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Results for “DNA oxidative damage”

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At least 37 records · Page 2Linked to original sources
PubMed1976

Evidence of repair of DNA damage induced by 4-hydroxyaminoquinoline 1-oxide in guinea pig pancreatic slices in vitro.

In vitro exposure of guinea pig pancreatic slices to 4-hydroxyaminoquinoline 1-oxide (HAQO) resulted in increased [methyl-3H]thymidine ([3H]TdR) incorporation into DNA, both in the presence and absence of hydroxyurea (HU). Normal DNA replicative synthesis, but not DNA repair synthesis, was suppressed by HU. The increase in [3H]TdR incorporation into DNA damage induced by HAQO. Exposure of pancreatic slices to 10(-6) to 10(-5) M concentrations of HAQO did not significantly increase thymidine incorporation; however, a 15-min exposure to 10(-4) M HAQO induced a significant increase in HU-insensitive [3H]TdR incorporation into DNA. Kinetics of [3H]TdR incorporation suggests that most of the DNA repair synthesis occurs during the 2 hr following HAQO-induced DNA damage.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed2026

Maternal high-fat diet modulates lupus nephritis through fetal Wnt-steroid hormone and epigenetic reprogramming in MRL/lpr mouse offspring.

We previously investigated whether maternal high-fat diet (HFD) exposure alters lupus nephritis (LN) progression in MRL/lpr offspring. Contrary to expectation, maternally HFD-exposed offspring showed delayed and attenuated nephritic progression compared with control diet offspring. The maternal HFD developmental impact on LN remains unclear. Here, integrated amniotic fluid metabolomics and fetal liver transcriptomics revealed that maternal HFD reshaped the intrauterine molecular environment, particularly involving steroid hormone biosynthesis and Wnt/β-catenin-associated regulatory networks. Methylome profiling further demonstrated broad CpG hypomethylation, immune-related differentially methylated region enrichment, and an inverse association between global CpG methylation and oxidative genomic DNA damage. Among candidate regulatory nodes, Axin2, a canonical Wnt/β-catenin target and feedback regulator, emerged as a potential link between fetal nutritional exposure, epigenetic remodeling, and persistent pathway modulation. Although whole-locus and gene body methylation of Axin2 were not markedly altered, promoter-region methylation showed an increasing tendency under maternal HFD exposure. In adult offspring, maternal HFD was associated with reduced Axin2 protein expression, decreased Wnt-responsive transcripts, increased peripheral corticosterone levels, and attenuation of LN progression. The inverse association between Axin2 expression and corticosterone further suggested coupling between suppressed Wnt pathway output and steroid hormone remodeling. Together, these findings support a developmental model in which maternal HFD reshapes the fetal intrauterine environment and establishes a persistent Wnt-steroid hormone-epigenetic regulatory axis that unexpectedly attenuates LN progression in genetically susceptible offspring.

Axin2↗
PubMed2026

Low-pass whole-genome sequencing reveals genomic diversity and ecotype-specific adaptation in indigenous Tigrayan chickens.

Indigenous chickens play a critical role in food security and climate resilience in smallholder systems, yet their genomic diversity and adaptive potential remain insufficiently characterised. This study employed low-pass whole-genome sequencing (LP-WGS; 0.2-1.99×) to investigate genomic diversity, population structure, inbreeding and candidate environment-associated genomic variation in 33 chickens from highland, midland, and lowland agroecologies in the Tigray region of northern Ethiopia. After imputation and stringent filtering, 23.4 million high-confidence SNPs were retained, including ~ 17% novel variants, indicating substantial uncharacterised genetic diversity in these populations. SNP density (13.8 ± 8.6 SNPs/kb) was comparable to values reported from high-coverage Ethiopian chicken datasets, demonstrating the suitability of LP-WGS for population genomics in resource-limited settings. Marked differences in genomic diversity were observed among ecotypes: midland chickens showed the highest nucleotide diversity (π = 0.00267), followed by lowland (π = 0.00233), whereas highland chickens showed the lowest diversity (π = 0.00203) and elevated genomic inbreeding (FROH and FHOM ≈ 0.18). Population structure analyses revealed clear genetic separation among ecotypes. PCA (13.91% variation explained) distinguished lowland chickens along PC1 and separated highland from midland along PC2, while ADMIXTURE and FST patterns supported three major ancestral genomic backgrounds. Functional annotation of private missense variants uncovered distinct adaptive signatures reflecting the contrasting agroecological conditions. Highland chickens showed enrichment of candidate genes potentially involved in physiological processes relevant to high-altitude environments, including cold response, angiogenesis, cardiovascular regulation and metabolic homeostasis (eg., PARP1, ACOX2, ITGB3, EDNRB, SOX8, and SOX10). Midland chickens exhibited candidate signals of selection in genes with known roles in innate antiviral immunity, bacterial defence and inflammatory regulation (eg., BAK1, CLSTN1, CYSLTR1, CYSLTR2, CXCR7, GIPR, DSCAM, GDAP1, TLR3, TLR4, TLR7, IFIH1, ADORA1, EPHB1, and TMPRSS2). Lowland chickens displayed candidate variants associated with heat-stress response, DNA damage repair, oxidative balance and cardiovascular support under extreme temperatures (e.g., MLH1, BDKRB1, GPR19, FLT1, CCL18, TGM2, and RAMP3). Overall, the results indicate substantial genomic differentiation among ecotypes and suggest candidate environment-associated genetic divergence across Tigray's diverse agroecological zones. These populations may represent important reservoirs of adaptive genetic variation for climate-resilient poultry breeding, warranting further functional validation and conservation-oriented management.

Animals↗
PubMed2024

Small noncoding RNAs and sperm nuclear basic proteins reflect the environmental impact on germ cells.

BACKGROUND: Molecular techniques can complement conventional spermiogram analyses to provide new information on the fertilizing potential of spermatozoa and to identify early alterations due to environmental pollution. METHODS: Here, we present a multilevel molecular profiling by small RNA sequencing and sperm nuclear basic protein analysis of male germ cells from 33 healthy young subjects residing in low and high-polluted areas. RESULTS: Although sperm motility and sperm concentration were comparable between samples from the two sites, those from the high-pollution area had a higher concentration of immature/immune cells, a lower protamine/histone ratio, a reduced ability of sperm nuclear basic proteins to protect DNA from oxidative damage, and an altered copper/zinc ratio in sperm. Sperm levels of 32 microRNAs involved in intraflagellar transport, oxidative stress response, and spermatogenesis were different between the two areas. In parallel, a decrease of Piwi-interacting RNA levels was observed in samples from the high-polluted area. CONCLUSIONS: This comprehensive analysis provides new insights into pollution-driven epigenetic alterations in sperm not detectable by spermiogram.

Male↗
PubMed1976

Breakage of human cell DNA after exposure to 3-methylcholanthrene-11,12-oxide.

Damage to and repair of DNA isolated from human neonatal and fetal skin cells were measured by alkaline sucrose gradient analysis. 3-Methylcholanthrene did not induce single-strand breaks in DNA of the cells in culture, whereas the 11,12-oxide of 3-methylcholanthrene was very effective in this regard. The cis-1,2-dihydroxy, trans-11,12-dihydroxy, and cis-11,12-dihydroxy derivatives of 3-methylcholanthrene exerted little effect. The breaks in DNA caused by 3-methylcholanthrene oxide occurred during a 60-min incubation period and were repaired during the following 60 min. Methylmethane sulfonate also induced breaks in the DNA within 60 min.

Cells, Cultured↗
PubMed1978

Chromosome damage and DNA repair induced in human fibroblasts by UV and cholesterol oxide.

In human fibroblasts, cholesterol oxide induced a similar degree of chromosome damage (8.6% of metaphases) and DNA repair synthesis (8-10% of cells with lightly-labelled nuclei) as low doses of ultraviolet light (UV), but did not produce single-strand DNA breaks or DNA damage detectable by inhibition of thymidine incorporation. Chromosome aberrations were detected up to 8 weeks after treatment with cholesterol oxide and UV. Combined treatments had almost additive effects on the frequency of chromosome aberrations but not on repair synthesis. Multiple daily doses of UV did not cause more aberrations than a single dose. Attempts to transform two fibroblast strains from normal donors and three derived from melanoma patients using single and combined treatments of UV, cholesterol oxide and hyperthermia (40 degrees) were unsuccessful.

Adolescent↗
PubMed2025

Transcriptional benchmark dose modeling of ultraviolet radiation-induced genomic activation in mouse skin.

The in vivo transcriptional response of mouse skin to ultraviolet radiation (UV-R) exposure reveals key genomic alterations associated with UV-R-induced damage but it does not provide precise dose thresholds for these effects. These initial findings provided the impetus to advance dose-response characterization by integrating benchmark dose (BMD) modeling with transcriptomic data, aiming to identify biologically relevant points of departure for gene and pathway activation. To accomplish this, mice were exposed to five erythemally weighted UV-R doses (0-40 mJ/cm2) emitted from a UV-emitting tanning device, across six post-exposure timepoints (0-96 h). Four analytical methods were used to estimate BMDs, with the lowest consistent response dose (LCRD) approach yielding the most sensitive estimates (1.21-3.44 mJ/cm2). Transcriptomic responses revealed activation of shared pathways related to DNA damage and cancer, oxidative stress and metabolism, inflammation and immunity, and hormonal disruption. Notably, the majority of LCRD BMD estimates (1.21-3.44 mJ/cm2) were lower than the International Electrotechnical Commission standard actinic exposure limit (3 mJ/cm2 (erythemally weighted)) for broadband UV-R (200-400 nm) for unprotected skin and the eye for an 8 h period. These findings suggest that transcriptomic BMD modeling can detect early biological responses to UV-R at doses lower than current exposure limits.

Animals↗
PubMed1978

DNA damage during the peroxidase-catalyzed aerobic oxidation of isobutanal.

The aerobic oxidation of isobutanal catalyzed by peroxidase, when carried out in the presence of DNA, produces alkali-sensitive bonds in this macromolecule. Neither the initial components of this reaction nor the final stable products are responsible for this effect. Since triplet acetone has been recently identified as an intermediate in this oxidation (Durán, N., Faria Oliviera, O.M.M., Haun, M. and Cilento, G. (1977) J. Chem. Soc. Chem. Commun., 442--443), this species is a likely candidate for the entity which brings about the lesions, via transfer of its electronic energy to DNA.

Aerobiosis↗
PubMed1975

Organ-specific DNA damage induced in mice by the organotropic carcinogens 4-nitroquinoline 1-oxide and dimethylnitrosamine.

The extent of DNA fragmentation induced in lung, kidney, and liver of mice injected with the chemical carcinogens 4-nitroquinoline 1-oxide (4NQO), dimethylnitrosamine (DMN) and the noncarcinogenic 4-aminoquinoline 1-oxide (4AQO) was estimated by the alkaline sucrose gradient technique. A floating of minced lung tissue pieces in the alkaline lysing solution on top of the gradients afforded a gentle method of lung DNA extraction. This technique minimized mechanical shearing of lung DNA and permitted comparisons to be made with liver and kidney DNA sedimentation patterns. The extent of DNA damage induced by 4NQO followed the order: lung, kidney, liver, while that induced by DMN followed the order: liver, kidney, lung. The sites of greatest DNA damage appeared to correlate with sites of high levels of DNA repair synthesis and the sites of tumor induction. No DNA damage was induced by the noncarcinogenic 4-aminoquinoline 1-oxide (4AQO).

4-Nitroquinoline-1-oxide↗
PubMed1975

Excision-repair of 4-nitroquinolin-1-oxide damage responsible for killing, mutation, and cancer.

Excision-repair of DNA base damage produced by 4-nitroquinoline-1-oxide (4NQO) was compared in Escherichia coli, human cells, and mouse cells. Paper chromotography of acid hydrolysates of DNA extracted from cells treated with 3H-labeled 4NQO revealed four peaks; two kinds of 4NQO-guanine adduct, one kind of 4NQO-adenine adduct, and free 4-aminoquinoline-1-oxide (4AQO). About 80% of the initially formed 4NQO-purine adducts were excised from DNA in E. coli uvrA+ cells during 60 min postincubation, but not at all in uvrA- (excisionless for uv damage) cells. Normal human cells excised about 60% of 4NQO-purine adducts during 24 hr postincubation, but xeroderma pigmentosum (excisionless) cells did not. A mouse cell line susceptible to repair of 4NQO-induced pretransformational damage also showed excision-repair ability for the 4NQO adducts. From these and other results, we conclude that the 4NQO-purine adducts and unstable 4NQO-guanine products (which release 4AQO) are, like pyrimidine dimers, repairable by excision-repair universal among E. coli, mouse, and human being, and that unexcised ones are probably the major cause of killing, mutation, and cancer.

4-Nitroquinoline-1-oxide↗
PubMed1978

Application of alkaline sucrose gradient sedimentation to the study of DNA damage and its repair in mammalian cells treated with methylmethanesulfonate and 4-nitroquinoline-1-oxide.

KB cells and L cells were treated with methylmethanesulfonate (MMS) or 4-nitroquinoline-1-oxide (4 NQO) and the resulting damage to DNA and its repair were examined by sedimentation in an alkaline sucrose gradient. The sedimentation profiles obtained were found to be the resultant of a complex interrelationship between drug dosage, duration of the lysis period and the repair capacity of the cells. A systematic study of these variables was made which led to a plausible and useful interpretation of the sedimentation profiles. Both drugs produce two kinds of DNA modifications which show up as a single-strand breaks but affect the sedimentation profile in characteristic ways. One of these modifications which is quite alkali-labile can be studied using a 30-min lysis period. The other modification is less alkali-labile and can be studied using a long lysis period. Both KB cells and L cells can repair the former type of damage but only KB cells can repair the latter type of damage.

4-Nitroquinoline-1-oxide↗
PubMed1975

Reparable lethal DNA damage produced by enzyme-activated 4-hydroxyaminoquinoline 1-oxide.

4-Hydroxyaminoquinoline 1-oxide (4HAQO), the proximate form of a carcinogen 4-nitroquinoline 1-oxide (4NQO), was activated by 4HAQO-activating enzyme to react with transforming DNA of Bacillus subtilis. Inactivation of the transforming activity proceeded in parallel with the extent of binding of enzyme-activated 4HAQO to DNA. The inactivated DNA was susceptible to host-cell reactivation (Hcr) as judged from the difference in the surviving activity assayed with Hcr plus and Hcr- hosts, indicating the reparability of the DNA damage. The enzymatic binding of 4HAQO did not induce strand breaks in DNA as measured by its sedimentation rate in alkaline sucrose density gradient. It is estimated that the activated 4HAQO binding has almost the same efficiency of inactivating the transforming DNA as pyrimidine dimers induced by UV radiation. The results indicate that the activating enzyme is responsible for intracellular reaction of 4HAQO with DNA.

Bacillus subtilis↗
PubMed1975

Recovery of a DNA-protein complex in cultured mammalian cells from damage caused by 4-nitroquinoline 1-oxide.

Treatment of FM3A cells with 4-nitroquinoline 1-oxide caused a decrease in the sedimentation velocity of a DNA-protein complex, but did not cause a dissociation of the complex, as revealed by neutral sucrose gradient centrifugation. Microscopic autoradiography of the complex spread on a Millipore filter, demonstrated that treatment of the cells with 4-nitroquinoline 1-oxide, or of the complex with Pronase E, gave rise to a relaxed mass of DNA fibers, in contrast to a compact mass of DNA from control cells. The damage to the DNA-protein compelx was repaired completely by incubation of the cells in a medium without 4-nitroquinoline 1-oxide. The following metabolic inhibitors had no effect on the repair of the complex: inhibitors of nucleic acid synthesis, alpha-amanitine, cordycepin, 2-mercapto-1-(beta-4-pyridethyl)benzimidazol, 1-beta-D-arabinofuranosylcytosine, 5-fluorodeoxyuridine, and hydroxyurea; inhibitors of protein synthesis, cycloheximide and puromycin; an inhibitor of the dark repair process in a variety of biological systems, caffeine; inhibitors of the microtubular and microfilament system, Colcemid and cytochalasin B, respectively; and inhibitors of energy metabolism, 2,4-dinitrophenol, KCN, iodoacetic acid, ouabain, and an atmosphere of nitrogen. Acriflavine and actinomycin D, which are known to intercalate into DNA, caused a decrease in the sedimentation velocity of the DNA-protein complex; therefore, the effects of these agents on the recovery process remained unsolved. The repair process of the complex was, however, demonstrated to be temperature dependent. The process was inhibited at 10 degrees, retarded at 28 degrees, but accelerated at 40 degrees as compared with the rate at 37 degrees.

4-Nitroquinoline-1-oxide↗
PubMed2026

Protein persulfidation emerges as a conserved component of the redox response to DNA damage.

Genotoxic stress is frequently accompanied by alterations in cellular redox homeostasis; however, the mechanisms linking redox regulation to the DNA damage response (DDR) remain incompletely understood. Here, we investigated the early redox response to DNA damage induced by methyl methanesulfonate (MMS) in Saccharomyces cerevisiae, focusing on cysteine oxidative post-translational modifications (PTM). We show that activation of the DNA damage response is accompanied by rapid redox changes that occur in the absence of a generalized oxidative stress response. MMS exposure promotes selective remodeling of cysteine oxidative modifications, characterized by decreased free thiols, robust induction of protein persulfidation, and comparatively modest changes in sulfenylation. These alterations are accompanied by increased intracellular hydrogen sulfide levels, supporting the involvement of reactive sulfur species in the cellular response to DNA damage. Proteome-wide analyses revealed that cysteine oxidative modifications preferentially target proteins involved in central metabolism, nucleotide biosynthesis, and genome maintenance. Consistent with these observations, MMS-induced genotoxic stress promotes metabolic adaptation characterized by increased mitochondrial respiration, elevated ATP production, and mitochondrial morphological remodeling, linking bioenergetic adaptation to redox regulation. Importantly, perturbation of intracellular redox balance using N-acetylcysteine compromises survival under DNA-damaging conditions, supporting a functional role for redox signaling during the DDR. Finally, MMS treatment also induces protein persulfidation in mammalian cells. Moreover, exposure to etoposide, a mechanistically distinct genotoxic agent that induces DNA double-strand breaks through topoisomerase II inhibition, showed a similar trend, suggesting that protein persulfidation may not be restricted to alkylation-induced DNA damage. Together our findings identify protein persulfidation as a prominent component of the redox response to DNA damage and provide new insight into the functional interplay between mitochondrial metabolism, cysteine-based redox regulation, and genome maintenance.

Oxidation-Reduction↗
PubMed2023

Spontaneous allelic variant in deafness-blindness gene Ush1g resulting in an expanded phenotype.

Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target-specific, directed mutagenesis or phenotypic selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain genetic integrity in response to spontaneously induced damage. Mice deficient in the DNA glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion DNA synthesis past oxidatively induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting and circling. Mapping of the mutation that conferred these behaviors showed the introduction of a stop codon at amino acid 4 of the Ush1g gene. Ush1gbw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Consistent with other Usher type 1 models, Ush1gbw/bw mice had no substantial retinal degeneration compared with Ush1gbw /+ controls. In contrast to previously described Ush1g alleles, this new allele provides the first knockout model for this gene.

Mice↗
PubMed2026

Genotoxic Activity of Cerastes cerastes Viper Venom Using Alkaline Single-Cell Gel Electrophoresis.

In Morocco, Cerastes cerastes snake is responsible for numerous cases of human envenomation, leading to both local and systemic pathophysiological disturbances. This study provides a first preliminary evaluation of cytotoxic and genotoxic effects of its venom on genomic material (Deoxyribonucleotide acid: DNA). The venom protein profile was characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its median lethal dose (LD50) was determined by intraperitoneal injection in mice. Genotoxicity was assessed using the alkaline comet assay (single-cell gel electrophoresis) on peripheral blood cells following in vitro and in vivo venom treatments with sampling performed between 1 and 24 h after exposure. Concurrently, cell death was evaluated using the trypan blue exclusion assay as an indicator of venom-induced cytotoxicity. DNA damage parameters, including percentage of DNA in the head, tail and tail length, were quantified using OpenComet software. The venom exhibited a protein-rich composition and an LD50 of 34.64 µg/mouse. The comet assay revealed statistically significant DNA damage compared to the control group. Partial to complete DNA repair was noted after 24 h depending on the administered dose. These findings confirm those obtained with cell death assay. All results indicate that Moroccan C. cerastes venom induces transient DNA damage, potentially associated with oxidative stress mechanisms leading to cytotoxicity. It is primordial to characterize target venom-molecules exhibiting genetic failure in order to find an adequate therapeutic approach.

Cerastes cerastes venom↗
PubMed2026

From oxidative damage to actionable lesion: Telomeric 8-oxoGuanine and OGG1 modulation in aging and disease.

Oxidative stress is widely implicated in aging and chronic disease, but current insights have not led to the definition of a lesion state in the progression of disease or to broad guidance of therapy. So far, reactive oxygen species describe a chemical environment rather than a specific molecular entity. In contrast, 8-oxoG represents a defined oxidative DNA lesion with a defined genomic context impacting biological processes. Here, we propose that 8-oxoG and its downstream repair intermediates define a functionally relevant lesion state at telomeres. At chromosome ends, oxidized guanine can impair replication, activate DNA damage signalling, contribute to telomere attrition and drive senescence. Still, persistent lesions and the toxicity of downstream base excision repair intermediates contribute to this process. This distinction has direct therapeutic consequences: OGG1 inhibitors suppress inflammatory and transcriptional responses, whereas activators and organocatalytic switches promote lesion clearance. We propose that going forward, the choice between these strategies should depend on the dominant lesion state rather than global measures of oxidative stress.

Humans↗