Abstract
Liver fibrosis resulting from chronic liver damage constitutes a major health care burden worldwide; however, no antifibrogenic agents are currently available. Our previous study reported that the small molecule NPLC0393 extracted from the herb Gynostemma pentaphyllum exerts efficient antifibrotic effects both in vivo and in vitro. In this study, a TMT-based quantitative proteomic study using a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was performed to identify the potential target of NPLC0393. Combining this study with bioinformatic analysis of differentially expressed proteins between the CCl4 model and NPLC0393 treatment groups, we focused on the function of N-myc downstream-regulated gene 2 (NDRG2) involved in cell differentiation. In vitro studies showed that NPLC0393 prevented the TGF-β1 stimulation-induced decrease in the NDRG2 level in hepatic stellate cells (HSCs). Functional studies indicated that NDRG2 can inhibit the activation of HSCs by preventing the phosphorylation of ERK and JNK. Furthermore, knockdown of NDRG2 abolished the ability of NPLC0393 to inhibit HSC activation. In conclusion, these results provide information on the mechanism underlying the antifibrotic effect of NPLC0393 and shed new light on the potential therapeutic function of the TGF-β1/NDRG2/MAPK signaling axis in liver fibrosis.
Highlights
Liver fibrosis is a reversible wound healing response that occurs in chronic liver injury and is caused by viral infection, drug exposure, and metabolic and autoimmune disorders (Parola and Pinzani, 2019)
To discover proteins associated with the protective effects of NPLC0393 against CCl4-induced liver fibrosis and identify potent therapeutic targets, we performed tandem mass tag (TMT)-LCMS/MS-based proteomic studies of liver tissues obtained from normal mice (Con), mice with CCl4-induced fibrosis (CCl4) and mice with CCl4-induced fibrosis treated with NPLC0393 (CCl4 + NPLC0393) (n = 3 per group)
We applied TMT coupled with LC-MS/MS to screen the differentially expressed proteins in liver tissues between mice with CCl4induced fibrosis and mice with CCl4-induced fibrosis treated with NPLC0393
Summary
Liver fibrosis is a reversible wound healing response that occurs in chronic liver injury and is caused by viral infection, drug exposure, and metabolic and autoimmune disorders (Parola and Pinzani, 2019). Activation of hepatic satellite cells (HSCs) is a crucial event in fibrogenesis (Tsuchida and Friedman, 2017). The progression and resolution of fibrosis are complex processes, involving interactions among cells, soluble mediators (e.g., Tumor necrosis factor alpha, TNF-α), the ECM and intracellular signaling events (e.g., TGF-β1/Smad signaling) relevant to the fibrogenic process (Hernandez-Gea and Friedman, 2011). Given that fibrosis is the primary predictor of liver-related morbidity and mortality, the development and testing of antifibrotic strategies that can prevent, halt, or even reverse liver fibrosis are urgently needed (Bottcher and Pinzani, 2017)
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