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Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways
Author(s) -
TrujilloMurillo Karina,
RincónSánchez Ana Rosa,
MartínezRodríguez Herminia,
BosquesPadilla Francisco,
RamosJiménez Javier,
BarreraSaldaña Hugo A.,
Rojkind Marcos,
RivasEstilla Ana María
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22215
Subject(s) - kinase , protein kinase r , biology , protein kinase a , microbiology and biotechnology , ns2 3 protease , replicon , p38 mitogen activated protein kinases , ns3 , small interfering rna , virology , rna , hepatitis c virus , cyclin dependent kinase 2 , virus , biochemistry , dna , gene , plasmid
Abstract It has been reported that salicylates (sodium salicylate and aspirin) inhibit the replication of flaviviruses, such as Japanese encephalitis virus and dengue virus. Therefore, we considered it important to test whether acetylsalicylic acid (ASA) had anti–hepatitis C virus (HCV) activity. To this end, we examined the effects of ASA on viral replication and protein expression, using an HCV subgenomic replicon cell culture system. We incubated Huh7 replicon cells with 2‐8 mM ASA for different times and measured HCV‐RNA and protein levels by northern blot, real‐time polymerase chain reaction, and western analysis, respectively. We found that ASA had a suppressive effect on HCV‐RNA and protein levels (nearly 58%). ASA‐dependent inhibition of HCV expression was not mediated by the 5′‐internal ribosome entry site or 3′‐untranslated regions, as determined by transfection assays using bicistronic constructs containing these regulatory regions. However, we found that HCV‐induced cyclooxygenase 2 (COX‐2) messenger RNA and protein levels and activity and these effects were down‐regulated by ASA, possibly by a nuclear factor kappa B–independent mechanism. We also observed that the ASA‐dependent inhibition of viral replication was due in part to inhibition of COX‐2 and activation of p38 and mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase 1/2 (MEK1/2) mitogen‐activated protein kinases (MAPKs). Inhibition of these kinases by SB203580 and U0126, respectively, and by short interfering RNA silencing of p38 and MEK1 MAPK prevented the antiviral effect of ASA. Taken together, our findings suggest that the anti‐HCV effect of ASA in the Huh7 replicon cells is due to its inhibitory effect on COX‐2 expression, which is mediated in part by the activation of MEK1/2/p38 MAPK. Conclusion: These findings suggest the possibility that ASA could be an excellent adjuvant in the treatment of chronic HCV infection. (H EPATOLOGY 2008.)