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Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis.

ABSTRACT: Background: Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) indicated for the treatment of hepatocellular carcinoma (HCC). Its potential targets and molecular mechanisms are not clear. Therefore, this study intends to explore the molecular mechanism of YFJP based on network pharmacology analysis and in vitro validation.

Methods and results: Through univariate and multivariate analyses and survival analysis in HCC patients with or without YFJP treatment we found that drinking alcohol, alfafeto protein???400 ng/l, baseline portal vein tumor thrombus and total bilirubin level???18.8 ?M) were independent risk factors for poor prognosis, while red blood cell count???4?×?10⁹/l and TCM treatment were independent protective factors. Besides, YFJP prolonged the cumulative survival of HCC patients. Using online pharmacological methods, we obtained 58 relevant compounds and molecular 53 targets. By using scratch test, Transwell assay, EdU assay, and TUNEL staining, we found that YFJP-containing serum repressed the migration, invasion and proliferation of HCC cells in vitro, and induced cell apoptosis. Moreover, YFJP diminished the gene expression of TP53, CCND1, p-EGFR, EGF, VEGFA, JUN, IL6, COX-2, AKT1, and MAPK1 in HCC cells, but elevated the expression of ESR1 and CASP3.

Conclusions: Taken together, results showed that YFJP attenuated HCC progression through mediating effects on HCC-related genes.

SUBMITTER: Yan F

PROVIDER: S-EPMC7650191 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis.

Yan Fengna F Feng Miaomiao M Wang Xinhui X Wang Peng P Xie Yuqing Y Liu Xiaoli X Li Weihong W Yang Zhiyun Z

Cancer cell international 20201109 1

<h4>Background</h4>Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) indicated for the treatment of hepatocellular carcinoma (HCC). Its potential targets and molecular mechanisms are not clear. Therefore, this study intends to explore the molecular mechanism of YFJP based on network pharmacology analysis and in vitro validation.<h4>Methods and results</h4>Through univariate and multivariate analyses and survival analysis in HCC patients with or without YFJP treatm ...[more]

PMID: 33292207

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Project description:To identify the key drugs of Yangyin Fuzheng Jiedu prescription (YFJP) and investigate their therapeutic effects against hepatocellular carcinoma (HCC) and the potential mechanism using network pharmacology. The H22 tumor-bearing mouse model was established. Thirty male BALB/c mice were divided randomly into five groups. The mice were orally treated with either disassembled prescriptions of YFJP or saline solution continuously for 14 days. The mice were weighed every 2 days during treatment and the appearance of tumors was observed by photographing. The tumor inhibition rate and the spleen and thymus indexes were calculated. Hematoxylin and eosin and immunohistochemical staining were performed to observe the histological changes and tumor-infiltrating lymphocytes. Cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. The proportion of CD8+ T cells and the expression of programmed cell death protein 1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were analyzed using flow cytometry. The production of serum cytokines was detected using the Milliplex® MAP mouse high sensitivity T cell panel kit. The active components of the key drugs and HCC-related target proteins were obtained from the corresponding databases. The putative targets for HCC treatment were screened by target mapping, and potential active components were screened by constructing a component-target network. The interactive targets of putative targets were obtained from the STRING database to construct the protein-protein interaction network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed based on potential targets. The gene-gene inner and component-target-pathway networks were constructed and analyzed to screen the key targets. Western blotting was used to evaluate the protein expression of the key targets in the tumor-bearing mouse model. The binding activity of the key targets and compounds was verified by molecular docking. Among the three disassembled prescriptions of YFJP, the Fuzheng prescription (FZP) showed significant antitumor effects and inhibited weight loss during the treatment of H22 tumor-bearing mice. FZP increased the immune organ index and the levels of CD8+ and CD3+ T cells in the spleen and peripheral blood of H22 tumor-bearing mice. FZP also reduced the expression of PD-1, TIGIT, and TIM3 in CD8+ T cells and the production of IL-10, IL-4, IL-6, and IL-1β. Network pharmacology and experimental validation showed that the key targets of FZP in the treatment of HCC were PIK3CA, TP53, MAPK1, MAPK3, and EGFR. The therapeutic effect on HCC was evaluated based on HCC-related signaling pathways, including the PIK3-Akt signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. GO enrichment analysis indicated that FZP positively regulated the molecular functions of transferases and kinases on the cell surface through membrane raft, membrane microarea, and other cell components to inhibit cell death and programmed cell death. FZP was found to be the key disassembled prescription of YFJP that exerted antitumor and immunoregulatory effects against HCC. FZP alleviated T cell exhaustion and improved the immunosuppressive microenvironment via HCC-related targets, pathways, and biological processes.

Project description:BackgroundTaraxacum mongolicum (TM) is a widely used herb. Studies have reported that TM exhibits growth-inhibitory and apoptosis-inducing on multiple tumors, including hepatocellular carcinoma (HCC). The active ingredients, targets, and molecular mechanisms of TM against HCC need to be further elucidated.MethodsWe identified the active ingredients and targets of TM via HERB, PubChem, SwissADME, SwissTargetPrediction, and PharmMapper. We searched HCC targets from GeneCards, Comparative Toxicogenomics Database (CTD), and DisGeNET. Then, the intersection of drug targets and disease targets was uploaded to the STRING database to construct protein-protein interactions (PPI) networking whose topology parameters were analyzed in Cytoscape software to screen hub targets. Next, we used Metascape for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and we employed AutoDock vina, AMBER18 and PyMOL software along with several auxiliary tools for molecular docking and molecular dynamics (MD) simulation. Finally, based on the in silico findings, cellular experiments were conducted to investigate the effect of TM on HSP90AA1 gene expression.ResultsA total of 228 targets and 35 active ingredients were identified. Twenty two hub targets were selected through PPI networking construction for further investigation. The enrichment analysis showed that protein kinase binding, mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were mainly involved. Molecular docking and MD simulation results supported good interaction between HSP90 protein and Austricin/Quercetin. The in vitro assay showed that TM inhibited the proliferation of HepG2 cells and the expression of HSP90AA1 gene.ConclusionsThis study is the first to use network pharmacology, molecular docking, MD simulation and cellular experiments to elucidate the active ingredients, molecular targets, and key biological pathways responsible for TM anti-HCC, providing a theoretical basis for further research.

Dataset Information

Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis.

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Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis.

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