Abstract
Hepatitis C virus (HCV) chronically infects 2–3% people of the global population, which leads to liver cirrhosis and hepatocellular carcinoma. Drug resistance remains a serious problem that limits the effectiveness of US Food and Drug Administration (FDA)-approved direct-acting antiviral (DAA) drugs against HCV proteins. The objective of our study was to discover new antivirals from natural products to supplement current therapeutics. We demonstrated that lobohedleolide, isolated from the Formosan soft coral Lobophytum crassum, significantly reduced HCV replication in replicon cells and JFH-1 infection system, with EC50 values of 10 ± 0.56 and 22 ± 0.75 μM, respectively, at non-toxic concentrations. We further observed that the inhibitory effect of lobohedleolide on HCV replication is due to suppression of HCV-induced cyclooxygenase-2 (COX-2) expression. Based on deletion-mutant analysis of the COX-2 promoter, we identified CCAAT/enhancer-binding protein (C/EBP) as a key transcription factor for the down-regulation of COX-2 by lobohedleolide, through which lobohedleolide decreased the phosphorylation of c-Jun NH2-terminal protein kinase and c-Jun to suppress HCV-induced C/EBP expression. The combination treatment of lobohedleolide with clinically used HCV drugs synergistically reduced HCV RNA replication, indicating that lobohedleolide exhibited a high biomedical potential to be used as a supplementary therapeutic agent to control HCV infection.
Highlights
Hepatitis C virus (HCV) is a pathogen of high risk causing chronic liver diseases, including hepatic fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC)[1]
Several studies have indicated that the inhibition of COX-2 by selective inhibitors or naturally available compounds could possibly be used as a strategy for inflammation treatment, cancer prevention, and suppression of virus replication[26,27,28]
We demonstrated that lobohedleolide significantly reduced the HCV-induced COX-2 transcription, protein synthesis, and its metabolite prostaglandin E2 (PGE2) production, resulting in the suppression of HCV replication (Figs 1 and 2)
Summary
Hepatitis C virus (HCV) is a pathogen of high risk causing chronic liver diseases, including hepatic fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC)[1]. The expression of COX-2 is tightly controlled in most of the tissues and is induced at the sites of inflammation by several extracellular and intracellular stimuli, including reactive oxygen species, chemicals, and viral infections. Both nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways have been well characterized to activate COX-2 transcription[15]. Previous studies have shown that lobohedleolide, isolated from the Formosan soft coral Lobophytum crassum, exhibited anti-inflammatory activity through the suppression of COX-2 expression in vitro and in vivo[19,20]. We investigated the effect of lobohedleolide on HCV replication and further clarified whether the molecular mechanisms were down-regulation of HCV-induced COX-2 expression
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