8-hydroxyguanine and Inflammation

8-Oxo-7,8-dihydroguanine (8-oxo-G) is a key biomarker of oxidative damage to DNA in cells, and its genotoxicity is well-studied. In recent years, it has been confirmed experimentally that free 8-oxo-G and molecules containing it are not merely inert products of DNA repair or degradation, but they are actively involved in intracellular signaling. In this review, data are systematized indicating that free 8-oxo-G and oxidized (containing 8-oxo-G) extracellular DNA function in the body as mediators of stress signaling and initiate inflammatory and immune responses to maintain homeostasis under the action of external pathogens, whereas exogenous 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) exhibits pronounced antiinflammatory and antioxidant properties. This review describes known action mechanisms of oxidized guanine and 8-oxo-G-containing molecules. Prospects for their use as a therapeutic target are considered, as well as a pharmaceutical agent for treatment of a wide range of diseases whose pathogenesis is significantly contributed to by inflammation and oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Deoxyguanosine; DNA Damage; DNA Repair; Guanine; Humans; Inflammation; Oxidative Stress

Asthma is characterized by reversible airway narrowing, shortness of breath, wheezing, coughing, and other symptoms driven by chronic inflammatory processes, commonly triggered by allergens. In 90% of asthmatics, most of these symptoms can also be triggered by intense physical activities and severely exacerbated by environmental factors. This condition is known as exercise-induced asthma (EIA). Current theories explaining EIA pathogenesis involve osmotic and/or thermal alterations in the airways caused by changes in respiratory airflow during exercise. These changes, along with existing airway inflammatory conditions, are associated with increased cellular levels of reactive oxygen species (ROS) affecting important biomolecules including DNA, although the underlying molecular mechanisms have not been completely elucidated. One of the most abundant oxidative DNA lesions is 8-oxoguanine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) during the base excision repair (BER) pathway. Whole-genome expression analyses suggest a cellular response to OGG1-BER, involving genes that may have a role in the pathophysiology of EIA leading to mast cell degranulation, airway hyperresponsiveness, and bronchoconstriction. Accordingly, this review discusses a potential new hypothesis in which OGG1-BER-induced gene expression is associated with EIA symptoms.

Topics: Animals; Asthma; Bronchoconstriction; DNA; DNA Glycosylases; DNA Repair; Exercise; Guanine; Humans; Inflammation; Lipid Peroxidation; Mast Cells; Mice; Oxidative Stress; Physical Conditioning, Animal; Reactive Oxygen Species; Signal Transduction

Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular levels of reactive oxygen species (ROS) at the site of exposure. ROS not only function as intracellular signaling entities, but also induce damage to cellular molecules including DNA. Among the several dozen ROS-induced DNA base lesions generated in the genome, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant because of guanine's lowest redox potential among DNA bases. In mammalian cells, 8-oxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in DNA has traditionally been associated with mutagenesis, as well as various human diseases and aging processes, while the free 8-oxoG base in body fluids is one of the best biomarkers of ongoing pathophysiological processes. In this review, we discuss the biological significance of the 8-oxoG base and particularly the role of OGG1-BER in the activation of small GTPases and changes in gene expression, including those that regulate pro-inflammatory chemokines/cytokines and cause inflammation.

Topics: Animals; Body Fluids; Chronic Disease; Cytokines; DNA Damage; DNA Glycosylases; DNA Repair; Environmental Pollutants; Enzyme Activation; Epithelial Cells; Gene Expression Regulation; GTP Phosphohydrolases; Guanine; Humans; Inflammation; Lung Diseases; Mice; Mice, Inbred BALB C; Mice, Knockout; Mutagenesis; Oxidative Stress; Reactive Oxygen Species; Respiratory System; RNA Interference

Despite the long held hypothesis that oxidant stress results in accumulated oxidative damage to cellular macromolecules and subsequently to aging and age-related chronic disease, it has been difficult to consistently define and specifically identify markers of oxidant stress that are consistently and directly linked to age and disease status. Inflammation because it is also linked to oxidant stress, aging, and chronic disease also plays an important role in understanding the clinical implications of oxidant stress and relevant markers. Much attention has focused on identifying specific markers of oxidative stress and inflammation that could be measured in easily accessible tissues and fluids (lymphocytes, plasma, serum). The purpose of this review is to discuss markers of oxidant stress used in the field as biomarkers of aging and age-related diseases, highlighting differences observed by race when data is available. We highlight DNA, RNA, protein, and lipid oxidation as measures of oxidative stress, as well as other well-characterized markers of oxidative damage and inflammation and discuss their strengths and limitations. We present the current state of the literature reporting use of these markers in studies of human cohorts in relation to age and age-related disease and also with a special emphasis on differences observed by race when relevant.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Aging; Animals; Biomarkers; Deoxyguanosine; DNA Breaks, Double-Stranded; Erythrocytes; Free Radicals; Glutathione; Guanine; Heme; Humans; Inflammation; Isoprostanes; Lipid Peroxidation; Oxidants; Oxidative Stress; Reactive Oxygen Species

Exposure to combustion-derived particles, quartz and asbestos is associated with increased levels of oxidized and mutagenic DNA lesions. The aim of this survey was to critically assess the measurements of oxidatively damaged DNA as marker of particle-induced genotoxicity in animal tissues. Publications based on non-optimal assays of 8-oxo-7,8-dihydroguanine by antibodies and/or unrealistically high levels of 8-oxo-7,8-dihydroguanine (suggesting experimental problems due to spurious oxidation of DNA) reported more induction of DNA damage after exposure to particles than did the publications based on optimal methods. The majority of studies have used single intracavitary administration or inhalation with dose rates exceeding the pulmonary overload threshold, resulting in cytotoxicity and inflammation. It is unclear whether this is relevant for the much lower human exposure levels. Still, there was linear dose-response relationship for 8-oxo-7,8-dihydroguanine in lung tissue without obvious signs of a threshold. The dose-response function was also dependent on chemical composition and other characteristics of the administered particles, whereas dependence on species and strain could not be equivocally determined. Roles of cytotoxicity or inflammation for oxidatively induced DNA damage could not be documented or refuted. Studies on exposure to particles in the gastrointestinal tract showed consistently increased levels of 8-oxo-7,8-dihydroguanine in the liver. Collectively, there is evidence from animal experimental models that both pulmonary and gastrointestinal tract exposure to particles are associated with elevated levels of oxidatively damaged DNA in the lung and internal organs. However, there is a paucity of studies on pulmonary exposure to low doses of particles that are relevant for hazard/risk assessment.

Topics: Animals; Asbestos; Cell Survival; Disease Models, Animal; DNA; DNA Damage; Dose-Response Relationship, Drug; Gastrointestinal Tract; Guanine; Humans; Inflammation; Lung; Mutagens; Nanotubes, Carbon; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Quartz

Nitric oxide (NO) and superoxide rapidly react to yield peroxynitrite. Peroxynitrite is a potent oxidant which reacts with proteins, lipids, and DNA. The present paper overviews the various DNA modifications induced by exposure to peroxynitrite or NO and superoxide concurrently, with special reference to the formation of 8-nitroguanine and 8-oxoguanine as well as the induction of DNA single strand breakage. In addition, we review the secondary processes that may follow the process of DNA damage, such as activation of the nuclear enzyme, poly(ADP-ribose) synthetase, apoptosis, and carcinogenesis.

Topics: Animals; Apoptosis; Cell Transformation, Neoplastic; DNA; DNA Damage; Guanine; Humans; Inflammation; Nitrates; Nitric Oxide; Oxidants; Poly(ADP-ribose) Polymerases; Superoxides

It has been reported that oxidative stress and chronic inflammation may be involved in the pathogenesis of polycystic ovary syndrome (PCOS). 8-oxoguanine DNA glycosylase (OGG1) is the main glycosylase that catalyzes the excision of DNA oxidation products. In this study, we investigated the role and potential mechanisms of OGG1 in the development of PCOS. We first analyzed OGG1 levels in serum and follicular fluid (FF) of PCOS patients, and significantly elevated OGG1 levels were noted in PCOS patients. We similarly observed a significant upregulation of OGG1 expression levels in ovarian tissue of the dehydroepiandrosterone (DHEA)-induced PCOS rat model. In addition, increased apoptosis and increased production of reactive oxygen species (ROS) were observed after the addition of OGG1-specific inhibitor (TH5487) in human granulosa-like tumor cell line (KGN) cells following a concentration gradient, along with a significant decrease in mRNA levels of inflammatory factors such as CXCL2, IL-6, MCP1, IL-1β, and IL-18. Significant decreases in protein phosphorylation levels of P65 and IκBα were also observed in cells. In addition, we found a significant positive correlation between OGG1 and IL-6 expression levels in human and DHEA-induced PCOS rat models. In conclusion, our results suggest that OGG1 might be involved in the pathogenesis of PCOS by regulating the secretion of IL-6 through NF-κB signaling pathway, and there might be a balance between the inhibition of oxidative stress and the promotion of chronic inflammation by OGG1 on KGN cells.

Topics: Animals; Benzimidazoles; Dehydroepiandrosterone; DNA Glycosylases; Female; Guanine; Humans; Inflammation; Interleukin-6; NF-kappa B; Piperidines; Polycystic Ovary Syndrome; Rats; Signal Transduction

A growing body of evidence suggests that elevated levels of reactive oxygen species (ROS) in the airways caused by exposure to gas phase pollutants or particulate matter are able to activate dendritic cells (DCs); however, the exact mechanisms are still unclear. When present in excess, ROS can modify macromolecules including DNA. One of the most abundant DNA base lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which is repaired by the 8-oxoguanine DNA glycosylase 1 (OGG1)-initiated base excision repair (BER) (OGG1-BER) pathway. Studies have also demonstrated that in addition to its role in repairing oxidized purines, OGG1 has guanine nucleotide exchange factor activity when bound to 8-oxoG. In the present study, we tested the hypothesis that exposure to 8-oxoG, the specific product of OGG1-BER, induces functional changes of DCs. Supporting our hypothesis, transcriptome analysis revealed that in mouse lungs, out of 95 genes associated with DCs' function, 22 or 42 were significantly upregulated after a single or multiple intranasal 8-oxoG challenges, respectively. In a murine model of allergic airway inflammation, significantly increased serum levels of ovalbumin (OVA)-specific IgE antibodies were detected in mice sensitized via nasal challenges with OVA+8-oxoG compared to those challenged with OVA alone. Furthermore, exposure of primary human monocyte-derived DCs (moDC) to 8-oxoG base resulted in significantly enhanced expression of cell surface molecules (CD40, CD86, CD83, HLA-DQ) and augmented the secretion of pro-inflammatory mediators IL-6, TNF and IL-8, whereas it did not considerably influence the production of the anti-inflammatory cytokine IL-10. The stimulatory effects of 8-oxoG on human moDCs were abolished upon siRNA-mediated OGG1 depletion. Collectively, these data suggest that OGG1-BER-generated 8-oxoG base-driven cell signaling activates DCs, which may contribute to initiation of both the innate and adaptive immune responses under conditions of oxidative stress.

Topics: Adaptive Immunity; Animals; Chemokines; Cytokines; Dendritic Cells; DNA; DNA Glycosylases; DNA Repair; Female; Gene Expression Profiling; Guanine; Guanine Nucleotide Exchange Factors; Humans; Immunoglobulin E; Immunoglobulin M; Inflammation; Mice; Mice, Inbred BALB C; Monocytes; Oxidative Stress; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzimidazoles; DNA Glycosylases; DNA Repair; Enzyme Inhibitors; Gene Expression; Gene Knockout Techniques; Guanine; HEK293 Cells; Humans; Inflammation; Jurkat Cells; Mice; Mice, Mutant Strains; NF-kappa B; Piperidines; Promoter Regions, Genetic; Tumor Necrosis Factor-alpha

Human 8-oxoguanine DNA glycosylase 1 (OGG1) is the major DNA repair enzyme that plays a key role in excision of oxidative damaged DNA bases such as 8-oxoguainine (8-oxoG). Recent studies suggest another function of OGG1, namely that it may be involved in the endotoxin- or oxidative stress-induced inflammatory response. In this study, we investigated the role of OGG1 in the inflammatory response. OGG1 expression is increased in the organs of endotoxin-induced or myelin oligodendrocyte glycoprotein (MOG)-immunized mice and immune cells, resulting in induction of the expression of pro-inflammatory mediators at the transcriptional levels. Biochemical studies showed that signal transducer and activator of transcription 1 (STAT1) plays a key role in endotoxin-induced OGG1 expression and inflammatory response. STAT1 regulates the transcriptional activity of OGG1 through recruiting and binding to the gamma-interferon activation site (GAS) motif of the OGG1 promoter region, and chromatin remodeling by acetylation and dimethylation of lysine-14 and -4 residues of histone H3. In addition, OGG1 acts as a STAT1 coactivator and has transcriptional activity in the presence of endotoxin. The data presented here identifies a novel mechanism, and may provide new therapeutic strategies for the treatment of endotoxin-mediated inflammatory diseases.

Topics: Animals; Chromatin Assembly and Disassembly; DNA Damage; DNA Glycosylases; DNA Repair; Endotoxins; Gene Expression Regulation; Guanine; Humans; Inflammation; Interferon-gamma; Mice; Myelin-Oligodendrocyte Glycoprotein; Oxidative Stress; Promoter Regions, Genetic; STAT1 Transcription Factor; Transcriptional Activation

Oxidative DNA damage may be a risk factor for development of various pathologies, including malignancy. We studied inflammation triggered modulation of repair activity in the intestines of three weeks old rats injected i.p. with E.coli or S. typhimurium lipopolysaccharides (LPS) at doses of 1, 5 or 10 mg/kg. Subsequent formation in these animals of colonic preneoplastic lesions, aberrant crypt foci (ACF) was also investigated. Five days after LPS administration no differences were observed in repair rate of 1,N(6)-ethenoadenine (εA), 3,N(4)-ethenocytosine (εC) and 8-oxoguanine (8-oxoG) in intestines of these rats, as measured by the nicking assay. However a significant increase in all three repair activities was found within one and two months after S. typhimurium LPS treatment. E. coli LPS significantly increased only the 8-oxoG repair. S. typhimurium LPS stimulated mRNA transcription of pro-inflammatory proteins, lipooxygenase-12 and cyclooxygenase-2, as well as some DNA repair enzymes like AP-endonuclease (Ape1) and εC-glycosylase (Tdg). mRNA level of DNA glycosylases excising εA (MPG) and 8-oxoG (OGG1) was also increased by LPS treatment, but only at the highest dose. Transcription of all enzymes increased for up to 30 days after LPS, and subsequently decreased to the level observed before treatment, with the exception of APE1, which remained elevated even two months after LPS administration. Thus, the repair efficiency of εA, εC and 8-oxoG depends on the availability of APE1, which increases OGG1 and TDG turnover on damaged DNA, and presumably stimulates MPG. One and two months after administration of E. coli or S. typhimurium LPS, the number of aberrant crypt foci in rat colons increased in a dose and time dependent manner. Thus, inflammation stimulates the repair capacity for εA, εC and 8-oxoG, but simultaneously triggers the appearance of preneoplastic changes in the colons. This may be due to increased oxidative stress and imbalance in DNA repair.

Topics: Adenine; Animals; Animals, Newborn; Arachidonate 12-Lipoxygenase; Colon; Colonic Neoplasms; Cyclooxygenase 2; Cytosine; DNA Damage; DNA Repair; Escherichia coli; Guanine; Inflammation; Lipopolysaccharides; Oxidative Stress; Precancerous Conditions; Rats, Wistar; Salmonella typhimurium

Oxidative stress and reactive oxygen species (ROS)-induced DNA base damage are thought to be central mediators of UV-induced carcinogenesis and skin aging. However, increased steady-state levels of ROS-induced DNA base damage have not been reported after chronic UV exposure. Accumulation of ROS-induced DNA base damage is governed by rates of lesion formation and repair. Repair is generally performed by Base Excision Repair (BER), which is initiated by DNA glycosylases, such as 8-oxoguanine glycosylase and Nei-Endonuclease VIII-Like 1 (NEIL1). In the current study, UV light (UVB) was used to elicit protracted low-level ROS challenge in wild-type (WT) and Neil1

Topics: Animals; Cytokines; DNA Damage; DNA Glycosylases; DNA Repair; Gene Expression Profiling; Gene Expression Regulation; Guanine; Inflammation; Mice; Mice, Knockout; Neutrophil Infiltration; Oxidative Stress; Pyrimidines; Reactive Oxygen Species; Skin; Thymine; Ultraviolet Rays; Uracil

Inhaled particulate matter (PM) might influence many adverse health effects in human body, including increased exacerbations of pulmonary and cardiovascular diseases. In this study, we examined the associations between PM and pulmonary adverse effects. Two types of particles, Asian dust (AD) and titanium dioxide (TiO(2)), were administered intratracheally to C57BL/6 mice. The mice were exposed to saline and saline suspensions of 20 mg/kg of AD, TiO(2) particles twice a week for 12 weeks. Following exposure with these particles, the lungs were analyzed histopathologically by hematoxylin and eosin (H&E) and Masson's trichrome (MT) staining. Oxidative injuries were determined by immunohistochemistry (IHC) for 8-oxoguanine in the lungs and Comet assays in peripheral blood mononuclear cells (PBMCs) of C57BL/6 mice. Mice exposed to AD and TiO(2) showed significant inflammatory changes and oxidative damages in the lungs as compared with the control group. DNA damage in PBMCs was also increased significantly in AD and TiO(2)-exposed mice. However, lung fibrosis was minimal and there was no significant difference between PM exposed and control mice. Exposure to AD and TiO(2) particles-induced similar inflammatory damages in the lungs and elicited oxidative DNA damage in the PBMCs.

Topics: Air Pollutants; Animals; Comet Assay; DNA Damage; Dust; Fibrosis; Guanine; Inflammation; Leukocytes, Mononuclear; Lung; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Particle Size; Particulate Matter; Titanium

Helicobacter pylori infection is responsible for inflammation, increased production of reactive oxygen species and oxidatively damaged DNA in the gastric mucosa. There is also evidence which suggests that H.pylori infection may lead to the development of several extragastroduodenal pathologies with reactive oxygen species involvement. In order to assess whether the infection may impose oxidatively damaged DNA not only in the target organ (stomach) but in other organs as well we decided, for the first time, to analyse the two kinds of oxidatively damaged DNA biomarkers: urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanine (8-oxoGua) as well as the level of oxidatively damaged DNA in leukocytes. Using high performance liquid chromatography prepurification/gas chromatography with isotope dilution mass detection methodology, we examined the amount of oxidatively damaged DNA products excreted into urine and the amount of 8-oxodG in the DNA of leukocytes' (with the the HPLC/EC technique) in three groups of children: (i) control group, (ii) H.pylori infected children and (iii) children with gastritis where H.pylori infection was excluded. The levels of 8-oxodG in DNA isolated from leukocytes of H.pylori infected patients and in the group with gastritis without H.pylori infection were significantly higher than in DNA isolated from the control group. The mean level of 8-oxoGua in urine samples of children infected with H.pylori was significantly lower than in the urine of the group with gastritis without H.pylori infection. The data suggest that inflammation itself, not just H.pylori infection, is responsible for the observed rise of 8-oxodG level in leukocytes. However, the observed decrease in the level of modified base in urine seems to be specific for H.pylori infection and possibly linked with nitric oxide mediated inhibition of a key base excision repair enzyme (human 8-oxo-7, 8-dihydroguanine glycosylase) responsible for the repair of 8-oxo-7,8-dihydroguanine.

Topics: Adolescent; Biomarkers; Case-Control Studies; Child; Chromatography, High Pressure Liquid; DNA Damage; Female; Gastritis; Guanine; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Leukocytes; Male; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species

There is still intensive debate on the variability in the biological activities of different quartz species. Therefore we examined in a rat lung model the inflammatory, fibrogenic and genotoxic characteristics of four commercial quartz flours. The samples, two with probably low activity and two with probably high activity were selected from a panel of 16 samples on the basis of in vitro investigations. Rats were exposed by a single intratracheal injection of 0.6, 1.2 and 2.4 mg quartz samples per lung or with 1.2 mg standard quartz DQ12. After 90 days the inflammatory response was measured in the bronchoalveolar lavage fluid, as well as the content of 8-oxoguanine in the DNA of the lung cells. Additionally mutated p53 protein was determined. The four quartz samples revealed specific differences in all parameters investigated. In good agreement with the in vitro results the two samples expected as lowly active showed only weak inflammatory and no genotoxic reactions in the rat lungs. In contrast the two samples suspected as highly reactive induced a pronounced inflammatory response and for one of the samples genotoxic effects could be proven. The results raised here show a broad spectrum of biological activities dependent on the type of quartz from almost inert to genotoxic and highly inflammatory.

Topics: Animals; DNA Damage; Dust; Female; Guanine; Inflammation; Lung; Oxidative Stress; Pulmonary Fibrosis; Quartz; Rats; Rats, Wistar