Oxidative DNA Damage Research Articles

Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being.

Quercetin has a protective impact on human umbilical vein endothelial cells against tungsten carbide cobalt nanoparticle-induced cytotoxicity, oxidative stress, apoptosis

Oxidative stress is a pivotal factor in the pathogenesis of various cancer diseases. In fact, oxidative DNA damage is described as the type of damage probably to occur in cancer cells. This study examined the protective impact of the polyphenolic compound quercetin on human umbilical vein endothelial (HUVEC) cells against tungsten carbide cobalt nanoparticles (WC-Co NPs)-induced oxidative stress, cytotoxicity, and apoptosis. One of the most often used models for studying endothelial cells in vitro is the human umbilical vein epithelial cell. Scanning electron microscope (SEM) and transmission electron microscopy (TEM) were used to measure the size of the NPs prior to WC-Co NPs treatment. WC-Co NPs had a polygonal form and measured 45.26 ± 1 nm in size. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),neutral red uptake(NRU) and lactate dehydrogenase (LDH) assays, the cytotoxicity of WC-Co NPs on HUVECs cells was assessed. The cytotoxicity of NPs increased in a concentration-dependent way. The MTT result was used to calculate the median inhibitory concentration (IC50) for HUVEC cells at 24 h, which came out to be 23.14 μg/ml. Intracellular reactive oxygen species(ROS) and lipid peroxidation(LPO) levels were elevated at 17 g/ml WC-Co NPs and then reduced in HUVECs cells upon immediate exposure to 150 µM quercetin (QR). Using JC-1 staining, the loss of mitochondrial membrane potential(MMP) in control, WC-Co NPs alone and WC-Co NPs plus QR exposed cell were evaluated. In HUVECs cells, maximum apoptotic cells were seen at increasing NPs concentrations. Based on the impacts of NPs on HUVECs cells, the data suggests that QR may work on the process of scavenging ROS, which is responsible for DNA repair. Consequently, the above findings highlight the significance of these QR as defenses against DNA damage brought on by oxidative stress, which frequently happens in a number of cancer disorders.

OGG1: An emerging multifunctional therapeutic target for the treatment of diseases caused by oxidative DNA damage.

Oxidative DNA damage-related diseases, such as incurable inflammation, malignant tumors, and age-related disorders, present significant challenges in modern medicine due to their complex molecular mechanisms and limitations in identifying effective treatment targets. Recently, 8-oxoguanine DNA glycosylase 1 (OGG1) has emerged as a promising multifunctional therapeutic target for the treatment of these challenging diseases. In this review, we systematically summarize the multiple functions and mechanisms of OGG1, including pro-inflammatory, tumorigenic, and aging regulatory mechanisms. We also highlight the potential of OGG1 inhibitors and activators as potent therapeutic agents for the aforementioned life-limiting diseases. We conclude that OGG1 serves as a multifunctional hub; the inhibition of OGG1 may provide a novel approach for preventing and treating inflammation and cancer, and the activation of OGG1 could be a strategy for preventing age-related disorders. Furthermore, we provide an extensive overview of successful applications of OGG1 regulation in treating inflammatory, cancerous, and aging-related diseases. Finally, we discuss the current challenges and future directions of OGG1 as an emerging multifunctional therapeutic marker for the aforementioned challenging diseases. The aim of this review is to provide a robust reference for scientific researchers and clinical drug developers in the development of novel clinical targeted drugs for life-limiting diseases, especially for incurable inflammation, malignant tumors, and age-related disorders.

Deciphering the link: A cutting-edge exploration of the intriguing connection between recurrent pregnancy loss and rare earth elements-Lutetium, praseodymium, samarium, dysprosium, and cerium.

To evaluate the levels of serum rare earth elements (REEs): lutetium [Lu], praseodymium [Pr], samarium [Sm], dysprosium [Dy], and cerium [Ce] in pregnant women with recurrent pregnancy loss (RPL) and evaluate their relationship with total antioxidant capacity (TAC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA damage. A case-controlled study was conducted on a cohort of 60 female participants, with first-trimester healthy pregnant women as the control group and pregnant women with a history of consecutive abortions as the recurrent pregnancy loss (RPL) group. Following blood collection, serum concentrations of Lu, Pr, Sm, Dy, and Ce were measured using an inductively coupled plasma mass spectrophotometer (ICP-MS). Oxidative stress and DNA damage were evaluated through TAC and DNA damage marker (8-OHdG). Serum levels of Lu, Pr, Sm, Dy, and Ce were higher in women with RPL compared with control (P < 0.001). Intriguingly, a strong significant negative correlation was observed between TAC and REEs (P < 0.05). Lu, Dy, and Ce demonstrated a significant positive correlation with increased DNA damage in the RPL group (P < 0.05). Contrary, there was no evidence of a correlation between 8-OHdG and Pr and Sm. The study highlights a potential association between Lu, Sm, Dy, and Ce and an increased risk of RPL, highlighting REE-induced toxicity as a major risk factor for RPL. The outcome of the study is to advance our understanding of the interplay between rare earth elements and RPL, with potential implications for reproductive medicine, environmental health, and the development of preventive strategies for individuals at risk of RPL.

Short Peptides Protect Fibroblast-Derived Induced Neurons from Age-Related Changes

Neurons become more vulnerable to stress factors with age, which leads to increased oxidative DNA damage, decreased activity of mitochondria and lysosomes, increased levels of p16, decreased LaminB1 proteins, and the depletion of the dendritic tree. These changes are exacerbated in vulnerable neuronal populations during the development of neurodegenerative diseases. Glu-Asp-Arg (EDR) and Lys-Glu-Asp (KED), and Ala-Glu-Asp-Gly (AEDG) peptides have previously demonstrated neuroprotective effects in various models of Alzheimer’s disease. In this study, we investigated the influence of EDR, KED, and AEDG peptides on the aging of fibroblast-derived induced neurons. We used a new in vitro cellular model of human neuronal aging based on the transdifferentiation of aged dermal fibroblasts from elderly donors into induced cortical neurons. All peptides promote the arborization of the dendritic tree, increasing both the number of primary processes and the total length of dendrites. Tripeptides have no effect on the activity of mitochondria and lysosomes and the level of p16 protein in induced neurons. EDR peptide reduces oxidative DNA damage in induced neurons derived from elderly donor fibroblasts. Short peptides partially protect induced neurons from age-related changes and stimulate dendritogenesis in neurons. They can be recommended for use as neuroprotective agents.

Role of Vitamin C on methotrexate-induced nephrotoxicity in psoriasis context: A preclinical assessment

Methotrexate (MTX) is the most prescribed drug for systemic treatment of psoriasis. However, its clinical use is limited by its nephrotoxicity, which antioxidants can attenuate. This study evaluates the impact of vitamin C (vitC), a well-known antioxidant, on nephrotoxicity induced by high MTX doses in the context of psoriasis. To achieve this purpose, the kidney injury triggered by acute MTX exposure was established in an imiquimod-induced psoriasis-like mouse model. Mice were randomly divided into six groups: group 1 (control); group 2 (Imiquimod, IMQ), group 3 (IMQ+vitC 175 mg/kg/day); group 4 (MTX 20 mg/kg i.p); group 5 (IMQ+MTX 20 mg/kg) and group 6 (IMQ+MTX 20 mg/kg + vitC 175 mg/kg/day). The effects of these treatments were determined by considering the evolution of IMQ-induced skin lesions and serum creatinine levels. Moreover, histopathological analysis, lipid peroxidation, oxidative stress, and TNF-α production were determined in kidney tissue. Results showed that vitC attenuates renal damage in the context of IMQ-induced psoriasis. However, the opposite occurs when administered with IMQ+MTX, worsening skin psoriasis lesions and exacerbating acute renal tubular necrosis and oxidative DNA damage. These results establish new clues about the MTX-induced nephrotoxicity in the psoriasis context and the putative protective effects of vitC. It suggests that vitC supplementation could help attenuate the renal damage promoted by the psoriatic pathological environment. However, it should be avoided in psoriasis patients with renal dysfunction treated with MTX.

Abstract A033: Pro-inflammatory tumor cells drive CD4+ T cell localization within heterogeneous tumors

Abstract Immunotherapies such as immune checkpoint inhibitors (ICIs) have greatly improved patient outcomes in multiple tumor types, but ICIs have failed to achieve responses in many patients. Meta-analyses of patient cohorts treated with ICIs have observed that worse clinical outcomes are strongly correlated with high levels of intratumoral genetic heterogeneity (ITH). ITH occurs when tumor cells mutate as they divide, typically due to oxidative stress or DNA damage from rapid proliferation and continued carcinogenic insults, generating tumor subclones. However, the mechanisms by which ITH impairs the anti-tumor immune response are not fully understood. We propose a novel mechanism for how ITH in highly T cell-infiltrated inflamed tumors can adversely affect T cell behavior. We hypothesize that strongly pro-inflammatory tumor subclones secreting robust pro-inflammatory chemokine profiles can dominate T cell trafficking within the tumor, resulting in a weakened immune response against other tumor subclones. Using a murine squamous cell skin carcinoma (SCC) model, we have demonstrated that in immune-inflamed tumors, the spatial distribution and behavior of tumor-infiltrating T cells is influenced by ITH. A strongly pro-inflammatory tumor line expressing an endogenous RFP fluorophore was mixed with a weakly pro-inflammatory tumor line expressing an endogenous YFP fluorophore at a 1:1 ratio. The resulting tumors contained distinct RFP+ and YFP+ regions. These were analyzed by immunofluorescence (IF) and by manually dissecting the tumors and analyzing each region by flow cytometry. Flow cytometry analysis determined that the strongly pro-inflammatory RFP+ regions contained significantly more total T cells and CD4+ T cells than YFP+ regions. Furthermore, FoxP3- “conventional” CD4+ T cells were significantly more likely to be “terminal effector-like” CD44+CD62L- in RFP+ regions, and significantly more likely to be “naïve-like” CD62L+CD44- in YFP+ regions. IF analysis confirmed the preferential distribution of CD4+ T cells in RFP+ regions, and observed that this spatial pattern was evident as early as 11 days after subcutaneous injection. Notably, this localization trend did not occur with CD8+ T cells, which were evenly dispersed throughout the tumors. ELISA analysis of lysates of both tumor cell lines determined that the pro-inflammatory RFP+ cell line secretes significantly higher levels of the chemokine CCL5, which has been observed by other studies to selectively mediate CD4+ T cell chemotaxis. These results demonstrate that intratumoral CD4+ trafficking is shaped by the spatial distribution of specific tumor subclones, and suggest tumor cell chemokine signaling may directly mediate T cell spatial localization and behavior within tumors. Citation Format: Robert Letchworth, Savannah Hughes, Abigail Keku, Melissa Reeves. Pro-inflammatory tumor cells drive CD4+ T cell localization within heterogeneous tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A033.

Intestinal inflammation, oxidative damage, and pathogenesis of intestinal Cryptosporidium in juvenile Asian sea bass (Lates calcarifer)

AbstractPiscine intestinal Cryptosporidium infection is a known cause of severe illness and mortality in juvenile Asian sea bass, with inflammation playing a central role. This inflammation triggers the generation of reactive oxygen species (ROS), leading to irreversible DNA damage and activation of apoptosis pathways. However, the specific impact of inflammation on ROS production, DNA damage, and apoptosis in this context remains unclear. This study investigated the pathogenic role of inflammation and ROS in causing DNA damage and cell apoptosis in piscine intestinal cryptosporidiosis. Forty‐four intestinal samples from 60‐ and 90‐day juvenile Asian sea bass were divided into four groups based on Cryptosporidium infection status. Histopathological evaluation and immunofluorescent analysis were conducted to assess ROS production, DNA damage, and cellular apoptosis markers. Results showed significantly higher inflammatory cell infiltration, intracellular ROS production, DNA damage, and cellular apoptosis in 60‐day infected fish compared to 90‐day infected fish. These findings underscore distinct responses in juvenile Asian sea bass to piscine intestinal cryptosporidiosis, highlighting severe inflammation, oxidative DNA damage, and cellular apoptosis, particularly in younger fish.

α-Terpineol Induces Shelterin Components TRF1 and TRF2 to Mitigate Senescence and Telomere Integrity Loss via A Telomerase-Independent Pathway.

Cellular senescence is a hallmark of aging characterized by irreversible growth arrest and functional decline. Progressive telomeric DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. Therefore, protecting telomeres from DNA damage is essential in order to avoid entry into senescence and organismal aging. In several organisms, including mammals, telomeres are protected by a protein complex named shelterin that prevents DNA damage at the chromosome ends through the specific function of its subunits. Here, we reveal that the nuclear protein levels of shelterin components TRF1 and TRF2 decline in fibroblasts reaching senescence. Notably, we identify α-terpineol as an activator that effectively enhances TRF1 and TRF2 levels in a telomerase-independent manner, counteracting the senescence-associated decline in these crucial proteins. Moreover, α-terpineol ameliorates the cells' response to oxidative DNA damage, particularly at the telomeric regions, thus preserving telomere length and delaying senescence. More importantly, our findings reveal the significance of the PI3K/AKT pathway in the regulation of shelterin components responsible for preserving telomere integrity. In conclusion, this study deepens our understanding of the molecular pathways involved in senescence-associated telomere dysfunction and highlights the potential of shelterin components to serve as targets of therapeutic interventions, aimed at promoting healthy aging and combating age-related diseases.

Electrochemical DNA Sensor Based on Poly(proflavine) Deposited from Natural Deep Eutectic Solvents for DNA Damage Detection and Antioxidant Influence Assessment

Electrochemical DNA sensors for DNA damage detection based on electroactive polymer poly(proflavine) (PPFL) that was synthesized at screen-printed carbon electrodes (SPCEs) from phosphate buffer (PB) and two natural deep eutectic solvents (NADESs) consisting of citric or malonic acids, D-glucose, and a certain amount of water (NADES1 and NADES2) were developed. Poly(proflavine) coatings obtained from the presented media (PPFLPB, PPFLNADES1, and PPFLNADES2) were electrochemically polymerized via the multiple cycling of the potential or potentiostatic accumulation and used for the discrimination of thermal and oxidative DNA damage. The electrochemical characteristics of the poly(proflavine) coatings and their morphology were assessed using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). The working conditions for calf thymus DNA implementation and DNA damage detection were estimated for all types of poly(proflavine) coatings. The voltammetric approach made it possible to distinguish native and chemically oxidized DNA while the impedimetric approach allowed for the successful recognition of native, thermally denatured, and chemically oxidized DNA through changes in the charge transfer resistance. The influence of different concentrations of conventional antioxidants and pharmaceutical preparations on oxidative DNA damage was characterized.

How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation.

Neutrophil extracellular traps (NETs) are intricate, DNA-based, web-like structures adorned with cytotoxic proteins. They play a crucial role in antimicrobial defense but are also implicated in autoimmune diseases and tissue injury. The process of NET formation, known as NETosis, is a regulated cell death mechanism that involves the release of these structures and is unique to neutrophils. NETosis is heavily dependent on the production of reactive oxygen species (ROS), which can be generated either through NADPH oxidase (NOX) or mitochondrial pathways, leading to NOX-dependent or NOX-independent NETosis, respectively. Recent research has revealed an intricate interplay between ROS production, DNA repair, and NET formation in different contexts. UV radiation can trigger a combined process of NETosis and apoptosis, known as apoNETosis, driven by mitochondrial ROS and DNA repair. Similarly, in calcium ionophore-induced NETosis, both ROS and DNA repair are key components, but only play a partial role. In the case of bacterial infections, the early stages of DNA repair are pivotal. Interestingly, in serum-free conditions, spontaneous NETosis occurs through NOX-derived ROS, with early-stage DNA repair inhibition halting the process, while late-stage inhibition increases it. The intricate balance between DNA repair processes and ROS production appears to be a critical factor in regulating NET formation, with different pathways being activated depending on the nature of the stimulus. These findings not only deepen our understanding of the mechanisms behind NETosis but also suggest potential therapeutic targets for conditions where NETs contribute to disease pathology.

Dysfunctional copper homeostasis in Caenorhabditis elegans affects genomic and neuronal stability

While copper (Cu) is an essential trace element for biological systems due to its redox properties, excess levels may lead to adverse effects partly due to overproduction of reactive species. Thus, a tightly regulated Cu homeostasis is crucial for health. Cu dyshomeostasis and elevated labile Cu levels are associated with oxidative stress and neurodegenerative disorders, but the underlying mechanisms have yet to be fully characterized. Here, we used Caenorhabditis elegans loss-of-function mutants of the Cu chaperone ortholog atox-1 and the Cu binding protein ortholog ceruloplasmin to model Cu dyshomeostasis, as they display a shifted ratio of total Cu towards labile Cu. We applied highly selective and sensitive techniques to quantify metabolites associated to oxidative stress with focus on mitochondrial integrity, oxidative DNA damage and neurodegeneration all in the context of a disrupted Cu homeostasis. Our novel data reveal elevated oxidative stress, compromised mitochondria displaying reduced ATP levels and cardiolipin content. Cu dyshomeostasis further induced oxidative DNA damage and impaired DNA damage response as well as neurodegeneration characterized by behavior and neurotransmitter analysis. Our study underscores the essentiality of a tightly regulated Cu homeostasis as well as mitochondrial integrity for both genomic and neuronal stability.

Toxicological Effects and Mechanisms of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) on Marine Organisms.

2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is a widely used brominated flame retardant belonging to persistent organic pollutants (POPs). After being released into the marine environment, BDE-47 can cause a range of toxic effects on marine organisms through bioaccumulation, biomagnification, and intergenerational transmission. These effects include lethality, impaired motility, photosynthetic toxicity, immune damage, liver toxicity, developmental impairments, and reproductive toxicity. This article reviews the latest research progress on the toxic effects and molecular mechanisms of BDE-47 mentioned above. The primary mechanisms underlying its toxicity include oxidative stress, DNA damage, cellular apoptosis, impaired metabolism, and activation of the MAPK signaling cascade.

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.

Ochratoxin A and Its Role in Cancer Development: A Comprehensive Review.

Background: Ochratoxin A (OTA) is widely recognized for its broad spectrum of toxic effects and is classified as a potential human carcinogen, placed in group 2B by the International Agency for Research on Cancer (IARC). Its presence in food and beverages poses a significant health hazard. Extensive research has documented the efficient absorption and distribution of OTA throughout the body via the bloodstream and tissues, underscoring the associated health risk. Additionally, ongoing studies aim to clarify the link between OTA exposure and carcinogenesis. The obtained results indicate a strong correlation between OTA and renal cell carcinoma (RCC), with potential associations with other malignancies, including hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and squamous cell carcinoma (SCC). OTA is implicated in oxidative stress, lipid peroxidation, apoptosis, DNA damage, adduct formation, miRNA deregulation, and distributions in the cell cycle, all of which may contribute to carcinogenesis. Conclusions: Despite significant research efforts, the topic remains inexhaustible and requires further investigation. The obtained results do not yield definitive conclusions, potentially due to species-specific differences in the animal models used and challenges in extrapolating these results to humans. In our review, we delve deeper into the potential mechanisms underlying OTA-induced carcinogenesis and discuss existing limitations, providing directions for future research.

Oxidative damage biomarkers and antioxidant enzymes in saliva of patients with peri-implant diseases

Objectives8-hydroxydeoxyguanosine (8-OHdG) and Malondialdehyde (MDA) are commonly used as markers to evaluate oxidative DNA and Lipid damage in disorders including chronic inflammatory diseases. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) protect tissues against oxidative injury from free oxygen radicals generated by various metabolic processes. The aim of this study was to evaluate 8-OHdG and MDA levels, and SOD and GPx activities in whole saliva of patients with peri-implant diseases.Materials and methodsA cross-sectional study was conducted on a sum of 60 age gender balanced; peri-implantitis (n = 20), peri-mucositis (n = 20) and healthy (n = 20) individuals. Unstimulated whole saliva samples were collected and to determine the clinical condition of each subject; the plaque index (PI), gingival index (GI), peri-implant probing pocket depth (PIPD), peri-implant presence of bleeding on probing (BOP) (with/without suppuration) and radiographic signs of crestal bone loss (BL) were measured. The salivary 8-OHdG level was measured using the ELISA method. SOD, GPx activities and MDA levels were determined spectrophotometrically.ResultsA total of 60 individuals had evaluations of 318 implants. In comparison to the peri-mucositis and peri-implantitis groups, the healthy group had significantly lower PI and GI scores (p < 0.001). The PIPD value differed amongst the groups, with the peri-implantitis group having the highest value (p < 0.001). Compared to the peri-mucositis and control groups, the peri-implantitis group had a significantly higher BL score (p < 0.001 and p < 0.001, respectively). The peri-implantitis group showed a significantly higher 8-OHdG level (p < 0.001; p < 0.001 respectively) than the peri-mucositis and control groups. Compared to the peri-mucositis and control groups, the peri-implantitis group had a significantly higher MDA level (p < 0.001 and p < 0.001, respectively). The peri-implantitis group had a significantly higher SOD level (p < 0.001 and p < 0.001, respectively) in comparison to the peri-mucositis and control groups. There was no significant difference in GPx levels between the peri-mucositis and control groups (p > 0.05), while the peri-implantitis group had significantly lower GPx levels than the peri-mucositis and control groups (p < 0.001 and p < 0.001, respectively).ConclusionsElevated levels of oxidative stress in saliva may indicate the onset of pathological bone loss surrounding the implant and may be an indication of peri-implantitis.Clinical relevanceIn peri-implant diseases, changes may occur in the levels of 8-OHdG, MDA, SOD and GPx in saliva, which may lead to a deterioration in the oxidant/antioxidant balance.

Human 8-Oxoguanine Glycosylase OGG1 Cleaves Abasic Sites and Covalently Conjugates to 3'-DNA Termini via Cysteine and Histidine Addition.

8-Oxoguanine glycosylase 1 (OGG1) repairs the major oxidative DNA damage, 8-oxo-2'-deoxyguanosine. It has been reported that OGG1 incises the most frequently formed DNA lesion, apurinic/apyrimidinic (AP) site, and in the process a stable DNA-OGG1 cross-link is formed. However, the chemical structure of the adduct is not characterized. Here, we report that DNA-OGG1 cross-links result from cysteine and histidine addition to incised AP sites at 3'-DNA termini.

The Human 8-oxoG DNA Glycosylase 1 (OGG1) Ser326Cys Polymorphism in Infertile Men.

8-hydroxy-2'-deoxyguanosine (8-OHdG) is a form of oxidative DNA damage caused by oxidative stress (OS), which is considered a major factor in male infertility. The cellular defense system against 8-OHdG involves base excision repair (BER) with the enzyme 8-Oxoguanine DNA glycosylase 1 (OGG1). However, studies on the single-nucleotide polymorphism (SNP) OGG1 Ser326Cys have demonstrated that the Cys326Cys genotype could be the cause of an increment in oxidative DNA damage. In this study, the OGG1 Ser326Cys polymorphism and its effect on DNA oxidation were evaluated in 118 infertile men. Polymorphic screening was performed using TaqMan allelic discrimination assays, and oxidative DNA damage was evaluated through the quantification of 8-OHdG and total antioxidant capacity (TAC); in addition, electrical bioimpedance spectroscopy (EBiS) measurements were used as a reference for different electrical properties associated with 8-OHdG concentrations. The detected Cys (G) allele frequency (0.4) was higher compared to the allele frequency reported in the "Allele Frequency Aggregator" (ALFA) and "Haplotype Map" (HapMap) projects for American populations (0.21-0.29), suggesting that the Cys (G) allele carrier could be a factor associated with American infertile populations. The values of 8-OHdG were twofold higher in carriers of the Cys326Cys (GG) genotype than the other genotypes and, in concordance, the TAC levels were threefold lower in Cys326Cys (GG) genotype carriers compared to the other genotypes. Moreover, the EBiS magnitude exhibited potential for the detection of different oxidative damage in DNA samples between genotypes. The Cys326Cys (GG) genotype is associated with oxidative DNA damage that could contribute to male infertility.

Role of oxidative stress in the occurrence of periodontitis in the background of metabolically associated diseases

Oxidative stress is an important component of slow pathological inflammation in metabolic diseases and chronic periodontitis. Periodontal diseases are interrelated with somatic pathology. This results in both local and systemic inflammatory reactions, which increases the risk of the onset and progression of somatic diseases. Psychological stress associated with oxidative stress with increased production of oxidants and oxidative damage is an important factor in the etiology of both periodontitis and metabolic disorders. Objective — to analyze the possible bond between chronic periodontitis, 8‑hydroxydeoxyguanosine (8‑OHdG), as a biomarker of oxidative stress, and cortisol in persons with metabolic‑associated diseases. Materials and methods. 68 people were surveyed, of which 47 had metabolically ‑associated diseases that were diagnosed according to domestic and international criteria. The control group consisted of systematically healthy people, representative by age and article that did not receive dental therapeutic and preventive measures for the last 6 months. The diagnosis of «chronic periodontitis» was carried out in accordance with existing recommendations provided at World Workshop on the Classification of Periodontal and Peri­Implant Diseases and Conditions (2017). The concentration of 8‑OHdG in plasma and the level of saliva cortisol were measured by the immunoenzyme method according to the manufacturer’s instructions. The arithmetic mean, standard error, and Student’s t‑test were calculated to compare the characteristics. Pearson’s correlation test was used to identify the relationship between the indicators. Results. Each of the groups had patients who had a healthy periodontium and those who had chronic periodontitis. The 8‑OHdG level in the main group was much higher (p&lt;0.001) than in the control group, and the difference in the concentration of 8‑OHdG was also observed between those patients who had periodontal disease and those who had a healthy periodontium. The level of salivary cortisol in patients with chronic periodontitis was much higher compared to patients with clinically healthy periodontium (p=0.00). A correlation was found between cortisol levels and the presence of periodontal disease (r=0.619; p=0.00), between plasma 8OHdG levels and the epithelial attachment loss index (r=0.537; p=0.00), the hygiene index (r=0.599; p=0.00), and between 8OHdG levels and salivary cortisol concentrations (r=0.292; p=0.036). Conclusions. Oxidative stress plays an important role in delayed pathological inflammation in both metabolic diseases and chronic periodontitis. 8‑OHdG is a key and universal biomarker for the evaluation of DNA oxidative damage. There is a positive relationship between the oxidative marker, periodontitis and cortisol.

The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells

Background/ObjectiveActive vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells. MethodsBone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/−) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups. ResultsABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins. ConclusionABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency. The translational potential of this articleThis study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.