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Betulinic acid exerts anti‐hepatitis C virus activity via the suppression of NF ‐κ B‐ and MAPK ‐ ERK 1/2‐mediated COX ‐2 expression
Author(s) -
Lin ChunKuang,
Tseng ChinKai,
Chen KaiHsun,
Wu ShihHsiung,
Liaw ChihChuang,
Lee JinChing
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13233
Subject(s) - mapk/erk pathway , hepatitis c virus , ns5b , kinase , viral replication , replicon , biology , virology , chemistry , pharmacology , virus , hepacivirus , microbiology and biotechnology , biochemistry , dna , plasmid
Background and Purpose This study was designed to evaluate the effect of betulinic acid ( BA ), extracted from A vicennia marina , on the replication of hepatitis C virus ( HCV ) and to investigate the mechanism of this BA ‐mediated anti‐ HCV activity. Experimental Approach HCV replicon and infectious systems were used to evaluate the anti‐ HCV activity of BA . Exogenous COX ‐2 or knock‐down of COX ‐2 expression was used to investigate the role of COX ‐2 in the anti‐ HCV activity of BA . The effects of BA on the phosphorylation of NF ‐κ B and on kinases in the MAPK signalling pathway were determined. The anti‐ HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti‐ HCV supplement. Key Results BA inhibited HCV replication in both A va5 replicon cells and in a cell culture‐derived infectious HCV particle system. Treatment with a combination of BA and IFN ‐α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX ‐2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX ‐2. In particular, BA down‐regulated HCV ‐induced COX ‐2 expression by reducing the phosphorylation of NF ‐κ B and ERK 1/2 of the MAPK signalling pathway. Conclusions and Implications BA inhibits HCV replication by suppressing the NF ‐κ B‐ and ERK 1/2‐mediated COX ‐2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV ‐infected patients.