Transfer of preclinical study data on the influence of cimicifuga racemosaon functional changes in the hippocampus during menopause.

Menopausal transition in women involves complex neurobiochemical changes linked to ovarian dysfunction, resulting in symptoms like vasomotor symptoms (VMS), sleep disturbances, anxiety, and cognitive impairments. Hormone replacement therapy is the first-line treatment. However, many women are reluctant to use HRT or have contraindications toward HRT and seek for alternatives. Non-hormonal therapies with extracts of Cimicifuga racemosa rhizomes like the isopropanolic extract (iCR, black cohosh) offer a promising alternative. A preclinical pilot study exploring iCR's effects on gene expression in the hippocampus and hypothalamus of ovarectomized (OVX) rats mimicking menopausal conditions identified important signaling pathways and CNS-based contributions to the multitargeted modes of action of iCR. Especially in the hippocampus, iCR compensated effects of OVX on gene expression profiles. These changes are reflected by the genes AVPR1A, GAL, CALCA, HCRT, PNOC, ESR1, ESR2 and TAC3 contributing to the formation of hot flushes or thermoregulation as well as to secondary effects such as blood pressure, metabolism, hormonal regulation, homeostasis, mood regulation, neuroendocrine modulation, regulation of sleep and arousal, and in learning, memory and cognition. To understand the mechanisms in the brain of estrogen-depressed animals (OVX) and subsequent iCR treatment we combined the results of the pilot study with those of up-to-date literature and tried to transfer the current knowledge to humans during menopausal transition and adaptation. Focus was laid on changes in the hippocampal function, that is disturbed by hormonal fluctuations, but can also be brought back into balance by iCR.

Antidepressant-like effects of Cimicifuga dahurica (Turcz.) Maxim. via modulation of monoamine regulatory pathways.

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways.

Study on the photosynthetic growth characters in Cimicifuga dahurica (Turcz.) Maxim under different supplemental light environments.

Cimicifuga dahurica (C. dahurica) is an important medicinal plant in the northern region of China. The best supplemental light environment helps plant growth, development, and metabolism. In this study, we used two-year-old seedlings as experimental materials. The white light as the control (CK). The different ratios of red (R) and blue (B) combined light were supplemented (T1, 2R: 1B, 255.37 µmol m-2·s-1; T2, 3R: 1B, 279.69 µmol m-2·s-1; T3, 7R: 1B, 211.16 µmol m-2·s-1). The growth characteristics, photosynthetic pigment content, photosynthesis and chlorophyll fluorescence parameters, and primary metabolite content were studied in seedlings. The results showed that: 1) The fresh weight from shoot, root, and total fresh weight were significantly (P < 0.05) increased under T2 and T3 treatment. 2) The contents of chlorophyll a (Chl a), chlorophyll b (Chl b), and total chlorophyll (Chl) were significantly (P < 0.05) increased under T2 treatment, and carotenoid (car) content was reduced. 3) The photochemical quenching (qP), the actual photosynthetic efficiency of PSII (Y(II)), and the photosynthetic electron transfer rate (ETR) from leaves were significantly (P < 0.05) increased under T1 treatment. The Net photosynthetic rate (Pn), stomatal conductance (Gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr) were significantly (P < 0.05) increased under T2 and T3 treatments. 4) A total of 52 primary metabolites were detected in C. dahurica leaves. Compared with CK, 14, 15, and 18 differential metabolites were screened under T1, T2, and T3 treatments. In addition, D-xylose, D-glucose, glycerol, glycolic acid, and succinic acid were significantly (P < 0.05) accumulated under the T2 treatment, which could regulate the TCA cycle metabolism pathway. The correlation analysis suggested that plant growth was promoted by regulating the change of D-mannose content in galactinol metabolism and amino sugar and nucleotide sugar metabolism. In summary, the growth of C. dahurica was improved under T2 treatment.

In-depth characterization of cycloartane triterpenoids and discovery of species-specific markers from three Cimicifuga species guided by a strategy that integrates in-source fragment elimination, diagnostic ion recognition, and feature-based molecular networking.

Characterization studies of the plant metabolome are crucial for revealing plant physiology, developing functional foods, and controlling quality. Mass spectrometry-based metabolite profiling allows unprecedented qualitative coverage of complex biological extract composition. However, the electrospray ionization used in metabolite profiling generates multiple artifactual signals for a single analyte, which makes it challenging to filter out redundant signals and organize the signals corresponding to abundant constituents. This study proposed a strategy integrating in-source fragments elimination, diagnostic ions recognition, and feature-based molecular networking (ISFE-DIR-FBMN) to simultaneously characterize cycloartane triterpenoids (CTs) from three medicinal Cimicifuga species. The results showed that 63.1 % of the measured ions were redundant. A total of 184 CTs were annotated, with 27.1 % being reported for the first time. It presents a promising approach to assess the composition of natural extracts, thus facilitating new ingredient registrations or natural-extracts-based drug discovery campaigns. Besides, chemometrics analysis of the three Cimicifuga species identified 32 species-specific markers, highlighting significant differences among them. The valuable information can enhance the sustainable utilization and further development of Cimicifuga resources. The codes involved in ISFE-DIR-FBMN are freely available on GitHub (https://github.com/LHJ-Group/ISFE-DIR-FBMN.git).

Study on the immune-enhancing and inhabiting transmissible gastroenteritis virus effects of polysaccharides from Cimicifuga rhizoma.

Cimicifugae rhizoma is a traditional Chinese herbal medicine in China, and modern pharmacological research showed that it has obvious antiviral activity. Many polysaccharides have been proved to have immune enhancement and antiviral activity, but there are few studies on the biological activity of Cimicifuga rhizoma polysaccharide (CRP). The aim was to explore the character of CRP and its effects on improving immune activity and inhibiting transmissible gastroenteritis virus (TGEV). The monosaccharide composition, molecular weight, fourier transform infrared spectra and electron microscopy analysis of CRP was measured. The effect of CRP on immune activity in lymphocytes and RAW264.7 cells were studied by colorimetry, FITC-OVA fluorescent staining and ELISA. The effect of CRP on TGEV-infected PK-15 cells was determined using Real-time PCR, Hoechst fluorescence staining, trypan blue staining, acridine orange staining, Annexin V-FITC/PI fluorescent staining, DCFH-DA loading probe, and JC-1 staining. Network pharmacology was used to predict the targets of CRP in enhancing immunity and anti-TGEV, and molecular docking was used to further analyze the binding mode between CPR and core targets. The results showed that CRP was mainly composed of glucose and galactose, and its molecular weight was 64.28 kDa. The content of iNOS and NO in CRP group were significantly higher than the control group. CRP (125 and 62.5 µg/mL) could significantly enhance the phagocytic capacity of RAW264.7 cells, and imprive the content of IL-1ß content compared with control group. 250 µg/mL of CRP possessed the significant inhibitory effect on TGEV, which could significantly reduce the apoptosis compared to TGVE group and inhibit the decrease in mitochondrial membrane potential compared to TGVE group. The mRNA expression of TGEV N gene in CRP groups was significantly lower than TGEV group. PPI showed that the core targets of immune-enhancing were AKT1, MMP9, HSP90AA1, etc., and the core targets of TGE were CASP3, MMP9, EGFR, etc. Molecular docking show that CRP has binding potential with target. These results indicated that CRP possessed the better immune enhancement effect and anti-TGEV activity.

Machine Learning-Based Analysis Reveals Triterpene Saponins and Their Aglycones in Cimicifuga racemosa as Critical Mediators of AMPK Activation.

Cimicifuga racemosa (CR) extracts contain diverse constituents such as saponins. These saponins, which act as a defense against herbivores and pathogens also show promise in treating human conditions such as heart failure, pain, hypercholesterolemia, cancer, and inflammation. Some of these effects are mediated by activating AMP-dependent protein kinase (AMPK). Therefore, comprehensive screening for activating constituents in a CR extract is highly desirable. Employing machine learning (ML) techniques such as Deep Neural Networks (DNN), Logistic Regression Classification (LRC), and Random Forest Classification (RFC) with molecular fingerprint MACCS descriptors, 95 CR constituents were classified. Calibration involved 50 randomly chosen positive and negative controls. LRC achieved the highest overall test accuracy (90.2%), but DNN and RFC surpassed it in precision, sensitivity, specificity, and ROC AUC. All CR constituents were predicted as activators, except for three non-triterpene compounds. The validity of these classifications was supported by good calibration, with misclassifications ranging from 3% to 17% across the various models. High sensitivity (84.5-87.2%) and specificity (84.1-91.4%) suggest suitability for screening. The results demonstrate the potential of triterpene saponins and aglycones in activating AMP-dependent protein kinase (AMPK), providing the rationale for further clinical exploration of CR extracts in metabolic pathway-related conditions.

AMPK Activation by Cimicifuga racemosa Extract Ze 450 Is Associated with Metabolic Effects and Cellular Resilience against Age-Related Pathologies in Different Tissue Cell Types.

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.

Guided isolation of enantiomeric lignans from Cimicifuga heracleifolia Kom. by antioxidant activity and molecular networking.

Under the guidance of antioxidant evaluation combined with molecular networking, six pairs of enantiomeric lignans including seven undescribed ones (1a, 2a/2b-4a/4b), along with five known analogs (1b, 5a/5b-6a/6b) were isolated from Cimicifuga heracleifolia Kom. Their structures were determined by extensive spectroscopic data analysis, including HRESIMS, 1D and 2D NMR, experimental and calculated ECD. All the enantiomeric isolates were evaluated for antioxidation by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging tests. Compounds 1a and 3a/3b exhibited great DPPH and ABTS scavenging activities. The results are of great value for understanding structurally interesting enantiomeric lignans with antioxidant activity from C. heracleifolia in depth and providing its further development in functional evaluation and drug development.

Hydroxy(phenyl)pyruvic acid reductase in Actaea racemosa L.: a putative enzyme in cimicifugic and fukinolic acid biosynthesis.

MAIN CONCLUSION: Hydroxy(phenyl)pyruvic acid reductase from Actaea racemosa catalyzes dual reactions in reducing 4-hydroxyphenylpyruvic acid as well as ß-hydroxypyruvic acid. It thus qualifies to be part of fukinolic and cimicifugic acid biosynthesis and also photorespiration. The accumulation of fukinolic acid and cimicifugic acids is mainly restricted to Actaea racemosa (Ranunculaceae) and other species of the genus Actaea/Cimicifuga. Cimicifugic and fukinolic acids are composed of a hydroxycinnamic acid part esterified with a benzyltartaric acid moiety. The biosynthesis of the latter is unclear. We isolated cDNA encoding a hydroxy(phenyl)pyruvic acid reductase (GenBank OR393286) from suspension-cultured material of A. racemosa (ArH(P)PR) and expressed it in E. coli for protein production. The heterologously synthesized enzyme had a mass of 36.51 kDa and catalyzed the NAD(P)H-dependent reduction of 4-hydroxyphenylpyruvic acid to 4-hydroxyphenyllactic acid or ß-hydroxypyruvic acid to glyceric acid, respectively. The optimal temperature was at 38 °C and the pH optimum at pH 7.5. NADPH is the preferred cosubstrate (Km 23 ± 4 µM). Several substrates are accepted by ArH(P)PR with ß-hydroxypyruvic acid (Km 0.26 ± 0.12 mM) followed by 4-hydroxyphenylpyruvic acid (Km 1.13 ± 0.12 mM) as the best ones. Thus, ArH(P)PR has properties of ß-hydroxypyruvic acid reductase (involved in photorespiration) as well as hydroxyphenylpyruvic acid reductase (possibly involved in benzyltartaric acid formation).

Phytochemistry and ethnopharmacological studies of genus Cimicifuga: A systematic and comprehensive review.

ETHNOPHARMACOLOGICAL USES: Black cohosh, also known as Cimicifuga sp., is one of the most widely used ethnomedicine for the treatment of major health issues in women. Some reports show that Cimicifuga sp. exhibit anti-cancer, anti-viral, anti-microbial, anti-pyretic, and anti-inflammatory properties. PURPOSE OF THIS REVIEW: The objective of this comprehensive review is to furnish current and exhaustive knowledge pertaining to the pharmacological, phytochemical, and therapeutic properties of Cimicifuga sp. MATERIALS AND METHODS: In this review, all the available information was collected on Cimicifugasp. via computerized search using Google Scholar, PubMed, Research Gate, Sci-Hub, supplementary resources (books, government reports, and Ph.D. theses). RESULT: The phytochemical investigation on Cimicifuga sp. has shown phytoconstituents such as triterpenoid glycosides, phenylpropanoid, flavonoids, saponin, lignan, nitrogenous compounds, alkaloids, 4α-Methyl steroids and some other component like monoterpene lactones cimicifugolides A-C etc. Cimicifuga conveys a wide scope of research on in-vitro and in-vivo pharmacological potential, like anti-cancer, anti-microbial, anti-viral, anti-inflammatory, estrogenic, anti-oxidant, anti-neoplastic, anti-depressant, anti-Alzheimer, and anti-climacteric properties. CONCLUSION: This article discusses the medicinal and traditional histories of various Cimicifuga species. Because quality control and safety assessments of Cimicifuga species are currently lacking, only a limited portion of the plant may be used as medication. The majority of current research focuses on triterpene glycosides. Although there are a variety of additional molecules that may have novel biological functions, systematic investigations of these compounds are lacking. The Cimicifuga plant has to go through a lot of studies before it can be completely used in clinics as a viable medicinal contender.

Purification and identification of oligosaccharides from Cimicifuga heracleifolia Kom. rhizomes.

Even though Cimicifuga sp. is widely used in functional foods around the world, the content and structure of its oligosaccharides remain unclear. Here, we isolated a mixture of oligosaccharides from Cimicifuga heracleifolia Kom. rhizomes with a yield of 9.5% w/w. Twenty-six oligosaccharide monomers from the mixture were purified using optimized SEC and HILIC techniques. The oligosaccharides were identified as belonging to two groups by using HPAEC-PAD, MALDI-TOF-MS, NMR and GC-MS methylation analyses. One group belongs to sucrose and inulin type fructo-oligosaccharides (FOS) {ß-d-Fruf-(2 â†’ 1)-[ß-d-Fruf-(2 ↔ 1)]n=1-12-α-d-Glcp} with a 3-14 degree of polymerization (DP). Oligosaccharides in the other group belong to the inulo-n-ose type FOS {ß-d-Fruf-(2 â†’ 1)-[ß-d-Fruf-(2 â†’ 1)]m=0-12-ß-d-Frup} with a DP of 2-14. This appears to be the first time that these oligosaccharides have been purified from Cimicifuga heracleifolia Kom., thus providing useful information concerning the utilization of Cimicifuga heracleifolia Kom. in functional foods.

NMR-tracking for 15,16-seco-cycloartane triterpenes from Cimicifuga acerina.

Twelve undescribed 15,16-seco-cycloartane triterpenoids, 15,16-seco-cimiterpenes C-N, as well as five previously reported analogs were isolated by NMR-tracking methods from the rhizomes of Cimicifuga acerina (Sieb. et Zucc.) Tanaka. Among them, 15,16-seco-cimiterpenes C-N were the first 15,16-seco-cycloartane triterpenoids featuring acetal or hemiacetal structures at C-15. The chemical structures of 15,16-seco-cimiterpenes C-N were determined based on comprehensive spectroscopic analysis, chemical method, and comparison with the previous literature data. After that, all these compounds were evaluated for their lipid-lowering effects on 3T3-L1 adipocytes.15,16-seco-cimiterpene D was found to exhibit a comparable reducing lipid effect at the concentration of 50 µM, with an inhibition rate at 35.96%.

Antibacterial actions of Ag nanoparticles synthesized from Cimicifuga dahurica (Turcz.) Maxim. and their application in constructing a hydrogel spray for healing skin wounds.

Cimicifuga dahurica (Turcz.) Maxim. is an edible natural food and a type of traditional herbal medicine with antipyretic and analgesic properties. In this study, we found that Cimicifuga dahurica (Turcz.) Maxim. extract (CME) has good skin wound healing qualities due to its antibacterial effects on both wound inflammation-related Gram positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram negative (Escherichia coli and Klebsiella pneumoniae) strains. Using CME as a reducing agent, CME-based Ag nanoparticles (CME-AgNPs) with an average particle size of 7 nm were synthesized. The minimum bactericidal concentration (MBC) of CME-AgNPs against the investigated bacterial species varied from 0.08 to 1.25 mg/mL, indicating much higher antibacterial activity than the pure CME. Additionally, a novel network-like thermosensitive hydrogel spray (CME-AgNPs-F127/F68) was developed and shown a skin wound healing rate of 98.40% in 14 days, demonstrating the spray's potential as a novel wound dressing that accelerates wound healing.

Effects of Cimicifuga racemosa (L.) Nutt on sexual function in women receiving tamoxifen for breast cancer.

To assess the effects of Cimicifuga racemosa (L.) Nutt on climacteric symptoms and sexual function in women receiving tamoxifen after breast cancer treatment. A prospective study of women treated at the Mastology Outpatient Clinic of the Department of Obstetrics and Gynecology of the Santa Casa de Sao Paulo School of Medical Science of the hospital was conducted between 2018 and 2021. Patients diagnosed with breast cancer that underwent surgical, radiotherapy and chemotherapy treatment more than one year prior, receiving tamoxifen, exhibited climacteric symptoms and were sexually active were selected. Total of 34 women were recruited and during outpatient visits completed sociodemographic questionnaire, Blatt-Kupperman Index (KI) and Female Sexual Function Index (FSFI). The group showed improvements in climacteric symptoms (p<.001) and sexual function (p=.011) after the 6-month follow-up. Cimicifuga racemosa (L.) Nutt promoted improvements in climacteric symptoms and sexual function in women surgically treated for breast cancer. Clinical Trials.gov ID: NCT02467686.Impact StatementWhat is already known on this subject? The medications used for the treatment of breast cancer can lead to important complaints of vasomotor manifestations with a negative impact on the success of their treatment, and cases have been described until their interruption. Cimicifuga racemosa (L.) Nutt. is described in several works as a therapy to alleviate these symptoms. Numerous works in the literature present climatic symptoms and sexual function with a selective approach to the themes.What do the results of this study add? Our study evaluated a group of women who were treated for breast cancer after menopause taking into account the following aspects: climacteric symptoms and sexual function. When we reviewed the literature, we did not find, so far, work similar to ours.What are the implications of these findings for clinical practice and/or further research? In clinical practice, assessing vasomotor symptoms and sexual response of breast cancer patients can contribute towards improving the lives of this patient group. Prescribing Cimicifuga racemosa (L.) Nutt in cases with climacteric complaints and poor sexual response can relieve distress and promote better health and life status for these women. Although the present investigation has generated important data on female breast cancer survivors, there are limitations regarding the number of participants. We recommend further clinical research with expansion of the sample studied and the results presented.

Cimicifuga racemosa (L.) Nutt. en el tratamiento de los síntomas vasomotores de la menopausia: revisión / Cimicifuga racemosa (L.) Nutt. in the treatment of vasomotor symptoms of menopause: a review

Introducción: Diversos estudios han puesto de manifiesto que los preparados a base de los rizomas y raíces de cimicífuga (Cimicifuga racemosa (L.) Nutt.) pueden ser útiles para aliviar los síntomas menopáusicos. El objetivo de este trabajo es realizar una revisión de la eficacia y seguridad de estos preparados en el tratamiento de los síntomas vasomotores de la menopausia. Método: Se realizó una búsqueda de los artículos publicados desde enero de 2005 a marzo de 2021 en el buscador de recursos de la Universidad de La Laguna, “el Punto Q”. Se seleccionaron los ensayos clínicos aleatorizados y controlados, que tuvieran las palabras claves en el resumen, texto o título, tanto en inglés como en español.Resultados:Se identificaron 13 ensayos clínicos que incluían los criterios de selección establecidos. Se encontró que los preparados de cimicífuga (principalmente extractos comerciales estandarizados en su contenido en principios activos) produjeron en la mayoría de los estudios una reducción significativa comparada con el placebo de los síntomas vegetativos (sofocos y sudores nocturnos) y psicológicos de la menopausia, así como una mejoría de la calidad de vida. No se observaron efectos adversos serios a las dosis utilizadas. Conclusiones: Los extractos de cimicífuga pueden ser eficaces y seguros para el tratamiento de los síntomas vegetativos y psicológicos de la menopausia, siendo bien tolerados. No obstante, son necesarios más ensayos clínicos con mayor número de pacientes, más extensos, uso de preparaciones estandarizadas, así como con criterios similares de inclusión y valoración de los síntomas, para obtener datos más concluyentes.(AU)

Introduction: Several studies have shown that preparations based on the rhizomes and roots of black cohosh (Cimicifuga racemosa (L.) Nutt.) can be useful in alleviating the menopausal symptoms. The aim of this study is to perform an update bibliographic review of the efficacy and safety of black cohosh in the treatment of the vasomotor symptoms of menopause. Method: A review of published articles from January 2005 to March 2021 in the resource search engine of the University of La Laguna, el punto Q”. Randomized and controlled clinical trials, which had the key words in the abstract, text or title, in both English and Spanish, were selected.Results:We found 13 trials which met the selection criteria. The studies reviewed showed that the black cohosh preparations (mainly commercial extracts standardized in their content of active ingredients) produced in most of the studies a significant reduction compared to placebo in the vegetative (hot flashes and night sweats) and psychological symptoms of menopause, as well as an improvement in the quality of life. No serious adverse effects were reported at the dose administered. Conclusions: Cimicifuga racemosa extracts can be effective and safe for the treatment of vegetative and psychological symptoms of menopause, being well tolerated. However, more clinical trials with a larger number of patients, more extensive, the use of standardized preparations, as well as similar criteria for inclusion and assessment of symptoms, are necessary to obtain more conclusive data.(AU)

Physiological Concentrations of Cimicifuga racemosa Extract Do Not Affect Expression of Genes Involved in Estrogen Biosynthesis and Action in Endometrial and Ovarian Cell Lines.

In postmenopausal women, estrogen levels exclusively depend on local formation from the steroid precursors dehydroepiandrosterone sulfate and estrone sulfate (E1-S). Reduced estrogen levels are associated with menopausal symptoms. To mitigate these symptoms, more women nowadays choose medicine of natural origin, e.g., Cimicifuga racemosa (CR), instead of hormone replacement therapy, which is associated with an increased risk of breast cancer, stroke, and pulmonary embolism. Although CR treatment is considered safe, little is known about its effects on healthy endometrial and ovarian tissue and hormone-dependent malignancies, e.g., endometrial and ovarian cancers that arise during menopause. The aim of our study was to examine the effects of CR on the expression of genes encoding E1-S transporters and estrogen-related enzymes in control and cancerous endometrial and ovarian cell lines. CR affected the expression of genes encoding E1-S transporters and estrogen-related enzymes only at very high concentrations, whereas no changes were observed at physiological concentrations of CR. This suggests that CR does not exert estrogenic effects in endometrial and ovarian tissues and probably does not affect postmenopausal women's risks of endometrial or ovarian cancer or the outcomes of endometrial and ovarian cancer patients.

Black cohosh efficacy and safety for menopausal symptoms. The Spanish Menopause Society statement.

OBJECTIVE: The increasing interest in Western countries regarding phytotherapy use to treat menopause-related symptoms has led the Spanish Menopause Society (AEEM) to update its position statement performed in 2009 on the role of black cohosh (Cimicifuga racemosa) for the treatment of menopausal symptoms. MATERIAL AND METHODS: A panel of experts from both clinical and research backgrounds were assembled to investigate the best available evidence. Selected studies were obtained by an electronic search, including the Internet search engines MEDLINE-Pubmed (1997-December 2021) and the Cochrane Controlled Trials Register. RESULTS: Most of the well-designed studies published in recent years have been conducted with the isopropanolic extract of black cohosh/C. racemosa. The most common dose is 40 mg/day capable of achieving a significant reduction in hot flushes (particularly in women with intense hot flushes) and an improvement in mood. Used at the recommended doses, C. racemose produces no significant adverse reactions. CONCLUSION: Black cohosh is an effective and safe treatment option for the relieving of vasomotor symptoms. Finally, further clinical trials with sufficient patient enrollment and longer study follow-up are needed.

Benefits of Black Cohosh (Cimicifuga racemosa) for Women Health: An Up-Close and In-Depth Review.

Women's health is an imminent concern worldwide, but it remains an ignored segment of research in most developing countries, and is yet to take the center stage in even developed nations. Some exclusive female health concerns revolve around both pathological and physiological aspects. These gender-specific maladies include breast, cervical, and ovarian cancers, and physiological concerns such as menopause and osteoporosis, which are often coexistent. Recently, women's health issues, including postmenopausal syndrome, have attracted the attention of researchers and practitioners alike, opening newer pharmaceutical research and clinical avenues. Although not counted as a disease, postmenopausal syndrome (PMS) is a female health phenomenon underpinned by hormonal depletion. Enhanced life expectancy in women has added to their suffering, and pharmacological interventions are needed. Amongst the available treatment modalities, the use of numerous botanicals has emerged as an efficient health management tool for women. Cimicifuga racemosa (CR or Black Cohosh) is a plant/herb which has been traditionally exploited and extensively used by women. This review is an attempt to compile and provide a summary of the importance of CR in complementary and alternative therapies for the improvement of various disorders related to women, such as menopausal syndrome, mammary cancer, and osteoporosis. It aims to systematically highlight the bioactive constituents, pharmacology, pharmacokinetics, therapeutic potentials, quality control processes, chromatographic techniques, and possible mechanisms of action of clinically effective phytomedicine for women's health. Various clinical trials and patents relating to CR and women's health have been collated. Furthermore, the plant and its related products have been considered from a regulatory perspective to reveal its commercial feasibility. The present review summarizes the existing data on CR focusing on women's health, which can help to introduce this traditional phytomedicine to the world and provide some reference for future drug development.

Secondary Metabolites with Anti-Inflammatory from the Roots of Cimicifuga taiwanensis.

The genus Cimicifuga is one of the smallest genera in the family Ranunculaceae. Cimicifugae Rhizoma originated from rhizomes of Cimicifuga simplex, and C. dahurica, C. racemosa, C. foetida, and C. heracleifolia have been used as anti-inflammatory, analgesic and antipyretic remedies in Chinese traditional medicine. Inflammation is related to many diseases. Cimicifuga taiwanensis was often used in folk therapy in Taiwan for inflammation. Phytochemical investigation and chromatographic separation of extracts from the roots of Cimicifuga taiwanensis has led to the isolation of six new compounds: cimicitaiwanins A-F (1-6, respectively). The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic data analysis (1D- and 2D-NMR, MS, and UV) and comparison with the literature data. The effect of some isolates on the inhibition of NO production in lipopolysaccharide-activated RAW 264.7 murine macrophages was evaluated. Of the isolates, 3-6 exhibited potent anti-NO production activity, with IC50 values ranging from 6.54 to 24.58 µM, respectively, compared with that of quercetin, an iNOS inhibitor with an IC50 value of 34.58 µM. This is the first report on metabolite from the endemic Taiwanese plant-C. taiwanensis.

Treat more than heat-New therapeutic implications of Cimicifuga racemosa through AMPK-dependent metabolic effects.

BACKGROUND: Cimicifuga racemosa extracts (CRE) have obtained a "well-established use status" in the treatment of postmenopausal (i.e., climacteric) complaints, which predominantly include vasomotor symptoms such as hot flushes and sweating, as well as nervousness, irritability, and metabolic changes. Although characteristic postmenopausal complaints are known for a very long time and the beneficial effects of CRE on climacteric symptoms are well accepted, both the pathophysiology of postmenopausal symptoms and the mechanism of action of CREs are not yet fully understood. In particular, current hypotheses suggest that changes in the α-adrenergic and serotonergic signaling pathways secondary to estrogen depletion are responsible for the development of hot flushes. PURPOSE: Some of the symptoms associated with menopause cannot be explained by these hypotheses. Therefore, we attempted to extend our classic understanding of menopause by integrating of partly age-related metabolic impairments. METHODS: A comprehensive literature survey was performed using the PubMed database for articles published through September 2021. The following search terms were used: (cimicifuga OR AMPK) AND (hot flush* OR hot flash* OR menopaus* OR osteoporos* OR cancer OR antioxida* OR cardiovasc*). No limits were set with respect to language, and the references cited in the articles retrieved were used to identify additional publications. RESULTS: We found that menopause is a manifestation of the general aging process, with specific metabolic changes that aggravate menopausal symptoms, which are accelerated by estrogen depletion and associated neurotransmitter dysregulation. Cimicifuga extracts with their metabolic effects mitigate climacteric symptoms but may also modulate the aging process itself. Central to these effects are effects of CRE on the metabolic key regulator, the AMP-activated protein kinase (AMPK). CONCLUSIONS: As an extension of this effect dimension, other off-label indications may appear attractive in the sense of repurposing of this herbal treatment.