Herbal components extracted from Acacia confusa and Lindera erythrocarpa suppress Hepatitis C Virus replication andthe mechanisms of anti-viral activity

• Main Authors: Wei-Chun Chen, 陳威均
• Other Authors: Jin-Ching Lee
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/88798375492481738148

碩士 === 高雄醫學大學 === 生物科技學系碩士班 === 99 === Chronic hepatitis C virus (HCV) infection continues to be an important cause of morbidity and mortality by chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) throughout the world. It is of tremendous importance to discover more effective and safer agents to improve the clinical treatment on HCV carriers. Here we reported that the n-butanol-methanol extract obtained from Acacia confusa plant, referred as ACSB-M4, and a phytocompound Lucidone isolated from the fruits of Lindera erythrocarpa Makino, exhibited the significant inhibition of HCV RNA replication. In the HCV replicon assay system, ACSB-M4 exhibited a strong anti-hepatitis C virus (HCV) replication activity, with an EC50 value and CC50/EC50 selective index (SI) of 5 ± 0.3 μg/ml and > 100. HCV RNA levels were dispersed by Lucidone in dose-dependant manner, with an IC50 of 15 ± 0.2 μM, as respectively. Besides, both ACSB-M4 and Lucidon showed synergistic effect in combination with IFN-α, HCV protease inhibitor (Telaprevir; VX-950), and polymerase inhibitor (2′-C-methylcytidine; NM-107) or Cyclosporin A (CsA) by a multiple linear logistic model and isobologram analysis. A complementary approach involving the overexpression of COX-2 protein in ACSB-M4-treated HCV replicon cells was used to evaluate the antiviral action at the molecular level. Results showed that the ACSB-M4 significantly suppressed COX-2 expression in HCV replicon cells. Notably, viral replication was gradually restored if COX-2 was added simultaneously with ACSB-M4, suggesting that the anti-HCV activity of ACSB-M4 was associated with down-regulation of COX-2, which was correlated with the suppression of nuclear factor-kappaB (NF-κB) activation. We found that Lucidone significantly induced heme oxygenase-1(HO-1) expression through the activation of transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2). In contrast, the inhibitory effect of Lucidon on HCV replication was gradually reversed with either treatment of specific HO-1 inhibitor SnPP treatment or small hairpin RNA (shRNA) against HO-1 expression, suggesting that the stimulation of HO-1 expression is involved in regulating HCV replication by Lucidone. Taken together, ACSB-M4 and Lucidon may serve as a potential protective agent for use in the management of patients with chronic HCV infection.