxification Decoction, has been proven effective for the treatment of psoriasis. However, the mechanism is yet to be deciphered. PURPOSE: To explore the mechanism of CS for the treatment of psoriasis. METHODS: The imiquimod-induced psoriasis-like lesion mouse model was used to identify the targets and the molecular mechanisms of CS. Network pharmacology combined with RNA-seq strategy was employed to predict the targets and mechanisms of CS for psoriasis. Metabolomics approaches were used to demonstrate the complexity of CS for the treatment of psoriasis. Finally, a compound-response-enzyme-gene network was constructed based on the multi-omics results to elucidate potential connections. RESULTS: The CS herb pair could significantly improve psoriatic lesions and reduce the inflammatory cell infiltration and proliferation of keratinocytes in skin lesions. Network pharmacology predicted that TNF, JNK, IL-6, and IL-1ß could be potential targets. RNA-seq data revealed that CS could significantly regulate genes and signaling pathways associated with Th17 responses, such as IL-36, IL-1ß, CCl2, CXCL16, keratin 14, keratin 5, and antimicrobial peptides S100A8 and S100A9 well as MAPK, mTOR, and other signaling pathways. Further experimental data validated that CS treatment remarkably reduced the expression of inflammatory cytokines and factors, such as CCL2, CCL7, IL1F6, IL-17, IL-23, IL-1ß, TNF-α, and IL-6, and inhibited the phosphorylation of p38 and ERK1/2. This indicated that CS exerts its therapeutic effect by inhibiting the MAPK signaling pathways. In addition, metabolomic analyses demonstrated that CS treatment improved seven metabolic pathways, these included phenylalanine, tyrosine, pyruvate metabolism, carnitine metabolism, etc. Four key metabolites (L-Arginine, L-Phenylalanine, L-Carnitine, O-Acetylcarnitine) and nine differential genes (CMA1, PCBD2, TPSAB1, TPSB2, etc.) were identified that affected amino acid metabolism, carnitine metabolism, and other pathways contributing to the infiltration of Th17 cells in psoriatic lesions. CONCLUSION: CS could alleviate IMQ-induced psoriasis-like dermatitis by reducing the expression of cytokines and chemokines mediated by the MAPK pathway, and improved amino acid and carnitine metabolism in vivo. Our study is the first to demonstrate the complex mechanism of CS for the treatment of psoriasis and provides a new paradigm to elucidate the pharmacological effects of Traditional Chinese Medicine (TCM) drugs for psoriasis from multiple perspectives.

Origin，Changes and Analysis of Efficacy of Cimicifugae Rhizoma / 中国实验方剂学杂志

Cimicifugae Rhizoma originated from Shennong′s Classic of Materia Medica（《神农本草经》）. Before the Jin-Yuan period （1115-1368 AD）， the efficacy of Cimicifugae Rhizoma was clearing heat and removing toxin whether it was recorded in herbal works or medical formularies. Since ZHANG Yuan-su in the Jin-Yuan period， its efficacy has changed， and that of raising Yang Qi has begun to appear. LI Dong-yuan and WANG Hao-gu followed ZHANG Yuan-su's point of view， and did not realize the efficacy of clearing heat and removing toxin and regarded Cimicifugae Rhizoma as a representative medicine for raising Yang Qi. During the Ming and Qing dynasties， the efficacy of Cimicifugae Rhizoma was mainly divided into two categories： both clearing heat and removing toxin and raising Yang Qi， and raising Yang Qi only. In modern times， the efficacy realized by previous generations is criticized， and two views emerge. One is inheriting the two-way theory of both clearing heat and removing toxin and raising Yang Qi. The other is that Cimicifugae Rhizoma is purely the medicine for clearing heat and removing toxin and its efficacy of raising Yang Qi is firmly refuted， which conforms to that of Cimicifugae Rhizoma before the Jin-Yuan period， and is also supported by Japanese scholars. Chinese Pharmacopoeia （1985） concludes that Cimicifugae Rhizoma has three major functions： releasing exterior and promoting eruption， clearing heat and removing toxin， and raising Yang Qi， which represents the current mainstream understanding of Cimicifugae Rhizoma in the academic world. Some contemporary scholars， including clinical physicians， medical historians， and pharmacists， still object to the raising Yang Qi of Cimicifugae Rhizoma. This article systematically sorted out the origin and changes of the efficacy of Cimicifugae Rhizoma， and analyzed the reasons for the changes. Combining philosophical thinking and modern pharmacology research， the authors also believe that Cimicifugae Rhizoma can not raise Yang Qi .

Cimicifugae Rhizoma Extract Attenuates Oxidative Stress and Airway Inflammation via the Upregulation of Nrf2/HO-1/NQO1 and Downregulation of NF-κB Phosphorylation in Ovalbumin-Induced Asthma.

Cimicifugae Rhizoma has been used as a medicinal herb for fever, pain, and inflammation in East Asia. We conducted this study because the effect of Cimicifugae Rhizoma extract (CRE) on allergic asthma has not yet been evaluated. To induce allergic airway inflammation, we intraperitoneally injected ovalbumin (OVA) mixed with aluminum hydroxide into mice twice at intervals of 2 weeks (Days 0 and 14) and then inhaled them thrice with 1% OVA solution using a nebulizer (Days 21 to 23). CRE (30 and 100 mg/kg) was administered orally daily for 6 days (Days 18 to 23). The mice showed remarkable reduction in allergic inflammation at 100 mg/kg of CRE, as evidenced by decreased inflammatory cell counts, pro-inflammatory cytokine levels, OVA-specific immunoglobulin E level, airway hyperresponsiveness, and production of mucus. Additionally, these effects were involved with the enhancement of heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase (NQO1), and nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduction of nuclear factor-κB (NF-κB) phosphorylation and matrix metalloproteinase-9 expression. Our findings indicated that CRE effectively protected against OVA-induced inflammation and oxidative stress via upregulation of the Nrf2/HO-1/NQO1 signaling and downregulation of NF-κB phosphorylation in asthma caused by OVA.

Research progress of Cimicifugae Rhizoma and prediction analysis on Q-marker / 中草药

Cimicifugae Rhizoma is contained in the "Shen Nong's Herbal Classic" and listed as the top grade. It is a traditional Chinese medicine for divergent wind and heat. In recent years, scholars have gradually deepened their research on various aspects of Cimicifugae Rhizoma, and its new chemical components and pharmacological effects have been discovered. Based on the review of the literature, the summary of its chemical composition and pharmacological effects, according to the definition of Q-marker, from the aspects of the source route, drug efficacy, traditional drug properties, and the significant components in different compatibility, the Q-marker of Cimicifugae Rhizoma is predicted, in order to provide a scientific basis for the quality evaluation of Cimicifugae Rhizoma.

Simultaneous determination of 19 constituents in Cimicifugae Rhizoma by HPLC-DAD and screening for antioxidants through DPPH free radical scavenging assay.

Cimicifugae Rhizoma (sheng ma) is a well-known traditional Chinese medicine, which has been demonstrated to possess anti-inflammatory, antipyretic and analgesic activities. In the present study, a simple and efficient HPLC-DAD (high-performance liquid chromatography coupled with diode array detection) method was developed and validated for simultaneous quantification of 19 chemical components (including 16 phenolic acids, one coumarin and two alkaloids) in Cimicifugae Rhizoma. The result indicated that this method could effectively evaluate the quality of Cimicifugae Rhizoma and provide a valuable reference for further study. Additionally, the antioxidant activity of Cimicifugae Rhizoma was evaluated by DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging assay. The results showed that the content of phenolic acids and antioxidant activity exhibited significant correlation coefficients.

Effect of Jiangxi Characteristic Processing Technology on Volatile Components of Cimicifugae Rhizoma / 中国实验方剂学杂志

Objective: To analyze the effect of honey bran stir-frying method in Zhang faction and honey chaff stir-frying method in Jianchang faction on the composition and relative content of volatile components in Cimicifugae Rhizoma. Method: The volatile oil in different processed products of Cimicifugae Rhizoma was extracted by steam distillation and analyzed by gas chromatography-mass spectrometry (GC-MS). The inlet temperature was 260℃, the transmission line temperature was 250℃, the carrier gas was helium, the flow rate was 1.0 mL·min-1, the split ratio was 10:1, the injection volume was 1 μL. The column temperature was set at 70℃ by programmed heating, rising to 150℃ by 2℃·min-1 and keeping it there for 2 min, rising to 240℃ by 6℃·min-1 and keeping it there for 3 min, rising to 300℃ by 25℃·min-1 and keeping it there for 2 min. The relative content of each component in volatile oil was calculated by peak area normalization method. Result: A total of 73 components were identified from raw products of Cimicifugae Rhizoma, 37 components were identified from honey bran stir-frying products, 93 components were identified from honey chaff stir-frying products, and 71 components were identified from honey stir-frying products. The relative content of n-hexadecanoic acid was the highest among all components in different processed products, accounting for 30.38%-46.47% of the total volatile components. In addition to fatty acids, volatile oils also contained alkanes, esters, alcohols, etc. There were 8 common components with relative content ≥ 1.0% in raw and processed products of Cimicifugae Rhizoma, after stir-frying with honey bran, the relative contents of these 8 components showed an upward trend, but showed a decreasing trend after stir-frying with honey chaff. Conclusion: After processing with Zhang faction method or Jianchang faction method, the composition and relative content of volatile components in Cimicifugae Rhizoma were significantly changed. This study can provide a scientific basis for explaining the processing mechanism of Jiangxi characteristic Cimicifugae Rhizoma decoction pieces.

Identification and differentiation of major components in three different "Sheng-ma" crude drug species by UPLC/Q-TOF-MS.

Cimicifugae Rhizoma (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.

Identification and differentiation of major components in three different "Sheng-ma" crude drug species by UPLC/Q-TOF-MS

Cimicifugae Rhizoma (Sheng ma) is a Ranunculaceae herb belonging to a composite family and well known in China. has been widely used in traditional Chinese medicine. Thecontains three varieties ((Turcz.),L. andKom.) 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,andand 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.

Induction of mast cell degranulation by triterpenoidal saponins obtained from Cimicifugae rhizoma.

Cimicifugae rhizoma has been widely used as a traditional herbal medicine to treat inflammation and menopausal symptoms. In this study, we found that some of the triterpenoidal saponins purified from the ethanol extract of Cimicifugae rhizoma dramatically induced histamine release. The structure-related induction of mast cell degranulation by them and the mechanism of action were determined. ß-Hexosaminidase release in HMC-1 cells was increased in a concentration-dependent manner, with maximal 6.5- and 8.5-fold increases, by 200 µg/mL 24-epi-7,8-didehydrocimigenol-3-O-xyloside (comp 1) and cimigenol 3-O-beta-d-xyloside (comp 4) compared with those treated with phorbol 12-myristate 13-acetate and A23187 (PMACI), respectively. However, ß-hexosaminidase release was not changed by 7,8-dihydrocimigenol (comp 3), or 23-OAc-shengmanol-3-O-xyloside (comp 7). These triterpenoidal saponins changed neither the intracellular Ca(2+ )level nor the activation of PKC, both of which play essential roles in histamine release. However, cromolyn and ketotifen, membrane stabilizers, effectively inhibited the ß-hexosaminidase release induced by comp 1 or comp 4 by 39 and 45%, respectively. Collectively, xylose on the cimigenol-related backbone among triterpene glycosides isolated from Cimicifugae rhizoma may play an important role in activating mast cells and induction of degranulation partly via membrane destabilization of mast cells.

Application of high resolution melting curve to identification of Cimicifugae Rhizoma / 药学学报

High-resolution-melting analysis (HRM) is a new technology derived from qPCR and is widely used in the study of polymorphism, genotyping, and single nucleotide mutation. Advantages of HRM include cost-effectiveness and time-efficiency over PCR-based genotyping. However, the application of HRM in the authentication of herbal products is still limited with few studies on the classification and identification of herbal products. In this study, Cimicifugae Rhizoma was used as an example to verify the stability and accuracy of HRM technique in identification of Chinese materia medica. HRM assay was established for identification based on ITS2 region of Cimicifugae Rhizomas and its adulterants (including 41 samples). Our findings showed that HRM allows not only the identification of adulteration but also the quantification of the most common admixture. This study is significant for better quality in the verification of the authenticity of herbal medicine. The method is promising for future identification of traditional Chinese medicinal materials.