Hesperetin derivative-7 inhibits PDGF-BB-induced hepatic stellate cell activation and proliferation by targeting Wnt/β-catenin pathway

Liver fibrosis results from a continuous wound-healing response of the liver to repeated injury. Hesperidin (HDN) is a naturally occurring flavanone glycoside, which is extracted from fruit peels of the genus citrus. Previous studies focused on the anti-inflammation, anti-tumor and anti-oxidant roles of HDN. However, the role of HDN in hepatic fibrosis is still unknown. Here, we evaluated the role of HDND-7, a derivative of HDN which has better water solubility and bioavailability, in the activation and proliferation of PDGF-BB-induced hepatic stellate cells (HSCs), then we investigated the anti-fibrotic effect of HDND-7 in CCl4-induced mouse model of liver fibrosis. The study aimed to determine whether HDND-7 could affect the survival of HSC-T6 in vitro, while evaluating its anti-fibrotic efficacy on CCl4-induced liver fibrosis in Kunming mice. Our results revealed that HDND-7 inhibited the proliferation and activation of PDGF-BB-treated HSC-T6 cells in a time- and dose-dependent manner. In addition, administration of HDND-7 significantly attenuated liver fibrosis, as evident by the dramatic down-regulation of alpha-smooth muscle actin (alpha-SMA) and type I collagen alpha-1 (Col1 alpha 1) in both mRNA and protein levels in vivo and in vitro. Furthermore, we also found that HDND-7 decreased the expression of beta-catenin and the downstream proteins, cydind1 and C-myc, indicating that HDND-7 may inhibit the activation and proliferation of PDGF-BB-induced HSC-T6 and attenuate liver fibrosis, at least in part, through targeting the Wnt/beta-catenin signaling pathway. Hence HDND-7 might be employed as a promising natural supplement for liver fibrosis drug therapy. (C) 2015 Elsevier B.V. All rights reserved.