- 學位論文
Silibinin和Glycyrrhizin抑制C型肝炎病毒複製 及TGF-b1誘導之肝臟纖維化之能力探討
The inhibitory capabilities of Silibinin and Glycyrrhizin on hepatitis C virus replication and TGF-b1-induced liver fibrosis
摘要
C型肝炎病毒的感染常常會造成急、慢性的肝臟損傷，進而造成肝纖維、肝硬化或肝癌。目前C型肝炎病毒的主要治療方式是以長效型的干擾素合併ribavirin處理，但由於費用昂貴又常伴隨有嚴重的副作用，且易有抗藥性的產生，因此開發新的C型肝炎病毒和肝臟纖維化治療藥物是非常急迫的。本篇研究主要想探討silibinin及glycyrrhizin是否能取代或降低干擾素使用劑量且能有效的抑制病毒複製；另一方面更進一步探討是否也具有抑制肝臟纖維化的能力。Semi-quantitative PCR和Western blot的實驗結果顯示，silibinin或glycyrrhizin單獨處理細胞24、48或72小時後皆無法有效的抑制C型肝炎病毒的複製，另外silibinin和glycyrrhizin合併低劑量的干擾素處理細胞24小時後，也無法有效的抑制C型肝炎病毒複製；另一方面silibinin可抑制TGF-β1誘導活化的肝星狀細胞大量表現α-SMA mRNA、蛋白及type I collagen mRNA，而Glycyrrhizin則可抑制α-SMA RNA和蛋白大量表現，而進一步的研究更發現，silibinin和glycyrrhizin是藉由抑制Smad、p38-MAPK及Akt訊息傳遞途徑，進而抑制了α-SMA和type I collagen大量表現。根據本實驗結果，我們初步證實silibinin和glycyrrhizin具有抑制TGF-β1所誘導的肝臟纖維化的能力。
並列摘要
Chronic Hepatitis C virus (HCV) infection may lead to the liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. The current standard-of-care for HCV infection is a long-term administration of pegIFNα and ribavirin with only approximately 50% response rate for genotype 1 infected patients while side effects of various severities and viral resistance may lead to treatment failure. Therefore, development of new or auxiliary remedies to improve response rate or alleviate side effects will be of great value. In this study, silibinin and glycyrrhizin, two compounds extracted from herbs, were tested for their capability for repressing viral replication (with a Huh7 cell line harboring HCV replicon as the replication model) or fibrosis progressing (with TGF-β1-induced fibrogenesis on a HSC cell line). While results showing that both compounds have no direct effect on HCV replication, silibinin and glycyrrhizin both can suppress the expression levels of fibrosis-related molecules, including α-SMA and type I collagen. Further molecular studies demonstrated that silibinin and glycyrrhizin inhibited α-SMA and type I collagen overexpression by regulating pathways involved Smad, p38-MAPK and AKT. Results from this study suggested that silibinin and glycyrrhizin may possess inhibitory capability for the progression of liver fibrogenesis.