Rutin Ameliorates Hepatic Fibrosis via Targeting Hepatic Stellate Cells’ Activation, Proliferation and Apoptosis

Abstract

ABSTRACT Despite rutin, extracted from black mulberry, has several pharmacological activities, its exact effect against hepatic fibrosis remains incompletely identified. Accordingly, this study investigates whether rutin is a promising candidate for treating hepatic fibrosis and to clarify its underlying antifibrotic mechanisms in vitro and in vivo. In vitro studies were performed on hepatic stellate cell line (HSC-T6) whereas liver fibrosis was established in rats via chronic thioacetamide (TAA)-intoxication. Rats were divided into (i) normal, (ii) TAA-intoxicated rats; TAA-intoxicated rats treated with (iii) silymarin or (iv) rutin. Levels of ALT, AST, platelet-derived growth factor-BB (PDGF-BB), tissue inhibitor metalloproteinases type-1 (TIMP-1), hydroxyproline and expression of proliferating cellular nuclear antigen (PCNA) together with histological changes were examined. Activities of rutin on TGF-β1, α-smooth muscle actin (α-SMA) and caspase-3 were measured in vitro and in vivo. Rutin exhibited no marked HSC-T6 cell death (IC50 = 460 µg.ml−1), however, it showed reduction in HSCs activation (low TGF-β1 level and α-SMA positive cells) and induced apoptosis (high caspase-3 positive cells). Rutin also ameliorated liver functions, reduced hepatic levels of PDGF-BB, TGF-β1, TIMP-1, hydroxyproline and restored PCNA, together with attenuation in fibrosis score (S1 vs S4). Rutin could be a promising candidate for treating hepatic fibrosis through down-regulation of HSCs activation and induction of apoptosis.