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

Ahmed, Nabeel; Chakrabarty, Anindita; Guengerich, F. Peter; Chowdhury, Goutam

doi:10.1021/acs.chemrestox.0c00299

Cited by 14 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To confirm the formation of win-DNA adduct, we treated ctDNA with win, precipitated the DNA using 70% ethanol and 0.3 M sodium acetate, digested it to 2′-deoxynucleosides with nucleases and phosphatases ( Chowdhury et al, 2014 , Ahmed et al, 2020 ) and finally analyzed it using LC-tandem MS following the m / z 738 → 152 transition. As expected we did see a peak with a retention time of 8.6 min ( Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha)

Siddiqui

Ahmed

Goswami

et al. 2021

Current Research in Toxicology

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha)

Siddiqui

Ahmed

Goswami

et al. 2021

Current Research in Toxicology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is analogous to the detoxification of genotoxic, low molecular weight α,β-unsaturated aldehydes such as acrolein and 4-hydroxy-2( E )-nonenal by conjugate addition of glutathione. ,,− The α,β-unsaturated aldehyde generated at AP-derived strand breaks is highly electrophilic and can generate DNA–DNA interstrand cross-links via conjugate addition of nucleobases on the opposing strand. , Conjugate addition of GSH to the α,β-unsaturated aldehyde residue in the 3′ trans -PUA end group prevents this type of reaction, thus mitigating the toxicities associated with the formation of difficult-to-repair interstrand DNA cross-links. There are a handful of examples where GSH quenches other electrophilic intermediates generated within DNA. − …”

Section: Discussionmentioning

confidence: 99%

Reconsidering the Chemical Nature of Strand Breaks Derived from Abasic Sites in Cellular DNA: Evidence for 3′-Glutathionylation

et al. 2022

View full text Add to dashboard Cite

The hydrolytic loss of coding bases from cellular DNA is a common and unavoidable reaction. The resulting abasic sites can undergo β-elimination of the 3′-phosphoryl group to generate a strand break with an electrophilic α,β-unsaturated aldehyde residue on the 3′-terminus. The work reported here provides evidence that the thiol residue of the cellular tripeptide glutathione rapidly adds to the alkenal group on the 3′-terminus of an AP-derived strand break. The resulting glutathionylated adduct is the only major cleavage product observed when β-elimination occurs at an AP site in the presence of glutathione. Formation of the glutathionylated cleavage product is reversible, but in the presence of physiological concentrations of glutathione, the adduct persists for days. Biochemical experiments provided evidence that the 3′-phosphodiesterase activity of the enzyme apurinic/ apyrimidinic endonuclease (APE1) can remove the glutathionylated sugar remnant from an AP-derived strand break to generate the 3′OH residue required for repair via base excision or single-strand break repair pathways. The results suggest that a previously unrecognized 3′glutathionylated sugar remnantand not the canonical α,β-unsaturated aldehyde end groupmay be the true strand cleavage product arising from β-elimination at an abasic site in cellular DNA. This work introduces the 3′glutathionylated cleavage product as the major blocking group that must be trimmed to enable repair of abasic site-derived strand breaks by the base excision repair or single-strand break repair pathways.

show abstract

“…It has been concluded from previously published literature that various risk factors associated with high mortality rates of COVID-19 are usually associated with low baseline GSH levels or impaired GSH metabolism; thus, GSH depletion may play a central role in COVID-19 mortality and pathophysiology [ 19 ]. The role of GSH in the protection of DNA from peroxynitrile-mediated damage, which is characteristic of acute inflammatory reactions, has been shown early [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Association of Low Molecular Weight Plasma Aminothiols with the Severity of Coronavirus Disease 2019

Kryukov¹,

Ivanov

Karpov³

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Objective. Aminothiols (glutathione (GSH), cysteinylglycine (CG)) may play an important role in the pathogenesis of coronavirus disease 2019 (COVID-19), but the possible association of these indicators with the severity of COVID-19 has not yet been investigated. Methods. The total content ( t ) and reduced forms ( r ) of aminothiols were determined in patients with COVID-19 ( n = 59 ) on admission. Lung injury was characterized by computed tomography (CT) findings in accordance with the CT0-4 classification. Results. Low tGSH level was associated with the risk of severe COVID-19 ( tGSH ≤ 1.5 μ M , mild vs. moderate/severe: risk ratio RR = 3.09 , p = 0.007 ) and degree of lung damage ( tGSH ≤ 1.8 μ M , CT < 2 vs. CT ≥ 2 : RR = 2.14 , p = 0.0094 ). The rGSH level showed a negative association with D-dimer levels ( ρ = − 0.599 , p = 0.014 ). Low rCG level was also associated with the risk of lung damage ( rCG ≤ 1.3 μ M , CT < 2 vs. CT ≥ 2 : RR = 2.28 , p = 0.001 ). Levels of rCG ( ρ = − 0.339 , p = 0.012 ) and especially tCG ( ρ = − 0.551 , p = 0.004 ) were negatively associated with platelet count. In addition, a significant relationship was found between the advanced oxidation protein product level and tGSH in patients with moderate or severe but not in patients with mild COVID-19. Conclusion. Thus, tGSH and rCG can be seen as potential markers for the risk of severe COVID-19. GSH appears to be an important factor to oxidative damage prevention as infection progresses. This suggests the potential clinical efficacy of correcting glutathione metabolism as an adjunct therapy for COVID-19.

show abstract

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

Cited by 14 publications

References 33 publications

DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha)

DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha)

Reconsidering the Chemical Nature of Strand Breaks Derived from Abasic Sites in Cellular DNA: Evidence for 3′-Glutathionylation

Association of Low Molecular Weight Plasma Aminothiols with the Severity of Coronavirus Disease 2019

Contact Info

Product

Resources

About