scholarly journals Role of Human NADPH Quinone Oxidoreductase (NQO1) in Oxygen-Mediated Cellular Injury and Oxidative DNA Damage in Human Pulmonary Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Rebecca Burke ◽  
Chun Chu ◽  
Guo-Dong Zhou ◽  
Vasanta Putluri ◽  
Nagireddy Putluri ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Viability ◽  
Oxidative Dna Damage ◽  
Oxidative Injury ◽  
Protective Role ◽  
Dna Lesions ◽  
Quinone Oxidoreductase ◽  
Pulmonary Cells ◽  
In Cells

Supplemental oxygen administration is frequently used in premature infants and adults with pulmonary insufficiency. NADPH quinone oxidoreductase (NQO1) protects cells from oxidative injury by decreasing reactive oxygen species (ROS). In this investigation, we tested the hypothesis that overexpression of NQO1 in BEAS-2B cells will mitigate cell injury and oxidative DNA damage caused by hyperoxia and that A-1221C single nucleotide polymorphism (SNP) in the NQO1 promoter would display altered susceptibility to hyperoxia-mediated toxicity. Using stable transfected BEAS-2B cells, we demonstrated that hyperoxia decreased cell viability in control cells (Ctr), but this effect was differentially mitigated in cells overexpressing NQO1 under the regulation of the CMV viral promoter, the wild-type NQO1 promoter (NQO1-NQO1), or the NQO1 promoter carrying the SNP. Interestingly, hyperoxia decreased the formation of bulky oxidative DNA adducts or 8-hydroxy-2 ′ -deoxyguanosine (8-OHdG) in Ctr cells. qPCR studies showed that mRNA levels of CYP1A1 and NQO1 were inversely related to DNA adduct formation, suggesting the protective role of these enzymes against oxidative DNA injury. In SiRNA experiments entailing the NQO1-NQO1 promoter, hyperoxia caused decreased cell viability, and this effect was potentiated in cells treated with CYP1A1 siRNA. We also found that hyperoxia caused a marked induction of DNA repair genes DDB2 and XPC in Ctr cells, supporting the idea that hyperoxia in part caused attenuation of bulky oxidative DNA lesions by enhancing nucleotide excision repair (NER) pathways. In summary, our data support a protective role for human NQO1 against oxygen-mediated toxicity and oxidative DNA lesions in human pulmonary cells, and protection against toxicity was partially lost in SNP cells. Moreover, we also demonstrate a novel protective role for CYP1A1 in the attenuation of oxidative cells and DNA injury. Future studies on the mechanisms of attenuation of oxidative injury by NQO1 should help in developing novel approaches for the prevention/treatment of ARDS in humans.

Influence of metallothionein-1 localization on its function

2001 ◽  
Vol 355 (2) ◽  
pp. 473-479 ◽  
Author(s):  
Marilyne LEVADOUX-MARTIN ◽  
John E. HESKETH ◽  
John H. BEATTIE ◽  
Heather M. WALLACE
Keyword(s):  
Dna Damage ◽  
Uv Light ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Protective Role ◽  
S Phase ◽  
Coding Region ◽  
Ovary Cells ◽  
In Cells

Metallothioneins (MTs) have a major role to play in metal metabolism, and may also protect DNA against oxidative damage. MT protein has been found localized in the nucleus during S-phase. The mRNA encoding the MT-1 isoform has a perinuclear localization, and is associated with the cytoskeleton; this targeting, due to signals within the 3′-untranslated region (3′-UTR), facilitates nuclear localization of MT-1 during S-phase [Levadoux, Mahon, Beattie, Wallace and Hesketh (1999) J. Biol. Chem. 274, 34961-34966]. Using cells transfected with MT gene constructs differing in their 3′-UTRs, the role of MT protein in the nucleus has been studied. Chinese hamster ovary cells were transfected with either the full MT gene (MTMT cells) or with the MT 5′-UTR and coding region linked to the 3′-UTR of glutathione peroxidase (MTGSH cells). Cell survival following exposure to oxidative stress and chemical agents was higher in cells expressing the native MT gene than in cells where MT localization was disrupted, or in untransfected cells. Also, MTMT cells showed less DNA damage than MTGSH cells in response to either hydrogen peroxide or mutagen. After exposure to UV light or mutagen, MTMT cells showed less apoptosis than MTGSH cells, as assessed by DNA fragmentation and flow cytometry. The data indicate that the perinuclear localization of MT mRNA is important for the function of MT in a protective role against DNA damage and apoptosis induced by external stress.

Protective role of eugenol on arsenic induced oxidative DNA damage and modulatory effect of GSTO2 polymorphism

2018 ◽  
Vol 42 (5) ◽  
pp. e12565 ◽  
Author(s):  
Surbhi Bal ◽  
Anita Yadav ◽  
Neha Verma ◽  
Neeraj K. Aggarwal ◽  
Ranjan Gupta
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Protective Role

Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

2020 ◽  
Author(s):  
Kang Zhou ◽  
Yan Xu ◽  
Qiong Wang ◽  
Lini Dong
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Protective Role ◽  
Human Cardiomyocytes ◽  
Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

Role of oxidative DNA damage in the mechanism of fecapentaene 12 genotoxicity

1994 ◽  
Vol 15 (11) ◽  
pp. 2559-2566 ◽  
Author(s):  
T.M.C.M. de Kok ◽  
D.M.F.A. Pachen ◽  
J.M.S. van Maanen ◽  
M.V.M. Lafleur ◽  
E.J. Westmijze ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage

scholarly journals Genotoxicity and Gene Expression in the Rat Lung Tissue following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NM)

Nanomaterials ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1502
Author(s):  
Fátima Brandão ◽  
Carla Costa ◽  
Maria João Bessa ◽  
Elise Dumortier ◽  
Florence Debacq-Chainiaux ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Amorphous Silica ◽  
Oxidative Dna Damage ◽  
Intratracheal Instillation ◽  
Dna Lesions ◽  
Lung Cells ◽  
Rat Lung ◽  
Inhalation Study

Several reports on amorphous silica nanomaterial (aSiO2 NM) toxicity have been questioning their safety. Herein, we investigated the in vivo pulmonary toxicity of four variants of aSiO2 NM: SiO2_15_Unmod, SiO2_15_Amino, SiO2_7 and SiO2_40. We focused on alterations in lung DNA and protein integrity, and gene expression following single intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO2_7, using TiO2_NM105 as a benchmark NM. In the instillation study, a significant but slight increase in oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO2_15_Amino was observed in the recovery (R) group. Exposure to SiO2_7 or SiO2_40 markedly increased oxidative DNA lesions in rat lung cells of the exposure (E) group at every tested dose. This damage seems to be repaired, since no changes compared to controls were observed in the R groups. In STIS, a significant increase in DNA strand breaks of the lung cells exposed to 0.5 mg/m3 of SiO2_7 or 50 mg/m3 of TiO2_NM105 was observed in both groups. The detected gene expression changes suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage. Overall, all tested aSiO2 NM were not associated with marked in vivo toxicity following instillation or STIS. The genotoxicity findings for SiO2_7 from instillation and STIS are concordant; however, changes in STIS animals were more permanent/difficult to revert.

scholarly journals Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors

2018 ◽  
Vol 115 (52) ◽  
pp. E12285-E12294 ◽  
Author(s):  
Lavinia C. Dumitrache ◽  
Mikio Shimada ◽  
Susanna M. Downing ◽  
Young Don Kwak ◽  
Yang Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Brain Tumors ◽  
Oxidative Dna Damage ◽  
Early Death ◽  
Etiologic Agent ◽  
Dna Lesions ◽  
Oxidative Modification ◽  
Early Gene ◽  
Content Type

Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as “APEX1” or “REF1”) is a key enzyme for the repair of oxidative DNA damage, although the specific role(s) for this enzyme in the development and maintenance of the nervous system is largely unknown. Here, using conditional inactivation of murine Ape1, we identify critical roles for this protein in the brain selectively after birth, coinciding with tissue oxygenation shifting from a placental supply to respiration. While mice lacking APE1 throughout neurogenesis were viable with little discernible phenotype at birth, rapid and pronounced brain-wide degenerative changes associated with DNA damage were observed immediately after birth leading to early death. Unexpectedly, Ape1Nes-cre mice appeared hypothermic with persistent shivering associated with the loss of thermoregulatory serotonergic neurons. We found that APE1 is critical for the selective regulation of Fos1-induced hippocampal immediate early gene expression. Finally, loss of APE1 in combination with p53 inactivation resulted in a profound susceptibility to brain tumors, including medulloblastoma and glioblastoma, implicating oxidative DNA lesions as an etiologic agent in these diseases. Our study reveals APE1 as a major suppressor of deleterious oxidative DNA damage and uncovers specific and broad pathogenic consequences of respiratory oxygenation in the postnatal nervous system.

scholarly journals Potential role of oxidative DNA damage in the impact of PNPLA3 variant (rs 738409 C>G) in hepatocellular carcinoma risk

Hepatology ◽  
2014 ◽  
Vol 60 (3) ◽  
pp. 1110-1111 ◽  
Author(s):  
Emeric Limagne ◽  
Vanessa Cottet ◽  
Alexia Karen Cotte ◽  
Samia Hamza ◽  
Patrick Hillon ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Potential Role ◽  
The Impact ◽  
Carcinoma Risk
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