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To Unveil the Molecular Mechanisms of Qi and Blood through Systems Biology-Based Investigation into Si-Jun-Zi-Tang and Si-Wu-Tang formulae.

ABSTRACT: Traditional Chinese Medicine (TCM) is increasingly getting clinical application worldwide. But its theory like QI-Blood is still abstract. Actually, Qi deficiency and blood deficiency, which were treated by Si-Jun-Zi-Tang (SJZT) and Si-Wu-Tang (SWT) respectively, have characteristic clinical manifestations. Here, we analyzed targets of the ingredients in SJZT and SWT to unveil potential biologic mechanisms between Qi deficiency and blood deficiency through biomedical approaches. First, ingredients in SWT and SJZT were retrieved from TCMID database. The genes targeted by these ingredients were chosen from STITCH. After enrichment analysis by Gene Ontology (GO) and DAVID, enriched GO terms with p-value less than 0.01 were collected and interpreted through DAVID and KEGG. Then a visualized network was constructed with ClueGO. Finally, a total of 243 genes targeted by 195 ingredients of SWT formula and 209 genes targeted by 61 ingredients of SJZT were obtained. Six metabolism pathways and two environmental information processing pathways enriched by targets were correlated with 2 or more herbs in SWT and SJZT formula, respectively.

SUBMITTER: Sun J

PROVIDER: S-EPMC5039637 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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To Unveil the Molecular Mechanisms of Qi and Blood through Systems Biology-Based Investigation into Si-Jun-Zi-Tang and Si-Wu-Tang formulae.

Sun Jing J Zhang Li L He Yujun Y Zhang Kun K Wu Liping L Fan Yongsheng Y Xie Zhijun Z

Scientific reports 20160928

Traditional Chinese Medicine (TCM) is increasingly getting clinical application worldwide. But its theory like QI-Blood is still abstract. Actually, Qi deficiency and blood deficiency, which were treated by Si-Jun-Zi-Tang (SJZT) and Si-Wu-Tang (SWT) respectively, have characteristic clinical manifestations. Here, we analyzed targets of the ingredients in SJZT and SWT to unveil potential biologic mechanisms between Qi deficiency and blood deficiency through biomedical approaches. First, ingredien ...[more]

PMID: 27677604

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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:Intestinal mucositis is a common toxicity of many anti-neoplastic therapies that negatively influences health, the quality of life, economic outcomes, and even the success of cancer treatment. Unfortunately, there is presently no optimal medicine that is able to effectively manage this condition. l-glutamine is one of the most frequently used agent in practice among the limited treatment choices due to its safety and inexpensiveness despite there being a lack of evidence. Previous studies indicated that l-glutamine may alleviate mucositis and mucosal atrophy but failed to improve patients' macroscopic conditions, such as the occurrence of diarrhea. A compound glutamine capsule (G-SJZ), composed of l-glutamine and the traditional Chinese herbal formula Si-Jun-Zi-Tang, has been used in China for 23 years to treat many types of gastrointestinal diseases, including gastrointestinal reactions induced by radiotherapy and chemotherapy. However, the exact effect of G-SJZ on intestinal mucositis is unclear, and moreover, whether l-glutamine combined with Si-Jun-Zi-Tang is more effective than l-glutamine alone have not been studied. In the current study, we explored the effects of G-SJZ and l-glutamine in a mouse model of intestinal mucositis induced by 5-fluorouracil (5-Fu). The results revealed that pretreatment with G-SJZ ameliorated the physical manifestations of weight loss and the severity of diarrhea following continuous 5-Fu injections in mice. Likewise, the histopathological damage and the destruction of villus and crypt structures in the intestinal mucosa as well as the increase in circulating intestinal injury markers caused by 5-Fu were reversed with G-SJZ pretreatment. Furthermore, the protective effect of G-SJZ was accompanied by modulations in the immunohistochemical expression of tight junction proteins. Interestingly, although treatment with a dose of l-glutamine alone that was equivalent to the dose in G-SJZ also showed a protective effect, it did not appear to be as strong as treatment with G-SJZ. Si-Jun-Zi-Tang in G-SJZ may compensate for the deficiencies of l-glutamine in this model which seems not to be related to the regulation of tight junction proteins. Our study is the first to suggest that the combined use of l-glutamine and Si-Jun-Zi-Tang might be more effective than l-glutamine alone despite exact mechanism still needs further study. Because of the limited number of therapeutic agents, G-SJZ is likely to be a preferable choice for intestinal mucositis.

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.

Dataset Information

To Unveil the Molecular Mechanisms of Qi and Blood through Systems Biology-Based Investigation into Si-Jun-Zi-Tang and Si-Wu-Tang formulae.

Publications

To Unveil the Molecular Mechanisms of Qi and Blood through Systems Biology-Based Investigation into Si-Jun-Zi-Tang and Si-Wu-Tang formulae.

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