Resveratrol increases the activation markers and changes the release of inflammatory cytokines of hepatic stellate cells

Abstract

The phytoalexin Resveratrol (3,5,4′-trihydroxystilbene; RSV) has been related to numerous beneficial effects on health by its cytoprotection and chemoprevention activities. Liver fibrosis is characterized by the extracellular matrix accumulation after hepatic injury and can lead to cirrhosis. Hepatic stellate cells (HSC) play a crucial role during fibrogenesis and liver wound healing by changing their quiescent phenotype to an activated phenotype for protecting healthy areas from damaged areas. Strategies on promoting the activated HSC death, the quiescence return or the cellular activation stimuli decrease play an important role on reducing liver fibrosis. Here, we evaluated the RSV effects on some markers of activation in GRX, an HSC model. We further evaluated the RSV influence in the ability of GRX on releasing inflammatory mediators. RSV at 1 and 10 µM did not alter the protein content of α-SMA, collagen I and GFAP; but 50 µM increased the content of these activation-related proteins. Also, RSV did not change the myofibroblast-like morphology of GRX. Interestingly, RSV at 10 and 50 µM decreased the GRX migration and collagen-I gel contraction. Finally, we showed that RSV triggered the increase in the TNF-α and IL-10 content in culture media of GRX while the opposite occurred for the IL-6 content. Altogether, these results suggested that RSV did not decrease the activation state of GRX and oppositely, triggered a pro-activation effect at the 50 µM concentration. However, despite the increase of TNF-α in culture media, these results on IL-6 and IL-10 secretion were in accordance with the anti-inflammatory role of RSV in our model.

Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways

“…I but had no effect on Col. I mRNA, which may be attributed to resveratrol promoting the degradation of intracellular Col. Taken together, these findings were consistent with those of previous reports (de Oliveira et al, 2021;Martins et al, 2014;Zhang et al, 2016), showing that resveratrol had a dose-dependent effect on HSC viability and inhibited HSC activation at higher doses.…”

“…In contrast, resveratrol decreased t‐HSC/Cl‐6 cell (rat HSC line) viability at very low concentrations (1.56 μM) at 24 hr (Zhang et al, 2016). de Oliveira et al (2021) suggested that resveratrol at 1 and 10 μM did not alter the protein levels of α‐SMA, collagen I, and glial fibrillary acidic protein (GFAP) in GRX cells (mouse HSC line). Resveratrol at 10 and 50 μM decreased GRX cell migration and collagen I contraction.…”

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

“…In this regard, RSV seems to play an interesting role in the regulation of de novo fibrogenesis deposition, acting on several key pathways [ 46 ]. In fact, RSV administration reduces portal pressures, the activation of hepatic stellate cells, and improves hepatic endothelial functioning in cirrhotic rats, with an overall positive effect on cirrhosis and portal hypertension [ 47 , 48 , 49 ]. Specifically, the administration of resveratrol (10 and 20 mg/kg/day) to cirrhotic rats for 2 weeks showed reductions in portal pressure without significant changes in systemic hemodynamics.…”

Carvacrol hinders the progression of hepatic fibrosis via targeting autotaxin and thioredoxin in thioacetamide-induced liver fibrosis in rat

“…4,5 Fibrotic tissue consists of collagen accumulation after chronic inflammation that is powered by a cascade of events involving cytokines production by both circulating immune cells and hepatic stellate cells (HSCs) which are considered the main producers of that extracellular material of the fibrotic tissue. 6,7 Activation and proliferation of HSCs are mediated by reactive oxygen species (ROS) and inflammatory cytokines. Activated HSCs promotes the expression of fibrotic biomarkers like (a-SMA) and (ATX) due to transformation of HSCs into myofibroblastic cells that secrete the large amounts of collagen, thereby producing liver fibrosis.…”