| Summary: | 博士 === 國立陽明大學 === 傳統醫學研究所 === 99 === Background and Aims: Hepatocyte apoptosis is a central feature of many liver diseases, leading to liver inflammation and fibrosis. During liver injury, hepatic stellate cells (HSCs), the key cell type for fibrogenesis, are phenotypically transformed from the lipid storing quiescent phenotype to proliferative, chemotactic, contractile and fibrogenic one with accumulation of extracellular matrix. In this study, we first investigated the effects of hepatocyte apoptotic bodies (ABs) on HSC activation. Using an AB-induced HSC migration model with activity-guided fractionation, a lignan, kaerophyllin was isolated from a widely used Chinese medicinal herb, Bupleurum scorzonerifolium (BS). The aim of this study is to evaluate the therapeutic effects of kaerophyllin and the possible underlying mechanisms.
Methods: Rat HSCs or human HSC cell line LX-2 cells were exposed to UV-irradiated hepatocyte ABs or TNF-α to investigate the anti-fibrotic and anti-inflammatory role of kaerophyllin in vitro. Roots of BS were extracted by aqueous ethanol. Under activity-guided fractionation, the EtOAc-soluble fraction was chromatographed to yield kaerophyllin (~0.18%). Liver fibrosis was induced by intraperitoneal injection of thioacetamide (TAA) twice per week for 6 weeks in Sprague-Dawley rats. Kaerophyllin (10 or 30 mg/kg) or curcumin (150 mg/kg, as a positive control) was given by gavage twice per day consecutively for 4 weeks starting 2 weeks after TAA injection.
Results: Hepatocyte ABs promoted HSC activation with increased expression of α-SMA, collagen I protein and pro-fibrogenic, pro-inflammatory genes. In addition, HSC migration and phaogcytosis were induced by ABs. Kaerophyllin significantly attenuated ABs-induced HSC migration and activation phenotypes. Peroxisome proliferator-activated receptor (PPAR-γ) activity was elevated by kaerophyllin that reduced the levels of inflammatory mediators in the presence of TNF-α. Furthermore, kaerophyllin reduced NF-κB activity with decreased p65 nuclear translocation. In the TAA rat model, kaerophyllin protected liver from injury by reducing serum AST and ALT levels, and by improving the histological architecture and fibrosis score.
Conclusions: Our results demonstrated that kaerophyllin protected the rat liver from TAA-caused injury and fibrogenesis by suppressing hepatic inflammation and inhibiting HSC activation. The present results provide a supporting evidence for the use of BS in traditional Chinese medicine.
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