Isorhamnetin Exerts Antifibrotic Effects by Attenuating Platelet-Derived Growth Factor-BB-induced HSC-T6 Cells Activation via Suppressing PI3K-AKT Signaling Pathway

Background: Currently, liver fibrosis is growing worldwide; unfortunately, there is no definite cure for this disease. Hence, understanding the molecular pathways involved in the development of liver fibrosis can help to find a proper treatment. In this study, we aimed to evaluate the effects of isorhamnetin as an antifibrotic agent on platelet-derived growth factor (PDGF)-BB-activated hepatic stellate cells (HSC)-T6 cells in a concentration-dependent manner. We have also attempted to assess signaling pathways that may affect liver fibrosis. Methods: PDGF-BB was used to activate the HSC-T6 rat hepatic stellate cell line. The activated cells were treated with Isorhamnetin for 24 h. Finally, we compared the mRNA expression level of COLA1 and α-SMA and also the level of phosphorylated AKT protein with the control group. Results: The obtained data revealed a significant increase in the expression level of the COLA1 and α-SMA genes (p > 0.05), as well as phosphorylated AKT protein, in the cells treated with PDGF-BB. In addition, 75 and 100 µM concentrations of Isorhamnetin markedly declined the COLA1 and α-SMA expression and also the phosphorylated AKT protein level in the HSC-T6 cells. Conclusion: Our findings suggest that Isorhamnetin decreases HSC-T6 activation, the expression of COLA1 and α-SMA, in vitro, which could act as an antifibrotic element to reduce and treat liver fibrosis disease.

Reducing Proteoglycan Synthesis and NOX Activity by ROCK Inhibitors: Therapeutic Targets in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arteries characterized by the accumulation of inflammatory cells in the arterial wall. Hypertension, dyslipidemia, and hyperglycemia are major risk factors of atherosclerosis. Rho-associated protein kinase (ROCK), a serine/threonine kinase, is a downstream effector of the small GTPase RhoA. ROCK is involved in different stages of atherosclerosis. Accumulating evidence has demonstrated that ROCK signaling plays vital roles in various cellular functions, such as contraction, migration, and proliferation of smooth muscle cells. Dysregulation of the ROCK pathway is associated with atherosclerosis and hypertension. Experimental studies have shown that ROCK inhibitors may have favorable effects in ameliorating atherosclerosis. ROCK signaling has a role in proteoglycan synthesis through transactivation of the TGF-ß receptor Type I (TßRI) mediated by G-protein-coupled receptor (GPCR) agonists (endothelin-1, angiotensin II and …), and ROCK inhibitors could decrease proteoglycan synthesis and atherosclerotic plaque formation. Based on the hypothesis that targeting ROCK pathway may be effective in ameliorating atherosclerosis, we suggest that ROCK inhibitors may have a potential therapeutic role in inhibition or slowing atherogenesis. However, for this hypothesis more research is needed.