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Evaluating the pharmacological mechanism of Chinese medicine Si-Wu-Tang through multi-level data integration.

ABSTRACT: Si-Wu-Tang (SWT) is a Traditional Chinese Medicine (TCM) formula widely used for the treatments of gynecological diseases. To explore the pharmacological mechanism of SWT, we incorporated microarray data of SWT with our herbal target database TCMID to analyze the potential activity mechanism of SWT's herbal ingredients and targets. We detected 2,405 differentially expressed genes in the microarray data, 20 of 102 proteins targeted by SWT were encoded by these DEGs and can be targeted by 2 FDA-approved drugs and 39 experimental drugs. The results of pathway enrichment analysis of the 20 predicted targets were consistent with that of 2,405 differentially expressed genes, elaborating the potential pharmacological mechanisms of SWT. Further study from a perspective of protein-protein interaction (PPI) network showed that the predicted targets of SWT function cooperatively to perform their multi-target effects. We also constructed a network to combine herbs, ingredients, targets and drugs together which bridges the gap between SWT and conventional medicine, and used it to infer the potential mechanisms of herbal ingredients. Moreover, based on the hypothesis that the same or similar effects between different TCM formulae may result from targeting the same proteins, we analyzed 27 other TCM formulae which can also treat the gynecological diseases, the subsequent result provides additional insight to understand the potential mechanisms of SWT in treating amenorrhea. Our bioinformatics approach to detect the pharmacology of SWT may shed light on drug discovery for gynecological diseases and could be utilized to investigate other TCM formulae as well.

SUBMITTER: Fang Z

PROVIDER: S-EPMC3817162 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Evaluating the pharmacological mechanism of Chinese medicine Si-Wu-Tang through multi-level data integration.

Fang Zhao Z Lu Bingxin B Liu Mingyao M Zhang Meixia M Yi Zhenghui Z Wen Chengping C Shi Tieliu T

PloS one 20131104 11

Si-Wu-Tang (SWT) is a Traditional Chinese Medicine (TCM) formula widely used for the treatments of gynecological diseases. To explore the pharmacological mechanism of SWT, we incorporated microarray data of SWT with our herbal target database TCMID to analyze the potential activity mechanism of SWT's herbal ingredients and targets. We detected 2,405 differentially expressed genes in the microarray data, 20 of 102 proteins targeted by SWT were encoded by these DEGs and can be targeted by 2 FDA-ap ...[more]

PMID: 24223693

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Project description:BACKGROUND: Si-Wu-Tang (SWT), comprising the combination of four herbs, Paeoniae, Angelicae, Chuanxiong and Rehmanniae, is one of the most popular traditional oriental medicines for women's diseases. In our previous study, the microarray gene expression profiles of SWT on breast cancer cell line MCF-7 were found similar to the effect of ?-estradiol (E2) on MCF-7 cells in the Connectivity Map database. METHODS: Further data analysis was conducted to find the main similarities and differences between the effects of SWT and E2 on MCF-7 gene expression. The cell proliferation assay on MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) cells were used to examine such estrogenic activity. The estrogenic potency of SWT was further confirmed by estrogen-responsive element (ERE) luciferase reporter assay in MCF-7 cells. RESULTS: Many estrogen regulated genes strongly up-regulated by E2 were similarly up-regulated by SWT, e.g., GREB1, PGR and EGR3. Of interest with regard to safety of SWT, the oncogenes MYBL1 and RET were strongly induced by E2 but not by SWT. Quantitative RT-PCR analysis revealed a highly concordant expression change in selected genes with data obtained by microarrays. Further supporting SWT's estrogenic activity, in MCF-7 but not in MDA-MB-231 cells, SWT stimulated cell growth at lower concentrations (< 3.0 mg/ml), while at high concentrations, it inhibits the growth of both cell lines. The growth inhibitory potency of SWT was significantly higher in MDA-MB-231 than in MCF-7 cells. The SWT-induced cell growth of MCF-7 could be blocked by addition of the estrogen receptor antagonist tamoxifen. In addition, SWT was able to activate the ERE activity at lower concentrations. The herbal components Angelicae, Chuanxiong and Rehmanniae at lower concentrations (< 3.0 mg/ml) also showed growth-inducing and ERE-activating activity in MCF-7 cells. CONCLUSIONS: These results revealed a new mechanism to support the clinical use of SWT for estrogen related diseases and possibly for cancer prevention. This study also demonstrated the feasibility of using microarray transcriptional profiling to discover phytoestrogenic components that are present in natural products.

Project description:To pursue a systematic approach to discovery of mechanisms of action of traditional Chinese medicine (TCM), we used microarrays, bioinformatics and the "Connectivity Map" (CMAP) to examine TCM-induced changes in gene expression. We demonstrated that this approach can be used to elucidate new molecular targets using a model TCM herbal formula Si-Wu-Tang (SWT) which is widely used for women's health. The human breast cancer MCF-7 cells treated with 0.1 µM estradiol or 2.56 mg/ml of SWT showed dramatic gene expression changes, while no significant change was detected for ferulic acid, a known bioactive compound of SWT. Pathway analysis using differentially expressed genes related to the treatment effect identified that expression of genes in the nuclear factor erythroid 2-related factor 2 (Nrf2) cytoprotective pathway was most significantly affected by SWT, but not by estradiol or ferulic acid. The Nrf2-regulated genes HMOX1, GCLC, GCLM, SLC7A11 and NQO1 were upregulated by SWT in a dose-dependent manner, which was validated by real-time RT-PCR. Consistently, treatment with SWT and its four herbal ingredients resulted in an increased antioxidant response element (ARE)-luciferase reporter activity in MCF-7 and HEK293 cells. Furthermore, the gene expression profile of differentially expressed genes related to SWT treatment was used to compare with those of 1,309 compounds in the CMAP database. The CMAP profiles of estradiol-treated MCF-7 cells showed an excellent match with SWT treatment, consistent with SWT's widely claimed use for women's diseases and indicating a phytoestrogenic effect. The CMAP profiles of chemopreventive agents withaferin A and resveratrol also showed high similarity to the profiles of SWT. This study identified SWT as an Nrf2 activator and phytoestrogen, suggesting its use as a nontoxic chemopreventive agent, and demonstrated the feasibility of combining microarray gene expression profiling with CMAP mining to discover mechanisms of actions and to identify new health benefits of TCMs.

Project description:BackgroundFibrotic liver injury is a progressive scarring event, which may permanently affect liver function and progress into devastating end-stage liver diseases due to the absence of effective therapies. Si-Wu-Tang (SWT), a traditional Chinese medicine formula used in clinic to treat gynecological disorders for centuries, has been investigated in recent preliminary findings for its role in alleviating chronic liver diseases. Here we aim to elucidate the therapeutic effects and possible mechanisms of SWT against fibrotic liver injury.MethodsUHPLC-MS/MS was performed to investigate the chemical characterization of SWT. After intragastrically administered with carbon tetrachloride (CCl4) every 3 days for 1-week, C57BL/6 mice were orally administered with SWT (5.2, 10.4 and 20.8 g/kg) once daily for 3 weeks along with CCl4 challenge. Liver function was determined by the measurement of serum biomarkers, hematoxylin and eosin (H&E) and Masson's trichrome staining. Intestinal inflammatory infiltration and the disruption of intestinal barrier were examined by H&E and E-cadherin immunohistochemical staining. The microbial composition of intestinal content was determined by 16S rRNA sequencing. Serum bile acids (BAs) profiling was analyzed by LC-MS/MS. Simultaneously, the expression of genes of interest was determined by qPCR and western blot.ResultsSWT exhibited remarkable therapeutic effects on CCl4-induced liver fibrosis, as indicated by improved collagen accumulation in livers, intestinal barrier injury and hepatic and intestinal inflammatory response. Results of 16S rRNA sequencing revealed that SWT treatment strikingly restructured intestinal microbiota in fibrotic mice by increasing the relative abundances of Bacteroides and Lachnoclostridium and decreasing the relative abundances of Alistipes and Rikenellaceae. UHPLC-MS/MS data suggested that SWT altered the composition of BAs in circulation as evidenced by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4 mice. Notably, SWT efficiently improved the imbalance of BA homeostasis in livers caused by CCl4 via activating farnesoid X receptor (FXR)-fibroblast growth factor 15 enterohepatic and FXR-small heterodimer partner hepatic pathways.ConclusionSWT decreased inflammatory response, reconstructed gut microbiota-mediated BA homeostasis as well as activated FXR pathways, which eventually protected against CCl4-induced fibrotic liver injury.

Project description:BackgroundYang Xin Tang (YXT) is a traditional Chinese herbal preparation which has been reported to improve cognitive function and memory in patients with dementia. As the underlying mechanism of action of YXT has not been elucidated, we examined the effects of YXT and its major herbal components in regulating gene transcription and molecular targets related to Alzheimer's disease (AD).MethodsAqueous and ethanol extracts of YXT and selected herbal components were prepared and validated by standard methods. A series of biochemical and cellular assays were employed to assess the ability of the herbal extracts to inhibit acetylcholinesterase, reduce β-amyloid aggregation, stimulate the differentiation of neural progenitor cells, suppress cyclooxygenase, and protect neurons against β-amyloid or N-methyl-D-aspartate-induced cytotoxicity. The effects of YXT on multiple molecular targets were further corroborated by a panel of nine reporter gene assays.ResultsExtracts of YXT and two of its constituent herbs, Poria cocos and Poria Sclerotium pararadicis, significantly inhibited β-amyloid aggregation and β-amyloid-induced cytotoxicity. A protective effect of the YXT extract was similarly observed against N-methyl-D-aspartate-induced cytotoxicity in primary neurons, and this activity was shared by extracts of Radix Astragali and Rhizoma Chuanxiong. Although the YXT extract was ineffective, extracts of Poria cocos, Poria Sclerotium pararadicis and Radix Polygalae inhibited acetylcholine esterase, with the latter also capable of upregulating choline acetyltransferase. YXT and its components significantly inhibited the activities of the pro-inflammatory cyclooxygenases. Additionally, extracts of YXT and several of its constituent herbs significantly stimulated the phosphorylation of extracellular signal-regulated kinases and cAMP-responsive element binding protein, two molecular targets involved in learning and memory, as well as in the regulation of neurogenesis.ConclusionsSeveral constituents of YXT possess multiple regulatory effects on known therapeutic targets of AD that range from β-amyloid to acetylcholinesterase. The demonstrated neuroprotective and neurogenic actions of YXT lend credence to its use as an alternative medicine for treating AD.

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Evaluating the pharmacological mechanism of Chinese medicine Si-Wu-Tang through multi-level data integration.

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Evaluating the pharmacological mechanism of Chinese medicine Si-Wu-Tang through multi-level data integration.

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