Abstract

Liver cirrhosis (LC) is a fibrotic lesion of liver tissue caused by the repeated progression of chronic hepatitis. The traditional Chinese medicine Gexia-Zhuyu formula (GXZY) has a therapeutic effect on LC. However, its pharmacological mechanisms on LC remain elucidated. Here, we used the network pharmacology approach to explore the action mechanisms of GXZY on LC. The compounds of GXZY were from the traditional Chinese medicine systems pharmacology (TCMSP) database, and their potential targets were from SwissTargetPrediction and STITCH databases. The disease targets of LC came from GeneCards, DisGeNET, NCBI gene, and OMIM databases. Then we constructed the protein-protein interaction (PPI) network to obtain the key target genes. And the gene ontology (GO), pathway enrichment, and expression analysis of the key genes were also performed. Subsequently, the potential action mechanisms of GXZY on LC predicted by the network pharmacology analyses were experimentally validated in LC rats and LX2 cells. A total of 150 components in GXZY were obtained, among which 111 were chosen as key compounds. The PPI network included 525 targets, and the key targets were obtained by network topological parameters analysis, whereas the predicted key genes of GXZY on LC were AR, JUN, MYC, CASP3, MMP9, GAPDH, and RELA. Furthermore, these key genes were related to pathways in cancer, hepatitis B, TNF signaling pathway, and MAPK signaling pathway. The in vitro and in vivo experiments validated that GXZY inhibited the process of LC mainly via the regulation of cells proliferation and migration through reducing the expression of MMP9. In conclusion, through the combination of network pharmacology and experimental verification, this study offered more insight molecular mechanisms of GXZY on LC.

Highlights

  • Liver cirrhosis (LC) develops from liver fibrosis (LF), and LF is a pathological process of collagen-based extracellular matrix (ECM) deposition in the liver (Tsuchida and Friedman, 2017; Kisseleva and Brenner, 2021)

  • We found that the mechanisms of Gexia-Zhuyu formula (GXZY) may be related to the pathways in cancer, hepatitis B, TNF signaling pathway, and MAPK signaling pathway derived from network pharmacology analysis

  • The pharmacological mechanisms of GXZY inhibition of LC was investigated by network pharmacological prediction and experimental validation

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Summary

Introduction

Liver cirrhosis (LC) develops from liver fibrosis (LF), and LF is a pathological process of collagen-based extracellular matrix (ECM) deposition in the liver (Tsuchida and Friedman, 2017; Kisseleva and Brenner, 2021). Inhibiting the production and deposition of ECM and promoting its degradation is an important strategy for treating hepatic fibrosis (She et al, 2020). It is believed that timely and aggressive treatment of liver fibrosis can inhibit or even reverse the development of cirrhosis (Schuppan et al, 2018; Roehlen et al, 2020), the etiological treatment of western medicine can help to inhibit or even reverse LC, such as long-term anti-hepatitis B virus (HBV) treatment. It is still necessary to explore the therapeutic effect and mechanisms of TCM compound prescription in anti-liver fibrosis and cirrhosis to find a novel and safe prevention strategy. Based on traditional Chinese medical science, TCM systematically prevents and treats complex liver diseases, which has a broad prospect (Song et al, 2018; Li et al, 2020)

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