scholarly journals ‘Liver let die’: oxidative DNA damage and hepatotropic viruses

2014 ◽  
Vol 95 (5) ◽  
pp. 991-1004 ◽  
Author(s):  
Martin R. Higgs ◽  
Philippe Chouteau ◽  
Hervé Lerat
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Response ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Large Body ◽  
Clinical Importance ◽  
Dna Lesions ◽  
Chronic Infections ◽  
The Impact

Chronic infections by the hepatotropic viruses hepatitis B virus (HBV) and hepatitis C virus (HCV) are major risk factors for the development of hepatocellular carcinoma (HCC). It is estimated that more than 700 000 individuals per year die from HCC, and around 80 % of HCC is attributable to HBV or HCV infection. Despite the clear clinical importance of virus-associated HCC, the underlying molecular mechanisms remain largely elusive. Oxidative stress, in particular DNA lesions associated with oxidative damage, play a major contributory role in carcinogenesis, and are strongly linked to the development of many cancers, including HCC. A large body of evidence demonstrates that both HBV and HCV induce hepatic oxidative stress, with increased oxidative DNA damage being observed both in infected individuals and in murine models of infection. Here, we review the impact of HBV and HCV on the incidence and repair of oxidative DNA damage. We begin by giving a brief overview of oxidative stress and the repair of DNA lesions induced by oxidative stress. We then review in detail the evidence surrounding the mechanisms by which both viruses stimulate oxidative stress, before focusing on how the viral proteins themselves may perturb the cellular response to oxidative DNA damage, impacting upon genome stability and thus hepatocarcinogenesis.

scholarly journals The NADPH Oxidase Isoform 1 Contributes to Angiotensin II-Mediated DNA Damage in the Kidney

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 586
Author(s):  
Anna Zimnol ◽  
Nora Spicker ◽  
Ronja Balhorn ◽  
Katrin Schröder ◽  
Nicole Schupp
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Dna Damage ◽  
Angiotensin Ii ◽  
Knockout Mice ◽  
Dna Lesions ◽  
Mouse Strains ◽  
Nadph Oxidases ◽  
Systemic Oxidative Stress ◽  
The Impact

In higher concentrations, the blood pressure regulating hormone angiotensin II leads to vasoconstriction, hypertension, and oxidative stress by activating NADPH oxidases which are a major enzymatic source of reactive oxygen species (ROS). With the help of knockout animals, the impact of the three predominant NADPH oxidases present in the kidney, i.e., Nox1, Nox2 and Nox4 on angiotensin II-induced oxidative damage was studied. Male wildtype (WT) C57BL/6 mice, Nox1-, Nox2- and Nox4-deficient mice were equipped with osmotic minipumps, delivering either vehicle (PBS) or angiotensin II, for 28 days. Angiotensin II increased blood pressure and urinary albumin levels significantly in all treated mouse strains. In Nox1 knockout mice these increases were significantly lower than in WT, or Nox2 knockout mice. In WT mice, angiotensin II also raised systemic oxidative stress, ROS formation and DNA lesions in the kidney. A local significantly increased ROS production was also found in Nox2 and Nox4 knockout mice but not in Nox1 knockout mice who further had significantly lower systemic oxidative stress and DNA damage than WT animals. Nox2 and Nox4 knockout mice had increased basal DNA damage, concealing possible angiotensin II-induced increases. In conclusion, in the kidney, Nox1 seemed to play a role in angiotensin II-induced DNA damage.

scholarly journals Cooperation of the Cockayne Syndrome Group B Protein and Poly(ADP-Ribose) Polymerase 1 in the Response to Oxidative Stress

2005 ◽  
Vol 25 (17) ◽  
pp. 7625-7636 ◽  
Author(s):  
Tina Thorslund ◽  
Cayetano von Kobbe ◽  
Jeanine A. Harrigan ◽  
Fred E. Indig ◽  
Mette Christiansen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Response ◽  
Genetic Disorder ◽  
Cockayne Syndrome ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Group B ◽  
Parp 1

ABSTRACT Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-1 to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage.

scholarly journals Distinct roles of XRCC1 in genome integrity in Xenopus egg extracts

2019 ◽  
Vol 476 (24) ◽  
pp. 3791-3804 ◽  
Author(s):  
Steven Cupello ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Polymerase Beta ◽  
Egg Extracts ◽  
Xenopus Egg ◽  
Xenopus Egg Extracts

Oxidative DNA damage represents one of the most abundant DNA lesions. It remains unclear how DNA repair and DNA damage response (DDR) pathways are co-ordinated and regulated following oxidative stress. While XRCC1 has been implicated in DNA repair, it remains unknown how exactly oxidative DNA damage is repaired and sensed by XRCC1. In this communication, we have demonstrated evidence that XRCC1 is dispensable for ATR-Chk1 DDR pathway following oxidative stress in Xenopus egg extracts. Whereas APE2 is essential for SSB repair, XRCC1 is not required for the repair of defined SSB and gapped plasmids with a 5′-OH or 5′-P terminus, suggesting that XRCC1 and APE2 may contribute to SSB repair via different mechanisms. Neither Polymerase beta nor Polymerase alpha is important for the repair of defined SSB structure. Nonetheless, XRCC1 is important for the repair of DNA damage following oxidative stress. Our observations suggest distinct roles of XRCC1 for genome integrity in oxidative stress in Xenopus egg extracts.

scholarly journals Antioxidant CoQ10 Restores Fertility by Rescuing Bisphenol A-Induced Oxidative DNA Damage in the Caenorhabditis elegans Germline

Genetics ◽  
2019 ◽  
Vol 214 (2) ◽  
pp. 381-395 ◽  
Author(s):  
Maria Fernanda Hornos Carneiro ◽  
Nara Shin ◽  
Rajendiran Karthikraj ◽  
Fernando Barbosa ◽  
Kurunthachalam Kannan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Bisphenol A ◽  
Oxidative Dna Damage ◽  
Low Cost ◽  
Endocrine Disrupting Chemicals ◽  
Human Reproductive ◽  
Low Cost Strategy ◽  
The Impact

Endocrine-disrupting chemicals are ubiquitously present in our environment, but the mechanisms by which they adversely affect human reproductive health and strategies to circumvent their effects remain largely unknown. Here, we show in Caenorhabditis elegans that supplementation with the antioxidant Coenzyme Q10 (CoQ10) rescues the reprotoxicity induced by the widely used plasticizer and endocrine disruptor bisphenol A (BPA), in part by neutralizing DNA damage resulting from oxidative stress. CoQ10 significantly reduces BPA-induced elevated levels of germ cell apoptosis, phosphorylated checkpoint kinase 1 (CHK-1), double-strand breaks (DSBs), and chromosome defects in diakinesis oocytes. BPA-induced oxidative stress, mitochondrial dysfunction, and increased gene expression of antioxidant enzymes in the germline are counteracted by CoQ10. Finally, CoQ10 treatment also reduced the levels of aneuploid embryos and BPA-induced defects observed in early embryonic divisions. We propose that CoQ10 may counteract BPA-induced reprotoxicity through the scavenging of reactive oxygen species and free radicals, and that this natural antioxidant could constitute a low-risk and low-cost strategy to attenuate the impact on fertility by BPA.

scholarly journals MO076REGULATION OF DIFFERENTIAL CELLULAR RESPONSE TO OXIDATIVE STIMULI IN SYSTEMIC LUPUS ERYTHEMATOSUS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Corina-Daniela Ene ◽  
Mircea Penescu ◽  
Simona Roxana Georgescu ◽  
Mircea Tampa ◽  
Ilinca Nicolae
Keyword(s):  
Oxidative Stress ◽  
Lupus Nephritis ◽  
Disease Activity ◽  
Cellular Response ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Activity Index ◽  
Group Versus ◽  
Control Group ◽  
Systemic Lupus

Abstract Background and Aims Interaction of reactive oxygen species (ROS) with lipids, proteins, nucleic acids and hydro carbonates promotes acute and chronic tissue damage, mediates immunomodulation and triggers autoimmunity in systemic lupus erythematous (SLE) patients. The aim of the study was to determine the pathophysiological mechanisms of the oxidative stress-related damage and molecular mechanisms to counteract oxidative stimuli in lupus nephritis. Method Our study included 82 volunteers with SLE: 38 SLE volunteers with lupus nephritis (LN group) and 44 SLE volunteers without renal impairment (non-LN group) and a control group of 40 healthy volunteers. LN was diagnosed by histological exam (optic microscopy, electronic microscopy and immunofluorescence). Disease activity was measured by systemic SLE disease activity index (SLEDAI), urinary protein/creatinine ration, anti-dsDNA, C3, C4 and urinary β2-microglobulin. In the present paper, we evaluated in serum: Results We detected high lipid peroxidation, elevated oxidative DNA damage, excess accumulation of reactive carbonylic compounds, important oxidation of carbohydrates, disulphide bonds formation and high nitrotyrosination with statistically significant differences between groups, when compared LN and non-LN groups with control group. When compared LN and non-LN groups, our results showed: 3-Nitrotyrosine levels, the decrease of total and native serum thiols, pentosidine levels, sRAGE level and OGG1 activity correlated with disease activity markers in both LN and non-LN groups, while AGE correlated with disease activity only in non-LN group. Conclusion The cellular response to oxidative stimuli in SLE is concreted in the amplification of oxidative degradation of lipids, proteins, nucleic acid, hydro carbonates and in alteration of endogenous strategies for suppression /modulating oxidative stress. The defective DNA repair mechanism via OGG1 and the reduced regulatory effect of sRAGE in activation AGE-RAGE axis in LN group versus non-LN could explain alteration of renal architecture and development of renal injury.

scholarly journals Overexpression of PCNA Attenuates Oxidative Stress-Caused Delay of Gap-Filling during Repair of UV-Induced DNA Damage

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yi-Chih Tsai ◽  
Yi-Hsiang Wang ◽  
Yin-Chang Liu
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Mammalian Cells ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Subsequent Treatment ◽  
Dna Lesions ◽  
Gap Filling ◽  
Repair Synthesis ◽  
Damage Site

UVC irradiation-caused DNA lesions are repaired in mammalian cells solely by nucleotide excision repair (NER), which consists of sequential events including initial damage recognition, dual incision of damage site, gap-filling, and ligation. We have previously shown that gap-filling during the repair of UV-induced DNA lesions may be delayed by a subsequent treatment of oxidants or prooxidants such as hydrogen peroxide, flavonoids, and colcemid. We considered the delay as a result of competition for limiting protein/enzyme factor(s) during repair synthesis between NER and base excision repair (BER) induced by the oxidative chemicals. In this report, using colcemid as oxidative stress inducer, we showed that colcemid-caused delay of gap-filling during the repair of UV-induced DNA lesions was attenuated by overexpression of PCNA but not ligase-I. PCNA knockdown, as expected, delayed the gap-filling of NER but also impaired the repair of oxidative DNA damage. Fen-1 knockdown, however, did not affect the repair of oxidative DNA damage, suggesting repair of oxidative DNA damage is not of long patch BER. Furthermore, overexpression of XRCC1 delayed the gap-filling, and presumably increase of XRCC1 pulls PCNA away from gap-filling of NER for BER, consistent with our hypothesis that delay of gap-filling of NER attributes the competition between NER and BER.

scholarly journals Oxidative stress in thyroid carcinomas: biological and clinical significance

2019 ◽  
Vol 26 (3) ◽  
pp. R131-R143 ◽  
Author(s):  
Rabii Ameziane El Hassani ◽  
Camille Buffet ◽  
Sophie Leboulleux ◽  
Corinne Dupuy
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Cell Transformation ◽  
Second Messengers ◽  
Cellular Functions ◽  
Thyroid Cells ◽  
Hormone Synthesis ◽  
The Impact

At physiological concentrations, reactive oxygen species (ROS), including superoxide anions and H2O2, are considered as second messengers that play key roles in cellular functions, such as proliferation, gene expression, host defence and hormone synthesis. However, when they are at supraphysiological levels, ROS are considered potent DNA-damaging agents. Their increase induces oxidative stress, which can initiate and maintain genomic instability. The thyroid gland represents a good model for studying the impact of oxidative stress on genomic instability. Indeed, one particularity of this organ is that follicular thyroid cells synthesise thyroid hormones through a complex mechanism that requires H2O2. Because of their detection in thyroid adenomas and in early cell transformation, both oxidative stress and DNA damage are believed to be neoplasia-preceding events in thyroid cells. Oxidative DNA damage is, in addition, detected in the advanced stages of thyroid cancer, suggesting that oxidative lesions of DNA also contribute to the maintenance of genomic instability during the subsequent phases of tumourigenesis. Finally, ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis through separate and unique mechanisms: they upregulate the expression of two distinct ‘professional’ ROS-generating systems, the NADPH oxidases DUOX1 and NOX4, which cause DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation.

scholarly journals DNA Damage and Its Cellular Response in Mother and Fetus Exposed to Hyperglycemic Environment

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jusciele Brogin Moreli ◽  
Janine Hertzog Santos ◽  
Clarissa Ribeiro Rocha ◽  
Débora Cristina Damasceno ◽  
Glilciane Morceli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Genetic Material ◽  
Endogenous Factors ◽  
Dna Repair Mechanisms ◽  
Scavenging Capacity ◽  
Repair Mechanisms ◽  
The Impact

The increased production of reactive oxygen species (ROS) plays a key role in pathogenesis of diabetic complications. ROS are generated by exogenous and endogenous factors such as during hyperglycemia. When ROS production exceeds the detoxification and scavenging capacity of the cell, oxidative stress ensues. Oxidative stress induces DNA damage and when DNA damage exceeds the cellular capacity to repair it, the accumulation of errors can overwhelm the cell resulting in cell death or fixation of genome mutations that can be transmitted to future cell generations. These mutations can lead to and/or play a role in cancer development. This review aims at (i) understanding the types and consequences of DNA damage during hyperglycemic pregnancy; (ii) identifying the biological role of DNA repair during pregnancy, and (iii) proposing clinical interventions to maintain genome integrity. While hyperglycemia can damage the maternal genetic material, the impact of hyperglycemia on fetal cells is still unclear. DNA repair mechanisms may be important to prevent the deleterious effects of hyperglycemia both in mother and in fetus DNA and, as such, prevent the development of diseases in adulthood. Hence, in clinical practice, maternal glycemic control may represent an important point of intervention to prevent the deleterious effects of maternal hyperglycemia to DNA.

scholarly journals Role of the Nfo and ExoA Apurinic/Apyrimidinic Endonucleases in Repair of DNA Damage during Outgrowth of Bacillus subtilis Spores

2008 ◽  
Vol 190 (6) ◽  
pp. 2031-2038 ◽  
Author(s):  
Juan R. Ibarra ◽  
Alma D. Orozco ◽  
Juan A. Rojas ◽  
Karina López ◽  
Peter Setlow ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Bacillus Subtilis ◽  
Spore Germination ◽  
Mutation Frequency ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Spontaneous Mutation ◽  
Dna Lesions ◽  
Spore Outgrowth

ABSTRACT Germination and outgrowth are critical steps for returning Bacillus subtilis spores to life. However, oxidative stress due to full hydration of the spore core during germination and activation of metabolism in spore outgrowth may generate oxidative DNA damage that in many species is processed by apurinic/apyrimidinic (AP) endonucleases. B. subtilis spores possess two AP endonucleases, Nfo and ExoA; the outgrowth of spores lacking both of these enzymes was slowed, and the spores had an elevated mutation frequency, suggesting that these enzymes repair DNA lesions induced by oxidative stress during spore germination and outgrowth. Addition of H2O2 also slowed the outgrowth of nfo exoA spores and increased the mutation frequency, and nfo and exoA mutations slowed the outgrowth of spores deficient in either RecA, nucleotide excision repair (NER), or the DNA-protective α/β-type small acid-soluble spore proteins (SASP). These results suggest that α/β-type SASP protect DNA of germinating spores against damage that can be repaired by Nfo and ExoA, which is generated either spontaneously or promoted by addition of H2O2. The contribution of RecA and Nfo/ExoA was similar to but greater than that of NER in repair of DNA damage generated during spore germination and outgrowth. However, nfo and exoA mutations increased the spontaneous mutation frequencies of outgrown spores lacking uvrA or recA to about the same extent, suggesting that DNA lesions generated during spore germination and outgrowth are processed by Nfo/ExoA in combination with NER and/or RecA. These results suggest that Nfo/ExoA, RecA, the NER system, and α/β-type SASP all contribute to the repair of and/or protection against oxidative damage of DNA in germinating and outgrowing spores.

scholarly journals Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 848
Author(s):  
Carla Enrica Gallenga ◽  
Maria Lonardi ◽  
Sofia Pacetti ◽  
Sara Silvia Violanti ◽  
Paolo Tassinari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinitis Pigmentosa ◽  
Cellular Response ◽  
Microglial Activation ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Micro Rna ◽  
Stress Protection ◽  
Endogenous Antioxidant ◽  
Therapy Target

Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor’s daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.

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