Oxidative DNA Damage Research Articles

Turmeric: from spice to cure. A review of the anti-cancer, radioprotective and anti-inflammatory effects of turmeric sourced compounds

Turmeric (Curcuma longa) has been extensively studied for its diverse pharmacological properties, including its potential role as an anticancer agent, antioxidant, and radioprotector. This review provides an overview of the chemical composition of turmeric, focusing on its main bioactive compounds, such as curcuminoids and volatile oils. Curcumin, the most abundant curcuminoid in turmeric, has been widely investigated for its various biological activities, including anti-inflammatory, antioxidant, and anticancer effects. Numerous in vitro and in vivo studies have demonstrated the ability of curcumin to modulate multiple signaling pathways involved in carcinogenesis, leading to inhibition of cancer cell proliferation, induction of apoptosis, and suppression of metastasis. Furthermore, curcumin has shown promising potential as a radioprotective agent by mitigating radiation-induced oxidative stress and DNA damage. Additionally, turmeric extracts containing curcuminoids have been reported to exhibit potent antioxidant activity, scavenging free radicals and protecting cells from oxidative damage. The multifaceted pharmacological properties of turmeric make it a promising candidate for the development of novel therapeutic strategies for cancer prevention and treatment, as well as for the management of oxidative stress-related disorders. However, further research is warranted to elucidate the underlying mechanisms of action and to evaluate the clinical efficacy and safety of turmeric and its bioactive constituents in cancer therapy and radioprotection. This review consolidates the most recent relevant data on turmeric’s chemical composition and its therapeutic applications, providing a comprehensive overview of its potential in cancer prevention and treatment, as well as in radioprotection.

Pathological Changes and Metabolic Adaptation in the Myocardium of Rats in Response to Chronic Variable Mild Stress

Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential therapeutic interventions for depression. While the behavioral and neurobiological effects of CVS have been extensively studied, its impact on myocardial function remains largely unexplored. To induce the CVS model, rats were exposed to various stressors over 40 days. Behavioral assessments confirmed depressive-like behavior. Biochemical analyses revealed alterations in myocardial metabolism, including changes in NAD+ and NADP+, and NADPH concentrations. Free amino acid analysis indicated disturbances in myocardial amino acid metabolism. Evaluation of oxidative DNA damage demonstrated an increased number of abasic sites in the DNA of rats exposed to CVS. Molecular analysis showed significant changes in gene expression associated with glucose metabolism, oxidative stress, and cardiac remodeling pathways. Histological staining revealed minor morphological changes in the myocardium of CVS-exposed rats, including increased acidophilicity of cells, collagen deposition surrounding blood vessels, and glycogen accumulation. This study provides novel insights into the impact of chronic stress on myocardial function and metabolism, highlighting potential mechanisms linking depression and cardiovascular diseases. Understanding these mechanisms may aid in the development of targeted therapeutic strategies to mitigate the adverse cardiovascular effects of depression.

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway

The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.

Quantifying the Level of 8-oxo-dG Using ELISA Assay to Evaluate Oxidative DNA Damage in MCF-7 Cells

Quantifying the Level of 8-oxo-dG Using ELISA Assay to Evaluate Oxidative DNA Damage in MCF-7 Cells

Deciphering the Effects of Different Types of Sunlight Radiation on Skin Function: A Review

Sunlight radiation is a fundamental component of our daily lives. Specifically, blue light as well as UV light appear to play a role in the development of oxidative stress, DNA damage, photoaging, and pigmentation through the chromophores in skin tissues. However, several skin problems like psoriasis, eczema, and atopic dermatitis can be avoided with short-duration exposures to low-energy blue light radiation or UV radiation. In addition, exploring the effects of blue light as well as UV radiation on skin is quite essential for the development of minimally invasive antiaging strategies and for the design of innovative cosmetic formulations in modern aesthetics and cosmetology. Thus, in this review, we present the advantages as well as the disadvantages of light radiation, with a special focus on blue light and UV radiation activity on the human skin. We also discuss the molecular action of blue light and UV radiation on human skin. Other types of light radiation are included to holistically approach the effect of light on human skin.

Silver and Copper Nanoparticle-Loaded Self-Assembled Pseudo-Peptide Thiourea-Based Organic-Inorganic Hybrid Gel with Antibacterial and Superhydrophobic Properties for Antifouling Surfaces.

The escalating threat of antimicrobial resistance has become a global health crisis. Therefore, there is a rising momentum in developing biomaterials with self-sanitizing capabilities and inherent antibacterial properties. Despite their promising antimicrobial properties, metal nanoparticles (MNPs) have several disadvantages, including increased toxicity as the particle size decreases, leading to oxidative stress and DNA damage that need consideration. One solution is surface functionalization with biocompatible organic ligands, which can improve nanoparticle dispersibility, reduce aggregation, and enable targeted delivery to microbial cells. The existing research predominantly concentrates on the advancement of peptide-based hydrogels for coating materials to prevent bacterial infection, with limited exploration of developing surface coatings using organogels. Herein, we have synthesized organogel-based coatings doped with MNPs that can offer superior hydrophobicity, oleophobicity, and high stability that are not easily achievable with hydrogels. The self-assembled gels displayed distinct morphologies, as revealed by scanning electron microscopy and atomic force microscopy. The cross-linked matrix helps in the controlled and sustained release of MNPs at the site of bacterial infection. The synthesized self-assembled gel@MNPs exhibited excellent antibacterial properties against harmful bacteria such as Escherichia coli and Staphylococcus aureus and reduced bacterial viability up to 95% within 4 h. Cytotoxicity testing against metazoan cells demonstrated that the gels doped with MNPs were nontoxic (IC50 > 100 μM) to mammalian cells. Furthermore, in this study, we coated the organogel@MNPs on cotton fabric and tested it against Gram +ve and Gram -ve bacteria. Additionally, the developed cotton fabric exhibited superhydrophobic properties and developed a barrier that limits the interaction between bacteria and the surface, making it difficult for bacteria to adhere and colonize, which holds potential as a valuable resource for self-cleaning coatings.

P04 How fibroblasts and azathioprine prepare the soil for cutaneous squamous cell carcinoma

Abstract Introduction and aims DNA damage-inducing immunosuppressive drugs such as azathioprine (AZA) act synergistically with ultraviolet (UV)A radiation and photosensitize the skin of immunosuppressed individuals, such as organ transplant recipients. These individuals have an increased risk of developing cutaneous squamous cell carcinoma (cSCC). The specific combination of AZA and UVA causes oxidative DNA damage that leaves behind a characteristic mutational signature in tumour keratinocytes of patients treated with AZA. However, as UVA radiation can penetrate the dermis, the impact of AZA/UVA on cells of the tumour microenvironment, such as fibroblasts, also need to be addressed. Fibroblasts are crucial for cSCC development and progression as they can switch to a protumourigenic phenotype. Methods Cell viability and senescence assays were performed to investigate the impact of AZA in combination with or without UVA on neonatal (nonsun-exposed) and adult (sun-exposed) human dermal fibroblasts. In addition, the impact of AZA/UVA-treated fibroblasts on the clonal growth properties of different cSCC cell models was investigated using three-dimensional (co)culture models. Results We found that AZA and UVA synergistically reduce the viability of both UV-naïve neonatal and sun-exposed adult dermal fibroblasts. In addition, combined AZA and UVA treatments lead to an increased percentage of senescent fibroblasts. We hypothesize that the aberrant secretome of these senescent fibroblasts can impact the growth behaviour of tumour cells. In a soft agar assay, the more malignant cSCC cells (MET-1) formed more and larger clonal spheroids and were less dependent on growth factors compared with spheroids formed by premalignant (PM-1) keratinocytes. Conclusions AZA and UVA act synergistically and potentiate a UVA-induced senescent fibroblast phenotype. The changed characteristics of these fibroblasts can impact the stem cell-like properties from premalignant and malignant keratinocytes. Combining keratinocyte and fibroblast culture models enables us to study how AZA/UVA promote the initiation and progression of cSCC.

Long-term calorie restriction reduces oxidative DNA damage to oligodendroglia and promotes homeostatic microglia in the aging monkey brain

Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain.

Uncovering the Role of Methylmercury on DNA Lesions at Cytotoxic Concentrations in Glutathione-Depleted Cells: Insights from Experimental and Computational Studies.

Organomercurials (RHg+), especially methylmercury (MeHg+) and ethylmercury (EtHg+), are considered to be more neurotoxic than the inorganic counterpart (Hg2+). They cause massive DNA damage in cells, especially in neurons, where cellular glutathione (GSH) levels are significantly low. However, the mechanism by which RHg+ exerts massive DNA damage at cytotoxic concentrations in brain cells remains obscure. In this study, we investigated the effect of RHg+ on the structural and electronic properties of nucleosides and its effects on DNA damage. The direct interaction of RHg+ with the nucleoside significantly weakens N-glycosidic bonds, decreases the C-H bond energy of sugar moieties, and increases the electrophilicity of the C8-center of purine bases. As a consequence, RHg+-conjugated DNA molecules are extremely labile and highly sensitive to any nucleophiles/radicals present in GSH-depleted cells and, thus, undergo enhanced oxidative and unusual alkylative DNA damage. We also report a functional model of organomercurial lyase, which showed excellent cytoprotective effect against RHg+-induced cytotoxicity; this reverses the activity of glutathione reductase inhibited by MeHgCl and ceases oxidative and alkylating DNA damage. This intriguing finding provides new mechanistic insight into the mode of action of organomercurials in GSH-depleted cells and their adverse effects on individuals with neurodegenerative disorders associated with oxidative stress.

Role of Quercetin in DNA Repair: Possible Target to Combat Drug Resistance in Diabetes.

Diabetes Mellitus (DM) is referred to as hyperglycemia in either fasting or postprandial phases. Oxidative stress, which is defined by an excessive amount of reactive oxygen species (ROS) production, increased exposure to external stress, and an excessive amount of the cellular defense system against them, results in cellular damage. Increased DNA damage is one of the main causes of genomic instability, and genetic changes are an underlying factor in the emergence of cancer. Through covalent connections with DNA and proteins, quercetin has been demonstrated to offer protection against the creation of oxidative DNA damage. It has been found that quercetin shields DNA from possible oxidative stress-related harm by reducing the production of ROS. Therefore, Quercetin helps to lessen DNA damage and improve the ability of DNA repair mechanisms. This review mainly focuses on the role of quercetin in repairing DNA damage and compensating for drug resistance in diabetic patients. Data on the target topic was obtained from major scientific databases, including SpringerLink, Web of Science, Google Scholar, Medline Plus, PubMed, Science Direct, and Elsevier. In preclinical studies, quercetin guards against DNA deterioration by regulating the degree of lipid peroxidation and enhancing the antioxidant defense system. By reactivating antioxidant enzymes, decreasing ROS levels, and decreasing the levels of 8-hydroxydeoxyguanosine, Quercetin protects DNA from oxidative damage. In clinical studies, it was found that quercetin supplementation was related to increased antioxidant capacity and decreased risk of type 2 diabetes mellitus in the experimental group as compared to the placebo group. It is concluded that quercetin has a significant role in DNA repair in order to overcome drug resistance in diabetes.

Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence

Transcription stress has been linked to DNA damage -driven aging, yet the underlying mechanism remains unclear. Here, we demonstrate that Tcea1−/− cells, which harbor a TFIIS defect in transcription elongation, exhibit RNAPII stalling at oxidative DNA damage sites, impaired transcription, accumulation of R-loops, telomere uncapping, chromatin bridges, and genome instability, ultimately resulting in cellular senescence. We found that R-loops at telomeres causally contribute to the release of telomeric DNA fragments in the cytoplasm of Tcea1−/− cells and primary cells derived from naturally aged animals triggering a viral-like immune response. TFIIS-defective cells release extracellular vesicles laden with telomeric DNA fragments that target neighboring cells, which consequently undergo cellular senescence. Thus, transcription stress elicits paracrine signals leading to cellular senescence, promoting aging.

Alternariol Monomethyl-Ether Induces Toxicity via Cell Death and Oxidative Stress in Swine Intestinal Epithelial Cells.

Alternariol monomethyl-ether (AME), together with altenuene and alternariol, belongs to the Alternaria mycotoxins group, which can contaminate different substrates, including cereals. The aim of the present study was to obtain a deeper understanding concerning the effects of AME on pig intestinal health using epithelial intestinal cell lines as the data concerning the possible effects of Alternaria toxins on swine are scarce and insufficient for assessing the risk represented by Alternaria toxins for animal health. Our results have shown a dose-related effect on IPEC-1 cell viability, with an IC50 value of 10.5 μM. Exposure to the toxin induced an increase in total apoptotic cells, suggesting that AME induces programmed cell death through apoptosis based on caspase-3/7 activation in IPEC-1 cells. DNA and protein oxidative damage triggered by AME were associated with an alteration of the antioxidant response, as shown by a decrease in the enzymatic activity of catalase and superoxide dismutase. These effects on the oxidative response can be related to an inhibition of the Akt/Nrf2/HO-1 signaling pathway; however, further studies are needed in order to validate these in vitro data using in vivo trials in swine.

Ultra-sensitive Tb3+/G-quadruplex fluorescence detection of oxidative DNA damage coupled with DNA glycosylase

Development of simple, sensitive and rapid sensing strategy for DNA damage induced by chemical reagents is urgent demand. In this assay, a Tb3+/G-quadruplex fluorescence system was proposed for the sensitive detection of DNA damage induced by Fenton reaction. The specific guanine-rich oligonucleotides can form G-quadruplex induced by Tb3+, leading to an enhancement of Tb3+ emission due to energy transfer from guanine to Tb3+. After a DNA damage reaction with Fenton reagents, an obvious fluorescence decrease was observed due to the structure change of Tb3+/G-quadruplex. which was also confirmed by polyacrylamide gel electrophoresis and circular dichroism. The Fe2+-mediated Fenton reaction with as low as 0.01 μM Fe2+ and 0.04 μM H2O2 induced oxidative DNA damage can be detected. Additionally, the human 8-oxoguanine DNA glycosylase (hOGG 1) was introduced to amplify DNA oxidation damage, by converting DNA oxidative nucleobases to strand break. Over 30-fold lower detection limit of 0.3 nM Fe2+ and 1.2 nM H2O2 was achieved. Alternative specific DNA damage or other DNA repair enzymes produced much less fluorescence decrease, demonstrating its good selectivity. It shows the potential to become a universal screening tool for the rapid and sensitive assessment of the genotoxicity of the overwhelming number of chemicals in environment.

Oxidative DNA damage contributes to usnic acid-induced toxicity in human induced pluripotent stem cell-derived hepatocytes.

Dietary supplements containing usnic acid have been increasingly marketed for weight loss over the past decades, even though incidences of severe hepatotoxicity and acute liver failure due to their overuse have been reported. To date, the toxic mechanism of usnic acid-induced liver injury at the molecular level still remains to be fully elucidated. Here, we conducted a transcriptomic study on usnic acid using a novel in vitro hepatotoxicity model employing human induced pluripotent stem cell (iPSC)-derived hepatocytes. Treatment with 20 μM usnic acid for 24 h caused 4272 differentially expressed genes (DEGs) in the cells. Ingenuity Pathway Analysis (IPA) based on the DEGs and gene set enrichment analysis (GSEA) using the whole transcriptome expression data concordantly revealed several signaling pathways and biological processes that, when taken together, suggest that usnic acid caused oxidative stress and DNA damage in the cells, which further led to cell cycle arrest and eventually resulted in cell death through apoptosis. These transcriptomic findings were subsequently corroborated by a variety of cellular assays, including reactive oxygen species (ROS) generation and glutathione (GSH) depletion, DNA damage (pH2AX detection and 8-hydroxy-2'-deoxyguanosine [8-OH-dg] assay), cell cycle analysis, and caspase 3/7 activity. Collectively, the results of the current study accord with previous in vivo and in vitro findings, provide further evidence that oxidative stress-caused DNA damage contributes to usnic acid-induced hepatotoxicity, shed new light on molecular mechanisms of usnic acid-induced hepatotoxicity, and demonstrate the usefulness of iPSC-derived hepatocytes as an in vitro model for hepatotoxicity testing and prediction.

Oxidative DNA damage promotes vascular aging associated with changes in extracellular matrix-regulating proteins.

Vascular aging is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular aging, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular aging. We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of aging, and ECM proteomics in mice from 22-72w. Vascular aging was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalised all parameters to 72w. ECM proteomics identified major changes in collagens with aging, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness. Vascular aging is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular aging, associated with changes in ECM regulatory proteins including LOX and WISP2.

An Overview Of The Biological Methods Used To Assess DNA Damage In Humans

The purpose of this work is to summarize the biological methods available for assessing DNA damage in humans at present. There are several methods for determining single-strand DNA breaks, alkali-labile sites, and crosslinks, including comet assays, micronucleus assays, cytogenetics (which include sister chromatid exchange and chromosomal aberration assays), DNA repair assays, oxidative DNA damage assays (measuring oxidized bases such as 8-oxo-7, 8-dihydro-2'-deoxyguanosine), and oxidized bases. There are many factors to consider when determining the best method, including how to achieve the study's objectives, what type of DNA damage to measure, and what resources are available. Combining different techniques may also contribute to a more comprehensive understanding of DNA damage and its effects on human health. By standardizing assays and advancing technology, we will be able to determine DNA damage in humans more accurately.

M1 polarization induction by lead and amyloid peptides in microglial cells: Implications for neurodegeneration process.

Neurodegeneration in conditions like Alzheimer's and Parkinson's disease is influenced by genetic and environmental factors. This study explores the potential neurodegenerative effects of lead (Pb) toxicity and amyloid beta peptides (Aβp 1-40 and Aβp 25-35) by promoting M1 polarization in microglial cells. To this end, we investigated and observed that IC50 concentrations of Pb (22.8 μM) and Aβp 25-35(29.6 μM). Our results demonstrated significant Pb uptake (31.13% at 25 μM Pb) and increased intracellular ROS levels (77.1%) upon treatment with Pb in combination of both Aβp 1-40 and Aβp 25-35. Protein carbonylation significantly increased (73.12 nmol/mL) upon treatment with Pb in combination of both Aβp 1-40 and Aβp 25-35, indicating oxidative damage and compromised cellular defenses against oxidative stress along with elevated DNA oxidative damage (164.9 pg/mL of 8-OH-dG) upon treatment with Pb in combination with both Aβp 1-40 and Aβp 25-35. Microglial polarization showed elevated M1 markers (inducible nitric oxide synthase and cyclooxygenase 2) and reduced M2 markers (arginase-1 and cluster of differentiation 206), suggesting Pb's role in inducing neurodegenerative microglial polarization. These findings provide insights into the complex molecular events contributing to Pb-induced neurotoxicity and neurodegenerative diseases.

Dapagliflozin suppresses diabetes-induced oxidative DNA damage and hypermethylation in mouse somatic cells

Diabetes mellitus is a complex metabolic disorder resulting from the interplay of environmental, genetic, and epigenetic factors that increase the risk of cancer development. However, it is unclear whether the increased cancer risk is due to poor glycemic control or the use of some antidiabetic medications. Therefore, we investigated the genetic and epigenetic changes in somatic cells in a mouse model of diabetes and studied whether multiple exposures to the antidiabetic medication dapagliflozin influence these changes. We also elucidated the mechanism(s) of these ameliorations. The micronucleus test and modified comet assay were used to investigate bone marrow DNA damage and methylation changes. These assays revealed that dapagliflozin is non-genotoxic in the tested regimen, and oxidative DNA damage and hypermethylation were significantly higher in diabetic mice. Spectrophotometry also evaluated oxidative DNA damage and global DNA methylation, revealing similar significant alterations induced by diabetes. Conversely, the dapagliflozin-treated diabetic animals significantly reduced these changes. The expression of some genes involved in DNA repair and DNA methylation was disrupted considerably in the somatic cells of diabetic animals. In contrast, dapagliflozin treatment significantly restored these disruptions and enhanced DNA repair. The simultaneous effects of decreased oxidative DNA damage and hypermethylation levels suggest that dapagliflozin can be used as a safe antidiabetic drug to reduce DNA damage and hypermethylation in diabetes, demonstrating its usefulness in patients with diabetes to control hyperglycemia and decrease the development of its subsequent complications.

Oxidative DNA damage and DNA repair in tuberculosis patients on anti tubercular therapy

Oxidative DNA damage and DNA repair in tuberculosis patients on anti tubercular therapy

Occupational exposure to lead causes oxidative DNA damage by modulating NRF2 and OGG1

Occupational exposure to lead causes oxidative DNA damage by modulating NRF2 and OGG1