Expression of Gastrointestinal Glutathione Peroxidase Is Inversely Correlated to the Presence of Hepatitis C Virus Subgenomic RNA in Human Liver Cells

Morbitzer, Monika; Herget, Thomas

doi:10.1074/jbc.m413730200

Cited by 41 publications

(43 citation statements)

References 53 publications

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“…We downregulated the expression of GPX2 in A549 cells by using siRNA targeting GPX2 mRNA ( Figure 7A) (22). To Western blot analysis of A549 cells transfected with Nrf2, keap1, or SS siRNA.…”

Section: Silencing Of Gpx2 By Sirna Sensitizes the Lung Epithelial Cementioning

confidence: 99%

Glutathione Peroxidase 2, the Major Cigarette Smoke–Inducible Isoform of GPX in Lungs, Is Regulated by Nrf2

Singh

Rangasamy

Thimmulappa

et al. 2006

Am J Respir Cell Mol Biol

207

137

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Disruption of NF-E2-related factor (Nrf2), a redox-sensitive basic leucine zipper transcription factor, causes early-onset and more severe emphysema due to chronic cigarette smoke. Nrf2 determines the susceptibility of lungs to cigarette smoke-induced emphysema in mice through the transcriptional induction of numerous antioxidant genes. The lungs of Nrf2Ϫ/Ϫ mice have higher oxidative stress as evident from the increased levels of lipid peroxidation (4-hydroxy-2-nonenal) and oxidative DNA damage (7,8-dihydro-8-Oxo-2deoxyguanosine) in response to cigarette smoke. Glutathione peroxidases (GPX) are the primary antioxidant enzymes that scavenge hydrogen peroxide and organic hydroperoxides. Among the five GPX isoforms, expression of GPX2 was significantly induced at both mRNA and protein levels in the lungs of Nrf2؉/؉ mice, in response to cigarette smoke. Activation of Nrf2 by specific knock down of the cytosolic inhibitor of Nrf2, Keap1, by small inhibitory RNA (siRNA) upregulated the expression of GPx2, whereas Nrf2 siRNA down-regulated the expression of GPX2 in lung epithelial cells. An ARE sequence located in the 5 promoter-flanking region of exon 1 that is highly conserved between mouse, rat, and human was identified. Mutation of this ARE core sequence completely abolished the activity of promoter-reporter gene construct. The binding of Nrf2 to the GPX2 antioxidant response element was confirmed by chromatin immunoprecipation, electrophoretic mobility shift assays, and site-directed mutagenesis. This study shows that GPX2 is the major oxidative stress-inducible cellular GPX isoform in the lungs, and that its basal as well as inducible expression is dependent on Nrf2.

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Section: Silencing Of Gpx2 By Sirna Sensitizes the Lung Epithelial Cementioning

confidence: 99%

Glutathione Peroxidase 2, the Major Cigarette Smoke–Inducible Isoform of GPX in Lungs, Is Regulated by Nrf2

Singh

Rangasamy

Thimmulappa

et al. 2006

Am J Respir Cell Mol Biol

207

137

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“…Glutathione peroxidase and catalase are key enzymes regulating the levels of ROS and protecting cells from ATO-induced damage (26). However, the gastrointestinal glutathione peroxidase was drastically downregulated in cells harboring HCV replicons, which are rendered more susceptible to oxidative stress (39). The glutathione redox system has been implicated in the cellular defense system (14,20).…”

Section: Discussionmentioning

confidence: 99%

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Kuroki

Ariumi

Ikeda

et al. 2009

J Virol

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Arsenic trioxide (ATO), a therapeutic reagent used for the treatment of acute promyelocytic leukemia, has recently been reported to increase human immunodeficiency virus type 1 infectivity. However, in this study, we have demonstrated that replication of genome-length hepatitis C virus (HCV) RNA (O strain of genotype 1b) was notably inhibited by ATO at submicromolar concentrations without cell toxicity. RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were also inhibited by ATO after the HCV infection. To clarify the mechanism of the anti-HCV activity of ATO, we examined whether or not PML is associated with this anti-HCV activity, since PML is known to be a target of ATO. Interestingly, we observed the cytoplasmic translocation of PML after treatment with ATO. However, ATO still inhibited the HCV RNA replication even in the PML knockdown cells, suggesting that PML is dispensable for the anti-HCV activity of ATO. In contrast, we found that N-acetyl-cysteine, an antioxidant and glutathione precursor, completely and partially eliminated the anti-HCV activity of ATO after 24 h and 72 h of treatment, respectively. In this context, it is worth noting that we found an elevation of intracellular superoxide anion radical, but not hydrogen peroxide, and the depletion of intracellular glutathione in the ATO-treated cells. Taken together, these findings suggest that ATO inhibits the HCV RNA replication through modulation of the glutathione redox system and oxidative stress.Hepatitis C virus (HCV) is the causative agent of chronic hepatitis, which progresses to liver cirrhosis and hepatocellular carcinoma. HCV is an enveloped virus with a positive singlestranded 9.6-kb RNA genome, which encodes a large polyprotein precursor of approximately 3,000 amino acid residues. This polyprotein is cleaved by a combination of the host and viral proteases into at least 10 proteins in the following order: core, envelope 1 (E1), E2, p7, nonstructural 2 (NS2), NS3, NS4A, NS4B, NS5A, and NS5B (30).Alpha interferon has been used as an effective anti-HCV reagent in clinical therapy for patients with chronic hepatitis C. The current combination treatment with pegylated alpha interferon and ribavirin, a nucleoside analogue, has been shown to improve the sustained virological response rate to more than 50% (15). However, the adverse effects of the combination therapy and the limited efficacy against genotype 1b warrant the development of new anti-HCV reagents.Arsenic trioxide (ATO) (As 2 O 3 , arsenite) has been used as a therapeutic reagent in acute promyelocytic leukemia, which bears an oncogenic PML-retinoic acid receptor alpha fusion protein resulting from chromosomal translocation (51,52,68,70). The ATO treatment induces complete remission through degradation of the aberrant PML-retinoic acid receptor ␣ (70). The PML tumor suppressor protein is required for formation of the PML nuclear body (PML-NB), also known as nuclear dot 10 or the PML oncogenic domain, which is often disrupted by i...

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“…This finding was not surprising given the lack of known direct anti-viral effects of antioxidants. A study reported that induction of gastrointestinal glutathione oxidase (which counteracts oxidative stress) by all trans retinoic acids, down-regulates HCV replicon in cell lines [6] . Adverse events that are attributable to therapy such as exacerbation of hypertension, pedal edema, and hypokalemia, are mostly related to pseudoaldosteronism associated with the 11-hydroxy-steroid dehydrogenase inhibitory activity of glycyrrhiza and L-glutathione.…”

Section: Discussionmentioning

confidence: 99%

“…These processes may contribute to fibrosis and carcinogenesis in chronic HCV [5] . Analysis of HCV-sub genomic RNA replicon cell lines has shown a drastic reduction in cellular glutathione peroxidase, increasing cellular susceptibility to oxidative stress [6] . Based on these data, a rationale for antioxidant treatment of chronic hepatitis C was suggested.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant therapy for chronic hepatitis C after failure of interferon: Results of phase II randomized, double-blind placebo controlled clinical trial

Gabbay

Zigmond²,

Pappo³

et al. 2007

WJG

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AIM:To assess the safety and efficacy of antioxidant therapy for patients with chronic hepatitis C virus (HCV) infection. METHODS:One hundred chronic HCV infection patients failed in interferon treatment were enrolled and randomly assigned to receive combined intravenous and oral antioxidants or placebo, or oral treatment alone. Primary end points were liver enzymes, HCV-RNA levels and histology. RESULTS:Combined oral and intravenous antioxidant therapy was associated with a significant decline in ALT levels in 52% of patients who received antioxidant therapy vs 20% of patients who received placebo (P = 0.05). Histology activity index (HAI) score at the end of treatment was reduced in 48% of patients who received antioxidant therapy vs 26% of patients who received placebo (P = 0.21). HCV-RNA levels decreased by 1-log or more in 28% of patients who received antioxidant therapy vs 12% who received placebo (P = NS). In part Ⅱ of the trial, oral administration of antioxidants was not associated with significant alterations in any of the end points. CONCLUSION:Antioxidant therapy has a mild beneficial effect on the inflammatory response of chronic HCV infection patients who are non-responders to interferon. Combined antiviral and antioxidant therapy may be beneficial for these patients.

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Expression of Gastrointestinal Glutathione Peroxidase Is Inversely Correlated to the Presence of Hepatitis C Virus Subgenomic RNA in Human Liver Cells

Cited by 41 publications

References 53 publications

Glutathione Peroxidase 2, the Major Cigarette Smoke–Inducible Isoform of GPX in Lungs, Is Regulated by Nrf2

Glutathione Peroxidase 2, the Major Cigarette Smoke–Inducible Isoform of GPX in Lungs, Is Regulated by Nrf2

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Antioxidant therapy for chronic hepatitis C after failure of interferon: Results of phase II randomized, double-blind placebo controlled clinical trial

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