Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E

Huang, Hua; Chen, Yan; Ye, Jin

doi:10.1073/pnas.0708423104

Cited by 80 publications

(74 citation statements)

References 22 publications

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“…It has been also described that HCV replication induces lipid peroxidation that in turn reduces the amount of HCV RNA. 30 In our HCV replicon system, quercetin was able to decrease HCV-induced lipoperoxidation, but only slightly, thus maintaining its ability to inhibit HCV replication. IFNa treatments also reduced HCV-induced ROS/RNS generation and lipid peroxidation as previously indicated in chronic hepatitis C patients.…”

Section: Discussionmentioning

confidence: 99%

“…At these very low concentrations, flavonoids exhibit no cellular toxicity and the limited antiperoxidative capacity does not interfere with their anti-HCV activity. 30 As shown in Figure 1b, all flavonoids were able to significantly reduce the HCV RNA copy number (K0.1: À 35%, K1: À 43%; T0.1: À 32%, T1: À 39%; T5: À 43%; A0.1: À 40%, A1: À 30%, vs non-treated cells), but quercetin appeared to be the most effective inhibitor of HCV replication at doses resembling human plasma concentrations upon quercetin supplementation. 31 In view of these findings, HCV-G1 cells were incubated with quercetin at concentrations of 0.1, 0.5, 1 and 5 mM alone or combined with IFNa 0.5 ( Figure 2).…”

Section: Quercetin Is the Most Effective Inhibitor Of Hcv Replicationmentioning

confidence: 99%

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Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Pisonero-Vaquero

García‐Mediavilla

Jorquera

et al. 2014

Laboratory Investigation

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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 mM), 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)a. 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)a-induced lipid accumulation in LXRa-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRa-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 LXRa 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 LXRa-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-LXRa-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.

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Section: Discussionmentioning

confidence: 99%

Section: Quercetin Is the Most Effective Inhibitor Of Hcv Replicationmentioning

confidence: 99%

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Pisonero-Vaquero

García‐Mediavilla

Jorquera

et al. 2014

Laboratory Investigation

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“…Host lipids and their synthesis affect viral infectious process (21,40,51,57). HCV RNA replication can be induced by saturated and monounsaturated fatty acids and inhibited by polyunsaturated fatty acids (18,21). HCV gene expression induces lipogenesis by stimulating the activation of the sterol regulatory element binding proteins, the master regulators of lipid/fatty acid biosynthetic pathways (51).…”

mentioning

confidence: 99%

Role of Oxysterol Binding Protein in Hepatitis C Virus infection

Amako

Sarkeshik

Hotta

et al. 2009

J Virol

118

126

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Hepatitis C virus (HCV) RNA genome replicates within the ribonucleoprotein (RNP) complex in the modified membranous structures extended from endoplasmic reticulum. A proteomic analysis of HCV RNP complexes revealed the association of oxysterol binding protein (OSBP) as one of the components of these complexes. OSBP interacted with the N-terminal domain I of the HCV NS5A protein and colocalized to the Golgi compartment with NS5A. An OSBP-specific short hairpin RNA that partially downregulated OSBP expression resulted in a decrease of the HCV particle release in culture supernatant with little effect on viral RNA replication. The pleckstrin homology (PH) domain located in the N-terminal region of OSBP targeted this protein to the Golgi apparatus. OSBP deletion mutation in the PH (⌬PH) domain failed to localize to the Golgi apparatus and inhibited the HCV particle release. These studies suggest a possible functional role of OSBP in the HCV maturation process.Hepatitis C virus (HCV) infection is one of the leading causes of chronic hepatitis. HCV infection is associated with cirrhosis, steatosis, and hepatocellular carcinoma (33). The HCV RNA genome of ϳ9.6 kb is translated via an internal ribosome entry site element on the rough endoplasmic reticulum (ER) as a polyprotein precursor of about 3,010 amino acids that is co-and posttranslationally processed by cellular and viral proteases into mature structural and nonstructural (NS) proteins (33). HCV replicates within ribonucleoprotein (RNP) complexes associated with modified ER membranous structures (15). Recent work implicated lipid droplets that emanate from the ER as sites of RNA replication (28,44). Almost all of the HCV NS proteins along with a variety of cellular factors are associated with the RNP complexes engaged in viral RNA replication (37). It is likely that these NS proteins not only participate in replication process but also are involved in the various steps of virion morphogenesis and assembly. Membrane-associated RNP complexes are generally composed of viral proteins, replicating RNA, host proteins, and altered cellular membranes (1). In this respect, a growing body of evidence implicates the functional role of NS5A in early steps of virion assembly and morphogenesis (3,27,45). NS5A is a phosphoprotein that migrates in sodium dodecyl sulfate gels as 56-kDa (basally phosphorylated) and 58-kDa (hyperphosphorylated) forms of proteins. The C-terminal domain III region of NS5A and the phosphorylated residue (Ser 457 ) are important for virion maturation (3, 27, 45). NS5A domain III contains the binding site for viral core protein, indicating the possible involvement of NS5A protein in virus assembly (27). NS5A anchors to the ER membrane by an N-terminal hydrophobic ␣-helix, and this attachment is needed for its key role(s) in viral replication (10). Studies suggest that phosphorylation of NS5A plays a functional role in viral replication (12). The hyperphosphorylated NS5A reduces its interaction with the human vesicle-associated membrane protein-associate...

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“…Indeed, fatty acids can either stimulate or inhibit HCV replication, depending on their degree of saturation [112]. Arachidonate, a polyunsaturated fatty acid, also inhibits HCV replication [112] via the lipid peroxidation induced by reactive oxygen species (ROS) derived from HCV replication that converts polyunsaturated fatty acids into reactive carbonyls that inactivate proteins [178]. These events can be prevented by treatment with the antioxidant vitamin E [178].…”

Section: Inhibitors Of Fatty Acid Biosynthesis As Potential Antiviralmentioning

confidence: 99%

“…Arachidonate, a polyunsaturated fatty acid, also inhibits HCV replication [112] via the lipid peroxidation induced by reactive oxygen species (ROS) derived from HCV replication that converts polyunsaturated fatty acids into reactive carbonyls that inactivate proteins [178]. These events can be prevented by treatment with the antioxidant vitamin E [178]. As a result of the connections between fatty acids and cholesterol biosynthetic pathways, inhibition of fatty acid synthesis can be also related to the reduction of the infection of HCV, through inhibition of the geranylgeranylation of cellular factors required for HCV replication [112,196].…”

Section: Inhibitors Of Fatty Acid Biosynthesis As Potential Antiviralmentioning

confidence: 99%

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

Martín-Acebes¹,

Vázquez-Calvo²,

Caridi³

et al. 2013

Lipid Metabolism

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Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E

Cited by 80 publications

References 22 publications

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Role of Oxysterol Binding Protein in Hepatitis C Virus infection

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

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