Curcumin inhibits hepatitis C virus replication via suppressing the Akt‐SREBP‐1 pathway

Kim, KyeongJin; Kim, Kook Hwan; Kim, Hye Young; Cho, Hyun Kook; Sakamoto, Naoya; Cheong, JaeHun

doi:10.1016/j.febslet.2009.12.019

Cited by 153 publications

(117 citation statements)

References 28 publications

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“…21 Furthermore, the combination of quercetin and IFNa exerted profound inhibitory effects on NS5A protein levels and HCV replication, as shown when curcumin and IFNa were combined. 34 Similarly, our results 35,36 In this regard, it has been described that quercetin may increase the antiviral gene expression regulated by the IFN-activated JAK-STAT pathway. 37 Nevertheless, the molecular mechanisms involved in quercetin-mediated impairment of HCV replication seem to be more complex.…”

Section: Discussionsupporting

confidence: 70%

“…Similarly, PI3K/AKT-sterol regulatory element binding protein (SREBP)-1c suppression by curcumin also inhibits HCV replication in an in vitro model. 34 In our in vitro model of LXRa overexpression, quercetin could exert its inhibitory effect on LXRa expression and lipid accumulation not only through modulation of PI3K pathway but also the expression of a large number of miRNAs involved in cell signaling and metabolism, which could in turn cause downregulation of CMV-expressed LXRa. 55 However, further investigations are required to study this issue.…”

Section: Discussionmentioning

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: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

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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“…24,26 Similarly, SREBP-1c suppression by curcumin also inhibits hepatitis C virus replication in an in vitro model. 52 In our replication model, LXRa knockdown decreases lipid accumulation as well as the expression of the lipogenic genes. siRNA LXRa-mediated lipogenic inhibition is accompanied by a partial blockage of HCV RNA replication and NS5A and core expression.…”

Section: Discussionmentioning

confidence: 99%

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

García‐Mediavilla

Pisonero-Vaquero

Lima-Cabello

et al. 2012

Laboratory Investigation

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Molecular mechanisms contributing to hepatitis C virus (HCV)-associated steatosis are not well established, although HCV gene expression has been shown to alter host cell cholesterol/lipid metabolism. As liver X receptors (LXRs) play a role as key modulators of metabolism signaling in the development of steatosis, we aimed to investigate in an HCV in vitro model the effect of HCV NS5A protein, core protein, and viral replication on the intracellular lipid accumulation and the LXRa-regulated expression of lipogenic genes. The effects of LXRa siRNA or agonist GW3965 treatment on lipogenesis and HCV replication capacity in our HCV replicon system were also examined. NS5A-and core-expressing cells and replicon-containing cells exhibited an increase of lipid accumulation by inducing the gene expression and the transcriptional activity of LXRa, and leading to an increased expression of its lipogenic target genes sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor-g, and fatty acid synthase. Transcriptional induction by NS5A protein, core protein, and viral replication occurred via LXR response element activation in the lipogenic gene promoter. No physical association between HCV proteins and LXRa was observed, whereas NS5A and core proteins indirectly upregulated LXRa through the phosphatidylinositol 3-kinase pathway. Finally, it was found that LXRa knockdown or agonist-mediated LXRa induction directly regulated HCV-induced lipogenesis and HCV replication efficiency in replicon-containing cells. Combined, our data suggest that LXRa-mediated regulation of lipogenesis by core and NS5A proteins may contribute to HCV-induced liver steatosis and to the efficient replication of HCV.

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“…The Huh7/Rep-Feo1b and Huh7.5-FGR-JC1-Rluc2A replicon reporter cells have been described previously [20,21]. To evaluate the anti-HCV activity of the compounds, HCV replicon reporter cells were seeded in 96 well plate at a confluence of 1 Â 10 4 cells/well.…”

Section: Hcv Replicon Based Luciferase Reporter Assaysmentioning

confidence: 99%

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Şenkardeş

Kaushik‐Basu

Durmaz

et al. 2016

European Journal of Medicinal Chemistry

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a b s t r a c tHepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. We have previously identified the hydrazideehydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 2 0 ,4 0 -difluoro-4-hydroxy-N'-(arylmethylidene) biphenyl-3-carbohydrazide (3a-t) as anti-HCV and anticancer agents. Results from evaluation of anti-HCV activity indicated that most of the synthesized hydrazone derivatives inhibited viral replication in the Huh7/Rep-Feo1b and Huh 7.5-FGR-JCI-Rluc2A reporter systems. Antiproliferative activities of increasing concentrations of 2 0 ,4 0 -difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5e40 mM) were assessed in liver cancer cell lines (Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475) with sulforhodamine B assay for 72 h. Compound 3b with 2-pyridinyl group in the hydrazone part exhibited promising cytotoxic activity against all cell lines with IC 50 values of 10, 10.34 16.21 4.74, 9.29 and 8.33 mM for Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G0 phase as an indicator of apoptotic cell death induction.

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Curcumin inhibits hepatitis C virus replication via suppressing the Akt‐SREBP‐1 pathway

Cited by 153 publications

References 28 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

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

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