Causes and consequences of oxidative stress in spermatozoa

2016 ◽  
Vol 28 (2) ◽  
pp. 1 ◽  
Author(s):  
Robert John Aitken ◽  
Zamira Gibb ◽  
Mark A. Baker ◽  
Joel Drevet ◽  
Parviz Gharagozloo
Keyword(s):  
Oxidative Stress ◽  
Oxidative Dna Damage ◽  
Membrane Lipids ◽  
Excision Repair ◽  
Ros Generation ◽  
Apoptotic Pathway ◽  
Positive Role ◽  
Developmental Abnormalities ◽  
Abasic Sites ◽  
Oxidative Attack

Spermatozoa are highly vulnerable to oxidative attack because they lack significant antioxidant protection due to the limited volume and restricted distribution of cytoplasmic space in which to house an appropriate armoury of defensive enzymes. In particular, sperm membrane lipids are susceptible to oxidative stress because they abound in significant amounts of polyunsaturated fatty acids. Susceptibility to oxidative attack is further exacerbated by the fact that these cells actively generate reactive oxygen species (ROS) in order to drive the increase in tyrosine phosphorylation associated with sperm capacitation. However, this positive role for ROS is reversed when spermatozoa are stressed. Under these conditions, they default to an intrinsic apoptotic pathway characterised by mitochondrial ROS generation, loss of mitochondrial membrane potential, caspase activation, phosphatidylserine exposure and oxidative DNA damage. In responding to oxidative stress, spermatozoa only possess the first enzyme in the base excision repair pathway, 8-oxoguanine DNA glycosylase. This enzyme catalyses the formation of abasic sites, thereby destabilising the DNA backbone and generating strand breaks. Because oxidative damage to sperm DNA is associated with both miscarriage and developmental abnormalities in the offspring, strategies for the amelioration of such stress, including the development of effective antioxidant formulations, are becoming increasingly urgent.

scholarly journals Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

2020 ◽  
Author(s):  
Juan Miguel Baquero ◽  
Carlos Benítez-Buelga ◽  
Varshni Rajagopal ◽  
Zhao Zhenjun ◽  
Raúl Torres-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Lines ◽  
Small Molecule ◽  
Oxidative Dna Damage ◽  
Genome Instability ◽  
Excision Repair ◽  
Small Molecule Inhibitor ◽  
Osteosarcoma Cell ◽  
Molecule Inhibitor

Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

scholarly journals Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress

2008 ◽  
Vol 29 (3) ◽  
pp. 794-807 ◽  
Author(s):  
Lyra M. Griffiths ◽  
Dan Swartzlander ◽  
Kellen L. Meadows ◽  
Keith D. Wilkinson ◽  
Anita H. Corbett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Intracellular Localization ◽  
Genotoxic Stress ◽  
Mitochondrial Oxidative Stress ◽  
Base Excision

ABSTRACT DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

scholarly journals Octadecaneuropeptide prevents toxicity induced by 6-hydroxydopamine in cultured rat astrocyte: involvement of the endogenous antioxidant systems and the intrinsic apoptotic pathway

2018 ◽  
Author(s):  
Hadhemi Kaddour ◽  
Yosra Hamdi ◽  
David Vaudry ◽  
Jérôme Leprince ◽  
Hubert Vaudry ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Antioxidant Systems ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Antioxidant Defences ◽  
Apoptotic Pathway

AbstractOxidative stress, associated with various neurodegenerative diseases, induces imbalance in ROS generation, impairs cellular antioxidant defences and finally triggers both neurons and astroglial cell death by apoptosis. Astrocytes specifically synthesize and release endozepines, a family of regulatory peptides, including the octadecaneuropeptide (ODN). We have previously reported that ODN is a potent neuroprotective agent that prevents 6-OHDA-induced apoptotic neuronal death. The purpose of the present study was to investigate the potential glioprotective effect of ODN on 6-OHDA-induced oxidative stress and cell death in cultured rat astrocytes. Incubation of astrocytes with graded concentrations of ODN (10−14 to 10−8 M) inhibited 6-OHDA-evoked cell death in a concentration- and time-dependent manner. In addition, ODN prevented the decrease of mitochondrial activity and caspase-3 activation induced by 6-OHDA. Toxin-treated cells exhibited high level of ROS associated with a generation of H2O2 and O2°-and a reduction of both SOD and catalase activities. Co-treatment of astrocytes with low concentrations of ODN dose dependently blocked 6-OHDA-evoked ROS production and inhibition of antioxidant enzymes activities. Taken together, these data demonstrate that ODN is a potent glioprotective agent that prevents 6-OHDA-induced oxidative stress and apoptotic cell death. ODN is thus a potential candidate to delay neuronal damages in various pathological conditions involving oxidative neurodegeneration.

scholarly journals Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

2020 ◽  
Author(s):  
Juan Miguel Baquero ◽  
Carlos Benítez-Buelga ◽  
Varshni Rajagopal ◽  
Zhao Zhenjun ◽  
Raúl Torres-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Lines ◽  
Small Molecule ◽  
Oxidative Dna Damage ◽  
Genome Instability ◽  
Excision Repair ◽  
Small Molecule Inhibitor ◽  
Osteosarcoma Cell ◽  
Molecule Inhibitor

Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

scholarly journals Oxidative Stress and Calcium Dyshomeostasis Mediated CPF-Induces EPC Cell Apoptosis and Necroptosis

2021 ◽  
Author(s):  
Zhiying Miao ◽  
Jiawen Cui ◽  
Meijin Yu ◽  
Xiaohua Teng
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Aquatic Organisms ◽  
Ros Generation ◽  
Organophosphate Insecticide ◽  
Epithelioma Papulosum Cyprini ◽  
Apoptotic Pathway ◽  
The Common ◽  
Stress Related Genes ◽  
Novel Concept

Abstract Chlorpyrifos (CPF) is a broadly used organophosphate insecticide, and as environmental contamination has been confirmed to be harmful to the health of humans and animals, the effects of CPF on fish are still unclear. We aim to detect whether CPF has effects on the common carps, and identify the mechanisms of the effects. In accordance with the IC50 of CPF for epithelioma papulosum cyprini (EPC) cells was 8.945 µM, 0, 3, 5 and 7 µM CPF were marked as C, L, M and H group. The results indicated that CPF exposure led to oxidative stress in EPC cells. Moreover, Calcium ion (Ca2+) imaging indicated that CPF triggers Ca2+ dyshomeostasis, as induced ER Ca2+ fluxed into cytoplasm and mitochondrial, and mediates endoplasmic reticulum (ER) stress and mitochondrial Ca2+ overload, which have further confirmed with the increased transcription of ER stress related genes. Meanwhile, CPF induced collapse of mitochondrial membrane potential (MMP), enhancement of ROS generation and depletion of ATP level in both cytoplasm and mitochondrial, substantiated mitochondrial dysfunction has been evoked. Besides, the AO/EB staining and flow cytometry analysis ascertained that CPF induces apoptosis and necroptosis in EPC cells. Hence, we further verified that via determining the expression of apoptotic pathway genes and necroptotic pathway genes. Consequently, we illuminated the mechanisms of CPF effects on the common carps from the perspective of Ca2+ homeostasis, and provided a novel concept for investigating the toxicity of CPF as environmental pollution on aquatic organisms.

scholarly journals Poly(ADP-ribose) polymerase 1 (PARP1) promotes oxidative stress–induced association of Cockayne syndrome group B protein with chromatin

2018 ◽  
Vol 293 (46) ◽  
pp. 17863-17874 ◽  
Author(s):  
Erica L. Boetefuer ◽  
Robert J. Lake ◽  
Kostiantyn Dreval ◽  
Hua-Ying Fan
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Rna Polymerase Ii ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Transcription Elongation ◽  
Cockayne Syndrome ◽  
Base Excision ◽  
Group B ◽  
Genomic Regions

Cockayne syndrome protein B (CSB) is an ATP-dependent chromatin remodeler that relieves oxidative stress by regulating DNA repair and transcription. CSB is proposed to participate in base-excision repair (BER), the primary pathway for repairing oxidative DNA damage, but exactly how CSB participates in this process is unknown. It is also unclear whether CSB contributes to other repair pathways during oxidative stress. Here, using a patient-derived CS1AN-sv cell line, we examined how CSB is targeted to chromatin in response to menadione-induced oxidative stress, both globally and locus-specifically. We found that menadione-induced, global CSB–chromatin association does not require CSB's ATPase activity and is, therefore, mechanistically distinct from UV-induced CSB–chromatin association. Importantly, poly(ADP-ribose) polymerase 1 (PARP1) enhanced the kinetics of global menadione-induced CSB–chromatin association. We found that the major BER enzymes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), do not influence this association. Additionally, the level of γ-H2A histone family member X (γ-H2AX), a marker for dsDNA breaks, was not increased in menadione-treated cells. Therefore, our results support a model whereby PARP1 localizes to ssDNA breaks and recruits CSB to participate in DNA repair. Furthermore, this global CSB–chromatin association occurred independently of RNA polymerase II–mediated transcription elongation. However, unlike global CSB–chromatin association, both PARP1 knockdown and inhibition of transcription elongation interfered with menadione-induced CSB recruitment to specific genomic regions. This observation supports the hypothesis that CSB is also targeted to specific genomic loci to participate in transcriptional regulation in response to oxidative stress.

Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4730-4735 ◽  
Author(s):  
Pål Aukrust ◽  
Luisa Luna ◽  
Thor Ueland ◽  
Rune F. Johansen ◽  
Fredrik Müller ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
T Cells ◽  
Hiv Infection ◽  
Base Excision Repair ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Base Excision

Abstract Several studies have reported enhanced oxidative stress in patients with HIV infection. An important pathophysiologic consequence of increased oxidative stress is endogenous DNA damage, and the base excision repair pathway is the most important mechanism to withstand such deleterious effects. To investigate the role of base excision repair in HIV infection, we examined 7,8-dihydro-8-oxoguanine (8-oxoG) levels as a marker of oxidative DNA damage and DNA glycosylase activities in CD4+ and CD8+ T cells of HIV-infected patients and controls. These results showed that the HIV-infected patients, particularly those with advanced disease, had increased levels of 8-oxoG in CD4+ T cells and marked declines in DNA glycosylase activity for the repair of oxidative base lesions in these cells. In contrast, CD8+ T cells from HIV-infected patients, with 8-oxoG levels similar to those in healthy controls, showed enhanced capacity to repair oxidative DNA damage. Finally, highly active antiretroviral therapy induced increased glycosylase activity in CD4+ T cells and normalized 8-oxoG levels. This imbalance between the accumulation of oxidative DNA damage and the capacity to repair such lesions in CD4+ T cells may represent a previously unrecognized mechanism involved in the numerical and functional impairment of CD4+ T cells in patients with HIV infection. (Blood. 2005; 105:4730-4735)

scholarly journals Protective Effects of Nargenicin A1 against Tacrolimus-Induced Oxidative Stress in Hirame Natural Embryo Cells

2019 ◽  
Vol 16 (6) ◽  
pp. 1044 ◽  
Author(s):  
Cheol Park ◽  
Da Kwon ◽  
Su Hwang ◽  
Min Han ◽  
Jin-Woo Jeong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Ros Generation ◽  
Protective Effects ◽  
Apoptotic Pathway ◽  
Embryo Cells ◽  
Ros Scavenger ◽  
Induced Apoptosis

Tacrolimus is widely used as an immunosuppressant to reduce the risk of rejection after organ transplantation, but its cytotoxicity is problematic. Nargenicin A1 is an antibiotic extracted from Nocardia argentinensis and is known to have antioxidant activity, though its mode of action is unknown. The present study was undertaken to evaluate the protective effects of nargenicin A1 on DNA damage and apoptosis induced by tacrolimus in hirame natural embryo (HINAE) cells. We found that reduced HINAE cell survival by tacrolimus was due to the induction of DNA damage and apoptosis, both of which were prevented by co-treating nargenicin A1 or N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, with tacrolimus. In addition, apoptosis induction by tacrolimus was accompanied by increases in ROS generation and decreases in adenosine triphosphate (ATP) levels caused by mitochondrial dysfunction, and these changes were significantly attenuated in the presence of nargenicin A1, which further indicated tacrolimus-induced apoptosis involved an oxidative stress-associated mechanism. Furthermore, nargenicin A1 suppressed tacrolimus-induced B-cell lymphoma-2 (Bcl-2) down-regulation, Bax up-regulation, and caspase-3 activation. Collectively, these results demonstrate that nargenicin A1 protects HINAE cells against tacrolimus-induced DNA damage and apoptosis, at least in part, by scavenging ROS and thus suppressing the mitochondrial-dependent apoptotic pathway.

scholarly journals The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites

2020 ◽  
Vol 295 (11) ◽  
pp. 3692-3707
Author(s):  
Alan G. Raetz ◽  
Douglas M. Banda ◽  
Xiaoyan Ma ◽  
Gege Xu ◽  
Anisha N. Rajavel ◽  
...  
Keyword(s):  
Dna Repair ◽  
Alkylating Agent ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dna Lesions ◽  
Repair Enzyme ◽  
Abasic Sites ◽  
Human Lymphoblastoid Cell ◽  
Ap Sites ◽  
Base Excision

Higher expression of the human DNA repair enzyme MUTYH has previously been shown to be strongly associated with reduced survival in a panel of 24 human lymphoblastoid cell lines exposed to the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). The molecular mechanism of MUTYH-enhanced MNNG cytotoxicity is unclear, because MUTYH has a well-established role in the repair of oxidative DNA lesions. Here, we show in mouse embryonic fibroblasts (MEFs) that this MNNG-dependent phenotype does not involve oxidative DNA damage and occurs independently of both O6-methyl guanine adduct cytotoxicity and MUTYH-dependent glycosylase activity. We found that blocking of abasic (AP) sites abolishes higher survival of Mutyh-deficient (Mutyh−/−) MEFs, but this blockade had no additive cytotoxicity in WT MEFs, suggesting the cytotoxicity is due to MUTYH interactions with MNNG-induced AP sites. We found that recombinant mouse MUTYH tightly binds AP sites opposite all four canonical undamaged bases and stimulated apurinic/apyrimidinic endonuclease 1 (APE1)-mediated DNA incision. Consistent with these observations, we found that stable expression of WT, but not catalytically-inactive MUTYH, enhances MNNG cytotoxicity in Mutyh−/− MEFs and that MUTYH expression enhances MNNG-induced genomic strand breaks. Taken together, these results suggest that MUTYH enhances the rapid accumulation of AP-site intermediates by interacting with APE1, implicating MUTYH as a factor that modulates the delicate process of base-excision repair independently of its glycosylase activity.

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.

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