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Protective Role of Glutathione against Peroxynitrite-Mediated DNA Damage During Acute Inflammation.

ABSTRACT: Inflammation is an immune response to protect against various types of infections. When unchecked, acute inflammation can be life-threatening, as seen with the current coronavirus pandemic. Strong oxidants, such as peroxynitrite produced by immune cells, are major mediators of the inflammation-associated pathogenesis. Cellular thiols play important roles in mitigating inflammation-associated macromolecular damage including DNA. Herein, we have demonstrated a role of glutathione (GSH) and other thiols in neutralizing the effect of peroxynitrite-mediated DNA damage through stable GSH-DNA adduct formation. Our observation supports the use of thiol supplements as a potential therapeutic strategy against severe COVID-19 cases and a Phase II (NCT04374461) open-label clinical trial launched in early May 2020 by the Memorial Sloan Kettering Cancer Center.

SUBMITTER: Ahmed N

PROVIDER: S-EPMC9297005 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Protective Role of Glutathione against Peroxynitrite-Mediated DNA Damage During Acute Inflammation.

Ahmed Nabeel N Chakrabarty Anindita A Guengerich F Peter FP Chowdhury Goutam G

Chemical research in toxicology 20200918 10

Inflammation is an immune response to protect against various types of infections. When unchecked, acute inflammation can be life-threatening, as seen with the current coronavirus pandemic. Strong oxidants, such as peroxynitrite produced by immune cells, are major mediators of the inflammation-associated pathogenesis. Cellular thiols play important roles in mitigating inflammation-associated macromolecular damage including DNA. Herein, we have demonstrated a role of glutathione (GSH) and other t ...[more]

PMID: 32894672

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Project description:Glutathione peroxidase 1 (GPX1) is a crucial antioxidant enzyme that prevented the harmful accumulation of intra-cellular hydrogen peroxide. GPX1 might contribute in limiting cochlear damages associated with aging or acoustic overexposure, but the function of GPX1 in the inner ear remains unclear. The present study was designed to investigate the effect of GPX1 on cochlear spiral ganglion neurons (SGNs) against oxidative stress induced by peroxynitrite, a versatile oxidant generated by the reaction of superoxide anion and nitric oxide. Here, we first found that the expression of GPX1 in cultured SGNs was downregulated after peroxynitrite exposure. Then, the GPX1 mimic ebselen and the gpx1 knockout (gpx1 -/-) mice were used to investigate the role of GPX1 in SGNs treated with peroxynitrite. The pretreatment with ebselen significantly increased the survived SGN numbers, inhibited the apoptosis, and enhanced the expression of 4-HNE in the cultured SGNs of peroxynitrite + ebselen group compared with the peroxynitrite-only group. On the contrary, remarkably less survived SGNs, more apoptotic SGNs, and the higher expression level of 4-HNE were detected in the peroxynitrite + gpx1 -/- group compared with the peroxynitrite-only group. Furthermore, rescue experiments with antioxidant N-acetylcysteine (NAC) showed that the expression of 4-HNE and the apoptosis in SGNs were significantly decreased, while the number of surviving SGNs was increased in peroxynitrite + NAC group compared the peroxynitrite-only group and in peroxynitrite + gpx1 -/- + NAC group vs. peroxynitrite + gpx1 -/- group. Finally, mechanistic studies showed that the activation of nuclear factor-kappa B (NF-κB) was involved in the SGNs damage caused by peroxynitrite and that GPX1 protected SGNs against peroxynitrite-induced damage, at least in part, via blocking the NF-κB pathway activation. Collectively, our findings suggest that GPX1 might serve as a new target for the prevention of nitrogen radical-induced SGNs damage and hearing loss.

Dataset Information

Protective Role of Glutathione against Peroxynitrite-Mediated DNA Damage During Acute Inflammation.

Publications

Protective Role of Glutathione against Peroxynitrite-Mediated DNA Damage During Acute Inflammation.

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