23-epi-26-Deoxyactein

Effects of 23-epi-26-deoxyactein on adipogenesis in 3T3-L1 preadipocytes and diet-induced obesity in C57BL/6 mice.[Pubmed:32570112]

Phytomedicine. 2020 Jun 5;76:153264.

BACKGROUND: The ethanolic extract of Actaea racemosa L. (Cimicifuga racemosa (L.) Nutt.) has recently been reported to ameliorate obesity-related insulin resistance, hyperlipidemia, and fatty liver in rodents. However, it remains unclear which A. racemosa components are responsible for these beneficial effects. PURPOSE: We aimed to examine the anti-obesity potential of 23-epi-26-Deoxyactein (DA), which is contained in the ethanolic extracts of A. racemosa. STUDY DESIGN AND METHODS: To evaluate the effects of DA on adipogenesis in 3T3-L1 preadipocytes and diet-induced obesity in C57BL/6 mice, in vitro and in vivo tests were performed. For in vitro assessment, we used Oil red O staining that showed lipid accumulation in differentiated 3T3-L1 cells. For in vivo tests, male 5-week-old C57BL/6 mice were fed with low-fat diet (LFD), high-fat diet (HFD), HFD with 10 mg/kg/d luteolin (LU; positive control drug), HFD with 1 mg/kg/d DA, and HFD with 5 mg/kg/d DA for 12 weeks, respectively. Glucose and insulin tolerance tests were performed at week 17. The lipid deposition of adipose tissue and liver was visualized by hematoxylin and eosin staining. Real-time PCR showed mRNA levels of genes involved in adipogenesis, lipogenesis, and lipolysis. AMPK signaling and SIRT1-FOXO1 pathway were assessed by real-time PCR and western blot. RESULTS: 10 muM DA and 20 muM LU treatments inhibited 3T3-L1 adipogenesis through down-regulating the expression of C/ebpalpha, C/ebpbeta, and Ppargamma, which are the critical adipogenic transcription factors. The in vivo results showed that 5 mg/kg/d DA and 10 mg/kg/d LU significantly lowered body weight gain, fat mass, and liver weight in HFD-fed mice. Meanwhile, DA and LU also reduced insulin resistance and serum lipoprotein levels in HFD-fed mice. Mechanistic studies showed that DA and LU promoted adipocyte lipolysis in mice through activating the AMPK signaling and SIRT1-FOXO1 pathway. CONCLUSION: The in vitro results indicate that 10 muM DA suppresses adipogenesis in 3T3-L1 preadipocytes. The in vivo treatment with 5 mg/kg/d DA ameliorates diet-induced obesity in mice, suggesting that DA is a promising natural compound for the treatment of obesity and related metabolic diseases.

Anticancer efficiency of cycloartane triterpenoid derivatives isolated from Cimicifuga yunnanensis Hsiao on triple-negative breast cancer cells.[Pubmed:30584366]

Cancer Manag Res. 2018 Dec 6;10:6715-6729.

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.

In Vitro and In Situ Characterization of Triterpene Glycosides From Cimicifuga racemosa Extract.[Pubmed:28827038]

J Pharm Sci. 2017 Dec;106(12):3642-3650.

Cimicifuga racemosa products are widely used in the treatment of climacteric symptoms. The aim of this study was to evaluate C racemosa extract Ze 450 according to Biopharmaceutics Classification System (BCS). Triterpene glycosides served as analytical marker and were evaluated for solubility and absorption properties. pH-dependent thermodynamic solubility was tested via shake flask method, and dissolution performance of a herbal medicinal product containing C 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. 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, and colon. The results indicate high bioavailability of triterpene glycosides from C racemosa extract Ze 450. With regard to BCS, triterpene glycosides can be classified into BCS class I (high solubility, high permeability).

Cycloartane Glycosides from the Roots of Cimicifuga foetida with Wnt Signaling Pathway Inhibitory Activity.[Pubmed:25693500]

Nat Prod Bioprospect. 2015 Feb 19;5(2):61-67.

Four new 9,19-cycloartane triterpenoids, cimilactone E (1), cimilactone F (2), 2'-O-(E)-butenoyl-23-epi-26-Deoxyactein (3), and 2',12beta-O-diacetylcimiracemonol-3-O-beta-d-xylopyranoside (4), together with four known constituents (5-8) were isolated from the roots of Cimicifuga foetida. The new structures were elucidated by extensive spectroscopic analysis. In addition, compounds 7 and 8 showed significant Wnt signaling pathway inhibitory activity, with IC50 values of 3.33 and 13.34 muM, respectively, using the luciferase reporter gene assay.

Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice.[Pubmed:25022210]

Phytomedicine. 2014 Sep 25;21(11):1382-9.

INTRODUCTION: It was the aim of the present experiments to examine potential antidiabetic effects of the Cimicifuga racemosa extract Ze 450. METHODS: Ze 450 and some of its components (23-epi-26-Deoxyactein, protopine and cimiracemoside C) were investigated in vitro for their effects on AMP-activated protein kinase (AMPK) compared to metformin in HepaRG cells. Ze 450 (given orally (PO) and intraperitonally (IP)), metformin (PO) and controls were given over 7 days to 68 male ob/ob mice. Glucose and insulin concentrations were measured at baseline and during an oral glucose tolerance test (OGTT). RESULTS: Ze 450 and its components activated AMPK to the same extent as metformin. In mice, Ze 450 (PO/IP) decreased significantly average daily and cumulative weight gain, average daily food and water intake, while metformin had no effect. In contrast to metformin, PO Ze 450 virtually did not change maximum glucose levels during OGTT, however, prolonged elimination. Ze 450 administered PO and IP decreased significantly post-stimulated insulin, whereas metformin did not. HOMA-IR index of insulin resistance improved significantly after IP and PO Ze 450 and slightly after metformin. In summary, the results demonstrate that Ze 450 reduced significantly body weight, plasma glucose, improved glucose metabolism and insulin sensitivity in diabetic ob/ob mice. In vitro experiments suggest that part of the effects may be related to AMPK activation. CONCLUSIONS: Ze 450 may have utility in the treatment of type 2 diabetes. However, longer term studies in additional animal models or patients with disturbed glucose tolerance or diabetes may be of use to investigate this further.

New 9, 19-cycloartane triterpenoid from the root of Cimicifuga foetida.[Pubmed:24863355]

Chin J Nat Med. 2014 Apr;12(4):294-6.

AIM: To study the 9, 19-cycloartane triterpenes from the roots of Cimicifuga foetida. METHOD: Chromatographic separations by silica gel, C18 reversed phase silica gel, and high-performance liquid chromatography (HPLC) were used. All of the structures were elucidated on the basis of spectroscopic analysis and chemical methods. RESULTS: Five 9, 19-cycloartane triterpenes, (3beta, 12beta, 15alpha, 24R)-12, 2'-diacetoxy-24, 25-epoxy-15-hydroxy-16, 23-dione-3-O-alpha-L-arabinopyranoside (1), actein (2), 23-epi-26-Deoxyactein (3), asiaticoside B (4), and 12beta-hydroxycimigenol (5) were isolated from the roots of Cimicifuga foetida. CONCLUSION: Compound 1 is a new triterpene with two acetoxy groups at C-2' and C-12.

Pharmacokinetics and bioavailability of cimicifugosides after oral administration of Cimicifuga foetida L. extract to rats.[Pubmed:22771280]

J Ethnopharmacol. 2012 Aug 30;143(1):249-55.

ETHNOPHARMACOLOGICAL RELEVANCE: Cimicifuga foetida L., a traditional Chinese medicine, has been used as an anti-inflammatory, antipyretic and analgesic remedy. The primary active constituents are believed to be present in the triterpene glycoside fraction. MATERIALS AND METHODS: To develop an LC-MS/MS assay for four major cimicifugosides [cimicifugoside H-1 (Cim A), 23-epi-26-Deoxyactein (Cim B), cimigenolxyloside (Cim C) and 25-O-acetylcimigenoside (Cim D)] obtained from C. foetida L. and apply it to investigate their pharmacokinetic (PK) properties and bioavailabilities through oral administration of C. foetida L. extract (12.5, 25 and 50mg/kg) and single intravenous (i.v.) doses (5mg/kg) of the individual cimicifugosides in rat. PK parameters were estimated by non-compartmental analysis. RESULTS: All calibration curves showed excellent linear regressions (all r>0.995) within the range of tested concentrations. The intra- and inter-day variations were <15% in terms of RSD. The molar ratio of Cims A, B, C, and D in the extract was 20.7:1.4:2.9:1. PK parameters for Cims A, B, C, and D following oral administration of the extract were respectively: C(max) 4.05-17.69, 90.93-395.7, 407.1-1180 and 21.56-45.09pmol/mL; T(max) 0.46-1.28, 2.00-4.67, 14.67-19.67 and 8.08-14.27h; absolute oral bioavailability (F) 1.86-6.97%, 26.8-48.5%, 238-319% and 32.9-48%. PK parameters after i.v. administration of individual cimicifugosides were respectively: elimination half-life 1.1, 2.5, 5.7 and 4.2h; clearance 15.7, 0.48, 0.24 and 1.13mL/hkg. CONCLUSIONS: Systemic exposure to Cims B, C and D following oral administration of the extract was significantly greater than to Cim A despite the predominance of Cim A in the extract. Significantly different clearance and interconversion from Cim A to Cim C probably accounts for the different exposure to the four cimicifugosides.

One new and six known triterpene xylosides from Cimicifuga racemosa: FT-IR, Raman and NMR studies and DFT calculations.[Pubmed:22465763]

Spectrochim Acta A Mol Biomol Spectrosc. 2012 Jul;93:10-8.

One new and six known triterpene xylosides were isolated from Cimicifuga racemosa (black cohosh, Actaea racemosa). The structure of a new compound, designated as isocimipodocarpaside (1), was established to be (24S)-3beta-hydroxy-24,25-oxiirane-16,23-dione-9,10-seco-9,19-cyclolanost-1(10),7 (8),9(11)-trien 3-O-beta-d-xylopyranoside, by means of (1)H and (13)C NMR, IR and Raman spectroscopies and Mass Spectrometry. The six known compounds are: 23-epi-26-deoxycimicifugoside (2), 23-epi-26-Deoxyactein (3), 25-anhydrocimigenol xyloside (4), 23-O-acetylshengmanol xyloside (5), 25-O-acetylcimigenol xyloside (6) and 3'-O-acetylcimicifugoside H-1 (7). On the basis of NMR data supported by DFT calculations of NMR shielding constants of (2), its structure, previously described as 26-deoxycimicifugoside was corrected and determined as 23-epi-26-deoxycimicifugoside. The (13)C CPMAS NMR spectra of the studied compounds (1)-(7) provided data on their solid-state interactions. The IR and Raman spectra in the CO, CC, and CH stretching vibration regions clearly discriminate different triterpenes found in C. racemosa.

Oral administration of Cimicifuga racemosa extract attenuates immobilization stress-induced reactions.[Pubmed:22428232]

Nat Prod Commun. 2012 Jan;7(1):15-8.

Dried rhizomes of Cimicifuga racemosa (CR), known as black cohosh, have been widely used as a herbal dietary supplement in the treatment of menopausal symptoms. Here we used experimental mouse stress models to investigate the role of anti-stress food factors, and found that a CR extract had stress-relieving effects. A single oral administration of CR extract (1,000 mg/kg) significantly attenuated plasma corticosterone and aspartate aminotransferase (AST) levels that had increased as a result of enforced immobilization. Bioassay-guided fractionation of the CR extract resulted in the isolation of 10 triterpenes, among which actein, 23-epi-26-Deoxyactein, and cimiracemoside F (100 mg/kg, per os) were shown to contribute to the anti-stress effects. Furthermore, the CR extract significantly prevented the development of water immersion stress-induced gastric mucosal ulcers in rats. We propose that the CR extract might be suitable for the prevention and treatment of stress-related disorders.

Simultaneous determination of cimicifugoside H-2, cimicifugoside H-1, 23-epi-26-deoxyactein, cimigenol xyloside and 25-O-acetylcimigenoside in beagle dog plasma by LC-MS/MS.[Pubmed:22285707]

J Pharm Biomed Anal. 2012 Mar 25;62:87-95.

A selective and sensitive LC-MS/MS method was developed and validated for the simultaneous determination of five constituents (cimicifugoside H-2, cimicifugoside H-1, 23-epi-26-Deoxyactein, cimigenol xyloside and 25-O-acetylcimigenoside) of Cimicifuga foetida L. in beagle dog plasma. The quantitation was performed on a LC-MS/MS with negative electrospray ionization in selected reaction monitoring (SRM) mode. A gradient mobile phase composed of methanol and water was used at a flow rate of 0.4 ml/min. All the analytes and internal standard (20 (S)-ginsenoside Rg3) were isolated from plasma samples by a liquid-liquid extraction method. The average extraction recoveries were 73-74% for cimicifugoside H-2, 89-94% for cimicifugoside H-1, 73-80% for 23-epi-26-Deoxyactein, 89-91% for cimigenol xyloside, 87-96% for 25-O-acetylcimigenoside, respectively. The method showed good linearity and no endogenous material interfered with all the five compounds and I.S. peaks. The lower limit of quantification (LLOQ) of all analytes was 0.5 ng/ml. The intra- and inter-day precision of analysis was less than 15% for each analyte at concentrations of 2.0, 50, 500 ng/ml, and the accuracy ranged from 85.8% to 107%. This method was successfully applied to reveal the pharmacokinetic properties of cimicifugoside H-2, cimicifugoside H-1, 23-epi-26-Deoxyactein, cimigenol xyloside and 25-O-acetylcimigenoside after oral administration.

Cytotoxic chemical constituents from the roots of Cimicifuga foetida. [corrected].[Pubmed:20121210]

J Nat Prod. 2010 Feb 26;73(2):93-8.

Seven new 9,19-cycloartane triterpene glycosides, 25-O-acetylcimigenol-3-O-[2'-O-(E)-2-butenoyl]-beta-d-xylopyranoside (1), 25-O-acetylcimigenol-3-O-[4'-O-(E)-2-butenoyl]-beta-d-xylopyranoside (2), 25-O-acetylcimigenol-3-O-[3'-O-acetyl]-beta-d-xylopyranoside (3), 25-O-acetylcimigenol-3-O-[4'-O-acetyl]-beta-d-xylopyranoside (4), 25-O-acetyl-12beta-acetoxycimigenol-3-O-beta-d-xylopyranoside (5), 3'-O-acetylactein (6), and 3'-O-acetyl-23-epi-26-Deoxyactein (7), together with eight known compounds (8-15), were isolated from the roots of Cimicifuga fetida. Their structures were established by spectroscopic and chemical methods. Most of these compounds showed more selective and higher cytotoxicity against the human HepG2 cell line than against the MCF7, HT29, and MKN28 cell lines. Compounds 2, 3, and 7 exhibited significant cytotoxicity against HepG2 cells, with IC(50) values of 1.29, 0.71, and 1.41 microM, respectively.