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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

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Praziquantel ameliorates CCl<sub>4</sub> -induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells.

Liu Jinfeng J Kong Delong D Qiu Jingfan J Xie Yanci Y Lu Zhongkui Z Zhou Chunlei C Liu Xinjian X Zhang Rong R Wang Yong Y

British journal of pharmacology 20191229 24

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>To avoid the effect of schistosomicidal activity of prazi ...[more]

PMID: 31412137

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Project description:AimChinese medicine CGA formula consists of polysaccharide from Cordyceps sinensis mycelia (CS-PS), gypenosides and amygdalin, which is derived from Fuzheng Huayu (FZHY) capsule for treating liver fibrosis. In this study we attempted to confirm the therapeutic effects of CGA formula in dimethylnitrosamine (DMN)-induced liver fibrosis in rats, and to identify the mechanisms of anti-fibrotic actions.MethodsRats were injected with DMN (10 mg·kg(-1)·d(-1), ip) for 3 consecutive days per week over a 4-week period. The rats then were orally administered with CGA formula (CS-PS 60 mg·kg(-1)·d(-1), gypenosides 50 mg·kg(-1)·d(-1) and amygdalin 80 mg·kg(-1)·d(-1)) daily in the next 2 weeks. CS-PS, gypenosides or amygdalin alone were administered as individual component controls, whereas colchicine and FZHY were used as positive controls. Serum biomarkers were measured. Hepatic injury, collagen deposition and stellate cell activation were examined. The MMP activities, expression of TIMP protein and proteins involved in the TGF-β1/Smad signaling pathways in liver tissues were assayed.ResultsIn DMN-treated rats, administration of CGA formula significantly decreased serum ALT, AST and total bilirubin and hepatic hydroxyproline levels, increased serum albumin level, and attenuated liver fibrosis as shown by histological examination. Furthermore, these effects were comparable to those caused by administration of FZHY, and superior to those caused by administration of colchicine or the individual components of CGA formula. Moreover, administration of CGA formula significantly decreased the protein levels of α-SMA, TGF-β1, TGF-β1 receptor (TβR-I), p-TβR-I, p-TβR-II, p-Smad2, p-Smad3, TIMP1 and TIMP2, as well as MMP2 and MMP9 activities in liver tissues of DMN-treated rats.ConclusionChinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats, and this effect was likely associated with the down-regulation of MMP2/9 activities, TIMP1/2 protein expression and the TGF-β1/Smad signaling pathways in the liver.

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

Publications

Praziquantel ameliorates CCl<sub>4</sub> -induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells.

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

Publications

Praziquantel ameliorates CCl<sub>4</sub> -induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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