Abstract
Background: 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. Methods: A carbon tetrachloride (CCl4)-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. Results: 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-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) 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-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation. Conclusion: 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.
Highlights
Liver fibrosis refers to histological changes induced by chronic inflammation resulting from multiple acute and chronic liver conditions, including infection with viral hepatitis B or C virus (HBV or HCV), alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease and biliary disease (Koyama and Brenner, 2017; Mendez-Sanchez et al, 2020; Sterling et al, 2020)
We examined the active components and mechanisms underlying the effects of SNS on liver fibrosis using network pharmacology analysis in combination with experimental validation, which were carried out in accordance with Network Pharmacology Evaluation Method Guidance-Draft (Li, 2021)
SNS treatment induced a remarkable decrease in the ALT and AST contents relative to the model group (p < 0.01) but had no obvious influence on the ratio of liver weight to body weight (Figures 1C–E)
Summary
Liver fibrosis refers to histological changes induced by chronic inflammation resulting from multiple acute and chronic liver conditions, including infection with viral hepatitis B or C virus (HBV or HCV), alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease and biliary disease (Koyama and Brenner, 2017; Mendez-Sanchez et al, 2020; Sterling et al, 2020). Liver injury can cause hepatic stellate cell (HSC) hyperactivity and promote extracellular matrix (ECM) accumulation (Cai et al, 2020). In this case, collagen fibers accumulate within the hepatocyte extracellular space, causing loss of blood supply to hepatocytes (Kisseleva and Brenner, 2020; Meurer et al, 2020). Recent treatments have mainly aimed to inactivate HSCs, protect against apoptosis of hepatic parenchymal cells (HPC), control inflammation and regulate metabolism of the extracellular matrix (ECM) (Hou et al, 2015; Zhou et al, 2019; Chan et al, 2020; Lambrecht et al, 2020). The therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear
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