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Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-\u03b3 and NF-\u03baB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further <jats:italic>in vivo<\/jats:italic> experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFN\u03b3, IL-1\u03b2 and TGF-\u03b21) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-\u03b1 and Act D <jats:italic>in vitro<\/jats:italic>. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained <jats:italic>in vitro<\/jats:italic> by SNS. These activities may be associated with SNS-induced NF-\u03baB suppression and PPAR-\u03b3 activation.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.<\/jats:p>","DOI":"10.3389\/fphar.2021.656115","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T14:27:39Z","timestamp":1625149659000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Siliang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiliang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"D1038","DOI":"10.1093\/nar\/gky1151","article-title":"OMIM.org: Leveraging Knowledge across Phenotype-Gene Relationships","volume":"47","author":"Amberger","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.jep.2017.11.015","article-title":"Protective Effect of Ethyl Acetate Fraction of Drynaria Quercifolia against CCl 4 Induced Rat Liver Fibrosis via Nrf2\/ARE and NF\u03baB Signalling Pathway","volume":"216","author":"Anuja","year":"2018","journal-title":"J. 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