Resveratrol Regulates Activated Hepatic Stellate Cells by Modulating NF‐κB and the PI3K/Akt Signaling Pathway

Abstract

In the present study, we investigated whether resveratrol could suppress the hepatic fibrogenesis in activated hepatic stellate cells. The immortalized rat hepatic stellate cells, t-HSC/Cl-6, were treated with resveratrol 1 h prior to lipopolysaccharide (LPS, 1 μg/mL). Resveratrol decreased t-HSC/Cl-6 cell viability at much lower concentrations within 24 h. Resveratrol pretreatment also decreased the LPS-induced protein expression of α-SMA and collagen I. In addition, resveratrol significantly reduced the protein expression of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), and the expression of phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated serine/threonine kinase B (Akt). Moreover, resveratrol markedly blocked the translocation of nuclear factor (NF)-κB in LPS-activated HSCs. Furthermore, resveratrol inhibited HSCs activation through stimulating LXRβ, but did not influence LXRα. Overall, we conclude that the antifibrotic effect of resveratrol is the result of blocking NF-κB activation and PI3K/Akt phosphorylation, which inhibits HSC activation to obstruct liver fibrosis. Thus, resveratrol may be a natural agent for preventing hepatic fibrosis.

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

“…The results showed that the FZHY formula exerted its protective effects against liver fibrosis primarily by regulating 15 pathways ( Figure 3B ), of which the TGF-beta signaling pathway has been reported ( Wang et al, 2012 ). In addition, although lots of references indicated that liver fibrosis was closely related to the other 14 pathways, such as hypoxia inducible factor-1 (HIF-1) signaling pathway ( Zhao et al, 2014 ), the forkhead box O (FoxO) signaling pathway ( Wu et al, 2015 ), the ErbB signaling pathway ( Scheving et al, 2016 ), the Chemokine signaling pathway ( Marra and Tacke, 2014 ), the thyroid hormone signaling pathway ( Bai et al, 2014 ), the estrogen signaling pathway ( Deng and He, 2007 ), the Ras signaling pathway ( Abbas et al, 2011 ), the phosphatidylinositol-3-kinase (PI3K-Akt) signaling pathway ( Zhang D.Q. et al, 2016 ), the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway ( Bai et al, 2014 ), the mammalian target of rapamycin (mTOR) signaling pathway ( Li et al, 2015 ), the PPAR signaling pathway ( Jiang et al, 2015 ), the mitogen-activated protein kinase (MAPK) signaling pathway ( Park et al, 2015 ), the toll-like receptor signaling pathway ( Aoyama et al, 2010 ), and the Wnt signaling pathway ( Miao et al, 2013 ); further experiments are needed to validate these findings.…”

Kyungheechunggan-tang suppresses inflammatory cytokines and fibrotic genes in LPS-induced RAW 264.7 cells and LX-2 cells

“…Inflammation and fibrosis play crucial roles in determining liver damage in a wide range of chronic liver diseases, including nonalcoholic fatty liver diseases (NAFLD), viral hepatitis, and alcoholic liver diseases 32) . Inflammation-driven pathological process in liver activates quiescent HSCs which leads to accumulation of collagen I and α-SMA 11) . Inversely, E2, and TNF-α 25), [35][36] .…”

“…As a result of the inflammation process, macrophagederived transforming growth factor (TGF)-β1 stimulates the activation of hepatic stellate cells (HSCs) [8][9] . Activated HSCs result in excessive accumulation of the extracellular matrix (ECM) including α-smooth muscle actin (SMA), type I collagen (collagen I), matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [10][11] . Liver fibrosis is a reversible state, but the possibility of recovery is substantially reduced if it progresses to cirrhosis or HCC [12][13][14] .…”

The Effects of Taoren‐Honghua Herb Pair on Pathological Microvessel and Angiogenesis‐Associated Signaling Pathway in Mice Model of CCl4‐Induced Chronic Liver Disease

“…KDR antibody can singlehandedly inhibit the pathological angiogenesis induced by VEGF through inhibition of the KDR downstream tyrosine kinase signal transduction system [ 22 ]. In receptor tyrosine kinase signal transduction system, the survival of vascular endothelial cell after proliferation and differentiation mainly depends on PI3K-Akt that is an important transduction pathway of survival signal; it participates in the angiogenesis-associated signaling pathway like VEGF-mediated endothelium signal transduction: PI3K and upstream VEGFR-2 (KDR) form compound and activate, generate second messenger, activate phosphoinositide dependent protein kinase (PDK), and activate the downstream serine-threonine protein kinase (Akt), and then generate the effect of vascular endothelial cell activation, so the level of activated Akt [which also is phosphorylated Akt (pAkt)] is the important index that represents the activity of PI3K-Akt [ 23 ]. So if this pathway is interrupted, the endothelium activation will be inhibited and pathological angiogenesis will be reduced.…”