2. Academic Validation
  3. Lobohedleolide suppresses hepatitis C virus replication via JNK/c-Jun-C/EBP-mediated down-regulation of cyclooxygenase-2 expression

Lobohedleolide suppresses hepatitis C virus replication via JNK/c-Jun-C/EBP-mediated down-regulation of cyclooxygenase-2 expression

  • Sci Rep. 2018 Jun 6;8(1):8676. doi: 10.1038/s41598-018-26999-w.
Chun-Kuang Lin 1 2,  Chin-Kai Tseng 3 4,  Chih-Chuang Liaw 1 5,  Chiung-Yao Huang 5,  Chih-Ku Wei 6,  Jyh-Horng Sheu 7 8 9,  Jin-Ching Lee 10 11 12 13
Affiliations

Affiliations

  • 1 Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 2 Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan.
  • 3 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 4 Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 5 Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 6 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 7 Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. sheu@mail.nsysu.edu.tw.
  • 8 Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. sheu@mail.nsysu.edu.tw.
  • 9 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. sheu@mail.nsysu.edu.tw.
  • 10 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan. jclee@kmu.edu.tw.
  • 11 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. jclee@kmu.edu.tw.
  • 12 Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan. jclee@kmu.edu.tw.
  • 13 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. jclee@kmu.edu.tw.
PMID: 29875371 DOI: 10.1038/s41598-018-26999-w
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.

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