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Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways.

ABSTRACT: Liver fibrosis is a major pathological feature of chronic liver diseases and there is no effective therapy program at present. Schisandrin B (Sch B) is the major bioactive ingredient of Schisandra chinensis, with antioxidative, anti-inflammatory, antitumor, and hepatoprotective properties. This study aimed to investigate the protective effect and related molecular mechanism of Sch B against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. The in vivo therapeutic effect of Sch B on liver fibrosis induced by CCl4 was examined in rats. In vitro, rat hepatic stellate cells (HSC-T6) were used to assess the effect of Sch B on the activation of HSCs. Sch B effectively attenuated liver damage and progression of liver fibrosis in rats, as evidenced by improved liver function and decreased collagen deposition. The effects of Sch B were associated with attenuating oxidative stress by activating nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling and suppressing HSC activation by inhibiting the transforming growth factor-β (TGF-β)/Smad signaling pathway. In an in vitro study, it was shown that Sch B inhibited TGF-β-induced HSC activation. Finally, Sch B significantly inhibited TGF-β1-stimulated phosphorylation of Smad and signaling of mitogen-activated protein kinases. This study demonstrates that Sch B prevents the progression of liver fibrosis by the regulation of Nrf2-ARE and TGF-β/Smad signaling pathways, and indicates that Sch B can be used for the treatment of liver fibrosis.

SUBMITTER: Chen Q

PROVIDER: S-EPMC5538685 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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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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Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways.

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