Caffeic acid phenethyl ester attenuates liver fibrosis via inhibition of TGF-β1/Smad3 pathway and induction of autophagy pathway.

Caffeic acid phenethyl ester (CAPE) has been reported to possess the hepatoprotective effect. This study was to investigate the mechanism underlying CAPE against liver fibrosis in a liver fibrosis model induced by toxic carbon tetrachloride (CCl4) in male Sprague-Dawley rats and in vitro in CAPE (5 μM, 10 μM, 15 μM) treated hepatic stellate cells (HSC-T6). We found that CAPE treatment remarkably attenuated CCl4-induced liver fibrosis by blocking the activation of HSCs as determined by the expression alternation of transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3), collage I, α-smooth muscle actin (α-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1. The hepatoprotective effects of CAPE were also associated with upregulation of autophasomes in HSCs as determined by transmission electron microscopy (TEM) detection. The in vitro study further confrimed that CAPE attenuated liver fibrogenesis via inducing authophagic markers including LC3, ATG5, Beclin 1 expressions, while inhibiting AKT/mTOR signaling in HSC-T6 cells. Thus, the protective effects of CAPE against liver fibrosis might due to the inhibition of TGF-β1/Smad3 signaling and induction of authophagy in HSCs.

Yang N ，Dang S ，Shi J ，Wu F ，Li M ，Zhang X ，Li Y ，Jia X ，Zhai S ... -  《-》

Ampelopsin attenuates carbon tetrachloride-induced mouse liver fibrosis and hepatic stellate cell activation associated with the SIRT1/TGF-β1/Smad3 and autophagy pathway.

Ampelopsin (Amp), a natural flavonoid found in the vine tea of Ampelopsis grossedentata, exhibited anti-cancer, anti-oxidant, anti-inflammatory, anti-apoptosis and hepatoprotective properties. The current study instigates the protective effect of Amp on carbon tetrachloride (CCl4)-induced hepatic fibrosis and explores its underlying mechanisms. The results indicated Amp decreased the levels of liver injury markers. Amp inhibited liver fibrosis, as indicated by decreases in hepatic collagen deposition, extracellular matrix (ECM) deposition and α-smooth muscle actin (α-SMA). Amp blocked the activation of hepaticstellate cells (HSCs) by decreasing the expression of collage I, α-SMA, tissue inhibitor of matrix metalloproteinases (TIMPs) 1, transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3) and increasing the expression of matrix metalloproteinases (MMPs) 9 and SIRT1 in the model of liver fibrosis and cultured HSCs. The sirtuin 1 (SIRT1) specific inhibitor Sirtinol activated the TGF-β1/Smad3 pathway and enhanced ECM accumulation. Attractively, Amp up-regulates the expression of autophagy-related proteins microtubule-associated protein light chain three II (LC3-II) and Beclin-1 in vivo and in vitro. However, depletion of autophagy by specific inhibitor 3-MA obviously abolished the inhibiting effect of Amp on HSC activation and hepatic fibrosis. Conclusively, these results suggest that Amp could decrease CCl4-induced hepatic fibrosis through regulating the SIRT1/TGF-β1/Smad3 and autophagy pathway.

Ma JQ ，Sun YZ ，Ming QL ，Tian ZK ，Yang HX ，Liu CM ... -  《-》

Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy.

Mao Y ，Zhang S ，Yu F ，Li H ，Guo C ，Fan X ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway.

Hepatic stellate cells (HSCs) are key mediators of fibrogenesis, and the regulation of their activation is now viewed as an attractive target for the treatment of liver fibrosis. Here, the authors investigated the ability of sauchinone, an active lignan found in Saururus chinensis, to regulate the activation of HSCs, to prevent liver fibrosis, and to inhibit oxidative stress in vivo and in vitro. Blood biochemistry and histopathology were assessed in CCl4-induced mouse model of liver fibrosis to investigate the effects of sauchinone. In addition, transforming growth factor-β1 (TGF-β1)-activated LX-2 cells (a human HSC line) were used to investigate the in vitro effects of sauchinone. Sauchinone significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of α-smooth muscle actin staining in mice. Sauchinone blocked the TGF-β1-induced phosphorylation of Smad 2/3 and the transcript levels of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 as well as autophagy in HSCs. Furthermore, sauchinone inhibited oxidative stress, as assessed by stainings of 4-hydroxynonenal and nitrotyrosine: these events may have a role in its inhibitory effects on HSCs activation. Sauchinone attenuated CCl4-induced liver fibrosis and TGF-β1-induced HSCs activation, which might be, at least in part, mediated by suppressing autophagy and oxidative stress in HSCs.

Lee JH ，Jang EJ ，Seo HL ，Ku SK ，Lee JR ，Shin SS ，Park SD ，Kim SC ，Kim YW ... -  《-》

Scoparone attenuates hepatic stellate cell activation through inhibiting TGF-β/Smad signaling pathway.

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. Scoparone, a major constituent isolated from Artemisia capillaris, was reported to possess hepatoprotective effect. However, the role of scoparone in liver fibrosis remains unknown. In the present study, we investigated the effects of scoparone on liver fibrosis in HSCs. Our results demonstrated that scoparoene inhibited the proliferation of HSCs exposed to transforming growth factor (TGF)-β1. In addition, scoparoene significantly suppressed TGF-β1-induced the expression of α-smooth muscle actin (α-SMA) and collagen I in HSC-T6 cells, as well as attenuated the expression of NADPH oxidase (NOX) isoforms expression and ROS production in TGF-β1-stimialted HSC-T6 cells. Mechanistically, scoparoene suppressed the phosphorylation level of Smad3 in TGF-β1-stimialted HSC-T6 cells. In conclusion, these findings showed that scoparone significantly inhibited the proliferation and activation of HSCs through the inactivation of TGF-β/Smad signaling pathway. These data provide that scoparone may have potential to treat liver fibrosis.

Liu X ，Zhao X 《-》