Antagonizing TGF-beta induced liver fibrosis by a retinoic acid derivative through regulation of ROS and calcium influx.

Transforming growth factor-beta1 (TGF-beta1) mediates the regulation of extracellular matrix via reactive oxygen species (ROS) and calcium influx, both are activators of hepatic stellate cells (HSC) which play a critical role in hepatic fibrogenesis. Hence one can use ROS assay as the main screening tool for molecules that might antagonize the process of liver fibrosis. A retinoic acid derivative isolated from the mycelium of Phellinus linteus that down-regulates ROS generation and calcium influx in HSC-T6 cells was thus obtained in our screening process. The retinoic acid derivative also reverses an early liver fibrosis, as assayed by liver contents of hydroxyproline, alpha-smooth muscle actin (alpha-SMA), and collagen 1A2, in an early liver fibrosis model we established previously where an inducible expression vector containing a TGF-beta gene was hydrodynamically transferred into a testing animal. Retinoic acid derivative thus acts both in vitro and in vivo to prevent liver fibrosis at an early phase.