Research On The Mechanism Of Action Of Zhizibaipi Decoction In The Treatment Of Liver Fibrosis Based On Network Pharmacolog

Objective:To explore the mechanism of Zhizibaipi Decoction（ZD）via network pharmacology and to validate the result via animal experiment so that we can provide the basic experimental evidence for further development of ZD and research of hepatic fibrosis.Method:Prime ingredients of ZD were screened from TCMSP online database;Hepatic-fibrosis-related genes were screened from CTD online database;The common targets of the ingredients and the disease were matched for further construction of herb-ingredient-target complex network via Cytoscape software;Protein-protein interaction network was constructed via STRING online tool,the result of which was visualized via Cytoscape software.Gene ontology and signal transduction pathway enrichment was conducted on DAVID online database.Sixty male C57 mice were randomly divided into control group,model group,ZD group,YC-1 group and sorafenib group.Mice in model group and each treatment group were intraperitoneally injected with CCl₄ olive-oil solution,3 times per week for 4weeks.Mice in control group were intraperitoneally injected with olive oil of the same dose.Two weeks after modeling,each treatment group was given the corresponding drug gavage once a day,the control group and model group were given the same dose of 0.3%sodium carboxymethyl cellulose solution（The gavage lasted for 14 days）;After the procedure,the effect of ZD on liver fibrosis was preliminarily evaluated through the general condition,liver function,liver pathological examination and the level of hydroxyproline in liver tissue.Then,the effect mechanism of ZD on liver fibrosis mice was studied by detecting the levels of IL-1,IL-6 and TNF-αin peripheral blood,the expression levels of genes related to liver inflammation and liver fibrosis,the expression levels of genes related to HIF-1 signaling pathway and the protein levels related to liver fibrosis and HIF-1 signaling pathway in liver tissue.Results:1.A total of 91 prime ingredients and 117 relevant targets were obtained for ZD preventing and treating hepatic fibrosis.The complex network showed that the active ingredients of Zhizi had the highest total degree value.Gene ontology enrichment analysis and signal transduction pathway analysis were used to obtain 35 ontological entries and 14 signaling pathways.2.ZD can reduce levels of ALT,AST,TBil,GGT and ALP in serum of liver-fibrosis mice,inhibit inflammatory cell infiltration and liver cell necrosis,and reduce collagen deposition in liver fibrosis mice.ZD can also reduce IL-1,TNF-αand IL-6levels in peripheral blood of liver-fibrosis mice,down-regulate the TNF-α,IL-6,α-SMA,Col-1,CD31 mRNA level,and up-regulate CD44 mRNA level;Additionally,ZD can down-regulate the expression of proteins in HIF-1 signaling pathway in liver fibrosis mice,and improve the hypoxia in the livers of hepatic-fibrosis mice.Conclusion:1.The network pharmacology indicated that ZD may prevent hepatic via HIF-1signaling pathway;Gancao may play the prime role in ZD preventing hepatic fibrosis;Glycyrol may be the prime monomer in ZD regulating HIF-1 signaling pathway;2.ZD can effectively treat hepatic fibrosis via protecting liver function,reducing liver tissue necrosis and alleviating inflammation;3.ZD can down-regulate the expression of NF-κB,TLR4,and HIF-1 to play an anti-fibrosis role.