Praziquantel ameliorates CCl₄ -induced liver fibrosis in mice by inhibiting TGF-?/Smad signalling via up-regulating Smad7 in hepatic stellate cells.

ABSTRACT: BACKGROUND AND PURPOSE:Praziquantel is a schistosomicide, which has been used for more than 30 years due to its efficiency, safety, and mild side effects. Previous studies showed that prolonged treatment with praziquantel suppressed the development of liver fibrosis in mice with schistosomiasis. In this study, we investigated the potential mechanisms underlying the antifibrotic effects of praziquantel. EXPERIMENTAL APPROACH:To avoid the effect of schistosomicidal activity of praziquantel against liver fibrosis induced by Schistosoma japonicum infection, we established a mouse model of carbon tetrachloride (CCl₄ )-induced liver fibrosis for in vivo studies and used TGF-?1-stimulated human hepatic stellate cell line (LX-2) in addition to other fibroblast-like cell line (MES13) and fibroblast cell line (NIH3T3) in vitro. Western blotting, immunohistochemistry, quantitative real-time PCR, siRNA, and immunofluorescence staining were utilized to assess the expression of key molecules in liver fibrosis and the TGF-?/Smad pathway. KEY RESULTS:Praziquantel significantly attenuated CCl₄ -induced liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs) and expression of collagen matrix via enhancement of Smad7 expression, which were confirmed in LX-2, MES13, and NIH3T3 cells in vitro. In contrast, knockdown of Smad7 in LX-2 cells prevented praziquantel-mediated inhibition of LX-2 cell activation and TGF-?1-mediated collagen type I ?1 induction, revealing the critical role of Smad7 in the antifibrotic effect of praziquantel during liver fibrosis. CONCLUSIONS AND IMPLICATIONS:PZQ exhibited a strong efficacy against liver fibrosis by inhibiting activation of HSCs via Smad7 up-regulation, suggesting potential broad utility in treatment of diseases characterized by liver fibrosis.

SUBMITTER: Liu J 

PROVIDER: S-EPMC6965681 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature