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Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin
- Source :
- Laboratory investigation; a journal of technical methods and pathology. 94(3)
- Publication Year :
- 2013
-
Abstract
- There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 μM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)α. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)α-induced lipid accumulation in LXRα-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRα-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRα upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRα-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRα-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.
- Subjects :
- Morpholines
Down-Regulation
Hepacivirus
Pharmacology
Biology
Fatty Acids, Nonesterified
Virus Replication
Antiviral Agents
Antioxidants
Pathology and Forensic Medicine
Cell Line
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Interferon
medicine
Humans
heterocyclic compounds
LY294002
Apigenin
Kaempferols
Liver X receptor
Molecular Biology
PI3K/AKT/mTOR pathway
Triglycerides
Liver X Receptors
Phosphoinositide-3 Kinase Inhibitors
Lipogenesis
Cell Biology
Orphan Nuclear Receptors
Reactive Nitrogen Species
Oxidative Stress
Biochemistry
chemistry
Viral replication
Chromones
Quercetin
Proto-Oncogene Proteins c-akt
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 15300307
- Volume :
- 94
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Laboratory investigation; a journal of technical methods and pathology
- Accession number :
- edsair.doi.dedup.....cb05271b9d2d34787b4921e90ca38889