8-hydroxy-2--deoxyguanosine and Inflammation

Inflammation can be induced by chronic infection, inflammatory diseases and physicochemical factors. Chronic inflammation is estimated to contribute to approximately 25% of human cancers. Under inflammatory conditions, inflammatory and epithelial cells release reactive oxygen (ROS) and nitrogen species (RNS), which are capable of causing DNA damage, including the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-nitroguanine. We reported that 8-nitroguanine was clearly formed at the sites of cancer induced by infectious agents including

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carcinogenesis; Deoxyguanosine; DNA Damage; Guanine; Humans; Inflammation; Mutation; Neoplasms; Nitric Oxide Synthase Type II; Reactive Nitrogen Species; Reactive Oxygen Species; Tumor Hypoxia

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

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

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and it is defined as a rise in the urinary albumin excretion (UAE) rate and abnormal renal function. Currently, changes in albuminuria are considered a hallmark of onset or progression of DN. However, some patients with diabetes have advanced renal pathological changes and progressive kidney function decline even if urinary albumin levels are in the normal range, indicating that albuminuria is not the perfect marker for the early detection of DN. The present article provides an overview of the literature reporting some relevant biomarkers that have been found to be associated with DN and that potentially may be used to predict the onset and/or monitor the progression of nephropathy. In particular, biomarkers of renal damage, inflammation, and oxidative stress may be useful tools for detection at an early stage or prediction of DN. Proteomic-based biomarker discovery represents a novel strategy to improve diagnosis, prognosis and treatment of DN; however, proteomics-based approaches are not yet available in most of the clinical chemistry laboratories. The use of a panel with a combination of biomarkers instead of urinary albumin alone seems to be an interesting approach for early detection of DN, including markers of glomerular damage (e.g., albumin), tubular damage (e.g., NAG and KIM-1), inflammation (e.g., TNF-α) and oxidative stress (e.g., 8-OHdG) because these mechanisms contribute to the development and outcomes of this disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylglucosaminidase; Albuminuria; Biomarkers; Deoxyguanosine; Diabetic Nephropathies; Disease Progression; Early Diagnosis; Hepatitis A Virus Cellular Receptor 1; Humans; Inflammation; Kidney; Membrane Glycoproteins; Neoplasm Proteins; Oxidative Stress; Prognosis; Proteomics; Receptors, Virus; Tumor Necrosis Factor-alpha

Reactive oxygen species (ROS) attack guanine bases in DNA easily and form 8-hydroxydeoxyguanosine (8-OHdG), which can bind to thymidine rather than cytosine, based on which, the level of 8-OHdG is generally regarded as a biomarker of mutagenesis consequent to oxidative stress. For example, higher levels of 8-OHdG are noted in Helicobacter pylori-associated chronic atrophic gastritis as well as gastric cancer. However, we have found that exogenous 8-OHdG can paradoxically reduce ROS production, attenuate the nuclear factor-κB signaling pathway, and ameliorate the expression of proinflammatory mediators such as interleukin (IL)-1, IL-6, cyclo-oxygenase-2, and inducible nitric oxide synthase in addition to expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX)-1, NOX organizer-1 and NOX activator-1 in various conditions of inflammation-based gastrointestinal (GI) diseases including gastritis, inflammatory bowel disease, pancreatitis, and even colitis-associated carcinogenesis. Our recent finding that exogenous 8-OHdG was very effective in either inflammation-based or oxidative-stress-associated diseases of stress-related mucosal damage has inspired the hope that synthetic 8-OHdG can be a potential candidate for the treatment of inflammation-based GI diseases, as well as the prevention of inflammation-associated GI cancer. In this editorial review, the novel fact that exogenous 8-OHdG can be a functional molecule regulating oxidative-stress-induced gastritis through either antagonizing Rac-guanosine triphosphate binding or blocking the signals responsible for gastric inflammatory cascade is introduced.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Biomarkers; Colitis; Deoxyguanosine; Gastrointestinal Diseases; Humans; Inflammation; Oxidative Stress; Reactive Oxygen Species; Stomach Neoplasms

Exercise is recommended for the management of type 2 diabetes, but its effects on diabetic nephropathy (DN) are still unknown. We hypothesized that appropriate exercise improves early DN via attenuation of inflammation and oxidative damage. Type 2 diabetic KK-A(y) mice, a spontaneous DN model, underwent two different kinds of exercise (i.e., moderate and low intensity). Sedentary mice or those undergoing an exercise regimen causing no significant body weight loss were used. We examined the urinary excretion of albumin, number of podocytes and macrophages, renal expressions of HIF-1α and MCP-1, and biomarkers of oxidative stress such as urinary 8-OHdG and serum SOD. Exercise reduced urinary levels of albumin and also maintained the number of podocytes in the exercised KK-A(y) mice independently of improvements of overweight and hyperglycemia, although moderate-intensity exercise increased expression of HIF-1α. Sedentary KK-A(y) mice showed increased expression of MCP-1 and infiltration of macrophage, increased urinary 8-OhdG, and decreased serum SOD levels compared with exercised KK-A(y) mice. On the whole, low-intensity exercise attenuates progression of early DN without affecting marked renal ischemia. Reduction rates of urinary albumin and maintained podocyte numbers, with parallel improvements in oxidative damage and inflammation, are related to beneficial effects of exercise in diabetic kidney disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albumins; Animals; Biomarkers; Cell Proliferation; Chemokine CCL2; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Ischemia; Macrophages; Male; Mice; Oxidative Stress; Podocytes; Rats; Superoxide Dismutase

Oxidative damage DNA is aninevitable, natural consequence of cellular metabolism resulting from formation of reactive oxygen species (ROS) including free oxygen radicals. However, the level ofthe damage may increase under conditions of oxidative stress, arising from exposure to a variety of physical or chemical insults. In this review we present the mechanisms by which oxidative damage to DNA may lead to pathological processes involved in the development of cancer, cardiovascular diseases and ageing. Furthermore, we describe mechanisms of DNA repair which play a key role in maintaining cellular function upon DNA insult. Among over 20 identified and described oxidative modifications of DNA bases only one derivative, namely 8-oxo-2'-deoxyguanosine (8-oxo-dG), has become a subject of intense research. Therefore, we are presenting methods of 8-oxo-dG detection as a marker of oxidatively damaged DNA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Autoimmune Diseases; Biomarkers; Deoxyguanosine; DNA Damage; DNA Repair; Hepatitis B; HIV Infections; Humans; Inflammation; Mass Spectrometry; Neoplasms; Oxidative Stress; Reactive Oxygen Species

Elevated LDL-C, lipoprotein(a) [Lp(a)], and inflammation are associated with greater risk for atherosclerotic cardiovascular events. Consumption of individual nut types decreases these risk factors but knowledge about the effect of mixed nuts on Lp(a) is limited. The objective of this study was to determine the effects of consuming 42.5 g/day of mixed nuts on LDL-C, Lp(a), and inflammatory markers in individuals with overweight or obesity.. Consumption of mixed nuts had no evidence of an effect on LDL-C or Lp(a) throughout the intervention. Notably, mixed nut consumption lowered body fat percentage without significant changes in body weight or BMI. Future studies with larger sample sizes investigating the changing trends of CRP, 8-oxodG, and TAC are warranted.. NCT03375866.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; Adult; Cardiometabolic Risk Factors; Cholesterol, LDL; Humans; Inflammation; Lipoprotein(a); Nuts; Obesity; Overweight; Risk Factors

As in human populations, advances in nutrition and veterinary care have led to an increase in the lifespan of companion animals. Detrimental physiological changes occurring later in life must be understood before interventions can be made to slow or reduce them. One important aspect of human aging is upregulation of the inflammatory response and increase in oxidative damage resulting in pathologies linked to chronic inflammation. To determine whether similar processes occur in the aging dog, changes in markers of inflammation and oxidative stress were investigated in 80 Labrador retrievers from adulthood to the end of life. Serum levels of immunoglobulin M (p < .001) and 8-hydroxy-2-deoxyguanosine (p < .001) increased with age, whereas no effect of age was detected for immunoglobulin G or C-reactive protein unless the last year of life was included in the analysis (p = .002). Baseline levels of heat shock protein 70 decreased with age (p < .001) while those after exposure to heat stress were maintained (p = .018). However, when excluding final year of life data, a decline in the heat shock protein 70 response after heat stress was observed (p = .004). These findings indicate that aging dogs undergo changes similar to human inflammaging and offer the possibility of nutritional or pharmacological intervention to delay or reduce these effects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aging; Animals; Biomarkers; C-Reactive Protein; Deoxyguanosine; Dogs; Female; HSP70 Heat-Shock Proteins; Immunoglobulin G; Immunoglobulin M; Immunosenescence; Inflammation; Longitudinal Studies; Male; Oxidative Stress; Random Allocation

The association of short-term air pollution filtration with cardiovascular health has been documented. However, the effect of long-term indoor air conditioner filtration on the association between air pollution and cardiovascular health is still unclear. We recruited 200 homemakers from Taipei and randomly assigned 100 of them to air filtration or control intervention; six home visits were conducted per year from 2013 to 2014. The participants under air filtration intervention during 2013 were reassigned to control intervention in 2014. The air pollution measurements consisted of particulate matter less than or equal to 2.5μm in diameter (PM

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Air Conditioning; Air Pollutants; Air Pollution, Indoor; Biomarkers; C-Reactive Protein; Cross-Over Studies; Deoxyguanosine; Female; Fibrinogen; Filtration; Humans; Hypertension; Inflammation; Male; Middle Aged; Oxidative Stress; Particulate Matter; Volatile Organic Compounds

We examined the effect of iron-containing prenatal vitamin-mineral supplements taken postpartum on biomarkers of iron status and oxidative stress. Lactating women (n = 114) were randomly assigned to consume daily one iron-free prenatal vitamin-mineral supplement plus either 27 mg of iron or placebo for approximately 3.5 months. The placebo group took the tablets between meals, while those given iron took the tablets either with (Fe-W) or between meals (Fe-B). Blood and urine samples were collected before and after the supplementation period to analyze hemoglobin (Hb), ferritin, hepcidin, transferrin saturation (TfSat), total plasma iron, and biomarkers of oxidative stress (isoprostane and 8-hydroxy-2-deoxyguanosine (8-OHdG)) and inflammation (C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP)). There was a trend toward a greater change in Hb among women in the Fe-B group compared to placebo (+2.5 vs. -3.7 g/L, respectively, p = 0.063). When the iron groups were combined, there was a greater change in Hb (+1.4 g/L) compared to placebo (p = 0.010). There were trends toward greater changes in TfSat (p = 0.087) and total plasma iron (p = 0.065) in the iron groups compared to placebo, yet no significant differences between the three groups in change in hepcidin (p = 0.291), isoprostane (p = 0.319), or 8-OHdG (p = 0.659), nor in change in ferritin among those with elevated CRP at baseline (60% of women; p = 0.946); among those without elevated CRP (40% of women), ferritin increased more in the iron groups compared to placebo (p = 0.001). Iron consumption during lactation moderately increased iron status, particularly among women without elevated CRP, and increased Hb, but did not significantly increase oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Body Mass Index; C-Reactive Protein; Deoxyguanosine; Dietary Supplements; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Inflammation; Iron; Isoprostanes; Lactation; Maternal Nutritional Physiological Phenomena; Nutritional Status; Orosomucoid; Oxidative Stress; Postpartum Period; Prenatal Care; Young Adult

Oxidative stress (OS) has been shown to play a role in the pathogenesis of sarcoidosis and previous studies have shown that anti-oxidants can reduce markers of oxidative stress and inflammation in the peripheral blood of sarcoidosis subjects. We investigated the effect of N-Acetyl-Cysteine (NAC) on oxidative stress and inflammatory markers in the lungs of sarcoidosis patients.. We randomized 11 sarcoidosis subjects to active therapy and 3 to placebo for 8 weeks in a double blinded study. Bronchoscopy with bronchoalveolar lavage was performed pre and post therapy. Our primary endpoint was TNF-α production from stimulated and unstimulated BAL cells. Secondary outcomes included measures of oxidative stress (GSH, 8-OHdG) levels in the BAL. In-vitro studies were also performed to assess the effect of NAC on lipopolysaccharide stimulated BAL cell production of TNF-α.. Eight subjects in the active group and 2 in the placebo group completed the study protocol. Eight weeks of oral NAC did not have a significant impact on TNF-α levels from BAL cells in-vivo in spite of a 59% increase in BAL GSH levels. Our in vitro studies showed a significant decline in TNF-α production from LPS stimulated BAL cells treated with 5 and 10 mM of NAC.. Oral NAC increased GSH levels but failed to suppress in-vivo TNF-α production in contrast to effects in-vitro. Anti-oxidant therapy may still play a role in the management of sarcoidosis but therapy with better bioavailability or potency is needed to suppress the lung inflammatory response.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Administration, Oral; Adult; Aged; Antioxidants; Bronchoalveolar Lavage Fluid; Deoxyguanosine; DNA; Double-Blind Method; Female; Glutathione; Humans; Inflammation; Lipopolysaccharides; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Sarcoidosis, Pulmonary; Tumor Necrosis Factor-alpha

Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Deoxyguanosine; Disease Progression; Female; Gene Expression; Humans; Hypoglycemic Agents; Inflammation; Interleukin-6; Male; Middle Aged; Oxidative Stress; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pioglitazone; Thiazolidinediones; Transcription Factors; Treatment Failure

Cumulative evidence indicates that oxidative stress and inflammation frequently occurs in patients undergoing maintenance hemodialysis (HD) and as a result of overproduction of reactive oxygen species (ROS) and a decrease of antioxidant defenses such as selenium (Se). Previous studies in our laboratory showed that the supplementation of 1 unit of Brazil nut (the richest known food source of Se) a day during 3 months is effective to improve Se status and increase glutathione peroxidase (GPx) levels in HD patients. The aim of this study was to evaluate the effect of Brazil nut supplementation on oxidative stress and inflammation markers in HD patients. Forty HD patients from Rio de Janeiro, Brazil were studied. All patients received one nut per day for 3 months. The Se plasma levels and GPx, 8-isoprostane, 8-hydroxy-2-deoxyguanosine (8-OHdG), and cytokine (TNF-α and IL-6) levels and lipid profile were determined before and after 3 months of supplementation. The plasma Se and GPx activity increased, while cytokines, 8-OHdG, and 8-isoprostane plasma levels decreased significantly after 3 months supplementation. HDL-c levels increased and LDL-c levels decreased significantly. These data suggest that the consumption of only one Brazil nut per day during 3 months was effective to reduce the inflammation, oxidative stress markers, and the atherogenic risk, thereby increasing the antioxidant defenses in HD patients. Our results indicate that Brazil nut as Se source plays an important role as an anti-inflammatory and antioxidant agent in HD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Bertholletia; Biomarkers; Cytokines; Deoxyguanosine; Dietary Supplements; Dinoprost; Glutathione Peroxidase; Humans; Inflammation; Lipids; Middle Aged; Nuts; Oxidative Stress; Renal Dialysis; Selenium; Time Factors; Treatment Outcome

The aim of this study was to demonstrate the safety and efficacy of H2-saline infusion for treatment of rheumatoid arthritis (RA). We conducted a randomized, double-blind, placebo-controlled investigation of the infusion of 1 ppm H2-dissolved saline (H2-saline) in 24 RA patients. Patients were randomized 1:1 to receive 500 ml of either H2-saline or placebo-saline, which was drop infused intravenously (DIV) daily for 5 days. The disease activity score in 28 joints (DAS28) was measured at baseline, immediately post infusion, and after 4 weeks. Therapeutic effects of H2-saline on joint inflammation were estimated by measuring serum biomarkers for RA, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), and urinary 8-hydroxydeoxyguanosine (8-OHdG). In the H2-infused group, average DAS28 decreased from 5.18 ± 1.16 to 4.02 ± 1.25 immediately post infusion and reached 3.74 ± 1.22 after 4 weeks. No significant decrease in DAS28 was observed in the placebo group throughout the study. IL-6 levels in the H2 group significantly decreased in 4 weeks by 37.3 ± 62.0% compared to baseline, whereas it increased by 33.6 ± 34.4% in the placebo group. TNFα levels did not change remarkably in the H2 or placebo groups in 4 weeks post-infusion compared to baseline. The relative ratio of 8-OHdG in the H2 group also significantly decreased by 4.7%. After 4 weeks, MMP3 was significantly reduced by 19.2% ± 24.6% in the H2 group, and increased by 16.9% ± 50.2% in the placebo group. Drop infusion of H2 safely and effectively reduced RA disease activity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Deoxyguanosine; Double-Blind Method; Female; Humans; Hydrogen; Inflammation; Interleukin-6; Joints; Male; Matrix Metalloproteinase 3; Middle Aged; Pilot Projects; Sodium Chloride; Tumor Necrosis Factor-alpha

As oxygen is essential for wound healing and there is limited diffusion across the stratum corneum into the epidermis, we wanted to evaluate whether the topical delivery of a total dissolved oxygen in dressing form on intact human subject skin would improve clinical and histologic skin functioning.. Fifty normal, healthy subjects completed a pilot clinical evaluation to assess the efficacy and tolerability of a dissolved oxygen dressing (OxygeneSys™-Continuous) to improve the health and appearance of intact skin.. Clinical analysis was performed on 50 subjects; histological and gene expression analysis was performed on 12 of the 50 subjects to assess the effect of the dissolved oxygen dressing.. Clinical data demonstrate that the dressing is well tolerated, and several measures of skin health and integrity showed improvements compared with a control dressing site. Skin hydration measurements showed a statistically significant increase in skin hydration at 0-4, 4-8, and 0-8 weeks (P < 0.05 at each time point). The blinded clinical investigator's grading of desquamation, roughness, and skin texture show significant decreases from baseline to the 8-week time point (P < 0.05). The dressings were removed prior to the blinded clinical investigator's grading. These data were supported by the histological and gene expression studies, which showed a general reduction in inflammatory response markers and transcription products (IL-6, IL-8, TNF-alpha, MMP-1, and MMP-12), while facilitating a general increase in structural skin proteins (collagen I, elastin, and filaggrin). Additionally, p53 signals from biopsy samples support the clinical investigator's observations of no safety concerns.. The data from this study demonstrate that the dressing has no deleterious effects and stimulates beneficial effects on intact, nonwounded skin.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Cutaneous; Aged; Aquaporin 3; Collagen Type I; Deoxyguanosine; Elastin; Female; Filaggrin Proteins; Gene Expression; Humans; Inflammation; Interleukin-1; Interleukin-6; Intermediate Filament Proteins; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 12; Middle Aged; Oxygen; Single-Blind Method; Skin; Skin Physiological Phenomena; Tumor Necrosis Factor-alpha

Autosomal dominant polycystic kidney disease (ADPKD) progresses more quickly to end-stage renal disease in patients with hypertension than in their normotensive counterparts. The authors investigated the effect of telmisartan versus enalapril on systolic and diastolic blood pressure (SBP and DBP), urinary albumin excretion (UAE), serum high mobility group box-1 protein (HMGB1), serum interleukin (IL)-6 and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in patients with hypertensive ADPKD.. Twenty patients with hypertensive ADPKD with good renal function were randomly assigned to 1 of 2 treatments: telmisartan 80 mg once daily (n = 10) or enalapril 10 mg once daily (n = 10). Treatment lasted 12 months. SBP, DBP, serum creatinine, UAE, HMGB1, IL-6 and urinary 8-OHdG levels were measured before and 6 and 12 months after treatment.. Both SBP and DBP were significantly reduced after treatment (P < 0.001) in both groups. Serum creatinine changed little during the experimental period in either group. UAE, serum HMGB1, serum IL-6 and urinary 8-OHdG levels were significantly decreased after treatment (UAE, HMGB1 and IL-6, P < 0.001; and 8-OHdG, P < 0.01 versus baseline levels) in both groups. However, the decreases in UAE, serum HMGB1 and serum IL-6 were significantly greater in the telmisartan group than in the enalapril group at 6 months (P < 0.05, P < 0.01 and P < 0.01, respectively) and 12 months (all, P < 0.05).. Telmisartan seems to be equivalent to enalapril in lowering BP, but telmisartan has more potent renoprotective, anti-inflammatory and antioxidative effects than enalapril in patients with hypertensive ADPKD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Biomarkers; Creatinine; Deoxyguanosine; Enalapril; Female; HMGB1 Protein; Humans; Hypertension; Inflammation; Interleukin-6; Male; Middle Aged; Oxidative Stress; Polycystic Kidney, Autosomal Dominant; Telmisartan

Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress in patients without arteriosclerosis. This study aimed to evaluate (1) whether an ARB (candesartan) decreases values for inflammatory parameters in hypertensive patients with type 2 diabetes mellitus of long duration accompanied by arteriosclerosis and (2) whether there any predictors of which patients would receive the benefits of organ protection by candesartan.. We administered candesartan therapy (12 mg daily) for 6 months and evaluated whether there was improvement in serum inflammatory parameters high molecular weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) in serum and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of lowering of blood pressure and inflammatory factors and the relationship between pulse pressure and inflammatory factors. Finally, we analyzed predictive factors in patients who received the protective benefit of candesartan.. After 6 months of treatment, significant improvements from baseline values were observed in all patients in HMW-ADN and PAI-1 but not in Hs-CRP, VCAM-1 and U-8-OHdG. Multilinear regression analysis was performed to determine which factors could best predict changes in HMW-ADN and PAI-1. Changes in blood pressure were not significant predictors of changes in metabolic factors in all patients. We found that the group with baseline pulse pressure <60 mmHg had improved HMW-ADN and PAI-1 values compared with the group with baseline pulse pressure ≥ 60 mmHg. These results suggest that pulse pressure at baseline could be predictive of changes in HMW-ADN and PAI-1.. Candesartan improved inflammatory parameters (HMW-ADN and PAI-1) in hypertensive patients with type 2 diabetes mellitus of long duration independent of blood pressure changes. Patients with pulse pressure <60 mmHg might receive protective benefits by candesartan.. UMIN000007921.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; C-Reactive Protein; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Inflammation; Inflammation Mediators; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Plasminogen Activator Inhibitor 1; Prospective Studies; Tetrazoles; Time Factors; Treatment Outcome; Vascular Cell Adhesion Molecule-1

Strenuous exercise induces inflammatory reactions together with high production of free radicals and subsequent muscle damage. This study was designed to investigate for the first time and simultaneously whether over-expression of inflammatory mediators, oxidative stress, and alterations in biochemical parameters induced by acute exercise could be prevented by melatonin. This indoleamine is a potent, endogenously produced free radical scavenger and a broad-spectrum antioxidant; consequently, it might have positive effects on the recovery following an exercise session. The participants were classified into two groups: melatonin-treated men (MG) and placebo-treated individuals (controls group, CG). The physical test consisted in a constant run that combined several degrees of high effort (mountain run and ultra-endurance). The total distance of the run was 50 km with almost 2800 m of ramp in permanent climbing and very changeable climatic conditions. Exercise was associated with a significant increase in TNF-α, IL-6, IL-1ra (in blood), and also an increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) and isoprostane levels (in urine), and indicated the degree of oxidative stress and inflammation induced. Oral supplementation of melatonin during high-intensity exercise proved efficient in reducing the degree of oxidative stress (lower levels of lipid peroxidation, with a significant increase in antioxidative enzyme activities); this would lead to the maintenance of the cellular integrity and reduce secondary tissue damage. Data obtained also indicate that melatonin has potent protective effects, by preventing over-expression of pro-inflammatory mediators and inhibiting the effects of several pro-inflammatory cytokines. In summary, melatonin supplementation before strenuous exercise reduced muscle damage through modulation of oxidative stress and inflammation signaling associated with this physical challenge.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Dietary Supplements; Exercise; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Isoprostanes; Male; Melatonin; Oxidative Stress; Tumor Necrosis Factor-alpha

We examined the effects of 2 calcium channel blockers, benidipine (T-, L-, and N-type) and amlodipine (L- and N-type), on renal, inflammatory, oxidative, and atherosclerosis markers in hypertensive patients with mild chronic kidney disease (CKD).. Forty hypertensive patients with CKD were assigned randomly to either of the 2 treatments: 8 mg benidipine once daily (n = 20, group A) or 5 mg amlodipine once daily (n = 20, group B). Treatment was continued for 12 months. Blood pressure, serum creatinine, estimated glomerular filtration rate, urinary protein excretion, urinary liver-type fatty acid-binding protein, interleukin-6, high mobility group box-1 protein, urinary 8-hydroxy-2'-deoxyguanosine, pulse wave velocity, intima-media thickness, and blood asymmetric dimethylarginine were monitored.. Blood pressure decreased equally in both groups (P < 0.001, at 6 and 12 months versus before treatment). Serum creatinine and estimated glomerular filtration rate changed little during the experimental period in each group. However, urinary protein excretion (P < 0.001), urinary liver-type fatty acid-binding protein (P < 0.001), urinary 8-hydroxy-2'-deoxyguanosine (P < 0.001), blood interleukin-6 (P < 0.001), blood high mobility group box-1 (P < 0.05), and pulse wave velocity (P < 0.01) decreased more in group A than in group B with 12 months of treatment. The percent reductions in intima-media thickness and blood asymmetric dimethylarginine were significantly greater in group A than in group B (P < 0.001).. Benidipine is more effective than amlodipine for protecting renal function and potentially for ameliorating atherosclerosis in hypertensive patients with mild CKD. T-type calcium channel blockers may be effective in patients with CKD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amlodipine; Atherosclerosis; Biomarkers; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Fatty Acid-Binding Proteins; Female; Humans; Inflammation; Kidney Failure, Chronic; Male; Proteinuria

Cholangiocarcinoma (CCA) is one of the oxidative stress-driven carcinogenesis through chronic inflammation. Insulin receptor substrate 1 (IRS1), an adaptor protein of insulin signaling pathways, is associated with the progression of many inflammation-related cancers. This study hypothesized that oxidative stress regulates IRS1 expression and that up-regulation of IRS1 induces CCA progression. The localizations of IRS1 and an oxidative stress marker (8-oxodG) were detected in CCA tissues using immunohistochemistry (IHC). The presence of IRS1 in CCA tissues was confirmed using immortal cholangiocyte cells (MMNK1), a long-term oxidative-stress-induced cell line (ox-MMNK1-L), and five CCA cell lines as cell culture models. IRS1 was overexpressed in tumor cells and this was associated with a shorter patient survival time and an increase in 8-oxodG. IRS1 expression was higher in ox-MMNK1-L cells than in MMNK1 cells. Knockdown of IRS1 by siRNA in two CCA cell lines led to inhibition of proliferation, cell cycle progression, migration, invasion, stemness, and oxidative stress resistance properties. Moreover, a transcriptomics study demonstrated that suppressing IRS1 in the KKU-213B CCA cell line reduced the expression levels of several genes and pathways involved in the cellular functions. The findings indicate that IRS1 is a key molecule in the connection between oxidative stress and CCA progression. Therefore, IRS1 and its related genes can be used as prognostic markers and therapeutic targets for CCA therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Humans; Inflammation; Insulin Receptor Substrate Proteins; Oxidative Stress

Oxidative stress (OS) and inflammation are known to play an important role in colorectal cancer (CRC). This study analyzed tumor, inflammatory and OS markers in CRC patients and in a control group. In addition, the evolution of these markers was evaluated after one-year of follow-up treatment. This was a longitudinal and prospective, observational study in 80 CRC patients who were candidates for tumor resection surgery and/or chemo-radiotherapy treatment and a healthy control group (n = 60). Subsequently, catalase (CAT), reduced glutathione (GSH), oxidized glutathione (GSSG) and GSSG/GSH ratio in serum and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and F2-IsoProstanes (F2-IsoPs) in urine at 1, 6 and 12 months after treatment was analyzed. Tumor markers (CEA and CA 19.9), as well as inflammatory markers-leukocytes, neutrophils, neutrophil/lymphocyte (N/L) index, platelets, fibrinogen, C-reactive protein (CRP), and interleukin 6 (IL6)- were also analyzed. As expected, levels of CEA and CA 19.9 and markers of inflammation, except CRP, were significantly higher in CRC compared to the control group. Regarding OS markers, a decrease in CAT and GSH and an increase in GSSG, GSSG/GSH ratio, 8-oxodG and F2-IsoPs were found in CRC patients compared to healthy controls at baseline. After treatment, an improvement of their inflammation profile was accompanied by a progressive recovery of antioxidant enzyme activities and the decline of oxidative byproducts both in serum and urine. Based on the results obtained, we propose the assay of urinary 8-oxodG and F2-IsoPs, as well as serum CAT, GSH, GSSG as a marker for the evaluation of OS and the clinical follow-up of CRC patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Biomarkers; Colorectal Neoplasms; Deoxyguanosine; Follow-Up Studies; Glutathione; Glutathione Disulfide; Humans; Inflammation; Oxidative Stress; Prospective Studies

Although accumulating evidence suggests an interplay between child abuse and inflammatory processes and the pathophysiology of mental disorders, few studies have investigated the cellular mechanisms related to this matter. Furthermore, no studies to date have evaluated cytokine, oxidative stress, and DNA damage levels in drug-naïve panic disorder (PD) patients and their possible association with childhood trauma. The aim of the present study was to determine the levels of the proinflammatory interleukin (IL)-1B, the oxidative stress marker TBARS, and  8-hydroxy-2' -deoxyguanosine (8-OHdG; representing DNA damage) in drug-naïve PD patients compared to controls. Furthermore, this investigation aimed to determine whether early-life trauma could predict peripheral levels of the previously mentioned markers in unmedicated PD patients. This work showed that drug-naïve PD patients presented elevated levels of TBARS and IL-1B but not 8-OHdG compared to healthy controls. In addition, sexual abuse during childhood was associated with increased levels of IL-1B in PD patients. Our findings suggest that the microglial NLRP3 inflammasome complex might be activated in drug-naïve PD patients. This study is the first to associated sexual abuse with increased levels of IL-1B in drug-naïve PD patients and to demonstrate that this population presents high concentrations of oxidative stress and inflammation markers but not DNA damage markers when compared to healthy controls. Independent replication of these findings would support further clinical trials of inflammasome inhibitory drugs in PD patients, which could lead to effective novel treatments for people with PD and contribute to elucidating pathophysiological differences depending on trauma exposure in the immune disturbances accompanying PD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Child; DNA Damage; Humans; Inflammasomes; Inflammation; Oxidative Stress; Panic Disorder; Sex Offenses; Thiobarbituric Acid Reactive Substances

Both genetic damage and inappropriate immune function are relevant to cancer of hexavalent chromium [Cr(VI)]. However, its associations with immune response and genetic damage development are poorly understood. To explore their associations and mediating effects, 1249 participants were included from the Occupational Chromate Exposure Dynamic Cohort, and their blood Cr concentrations were measured as internal exposure. A set of biomarkers including urinary 8-hydroxy-2' - deoxyguanosine (8-OHdG), micronucleus frequency (MNF) and mitochondrial DNA copy number (mtCN) was developed to evaluate the landscape of genetic damage of Cr(VI). Serum C-reactive protein (CRP) and first component of complement q (C1q) were measured to reflect immune inflammation. Multivariate linear regression and mediation analyses were applied to assess the potential associations and mediation effects. It was found that blood Cr level showed significant dose-dependent relationships with increasing of MNF and urinary 8-OHdG, while negative association with CRP and C1q. Furthermore, a 1-unit increase in CRP was associated with decreases of - 0.765 to - 0.254 in MNF, - 0.400 to - 0.051 in urinary 8-OHdG. 4.97% of the association between blood Cr level and the increased MNF was mediated by CRP. 11.58% of the relationship between concentration of blood Cr and urinary 8-OHdG was mediated by C1q. These findings suggested that Cr(VI) exposures might prompt genetic damage, possibly partial via worsening immune inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Chromates; Chromium; DNA Damage; Humans; Inflammation; Occupational Exposure

Topics: 8-Hydroxy-2'-Deoxyguanosine; Air Pollutants; Apoptosis; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Oxidative Stress; Polycyclic Aromatic Hydrocarbons; Reactive Oxygen Species

Zonulin is observed in animal models to regulate intestinal permeability and influenced by dietary intake, gut microbiota, and inflammation. We conducted a secondary analysis of a randomized controlled crossover trial (NCT03582306) in individuals with a BMI greater than 30 kg/m. Participants were provided with frozen GLV during the first or last four weeks (immediate or delayed intervention) of the twelve-week trial. Biological and anthropometric measures were taken at the beginning and at each four-week interval. A subset of 20 participants was selected for this secondary analysis of the intestinal permeability and inflammation-related biomarkers: serum and fecal zonulin; serum lipopolysaccharide binding protein (LBP), Alpha-1-acid glycoprotein 1 (ORM-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C-reactive protein; 8-hydroxy-2'-deoxyguanosine (8OHdG) and plasma Vitamin K1 as a marker of protocol adherence. Nutrient and food group intake from two-24-h dietary recalls collected at each time point were assessed. Fecal microbiota was measured by 16 s rRNA PCR sequencing. Changes in biological markers, dietary factors, and microbial taxa were assessed with Wilcoxon Sign Ranks Tests. Exploratory analyses of the relationship between changes in outcome variables were conducted with Spearman correlations.. No changes in serum and fecal zonulin and serum LBP were observed. Plasma Vitamin K (p = 0.005) increased, while plasma 8OHdG (p = 0.023) decreased during the intervention compared to the control. The only dietary factors that changed significantly were increases during intervention in Vitamin K and Dark GLV (p < 0.001 for both) compared to control. Fecal microbiota did not change significantly across all times points; however, change in serum zonulin was associated with change in Proteobacteria (ρ = - 0.867, p = 0.001) in females and Bifidobacterium (ρ = - 0.838, p = 0.009) and Bacteroidaceae (ρ = 0.871, p = 0.005) in men.. A high GLV dietary intervention increased serum zonulin levels and had no effect on fecal zonulin. Lack of concordance between several inflammation-associated biomarkers and zonulin corroborate recent reports of limited utility of zonulin in obese adults free of lower gastrointestinal disease. Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT03582306 (NCT03582306) registered on 07/11/2018.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Cross-Over Studies; Feces; Female; Haptoglobins; Humans; Inflammation; Obesity; Protein Precursors; Randomized Controlled Trials as Topic; Vegetables; Vitamin K

Acrylamide (ACR) exposure and consequent health hazards are alarming public health issues that attract worldwide concern. The World Health Organization urges more researches into health hazards from ACR exposure. However, whether and how ACR exposure increases cardiovascular risk remain unclear, and we sought to address these issues in this prospective cohort study conducted on 3024 general adults with 3-year follow-up (N = 871 at follow-up). Individual urinary ACR metabolites (N-Acetyl-S-(2-carbamoylethyl)-L-cysteine [AAMA] and N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine [GAMA]) as credible biomarkers of ACR exposure were detected to assess their cross-sectional and longitudinal relationships with 10-year cardiovascular disease (CVD) risk, a well measure of overall cardiovascular risk. Besides, biomarkers of oxidative stress (urinary 8-hydroxy-deoxyguanosine [8-OHdG] and 8-iso-prostaglandin-F2α [8-iso-PGF2α]) and inflammation (circulating mean platelet volume [MPV] and plasma C-reactive protein [CRP]) as well as plasma transforming growth factor-β1 (TGF-β1) were measured to assess their mediating/mechanistic roles in the relationships of ACR metabolites with 10-year CVD risk. We found AAMA, GAMA, and ΣUAAM (AAMA + GAMA) were cross-sectionally and longitudinally related to increased 10-year CVD risk with odds ratios (95% confidence intervals [CIs]) of 1.32 (1.04, 1.70), 1.81 (1.36, 2.40), and 1.40 (1.07, 1.82), respectively, and risk ratios (95% CIs) of 1.99 (1.10, 3.60), 2.48 (1.27, 4.86), and 2.13 (1.15, 3.94), respectively. Furthermore, 8-OHdG, 8-iso-PGF2α, MPV, CRP, and TGF-β1 were found to significantly mediate 8.06-48.92% of the ACR metabolites-associated 10-year CVD risk increment. In summary, daily ACR exposure of general adults was cross-sectionally and longitudinally associated with increased cardiovascular risk, which was partly mediated by oxidative stress, inflammation, and TGF-β1, suggesting for the first time that ACR exposure may well increase cardiovascular risk of general adult population partly by mechanisms of inducing oxidative stress, inflammation, and TGF-β1. Our findings have important public health implications that provide potent epidemiological evidence and vital mechanistic insight into cardiovascular risk increment from ACR exposure.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Acrylamide; Adult; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Heart Disease Risk Factors; Humans; Inflammation; Oxidative Stress; Prospective Studies; Risk Factors; Transforming Growth Factor beta1

Acrolein is a significant high priority hazardous air pollutant with pulmonary toxicity and the leading cause of most noncancer adverse respiratory effects among air toxics that draws great attention. Whether and how acrolein exposure impacts pulmonary function remain inconclusive.. To assess the association of acrolein exposure with pulmonary function and the underlying roles of oxidative DNA damage, inflammation, and pulmonary epithelium integrity.. Among 3,279 Chinese adults from the Wuhan-Zhuhai cohort, associations of urinary acrolein metabolites (N-Acetyl-S-(2-carboxyethyl)-L-cysteine, CEMA; N-Acetyl-S-(3-hydroxypropyl)-L-cysteine, 3HPMA) as credible biomarkers of acrolein exposure with pulmonary function were analyzed by linear mixed models. Joint effects of biomarkers of oxidative DNA damage (8-hydroxy-deoxyguanosine), inflammation (C-reactive protein, CRP), and pulmonary epithelium integrity (Club cell secretory protein, CC16) with acrolein metabolites on pulmonary function and the mediating roles of these biomarkers were assessed. Besides, a subgroup (N = 138) was randomly recruited from the cohort to assess the stabilities of acrolein metabolites and their longitudinal associations with pulmonary function change in three years.. Significant inverse dose-response relationships between acrolein metabolites and pulmonary function were found. Each 10-fold increment in CEMA, 3HPMA, or ΣUACLM (CEMA + 3HPMA) was cross-sectionally related to a 68.56-, 40.98-, or 46.02-ml reduction in FVC and a 61.54-, 43.10-, or 50.14-ml reduction in FEV. Acrolein exposure of general adults was cross-sectionally and longitudinally related to pulmonary function decline, which was aggravated and/or partly mediated by oxidative DNA damage, inflammation, and pulmonary epithelium injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acrolein; Adult; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Cysteine; Epithelium; Humans; Inflammation; Oxidative Stress

Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Chemokine CCL2; Colitis; Cytochrome P-450 CYP2E1; Dioxoles; Endotoxins; Ethanol; Furans; Heme Oxygenase-1; Inflammation; Interleukin-6; Lignans; Malondialdehyde; Mice; Nitric Oxide Synthase Type II; Oxidative Stress; Tight Junction Proteins; Tumor Necrosis Factor-alpha

The link between zinc exposure and glucose metabolism or the development of type 2 diabetes (T2D) is controversial, and underlying mechanisms are unclear. This study aimed to explore the associations of zinc exposure with glucose-insulin homeostasis traits and the long-term effects of zinc on the development of T2D, and further to estimate the potential roles of inflammation and oxidative damage in such relationships. We investigated 3890 urban adults from the Wuhan-Zhuhai cohort, and followed up every three years. Mixed linear model was applied to estimate dose-response associations between urinary zinc and glycemia traits [fasting plasma insulin (FPI), fasting plasma glucose (FPG), insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR), and β-cell dysfunction (homeostasis model assessment of β-cell function, HOMA-B)], as well as zinc and biomarkers for systemic inflammation (C-reactive protein) and oxidative damage (8-isoprostane and 8-hydroxy-2'-deoxyguanosine). Logistic regression model and Cox regression model were conducted to evaluate the relationships between urinary zinc and prevalence and incidence of T2D, respectively. We further performed mediation analysis to assess the roles of inflammation and oxidative damage biomarkers in above associations. At baseline, we observed significant dose-response relationships of elevated urinary zinc with increased FPI, FPG, HOMA-IR, and T2D prevalence and decreased HOMA-B, and such associations could be strengthened by increased C-reactive protein, 8-isoprostane, and 8-hydroxy-2'-deoxyguanosine. Elevated C-reactive protein significantly mediated 9.09% and 17.67% of the zinc-related FPG and HOMA-IR increments, respectively. In longitudinal analysis, a significantly positive association between urinary zinc and T2D incidence was observed among subjects with persistent high urinary zinc levels when compared with those with persistent low zinc levels. Our results suggested that high levels of zinc exposure adversely affected on glucose-insulin homeostasis and further contributed to increased risk of T2D cross-sectionally and longitudinally. Moreover, inflammatory response might play an important role in zinc-related glucose metabolic disorder.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Blood Glucose; C-Reactive Protein; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Oxidative Stress; Zinc

A human is exposed to a chemical mixture rather than a single chemical, particularly with the wide spread of nanomaterials. Therefore, the present study evaluated the combined exposure of lead acetate (Pb) and zinc oxide-nanoparticles (ZnO-NPs) compared to each metal alone on the thyroid gland of adult rats. A total of 30 adult male albino rats were divided into four groups, group I (control), group II received Pb (10 mg/kg), group III received ZnO-NPs (85 mg/kg) and group IV co-administrated the two metals in the same previous doses. The materials were gavaged for 8 weeks. The toxicity was assessed through several biochemical parameters. Our results revealed significant body weight reduction relative to increased thyroid weights, decreased both of serum-free triiodothyronine (FT3), tetra-iodothyronine (FT4), increased thyroid-stimulating hormone (TSH), increased serum and thyroid levels of Pb and zinc, significant elevation in tumor necrosis factor-α (TNF-α), reduction in interleukin 4 (IL4), upregulation of Bax, and downregulation of Bcl-2 genes. Additionally, there was significant overexpression of nuclear factor erythroid 2-related factor 2(Nrf2), 8-Hydroxydeoxyguanosine(8-OHdG), the elevation of tissues malondialdehyde (MDA), reduction of tissues total antioxidant capacity (TAC), and disruptive thyroid structural alterations in all metals groups with marked changes in the combined metals group. In conclusion, the combined exposure of Pb and ZnO-NPs induced pronounced toxic thyroid injury, pointing to additive effects in rats than the individual metal effects through different significant changes of disruptive thyroid structural alterations related to the loading of thyroid tissues with Pb and zinc metals producing oxidative stress that mediated inflammation and apoptosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Inflammation; Lead; Male; Nanoparticles; NF-E2-Related Factor 2; Oxidative Stress; Rats; Thyroid Gland; Zinc Oxide

To provide insights into the cause of e-cigarette (e-cig) associated lung injury, we examined the effects of propylene glycol (PG) and glycerol (G), two common solvent carriers used to deliver nicotine/flavor, on markers of oxidative stress and inflammation in female B6C3F1 mice which had been used successfully in tobacco smoke (TS)-induced lung carcinogenesis. Mice exposed to air and TS were used as negative and positive controls, respectively. Using LC-MS/MS, we showed that PG/G alone, in the absence of nicotine, significantly increased the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG or its tautomer 8-oxodG), a biomarker of DNA oxidative damage, in lung and plasma of mice; moreover, addition of nicotine (12 and 24 mg/mL) in e-cig liquid appears to suppress the levels of 8-oxodG. Exposure to e-cig aerosols or TS induced nonsignificant increases of plasma C-reactive protein (CRP), a biomarker of inflammation; nonetheless, the levels of fibronectin (FN), a biomarker of tissue injury, were significantly increased by e-cig aerosols or TS. Although preliminary, our data showed that exposure to e-cig aerosols induced a higher score of lung injury than did control air or TS exposure. Our results indicate that the B6C3F1 mouse model may be suitable for an in-depth examination of the impact of e-cig on lung injury associated with oxidative stress and inflammation and this study adds to the growing evidence that the use of e-cig can lead to lung damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aerosols; Animals; Biomarkers; Electronic Nicotine Delivery Systems; Female; Inflammation; Mice; Mice, Inbred Strains; Nicotine; Oxidative Stress

Neuroinflammation and oxidative stress have significant effects on cognitive deficiency in the pathophysiological development of Alzheimer's disease (AD). In the present study, we studied the influences of Ampelopsin (AMP) on proinflammatory cytokines (PICs, IL-1β, IL-6 and TNF-α), and products of oxidative stress 8-isoprostaglandin F2α (8-iso PGF2α, a product of oxidative stress); and 8-hydroxy-2'-deoxyguanosine (8-OHdG, a key biomarker of protein oxidation) in the hippocampus using a rat model of AD.. ELISA was used to examine PICs and oxidative stress production; and western blotting to examine NADPH oxidase (NOXs). The Spatial working memory tests and Morris water maze were utilized to assess cognitive functions.. We observed amplification of IL-1β, IL-6 and TNF-α as well as 8-iso PGF2α and 8-OHdG in the hippocampus of AD rats. AMP attenuated upregulation of PICs and oxidative stress production. AMP also inhibited NOX4 in the AD rat hippocampus. Notably, AMP mostly improved learning performance in AD rat and this was linked to signal pathways of PIC and oxidative stress.. AMP plays a significant role in improving the memory deficiency in AD rats via inhibition of signal pathways of neuroinflammation and oxidative stress, suggesting that AMP is likely to prospect in preventing and relieving development of the cognitive dysfunctions in AD as a complementary alternative intervention.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alzheimer Disease; Animals; Cognitive Dysfunction; Cytokines; Dinoprost; Disease Models, Animal; Flavonoids; Hippocampus; Inflammation; Male; Maze Learning; Memory, Short-Term; Neuroprotective Agents; Oxidative Stress; Rats

Increasing evidence indicates that oxidative damage and inflammation is present in patients with schizophrenia. In this study, we investigated the association between the serum concentrations of four typical oxidative stress and inflammatory biomarkers (monocyte chemotactic protein-1, heme oxygenase-1, interleukin-8, and 8-Hydroxydeoxyguanine) and schizophrenia using a case-control study design. In total, 44 patients with schizophrenia and 45 normal controls from Shandong Province, China were recruited. Fasting blood samples were collected from all participants and the serum concentration of the four biomarkers were analyzed by Enzyme-linked immunosorbent assay. The concentrations of monocyte chemotactic protein-1 and interleukin-8 were significantly higher in the patients than in the controls, while there was no significant difference in the serum concentrations of heme oxygenase-1 and 8-Hydroxydeoxyguanine. Moreover, the serum concentrations of monocyte chemotactic protein-1 and interleukin-8 in patients were positively correlated with severity of clinical symptoms. Dose-response relationships between serum biomarker concentrations and schizophrenia were observed. This study suggests that levels of monocyte chemotactic protein-1 and interleukin-8 are increased in patients with schizophrenia and correlated with positive symptom severity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Case-Control Studies; Chemokine CCL2; China; Enzyme-Linked Immunosorbent Assay; Female; Heme Oxygenase-1; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Oxidative Stress; Pilot Projects; Schizophrenia

Polycyclic aromatic hydrocarbons (PAHs) are key air pollutants that may contribute to the risk of numerous diseases by inducing inflammation and oxidative stress. Individuals with metabolic disorders may be more susceptible to PAH-induced inflammation and oxidative stress. To test this hypothesis, we designed a panel study involving 60 patients with pre-type 2 diabetes (pre-T2D) and 60 reference participants, and conducted up to seven repeated clinical examinations. Urinary metabolites of PAHs (i.e., OH-PAHs), measured as indicators of total PAH exposure, showed significant associations with markers of respiratory and systemic inflammation, including exhaled nitric oxide, interleukin (IL)-6 in exhaled breath condensate, and blood IL-2 and IL-8 levels and leucocyte count. The most significant effect was on urinary malondiadehyde (MDA), a marker of lipid peroxidation; a onefold increase of OH-PAHs was associated with 9.2-46.0% elevation in MDA in pre-T2D participants and 9.8-31.2% increase in healthy references. Pre-T2D participants showed greater increase in MDA, suggesting that metabolic disorder enhanced the oxidative damage induced by PAH exposure. This study revealed the association between PAH exposure and markers of inflammation and oxidative stress, and the enhanced responses of pre-T2D patients suggested that individuals with metabolic disorders were more susceptible to the adverse health effects of PAH exposure.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Environmental Exposure; Environmental Pollutants; Female; Humans; Inflammation; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Polycyclic Aromatic Hydrocarbons; Prediabetic State

Cigarette smoking is a key factor in systemic inflammation and oxidative stress, and it has also been associated with the loss of muscle strength and an elevated risk of pulmonary diseases. Thus, this study aimed to analyze the effects of cigarette smoking on the diaphragm muscle structure of postmortem samples.. Immunohistochemical techniques were used for muscle remodeling (metalloproteinases 2 and 9), inflammation (cyclooxygenase-2), oxidative stress (8-hydroxy-2'-deoxyguanosine), and vascularization (vascular endothelial growth factor). Hematoxylin and eosin stain was used for histopathological analysis and Picrosirius stain was used to highlight the collagen fibers.. Cigarette smokers had an increase of diaphragm muscle remodeling, oxidative stress, inflammation, and vascularization compared to non-smokers.. Diaphragm muscle structure may be negatively affected by cigarette smoking.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Autopsy; Cigarette Smoking; Cross-Sectional Studies; Cyclooxygenase 2; Diaphragm; Female; Humans; Inflammation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Oxidative Stress; Smokers; Vascular Endothelial Growth Factor A

Studies have shown that liraglutide, or human umbilical cord mesenchymal stem cell (hUC-MSCs) can improve non-alcoholic fatty liver disease (NAFLD). However there have been no studies on the combination of the two used to treat NAFLD. This study aimed to explore the therapeutic effects of combination of liraglutide and hUC-MSCs on liver injury in rats with type 2 diabetes mellitus (T2DM) and NAFLD, and further investigate their mechanisms. Sprague Dawley rats fed by a high fat and high sucrose diet were randomly divided into 5 groups, including NC group, T2DM/NAFLD group, liraglutide group (treated with liraglutide, 200 μg/kg, twice daily for 8 weeks), hUC-MSCs group (treated with hUC-MSCs at the first and fifth weeks), liraglutid＋hUC-MSCs group (treated with liraglutide and hUC-MSCs). Liver tissue was procured for histological examination, real-time qRT-PCR and Western blot analysis. After treatment, liraglutide and hUC-MSCs reduced serum ALT and AST levels, alleviate liver inflammation and improved liver histopathology. The expressions of inflammatory cytokines, TLR4 and NF-κB in serum and liver were significantly inhibited, particularly in the combination treatment group. Eight weeks after liraglutide or hUC-MSCs administration, FBG, HbA1c, HOMA-IR, ALT, AST, Liver wet eight and hepatic TLR4, NF-κB, IL-6, TNF-α, 8-OHdG mRNA and proteins were significantly decreased, and the levels of SOD expression were significantly increased in three treatment groups compared with T2DM/NAFLD group. This study suggests that liraglutide in combination with hUC-MSCs could significantly improve glycolipid metabolism, insulin resistance and liver injury in T2DM/NAFLD rats. Its mechanism may be related to the down-regulation of the TLR4/NF-κB inflammatory pathway and improvement in oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Combined Modality Therapy; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Liraglutide; Liver; Liver Neoplasms; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats, Sprague-Dawley; Superoxide Dismutase; Toll-Like Receptor 4; Umbilical Cord

This study aimed to investigate the protective effects of berberine (BBR) against D-galactose (D-gal)-induced renal aging in rats, pointing to its ability to modulate phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signalling, and to attenuate oxidative stress, inflammation and apoptosis. Renal aging was induced by subcutaneous injection of D-gal for six consecutive weeks along with simultaneous oral administration of BBR and compared to control rats and rats received individual doses of either drug. BBR treatment significantly reduced the serum levels of urea and creatinine, retrieved the alterations in kidney histopathology, and restored redox balance evidenced by alleviations of the level of malondialdehyde, 8-hydroxy-2'-deoxyguanosine and activating heme oxygenase-1 enzyme. Moreover, it markedly reduced the serum levels of pro-inflammatory mediators, along with down-regulation of PTEN expression, enhanced Akt activity, as well as significantly higher immunostaining of the anti-apoptotic marker (Bcl-2). These findings hold a great promise for the use of BBR as a protecting agent against renal aging.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Aging; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Berberine; Creatinine; Galactose; Gene Expression Regulation; Heme Oxygenase-1; Inflammation; Kidney; Male; Malondialdehyde; Oxidative Stress; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Rats; Renal Insufficiency; Signal Transduction; Urea

Celiac disease (CD) is a multifactorial, autoimmune, gluten-sensitive inflammatory disorder of the small intestine. Taking into account the pathogenesis of CD, a strict gluten-free diet (GFD) is the only treatment able to restore epithelium integrity and eliminate complications. The current study was designed to assess whether the use of a GFD is sufficient for maintaining a correct oxidative/antioxidant balance and ameliorating the evoked inflammatory signaling in young patients with CD.. The study covered 80 children, aged between 7 and 18 years, attending the Gastroenterology Service of the Gastroenterology, Hepatology and Child Nutrition Service from the Virgen de las Nieves Hospital in Granada. Children with CD diagnosed were included in the celiac group who followed a strict GFD for 2 years (n = 40) and the control group (n = 40) included healthy children, with negative serological screening. Soluble superoxide dismutase 1 and 2, total antioxidant status, 8-hydroxy-2'-deoxyguanosine, cortisol, melatonin and inflammatory parameters in plasma, 15-F2t-isoprostanes in urine, and DNA breaks in peripheral blood lymphocytes were analysed.. No differences were found in oxidative stress between CD patients and controls; however, IFN-γ, IL-1α, IP-10 and TNF-β were higher in the CD patients. VEGF was also higher than in the control group.. The GFD in the CD patients is enough to reduce the oxidative stress; however, in the case of the inflammatory signaling, the initial exposure to gluten prior to stablish the GFD is strong enough to induce an inflammatory state which is maintained (even when consuming the GFD); meanwhile the increase in VEGF recorded in the CD group could be a compensatory mechanism to restore the damaged mucosa and duodenal villous atrophy, due to its role in endothelial activation and generation of new functional and stable vascular networks.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Antioxidants; Celiac Disease; Child; Diet, Gluten-Free; Dinoprost; DNA; Female; Humans; Hydrocortisone; Inflammation; Male; Melatonin; Oxidative Stress; Signal Transduction; Spain; Superoxide Dismutase

Oxidative stress and low-grade systemic inflammation are common interrelated sequelae of chronic kidney disease (CKD) that associate with mortality. We investigated the association of serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, with mortality in CKD individuals and analyzed whether inflammation modifies the association.. In 376 individuals with a wide range of estimated glomerular filtration rate (eGFR); >60 ml/min (n = 53), 15-60 ml/min (n = 60) and <15 ml/min (n = 263), cut-off values of serum 8-OHdG, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF) as predictors of mortality were determined by ROC curves. We analyzed associations of 8-OHdG with inflammation markers and the overlapping effect of hsCRP, IL-6 and TNF on the association between 8-OHdG and all-cause mortality by multivariate generalized linear models.. In separate individual exposure analyses, higher 8-OHdG, hsCRP, and IL-6 (but not TNF) were each independently associated with increased risk of death in multivariate models adjusted for age, sex, diabetes mellitus, cardiovascular disease, protein-energy wasting, cohort calendar year, blood sample storage time and eGFR. For 8-OHdG, the multivariate relative risk ratio, RR. Serum 8-OHdG, a biomarker of oxidative DNA damage, is associated with increased all-cause mortality risk in individuals with a wide range of eGFR and this association is independent of inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; C-Reactive Protein; DNA Damage; Female; Glomerular Filtration Rate; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha

Adiponectin plays a role in asthma and obesity, but its effects and mechanism in obesity-related asthma remain elusive. This study aimed to evaluate the effects of adiponectin on airway inflammation and oxidative stress and to determine its mechanism in obesity-related asthma. Male C57BL6/J mice fed with a high-fat diet to induce obesity were sensitized and challenged with ovalbumin to induce asthma, and treated with adiponectin (1 mg/kg) and AMP-activated protein kinase (AMPK) inhibitor compound C (20 mg/kg) twice before the first ovalbumin challenge. We found exogenous adiponectin significantly reduced airway resistance, inflammatory infiltration in lung tissue, and cell counts in bronchoalveolar lavage fluid. Adiponectin inhibited great levels of eotaxin, myeloperoxidase, tumor necrosis factor-α, 8‑hydroxy‑2'‑deoxyguanosine, and nitric oxide in obesity-related asthma mice. Moreover, we found increased nuclear factor kappa B p65, inducible nitric oxide synthase and B-cell lymphoma 2 protein expression were down-regulated with adiponectin administration. Additionally, adiponectin elevated the lower levels of pAMPK and AMPK activity in lung tissue. These protective effects of adiponectin were reversed after treatment with the AMPK inhibitor compound C. Thus, we conclude that adiponectin alleviates exacerbation of airway inflammation and oxidative stress in a murine model of obesity-related asthma partly through AMPK signaling pathway.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; AMP-Activated Protein Kinases; Animals; Antioxidants; Asthma; Chemokine CCL11; Deoxyguanosine; Immunoglobulin E; Inflammation; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Obesity; Oxidative Stress; Random Allocation

To determine whether antenatal depression is associated with oxidative stress and inflammation, and secondarily, whether the association between antenatal depression and spontaneous preterm birth (SPTB) is mediated by these biomarkers.. The primary outcome included urine oxidative stress biomarkers 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane and plasma inflammatory biomarkers measured at 10, 18, and 26 weeks and averaged within individual. Linear and logistic regression models were used, adjusting for age, race, parity, and pre-pregnancy body mass index.. Among 462 women, 8-isoprostane was higher among depressed women (geometric mean: 299.96 pg/mL vs. 237.01 pg/mL; p = 0.001). In multivariable analyses, antenatal depression was significantly associated with an increase in average 8-isoprostane (β: 0.25; 95% CI: 0.05-0.44; p = 0.01). The association of antenatal depression with SPTB was partially mediated by 8-isoprostane. Antenatal depression was not associated with 8-OHdG or inflammatory biomarkers.. Antenatal depression was associated with higher oxidative stress across pregnancy, namely 8-isoprostane, and may impact SPTB via oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Case-Control Studies; Cytokines; Depression; Dinoprost; Female; Humans; Inflammation; Oxidative Stress; Pregnancy; Pregnancy Complications; Premature Birth; Regression Analysis; Young Adult

Methylmercury (MeHg) is a well-known environmental pollutant associated with neurological and developmental deficits in animals and humans. However, epidemiological data showed that people living in the Amazon region although exposed to MeHg do not present these effects probably due to the protective effect of certain foods. We hypothesized here if guarana, a highly caffeinated fruit and consumed on a daily basis by Amazon people, could have some protective effect against MeHg toxicity using two complementary approaches. To assess locomotor impairment and sleep disruption, we used fruit fly (Drosophila melanogaster) model, and to evaluate neuroinflammation, we used human SH-SY5Y neural cells by measuring inflammatory cytokines levels. Results showed that guarana had a protective effect on the locomotor activity of male fruit flies reducing the excessive sleepiness caused by MeHg and increasing daily activity. Also, guarana increased the viability of flies and attenuated neural cells mortality. In addition, guarana reduced all pro-inflammatory cytokines levels increased by MeHg, along with caspase-1, caspase -3, caspase-8, and 8-dOHG levels, whereas increased the anti-inflammatory (IL-10) cytokine levels, which was decreased by MeHg. Our study provides new insights on the protective effects of guarana on the viability, locomotor activity, sleep, and activity patterns in vivo and the in vitro neuronal anti-inflammatory effect against MeHg toxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Caspases; Cell Line; Circadian Rhythm; Deoxyguanosine; Drosophila melanogaster; Humans; Inflammation; Interleukin-10; Methylmercury Compounds; Neurons; Paullinia

Preclinical studies have demonstrated that maternal inflammation or neonatal hyperoxia adversely affects kidney maturation. This study explored whether prenatal lipopolysaccharide (LPS) exposure can augment neonatal hyperoxia-induced kidney injury.. Pregnant Sprague-Dawley rats received intraperitoneal injections of LPS (0.5 mg/kg) in normal saline (NS) or NS on 20 and 21 days of gestation. The pups were reared in room air (RA) or 2 weeks of 85% O. The rats exposed to maternal LPS or neonatal hyperoxia exhibited significantly higher kidney injury score, lower glomerular number, higher toll-like receptor 4 (TLR4), myeloperoxidase (MPO), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expressions, and higher MPO activity compared with the rats exposed to maternal NS and neonatal RA. The rats exposed to both maternal LPS and neonatal hyperoxia exhibited significantly lower glomerular number, higher kidney injury score, TLR4, MPO, and 8-OHdG expressions compared with the rats exposed to maternal LPS or neonatal hyperoxia.. Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury and the underlying mechanism may be related to activation of TLR4 and increased oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Animals, Newborn; Antibodies; Body Weight; Chorioamnionitis; Cytokines; Female; Hyperoxia; Inflammation; Kidney Diseases; Lipopolysaccharides; Maternal Exposure; Organ Size; Oxidative Stress; Oxygen; Peroxidase; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4

Zingerone (ZO), one of the active components of ginger (Zingiber officinale), is a phenolic alkanone with antioxidant, antiapoptotic, and anti-inflammatory properties. Cisplatin (CP) is a widely used chemotherapeutic drug for solid tumors, but its therapeutic use is limited due to dose-dependent nephrotoxicity. In the present study, we investigated the ameliorative effect of ZO against CP-induced nephrotoxicity. Intraperitoneal administration of single-dose CP (7 mg/kg body weight) on the first day enhanced kidney lipid peroxidation and reduced antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). CP increased serum urea and creatinine levels and disrupted histological integrity while causing a decrease aquaporin 1 (AQP1) level in the kidney tissues. CP induced inflammatory responses by elevating the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-33 (IL-33) and nuclear factor kappa B (NF-κB), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it also caused oxidative DNA damage and activation of apoptotic pathway by increasing of 8-hydroxy-2'-deoxyguanosine (8-OHdG), p53, cysteine aspartate-specific protease-3 (caspase-3), and Bcl-2-associated x protein (bax) while decreasing B cell lymphoma-2 (Bcl-2). However, treatment with ZO at a dose of 25 and 50 mg/kg b.wt. for 7 days significantly decreased oxidative stress, apoptosis, inflammation, and histopathological alterations while increased AQP1 levels in the kidney tissue. The results of the current study suggested that ZO as an effective natural product attenuates CP-induced nephrotoxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Apoptosis; Autophagy; Blood Urea Nitrogen; Catalase; Cisplatin; Deoxyguanosine; DNA Damage; Female; Glutathione; Glutathione Peroxidase; Guaiacol; Inflammation; Interleukin-6; Kidney; Lipid Peroxidation; Male; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Rats; Superoxide Dismutase; Toxicity Tests; Tumor Necrosis Factor-alpha

Diisodecyl phthalate (DIDP) is commonly used as a plasticizer in industrial and consumer products, however, its toxicity remains unclear. This study investigated the possible involvement of oxidative stress in DIDP-induced liver and kidney toxicity. Liver function and kidney function, tissue lesions, oxidative stress biomarkers, inflammatory mediators and apoptosis factors were investigated in this study. The results showed that oral exposure to DIDP induced a marked increase in lever of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urinary nitrogen (UREA) and creatinine (CREA), decrease in albumin (ALB) level, as well as causing hepatic and renal histopathological change. Investigation of the role of oxidative stress pathways showed that DBP exposure could lead to a significant increase in levels of reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB), while a decrease in glutathione (GSH) levels were observed. Administration of vitamin E to DIDP-treated mice restored these biochemical parameters to within normal levels, and resulted in less damage to livers and kidneys. Overall, these results suggest that the oxidative stress pathway is involved in DIDP-induced toxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Apoptosis; Caspase 3; Deoxyguanosine; Glutathione; Inflammation; Interleukin-1beta; Kidney; Liver; Male; Malondialdehyde; Mice, Inbred BALB C; NF-kappa B; Oxidative Stress; Phthalic Acids; Plasticizers; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

One mechanism by which alcoholic liver disease (ALD) progresses is oxidative stress and the generation of reactive oxygen species, among others due to the induction of cytochrome P-4502E1 (CYP2E1). Experimental data underline the key role of CYP2E1 because ALD could be partially prevented in rats by the administration of the specific CYP2E1 inhibitor chlormethiazole. As CYP2E1 is linked to the formation of carcinogenic etheno DNA adducts in ALD patients, a causal role of alcohol-induced CYP2E1 in hepatocarcinogenesis is implicated. The purpose of this study was to investigate CYP2E1 induction in ALD, and its correlation with oxidative DNA lesions and with hepatic histology.. Hepatic biopsies from 97 patients diagnosed with ALD were histologically scored for steatosis, inflammation, and fibrosis. CYP2E1 and the exocyclic etheno DNA adduct 1,N. A significant positive correlation was found between CYP2E1 and εdA (p < 0.0001) as well as between CYP2E1 and 8-OHdG (p = 0.039). Both CYP2E1 (p = 0.0094) and ɛdA (p < 0.0001) also correlated significantly with the stage of hepatic fibrosis. Furthermore, a significant correlation between the fibrosis stage and the grade of lobular inflammation (p < 0.0001) was observed. However, the amount of alcohol consumed did not correlate with any of the parameters determined.. These data suggest an important role of CYP2E1 in the generation of εdA, in the fibrotic progression of ALD, and thus in alcohol-mediated hepatocarcinogenesis. CYP2E1 may be a target in the treatment of ALD and a potential prognostic marker for disease progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carcinogenesis; Carcinoma, Hepatocellular; Cytochrome P-450 CYP2E1; Deoxyadenosines; Deoxyguanosine; Female; Fibrosis; Humans; Immunohistochemistry; Inflammation; Intra-Abdominal Fat; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Liver Neoplasms; Male; Middle Aged

Cisplatin (CP) is a widely used chemotherapeutic drug, effective against a variety of solid tumours, though its utility is limited due to its multiple organ toxicity. Zingerone (ZO), one of the most important components of dry ginger root, has several pharmacological activities, such as antioxidant, anti-inflammatory and anti-apoptotic properties. This study aimed to investigate the ameliorative effect of ZO on CP-induced ovarian and uterine toxicity in female rats. The rats were subjected to a prophylactic oral treatment of ZO (25 and 50 mg/kg body weight) for seven days to measure the protective effect against ovarian and uterine toxicity induced by a single (i.p.) of CP (7 mg/kg body weight) on the first day whereas the rats were sacrificed on the eighth day. The results showed that ZO decreased the serum FSH hormone level, increased the serum E2 hormone level, and also maintained the ovarian and uterine histological architecture and integrity. In addition, ZO obviously increased the measured activity of antioxidant enzymes (SOD, CAT and GPx) and the GSH content, and significantly reduced MDA levels. ZO was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, IL-1β, IL-6, COX-2 and iNOS in CP-induced ovarian and uterine damage. It also inhibited apoptosis and reduced oxidative DNA damage markers by the downregulation of caspase-3 and 8-OHdG expression coupled with an upregulated Bcl-2 level. The results indicate that ZO may be beneficial in ameliorating CP-induced oxidative stress, sex hormone imbalances, inflammation and apoptosis in ovarian and uterine tissues of female rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Apoptosis; Caspase 3; Catalase; Cisplatin; Cyclooxygenase 2; Deoxyguanosine; Estradiol; Female; Follicle Stimulating Hormone; Glutathione; Glutathione Peroxidase; Gonadal Steroid Hormones; Guaiacol; Inflammation; Interleukin-1beta; Interleukin-6; Malondialdehyde; NF-kappa B; Ovary; Oxidative Stress; Rats, Wistar; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Uterus

Reactive oxygen species contribute to periodontal tissue homeostasis under control of anti-oxidative responses. Disruption in this balance induces severe inflammation and extended tissue degradation.. Aim of this study was to identify the expression levels of nuclear factor, erythroid 2 like 2 (NFE2L2/NRF2), Parkinsonism associated deglycase (PARK7/DJ-1), kelch-like ECH associated protein 1 (KEAP1), and 8-hydroxy-deoxyguanosine (8-OHdG) in peri-implant mucosal tissues affected by peri-implantitis, and to compare the levels to those of periodontally diseased and healthy tissue samples.. Tissue biopsies were collected from systemically healthy, non-smoking 12 peri-implantitis patients, 13 periodontitis patients, and 13 periodontally healthy controls. Expression levels of NFE2L2/NRF2, PARK7/DJ-1, KEAP1, and 8-OHdG in tissue samples were analyzed immunohistochemically. Statistical analysis was performed by one-way ANOVA with Tukey's HSD test.. Inflammatory cell infiltration in the connective tissue and loss of architecture in the spinous layer of the epithelium were prominent in peri-implantitis. Proportions of 8-OHdG and PARK7/DJ-1 expressing cells were elevated in both peri-implantitis (P = .025 for 8-OHdG and P = .014 for PARK7/DJ-1) and periodontitis (P = .038 for 8-OHdG and P = .012 for PARK7/DJ-1) groups in comparison with controls. Staining intensities of 8-OHdG and PARK7/DJ-1 were higher in the periodontitis and peri-implantitis groups than in the control (P < .01) groups. There was no difference in the expression levels of NFE2L2/NRF2 between the groups. KEAP1 was not observed in any tissue sample.. Peri-implantitis is characterized by severe inflammation and architectural changes in the epithelium and connective tissue. The expressions of 8-OHdG and PARK7/DJ-1 are elevated in both peri-implantitis and periodontitis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Analysis of Variance; Biopsy; Deoxyguanosine; Female; Humans; Immunohistochemistry; Inflammation; Kelch-Like ECH-Associated Protein 1; Male; Middle Aged; Mucous Membrane; NF-E2-Related Factor 2; Oxidative Stress; Peri-Implantitis; Periodontitis; Periodontium; Protein Deglycase DJ-1; Reactive Oxygen Species; Turkey

Perturbations in normal fetal growth during pregnancy are associated with poor child and adult health outcomes. Inflammation and oxidative stress are recognized as important mechanisms in preeclampsia and preterm birth but have been examined less in relation to fetal growth. We hypothesized that maternal inflammation and oxidative stress in pregnancy would be associated with reduced fetal growth and sought to identify windows of vulnerability.. In a secondary analysis of 482 women from the LIFECODES birth cohort study, we measured inflammation (C-reactive protein [CRP] and the cytokines IL-1β, IL-6, IL-10, and TNF-α) and oxidative stress (8-isoprostane and 8-hydroxydeoxyguanosine [8-OHdG]) biomarkers in plasma and urine, respectively, at four time points during pregnancy. We examined associations between repeated measures of each marker and ultrasound (head and abdominal circumference, femur length, and a summary measure of estimated fetal weight) as well as delivery (birthweight) metrics of growth.. In adjusted repeated-measures models, an interquartile range (IQR) increase in CRP was associated with a 0.12 standard deviation decrease in fetal weight z-score (95% confidence interval, CI, -0.21, -0.02), which corresponds to approximately 50 g at 40-week gestation. The association was greatest in magnitude (ie, most negative) with CRP measured later in pregnancy. Oxidative stress markers were not associated with fetal weight, although both were inversely associated with head circumference and femur length.. Inflammation and oxidative stress markers measured later in pregnancy were associated with reduced fetal growth as measured by repeated ultrasound scans.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Birth Weight; Cytokines; Deoxyguanosine; Dinoprost; Female; Fetal Development; Humans; Infant, Newborn; Inflammation; Male; Oxidative Stress; Pregnancy; Ultrasonography, Prenatal; Young Adult

Rats with a normal birth weight (NBW) or intra-uterine growth retardation (IUGR) were fed basic diets (NBW and IUGR groups) or basic diets supplemented with curcumin (NC and IC groups) from 6 to 12 weeks. The body weight of IUGR rats was lower (P<0·05) than that of the controls. Rats with IUGR showed higher (P<0·05) concentrations of TNF-α, IL-1β and IL-6; higher (P<0·05) activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in their serum; and increased (P<0·05) concentrations of malondialdehyde (MDA), protein carbonyl (PC) and 8-hydroxy-2'-deoxyguanosine (8-OHDG) in the liver compared with the NBW rats. The livers of IUGR rats exhibited a lower (P<0·05) superoxide dismutase activity and decreased (P<0·05) metabolic efficiency of the hepatic glutathione redox cycle compared with those of the NBW rats. In response to dietary curcumin supplementation, concentrations of inflammatory cytokines and activities of AST and ALT in the serum and MDA, PC and 8-OHDG in the liver were lower (P<0·05), and the hepatic glutathione redox cycle in the liver was improved (P<0·05) in the IC group than in the IUGR group. These results were associated with lower (P<0·05) phosphorylated levels of the NF-κB pathway and Janus kinase 2 (JAK2) and higher (P<0·05) mRNA expression of genes involved in the nuclear factor, erythroid 2-like 2 (Nfe2l2)/antioxidant response element (ARE) pathway in the liver of the IC rats than that of the IUGR rats. Maternal undernutrition decreased birth weight and led to inflammation, oxidative damage and injury in rats. Curcumin appeared to be beneficial in preventing IUGR-induced inflammation, oxidative damage and injury by activating the expression of the NF-κB, JAK/STAT and Nfe2l2/ARE pathways in the liver.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Animals; Animals, Newborn; Aspartate Aminotransferases; ATP-Binding Cassette Transporters; Birth Weight; Caenorhabditis elegans Proteins; Curcumin; Cytokines; Deoxyguanosine; Dietary Supplements; Disease Models, Animal; Female; Fetal Growth Retardation; Gene Expression; Inflammation; Liver; Liver Diseases; Oxidation-Reduction; Oxidative Stress; Pregnancy; Rats

Increased activity of the three major physiological stress systems (immune-inflammatory system, hypothalamic-pituitary-adrenal-axis [HPA-axis], and autonomic nervous system [ANS]) is part of the pathophysiology of various somatic and psychiatric diseases. Oxidative damage is a key mechanism in both ageing and disease. Elucidating the relationship between these stress systems and oxidative damage would contribute to the understanding of the role of physiological stress in disease. This study therefore investigates associations between various measures of physiological stress and oxidative DNA (8-hydroxy-2'-deoxyguanosine, 8-OHdG) and lipid (F2-isoprostanes) damage.. Plasma 8-OHdG and F2-isoprostanes were measured using LC-MS/MS in 2858 subjects (aged 18-65). Plasma inflammation markers, salivary cortisol and ANS markers (three for each stress system) were determined. Linear regression analyses were adjusted for sociodemographics, sampling factors and medication.. 8-OHdG was positively associated with all inflammation markers (β=0.047-0.050, p<0.01), evening cortisol (β=0.073, p<0.001), and unexpectedly with low respiratory sinus arrhythmia (RSA) reflecting low ANS stress (β=0.073, p<0.001). F2-isoprostanes were associated with higher C-reactive protein (β=0.072, p<0.001), high ANS stress reflected in heart rate (β=0.064, p<0.001) and RSA (β=-0.076, p=0.001), but not with cortisol. Analyses investigating the cumulative impact of the stress systems demonstrated that the number of systems with ≥1 marker in the high risk quartile showed a positive linear trend with both 8-OHdG (p=0.030) and F2-isoprostanes (p=0.009).. This large-scale study showed that markers of inflammation, the HPA-axis and ANS are associated with oxidative DNA damage. Oxidative lipid damage is associated with inflammation and the ANS. Increased physiological stress across systems is associated with increasing oxidative damage in a dose-response fashion.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Autonomic Nervous System; Biomarkers; Deoxyguanosine; DNA; DNA Damage; F2-Isoprostanes; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Inflammation; Lipids; Male; Middle Aged; Oxidative Stress; Pituitary-Adrenal System; Saliva; Stress, Physiological; Tandem Mass Spectrometry

Excessive alcohol consumption is a risk factor associated with colorectal cancer; however, some studies have reported that moderate alcohol consumption may not contribute additional risk for developing colorectal cancer while others suggest that moderate alcohol consumption provides a protective effect that reduces colorectal cancer risk. The purpose of this study was to determine the effects of moderate voluntary alcohol (20% ethanol) intake on alternate days for 3 months in outbred Wistar rats on risk factors associated with colorectal cancer development. Colonic gene expression of cyclooxygenase-2, RelA, 8-oxoguanine DNA glycosylase 1, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase M1, and aldehyde dehydrogenase 2 were determined. Blood alcohol content, liver function enzyme activities, and 8-oxo-deoxyguanosine DNA adducts were also assessed. Alcohol-treated rats were found to have significantly lower 8-oxo-deoxyguanosine levels in blood, a marker of DNA damage. Alanine aminotransferase and lactate dehydrogenase were both significantly lower in the alcohol group. Moderate alcohol significantly decreased cyclooxygenase-2 gene expression, an inflammatory marker associated with colorectal cancer risk. The alcohol group had significantly increased glutathione-S-transferase M1 expression, an antioxidant enzyme that helps detoxify carcinogens, such as acetaldehyde, and significantly increased aldehyde dehydrogenase 2 expression, which allows for greater acetaldehyde clearance. Increased expression of glutathione-S-transferase M1 and aldehyde dehydrogenase 2 likely contributed to reduce mucosal damage that is caused by acetaldehyde accumulation. These results indicate that moderate alcohol may reduce the risk for colorectal cancer development, which was evidenced by reduced inflammation activity and lower DNA damage after alcohol exposure.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; Animals; Antioxidants; Colitis; Colorectal Neoplasms; Cyclooxygenase 2; Deoxyguanosine; DNA Damage; Ethanol; Gene Expression; Glutathione Transferase; Inflammation; Liver; Male; Rats; Rats, Wistar; Risk Factors

In this study, we aimed to identify the toxic effects of chlorpyrifos exposure on the tissues of common carp. For this purpose, we evaluated histopathological changes in the brain, gills, liver, kidney, testis, and ovaries after 21 days of chlorpyrifos exposure. Activation of 8-OHdG, cleaved caspase-3, and iNOS were assesed by immunofluorescence assay in chlorpyrifos-exposed brain and liver tissue. Additionally, we measured the expression levels of caspase-3, caspase-8, iNOS, MT1, CYP1A, and CYP3A genes in chlorpyrifos-exposed brain tissue, as well as the expression levels of FSH and LH genes in chlorpyrifos-exposed ovaries, using qRT-PCR. We observed severe histopathological lesions, including inflammation, degeneration, necrosis, and hemorrhage, in the evaluated tissues of common carp after both high and low levels of exposure to chlorpyrifos. We detected strong and diffuse signs of immunofluorescence reaction for 8-OHdG, iNOS, and cleaved caspase-3 in the chlorpyrifos-exposed brain and liver tissues. Furthermore, we found that chlorpyrifos exposure significantly upregulated the expressions of caspase-3, caspase-8, iNOS, and MT1, and also moderately upregulated CYP1A and CYP3A in the brain tissue of exposed carp. We also noted downregulation of FSH and LH gene expressions in chlorpyrifos-exposed ovary tissues. Based on our results, chlorpyrifos toxication caused crucial histopathological lesions in vital organs, induced oxidative stress, inflammation, and apoptosis in liver and brain tissues, and triggered reproductive sterility in common carp. Therefore, we can propose that chlorpyrifos toxication is highly dangerous to the health of common carp. Moreover, chlorpyrifos pollution in the water could threaten the common carp population. Use of chlorpyrifos should be restricted, and aquatic systems should be monitored for chlorpyrifos pollution.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Biomarkers; Carps; Caspase 3; Chlorpyrifos; Deoxyguanosine; Gene Expression; Genitalia; Gills; Inflammation; Kidney; Liver; Oxidative Stress; Water Pollutants, Chemical

Oxidative stress, DNA damage repair, and inflammation are three important reactions of sulfur mustard (SM) exposure. But molecular related chronological events in the earlier stage of SM exposure model are still unclear. In the research, reactive oxygen species (ROS) was measured by using flow cytometry. Cytokines were tested in Luminex method. Myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG) and glutathione (GSH) activity or levels in serum were determined by commercially available kits. Western blot was used to determination of phosphorylated histone 2A.X (γ-H2A.X). Results showed that the oxidative stress biomarker of ROS and 8-OHdG were significantly increased early at 0.5h of SM exposure, but GSH level was decreased at 0.5h. Similarly, SM increased γ-H2A.X level early at 2h, which reached to peak at 8h and recovered to normal at 24h. MPO and iNOS activity were also increased early at 2h and 0.5h respectively. However, all selected inflammation biomarkers, including IL-6, TNF-α, IL-1β, MCP-1, GM-CSF and IL-10 concentrations are all unchangeable in 2h. The results indicated that oxidative stress and DNA damage had happened more quickly than inflammation reaction. These chronological events may be due to uncovered generation of reactive oxygen species, DNA alkylation and oxidative DNA damage. In conclusion, this research showed that both oxidative stress and DNA damage are earlier events than inflammation in sulfur mustard toxic mouse model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cytokines; Deoxyguanosine; DNA Damage; Gene Expression Regulation; Inflammation; Injections, Subcutaneous; Male; Mice; Mustard Gas; Oxidative Stress; Reactive Oxygen Species

Topics: 8-Hydroxy-2'-Deoxyguanosine; Cardiomyopathies; Deoxyguanosine; Humans; Inflammation; Oxidative Stress; Sarcoidosis; Tachycardia, Ventricular

Using data collected before, during, and after the 2008 Summer Olympic Games in Beijing, this study examines associations between biomarkers of blood coagulation (vWF, sCD62P and sCD40L), pulmonary inflammation (EBC pH, EBC nitrite, and eNO), and systemic oxidative stress (urinary 8-OHdG) with sources of air pollution identified utilizing principal component analysis and with concentrations of three aldehydes of health concern. Associations between the biomarkers and the air pollution source types and aldehydes were examined using a linear mixed effects model, regressing through seven lag days and controlling for ambient temperature, relative humidity, gender, and day of week for the biomarker measurements. The biomarkers for pulmonary inflammation, particularly EBC pH and eNO, were most consistently associated with vehicle and industrial combustion, oil combustion, and vegetative burning. The biomarkers for blood coagulation, particularly vWF and sCD62p, were most consistently associated with oil combustion. Systemic oxidative stress biomarker (8-OHdG) was most consistently associated with vehicle and industrial combustion. The associations of the biomarkers were generally not significant or consistent with secondary formation of pollutants and with the aldehydes. The findings support policies to control anthropogenic pollution sources rather than natural soil or road dust from a cardio-respiratory health standpoint.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Air Pollutants; Air Pollution; Aldehydes; Biomarkers; Blood Coagulation; China; Chromatography, High Pressure Liquid; Deoxyguanosine; Environmental Monitoring; Female; Humans; Hydrogen-Ion Concentration; Inflammation; Male; Nitric Oxide; Nitrites; Oxidative Stress; Particle Size; Particulate Matter; Principal Component Analysis; Sports; Urine; Vehicle Emissions; Young Adult

We investigated the uptake and pharmacokinetics of l-ergothioneine (ET), a dietary thione with free radical scavenging and cytoprotective capabilities, after oral administration to humans, and its effect on biomarkers of oxidative damage and inflammation.. After oral administration, ET is avidly absorbed and retained by the body with significant elevations in plasma and whole blood concentrations, and relatively low urinary excretion (<4% of administered ET). ET levels in whole blood were highly correlated to levels of hercynine and S-methyl-ergothioneine, suggesting that they may be metabolites. After ET administration, some decreasing trends were seen in biomarkers of oxidative damage and inflammation, including allantoin (urate oxidation), 8-hydroxy-2'-deoxyguanosine (DNA damage), 8-iso-PGF2α (lipid peroxidation), protein carbonylation, and C-reactive protein. However, most of the changes were non-significant.. This is the first study investigating the administration of pure ET to healthy human volunteers and monitoring its uptake and pharmacokinetics. This compound is rapidly gaining attention due to its unique properties, and this study lays the foundation for future human studies.. The uptake and retention of ET by the body suggests an important physiological function. The decreasing trend of oxidative damage biomarkers is consistent with animal studies suggesting that ET may function as a major antioxidant but perhaps only under conditions of oxidative stress. Antioxid. Redox Signal. 26, 193-206.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Allantoin; Antioxidants; Betaine; Biomarkers; C-Reactive Protein; Deoxyguanosine; Drug Monitoring; Ergothioneine; Healthy Volunteers; Histidine; Humans; Inflammation; Oxidative Stress

Pathophysiological mechanisms that contribute to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) include oxidative stress and inflammation. We conducted a preliminary study to explore these mechanisms, to discuss their link in ALS, and to determine the feasibility of incorporating this combined analysis into current biomarkers research.. We enrolled 10 ALS patients and 10 controls. We measured the activities of glutathione peroxidase, glutathione reductase, superoxyde dismutase (SOD), and the levels of serum total antioxidant status (TAS), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and glutathione status (e.g. glutathione disulfide, GSSG/reduced glutathione, GSH). We analysed the concentrations of homocysteine, several cytokines, vitamins and metals by standard methods used in routine practice.. There was a significant decrease in TAS levels (p=0.027) and increase in 8-OHdG (p=0.014) and MDA (p=0.011) levels in ALS patients. We also observed a significantly higher GSSG/GSH ratio (p=0.022), and IL-6 (p=0.0079) and IL-8 (p=0.009) concentrations in ALS patients. Correlations were found between biological and clinical markers (homosysteine vs. clinical status at diagnosis, p=0.02) and between some biological markers such as IL-6 vs. GSSG/GSH (p=0.045) or SOD activity (p=0.017).. We confirmed the systemic alteration of both the redox and the inflammation status in ALS patients, and we observed a link with some clinical parameters. These promising results encourage us to pursue this study with collection of combined oxidative stress and inflammatory markers.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Biomarkers; Cytokines; Deoxyguanosine; Female; Glutathione Peroxidase; Glutathione Reductase; Homocysteine; Humans; Inflammation; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pilot Projects; Severity of Illness Index; Statistics as Topic

Preeclampsia is a prevalent and enigmatic disease, in part characterized by poor remodeling of the spiral arteries. However, preeclampsia does not always clinically present when remodeling has failed to occur. Hypotheses surrounding the "second hit" that is necessary for the clinical presentation of the disease focus on maternal inflammation and oxidative stress. Yet, the studies to date that have investigated these factors have used cross-sectional study designs or small study populations.. In the present study, we sought to explore longitudinal trajectories, beginning early in gestation, of a panel of inflammation and oxidative stress markers in women who went on to have preeclamptic or normotensive pregnancies.. We examined 441 subjects from the ongoing LIFECODES prospective birth cohort, which included 50 mothers who experienced preeclampsia and 391 mothers with normotensive pregnancies. Participants provided urine and plasma samples at 4 time points during gestation (median, 10, 18, 26, and 35 weeks) that were analyzed for a panel of oxidative stress and inflammation markers. Oxidative stress biomarkers included 8-isoprostane and 8-hydroxydeoxyguanosine. Inflammation biomarkers included C-reactive protein, the cytokines interleukin-1β, -6, and -10, and tumor necrosis factor-α. We created Cox proportional hazard models to calculate hazard ratios based on time of preeclampsia diagnosis in association with biomarker concentrations at each of the 4 study visits.. In adjusted models, hazard ratios of preeclampsia were significantly (P<.01) elevated in association with all inflammation biomarkers that were measured at visit 2 (median, 18 weeks; hazard ratios, 1.31-1.83, in association with an interquartile range increase in biomarker). Hazard ratios at this time point were the most elevated for C-reactive protein, for interleukin-1β, -6, and -10, and for the oxidative stress biomarker 8-isoprostane (hazard ratio, 1.68; 95% confidence interval, 1.14-2.48) compared to other time points. Hazard ratios for tumor necrosis factor-α were consistently elevated at all 4 of the study visits (hazard ratios, 1.49-1.63; P<.01). In sensitivity analyses, we observed that these associations were attenuated within groups typically at higher risk of experiencing preeclampsia, which include African American mothers, mothers with higher body mass index at the beginning of gestation, and pregnancies that ended preterm.. This study provides the most robust data to date on repeated measures of inflammation and oxidative stress in preeclamptic compared with normotensive pregnancies. Within these groups, inflammation and oxidative stress biomarkers show different patterns across gestation, beginning as early as 10 weeks. The start of the second trimester appears to be a particularly important time point for the measurement of these biomarkers. Although biomarkers alone do not appear to be useful in the prediction of preeclampsia, these data are useful in understanding the maternal inflammatory profile in pregnancy before the development of the disease and may be used to further develop an understanding of potentially preventative measures.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; C-Reactive Protein; Cohort Studies; Cytokines; Deoxyguanosine; Dinoprost; Female; Humans; Inflammation; Oxidative Stress; Pre-Eclampsia; Pregnancy; Proportional Hazards Models

Animal and clinical studies suggest a link between inflammation and oxidative stress. Because oxidative stress is an inherent part of inflammation, and inflammation is associated with behavioral aggression in lower mammals and humans, we hypothesized that markers of oxidative stress would be related to aggression in human subjects. In this case-control study, markers of oxidative stress and aggression were assessed in human subjects with histories of recurrent, problematic, impulsive aggressive behavior and in nonaggressive comparator subjects.. Plasma levels of 8-hydroxy-2'-deoxyguanosine and 8-isoprostane were examined in the context of measures of aggression and impulsivity in physically healthy subjects with intermittent explosive disorder (n = 69), nonaggressive subjects with Axis I or II disorders (n = 61), and nonaggressive subjects with no history of Axis I or II disorders (n = 67).. Levels of plasma 8-hydroxy-2'-deoxyguanosine and 8-isoprostane were significantly higher in subjects with intermittent explosive disorder compared with psychiatric or normal control subjects. In addition, both oxidative stress markers correlated with a composite measure of aggression; more specifically, 8-hydroxy-2'-deoxyguanosine correlated with measures reflecting a history of actual aggressive behavior in all subjects.. These data suggest a positive relationship between plasma markers of oxidative stress and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of aggression in human subjects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aggression; Biomarkers; Case-Control Studies; Deoxyguanosine; Diagnostic and Statistical Manual of Mental Disorders; Dinoprost; Disruptive, Impulse Control, and Conduct Disorders; Female; Humans; Impulsive Behavior; Inflammation; Male; Oxidative Stress; Psychiatric Status Rating Scales; Young Adult

The aim of this study was to examine the role of oxidative DNA damage in chronic liver inflammation in the evolution of hepatocellular carcinoma. The accumulated data demonstrated that oxidative DNA damage and chronic liver inflammation are involved in the transformation of normal hepatocytes and their evolution towards hepatocellular carcinoma. However, the levels of 8-oxy-2'-deoxy-guanosine (8-oxodG), a biomarker of oxidative DNA damage, were overestimated and underestimated in previous reports due to various technical limitations. The current techniques are not suitable to analyze the 8-oxodG levels in the non-malignant liver tissues and tumors of hepatocellular carcinoma patients unless they are modified. Therefore, in this study, the protocols for extraction and hydrolysis of DNA were optimized using 54 samples from hepatocellular carcinoma patients with various risk factors, and the 8-oxodG and 2'-deoxyguanosine (dG) levels were measured. The patients enrolled in the study include 23 from The Princess Alexandra Hospital and The Royal Brisbane and Women's Hospitals, Brisbane, Australia, and 31 from South Africa. This study revealed that the 8-oxodG/dG ratios tended to be higher in most non-malignant liver tissues compared to hepatocellular carcinoma tissue (p=0.2887). It also appeared that the ratio was higher in non-malignant liver tissue from Southern African patients (p=0.0479), but there was no difference in the 8-oxodG/dG ratios between non-malignant liver tissues and tumors of Australian hepatocellular carcinoma patients (p=0.7722). Additionally, this study also revealed a trend for a higher 8-oxodG/dG ratio in non-malignant liver tissues compared to tumoural tissues of patients with HBV. Significant differences were not observed in the 8-oxodG/dG ratios between non-cirrhotic and cirrhotic non-malignant liver tissues.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carcinogenesis; Carcinoma, Hepatocellular; Deoxyguanosine; DNA Damage; Hepatocytes; Humans; Inflammation; Liver; Liver Neoplasms; Oxidation-Reduction; Oxidative Stress

Chronic inflammation is associated with increased risk of cancer development, whereas the link between chronic inflammation and esophageal carcinogenesis is still obscure heretofore. This study aimed to investigate the relationship between chronic inflammation and DNA damage, as well as the possible role of DNA damage in esophageal carcinogenic process. Endoscopic esophageal biopsies from 109 individuals from Chaoshan littoral, a high-risk region for esophageal squamous cell carcinoma (ESCC), were examined to evaluate the association between chronic inflammation and histological severity, while additional 204 esophageal non-tumor samples from patients with ESCC were collected. Immunohistochemistry was performed to detect the oxidative DNA damage and DNA double-strand breaks (DSBs). Significantly positive correlation was observed between degree of chronic inflammation and esophageal precursor lesions (rs = 0.37, P < 0.01). Immunohistochemical analysis showed that oxidative DNA damage level was positively correlated with the degree of chronic inflammation (rs = 0.21, P < 0.05). Moreover, the level of oxidative DNA damage positively correlated with histological severity (rs = 0.49, P < 0.01). We found that the extent of DSBs was progressively increased with inflammation degree (P < 0.01) and the progression of precancerous lesions (P < 0.001). Collectively, these findings provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Carcinogenesis; Carcinoma, Squamous Cell; Chronic Disease; Deoxyguanosine; Disease Progression; DNA Damage; Esophageal Neoplasms; Esophagus; Female; Genomic Instability; Histones; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged

To evaluate the beneficial effects of hydroxysafflor yellow A (HSYA) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats, and to investigate the main pathophysiological mechanism of HSYA in preventing development of MCT-induced PAH.. Four groups (control, control with HSYA treatment, MCT-exposed, and MCT-exposed with HSYA treatment) were evaluated at day 28 following MCT exposure. Haemodynamic measurements, right ventricular hypertrophy, morphometry, inflammatory cytokines and oxidant expression were assessed.. HSYA significantly reduced haemodynamic changes, right ventricular hypertrophy and morphometric changes induced by exposure to MCT. HYSA also suppressed MCT-induced inflammation and oxidative stress in rat pulmonary tissue.. Experimental MCT-induced PAH may be reduced by HSYA treatment, and the mechanism may involve suppression of inflammation and oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Chalcone; Deoxyguanosine; Gene Expression Regulation; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation; Male; Malondialdehyde; Monocrotaline; Oxidative Stress; Quinones; Rats, Wistar; RNA, Messenger; Superoxide Dismutase; Vascular Remodeling

To explore influence of carbohydrates/fat proportions, dietary ingredients on telomere length shortening, oxidative stress and inflammation in a Chinese population with different glucose tolerance status.. Five hundred and fifty-six Chinese subjects without diabetes history underwent a 75 g, 2 h Oral Glucose Tolerance Test (OGTT). Subjects with diabetes (n = 159), pre-diabetes (n = 197), and normal glucose tolerance (n = 200) were screened. Dietary intakes were evaluated using a semi-quantitative food frequency questionnaire (FFQ). Peripheral blood leukocyte telomere length (LTL) was assessed using a real-time PCR assay. Blood lipid profile, levels of the oxidative stress indicators superoxide dismutase (SOD), glutathione reductase (GR), 8-oxo-2'-deoxyguanosine (8-oxo-dG) and inflammation indicators tumor necrosis factor (TNF-ɑ), interleukine-6 (IL-6) were measured. Levels of HbA1c, plasma glucose, insulin, and C peptide were also determined. Measurements were taken at 0 min, 30 min, 60 min, and 120 min after 75 g OGTT. Insulin sensitivity was evaluated by HOMA-IR. Basal insulin secretion index (HOMA-β), early phase disposition index (DI30) and total phase disposition index (DI120) indicate insulin levels at different phases of insulin secretion.. In patients with newly diagnosed diabetes, LTL adjusted by age was longer in HbA1c < 7 % group (log (LTL):1.93 ± 0.25) than in HbA1c ≥ 7 % group (log (LTL):1.82 ± 0.29). LTL was not associated with daily energy intake, diet fat, carbohydrates and protein proportions. Multiple linear regression analysis indicated that legumes, nuts, fish and seaweeds were protective factors for LTL shortening, and sweetened carbonated beverage was a risk factor for LTL shortening ( legumes: β = 0.105, p = 0.018; nuts: β = 0.110, p = 0.011; fish: β = 0.118, p = 0.007; seaweeds: β = 0.116, p = 0.009; sweetened carbonated beverage: β = -0.120, p = 0.004 ). Daily energy intake was positively associated with TNF-ɑ, IL-6 (TNF-ɑ: r = 0.125, p = 0.006;IL-6: r = 0.092, p =0.04). Fat, carbohydrate proportions were positively associated with TNF-ɑ (fat: r = 0.119, p = 0.008 ; carbohydrate: r = 0.094, p = 0.043). Seaweeds and dairy intake were negatively associated with 8-oxo-dG (seaweed: r = -0.496, p = 0.001;dairy: r = -0.246, p = 0.046 ), vegetables and fruits were positively associated with GR ( vegetables: r = 0.101, p = 0.034;fruits: r = 0.125, p = 0.045). Cereal, meat were positively associated with TNF-ɑ ( cereal: r = 0.091, p = 0.048 ; meat: r = 0.405, p = 0.009).. Diabetes patients with better plasma glucose (HbA1c < 7 %) had longer LTL, LTL could reflect plasma glucose status in diabetes patients. LTL were probably not influenced by diet carbohydrates/fat proportions but was associated with diet ingredients. Diet ingredients significantly impacted on markers of inflammation and oxidative stress, which probably had an effect on LTL.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Asian People; Biomarkers; Blood Glucose; China; Cross-Sectional Studies; Deoxyguanosine; Diet; Female; Glucose Intolerance; Glutathione Reductase; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leukocytes; Male; Middle Aged; Nutrition Surveys; Oxidative Stress; Superoxide Dismutase; Telomere; Tumor Necrosis Factor-alpha

It has been reported that equine recurrent airway obstruction (RAO) is a state of oxidative stress. Oxidant-antioxidant imbalance is known to increase the conversion of deoxyguanosine to 8-hydroxy-2-deoxyguanosine (8-OHdG) in DNA. 8-OHdG can easily be measured using ELISA tests in serum or urine samples. In this study, we analysed serum 8-OHdG levels in horses with recurrent airway obstruction and in healthy controls.. The study material consisted of seven healthy horses and seven horses with symptomatic RAO. All horses were exposed to moldy hay and straw for 48 h to induce clinical exacerbation of RAO. The serum 8-OHdG levels were determined using the ELISA Highly Sensitive 8-OHdG kit. The difference between the levels of 8-OHdG in healthy and RAO-affected horses was significant. The median level of 8-OHdG was 0.044 ng/ml in the healthy controls versus 0.498 ng/ml in RAO horses (P = 0.0021).. The results of the study strongly suggest that DNA damage coexists in the course of equine RAO. We therefore propose that future research should aim at the development of new drugs that target pro-inflammatory molecules, since DNA damage appears to be the result of chronic inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Airway Obstruction; Animals; Biomarkers; Deoxyguanosine; DNA; Enzyme-Linked Immunosorbent Assay; Horse Diseases; Horses; Inflammation; Oxidative Stress

Bisphenol-A (BPA) exposure occurs commonly and may adversely impact pregnancy. Endocrine disruption is posited as the primary mechanism of action, but oxidative stress and inflammation pathways may also be important. We investigated associations between BPA exposure and oxidative stress and inflammation in 482 pregnant women. Participants were recruited early in pregnancy and provided urine and plasma at up to four visits. We measured total BPA and two biomarkers of oxidative stress (8-hydroxydeoxyguanosine and 8-isoprostane) in urine from each visit. Inflammation markers, including C-reactive protein and four cytokines were measured in plasma from the same time points. In adjusted models, an interquartile range increase in BPA was associated with significant increases in both oxidative stress biomarkers (5-9% increase). Additionally, we observed significantly higher IL-6 concentrations in association with an interquartile range increase in BPA (8.95% increase). These systemic changes consequent to BPA exposure may mediate adverse birth outcomes and/or fetal development.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Benzhydryl Compounds; Biomarkers; C-Reactive Protein; Cytokines; Deoxyguanosine; Dinoprost; Endocrine Disruptors; Environmental Monitoring; Environmental Pollutants; Female; Fetus; Humans; Inflammation; Male; Oxidative Stress; Phenols; Pregnancy

This study examines the relationship between toner exposure and its health effects in terms of biomarkers which are known to assess the damages to humans caused by toxic material exposure.. The subjects were 1504 male workers aged below 50 in 2003 in a Japanese toner and photocopier manufacturing company. Personal exposure measurements, pulmonary function tests, chest X-ray examinations, biomarker measurement, and a questionnaire about respiratory symptoms were conducted. We will report about biomarker measurement in this study. Cross-sectional survey studies and a longitudinal study from 2003 to 2008 were conducted.. Few significant findings were associated with the toner exposure in both the cross-sectional and the longitudinal studies. The higher toner exposure concentrations did not induce effects on increasing biomarkers.. There was no evidence of excessive inflammatory, allergic, or oxidative stress reaction in toner-handling workers as compared to non-handling workers, despite some sporadically significant findings. There are no other reports of a longitudinal epidemiological study with regard to toner exposure; this report significantly contributes to toner exposure literature. Although in the current well-controlled working environment, the toner exposure concentrations are quite low; further studies are needed to completely understand the health effects toner may have, however small they may be.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; C-Reactive Protein; Chemical Industry; Cohort Studies; Cross-Sectional Studies; Cytokines; Deoxyguanosine; Humans; Hypersensitivity; Immunoglobulin E; Inflammation; Japan; Longitudinal Studies; Male; Manufactured Materials; Occupational Exposure; Oxidative Stress; Printing

Phenols and parabens are used in a multitude of consumer products resulting in ubiquitous human exposure. Animal and in vitro studies suggest that exposure to these compounds may be related to a number of adverse health outcomes, as well as potential mediators such as oxidative stress and inflammation. We examined urinary phenol (bisphenol A (BPA), triclosan (TCS), benzophenone-3 (BP-3), 2,4-dichlorophenol (24-DCP), 2,5-dichlorophenol (25-DCP)) and paraben (butyl paraben (B-PB), methyl paraben (M-PB), propyl paraben (P-PB)) concentrations measured three times during pregnancy in relation to markers of oxidative stress and inflammation among participants in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) project. Serum markers of inflammation (c-reactive protein (CRP), IL-1β, IL-6, IL-10, and tumor necrosis factor-α (TNF-α)) were measured twice during pregnancy (n=105 subjects, 187 measurements) and urinary markers of oxidative stress (8-hydroxydeoxyguanosine (OHdG) and isoprostane) were measured three times during pregnancy (n=54 subjects, 146 measurements). We used linear mixed models to assess relationships between natural log-transformed exposure and outcome biomarkers while accounting for within individual correlation across study visits. After adjustment for urinary specific gravity, study visit, maternal pre-pregnancy BMI, and maternal education, an interquartile range (IQR) increase in urinary BPA was associated with 21% higher OHdG (p=0.001) and 29% higher isoprostane (p=0.0002), indicating increased oxidative stress. The adjusted increase in isoprostane per IQR increase in marker of exposure was 17% for BP-3, 27% for B-PB, and 20% for P-PB (all p<0.05). An IQR increase in triclosan (TCS) was associated with 31% higher serum concentrations of IL-6 (p=0.007), a pro-inflammatory cytokine. In contrast, IQR increases in BP-3 and B-PB were significantly associated with 16% and 18% lower CRP, a measure of systemic inflammation. Our findings suggest that exposure to BPA, select parabens, and TCS during pregnancy may be related to oxidative stress and inflammation, potential mechanisms by which exposure to these compounds may influence birth outcomes and other adverse health effects, but additional research is needed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Benzhydryl Compounds; Benzophenones; Biomarkers; Body Mass Index; C-Reactive Protein; Chlorophenols; Deoxyguanosine; Educational Status; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-1beta; Interleukin-6; Isoprostanes; Maternal Exposure; Oxidative Stress; Parabens; Phenol; Phenols; Pregnancy; Pregnancy Outcome; Puerto Rico; Triclosan; Tumor Necrosis Factor-alpha; Young Adult

The role of obstructive sleep apnea (OSA) in the mortality and further cardiovascular risk in subjects with ischemic stroke remains a contentious issue. Oxidative stress and inflammatory reaction due to OSA have seldom been studied in stable ischemic stroke patients.. This cross-sectional, prospective study involved 92 consecutive ischemic stroke patients who were admitted to the Rehabilitation ward. All subjects received polysomnography and laboratory tests for oxidative stress and inflammatory biomarkers, including: C-reactive protein (CRP), interleukin 6 (IL-6), total antioxidant capacity (TAC), and urinary 8-hydroxy-2-deoxyguanosine. Differences in study variables between patients with or without severe OSA were compared, and multivariate linear regression analyses were used to assess the relationship between OSA severity and target biomarkers.. Participants in the severe OSA group were significantly older (p = 0.002), had a significantly higher risk of hypertension (p = 0.021) and a lower level of CRP (p = 0.006). Among the subjects with ischemic stroke and severe OSA, the levels of CRP, IL-6, and TAC were positively correlated with the desaturation index (DI) and the TAC levels were negatively correlated with mean arterial oxygen saturation (SaO2). Regression analysis results indicated that the TAC levels remained significantly and negatively correlated with mean SaO2 levels. Moreover, the CRP levels remained significantly correlated with the apnea-hypopnea index and DI after controlling for covariates.. The present study demonstrated that a preferentially adaptive antioxidative response to hypoxia emerges, and the role of OSA with respect to inflammatory reaction is attenuated, in ischemic stroke patients with OSA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Brain Ischemia; C-Reactive Protein; Cross-Sectional Studies; Deoxyguanosine; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Oxidative Stress; Polysomnography; Prospective Studies; Recurrence; Risk Factors; Severity of Illness Index; Sleep Apnea, Obstructive; Stroke

Severe burns with delayed resuscitation are associated with high morbidity which is attributed to ischemia-reperfusion injury. This study was undertaken to investigate the effect of hydrogen-rich saline known as a significant selective antioxidant on the inflammatory reaction induced by severe burns with delayed resuscitation. By establishing the model of severe burns with delayed resuscitation in rats, we recorded improvement on the mortality, secretion of cytokines and reaction of oxidative stress of rats treated with hydrogen-rich saline. We found that resuscitation by hydrogen-rich saline alleviated inflammation significantly. We further detected the change of the key nuclear factor NF-κB contributed to inflammation. The expression of both NF-κB and phosphorylated NF-κB in rats having severe burns with delayed resuscitation by hydrogen-rich saline was lower than that in rats with delayed resuscitation with Ringers' solution. Our data imply that hydrogen-rich saline significantly improves the inflammatory reaction in rats with severe burns with delayed resuscitation, possibly by inhibiting activation of NF-κB.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Analysis of Variance; Animals; Antioxidants; Burns; Cytokines; Deoxyguanosine; Disease Models, Animal; Fluid Therapy; Inflammation; Inflammation Mediators; Male; Monocytes; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resuscitation; Shock; Sodium Chloride

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Blood Proteins; Child; Chondroitinsulfatases; Creatinine; Cytokines; Deoxyguanosine; Enzyme Replacement Therapy; Erythrocytes; Female; Glutathione; Glycosaminoglycans; Humans; Inflammation; Isoprostanes; Male; Mucopolysaccharidosis IV; Oxidative Stress; Peroxidase; Superoxide Dismutase; Treatment Outcome; Tyrosine; Young Adult

To investigate well-controlled congenital hypothyroidism on the markers associated with early kidney injury and oxidative DNA damage.. Twenty-three children with euthyroid congenital hypothyroidism aged 3-6 years and 19 age- and gender-matched controls were enrolled. Serum levels of albumin, C-reactive protein, cysteine C, globulin, pre-albumin, and total protein were detected. Urine levels of albumin, fibrin degradation products, IgG, β2-microglobulin, and 8-hydroxydeoxyguanosine (8-OHdG) were also measured. Clinical and biochemical characteristics were evaluated between the two groups.. Serum levels of C-reactive protein were higher, but pre-albumin was lower in patients with congenital hyperthyroidism compared with the controls (all p<0.001). Urinary levels of IgG were higher in patients with congenital hyperthyroidism than in the controls (p=0.011). However, urinary levels of albumin excretion and 8-OHdG were similar to those in the controls. Serum pre-albumin levels were negatively correlated with urinary 8-OHdG levels (r=-0.479, p=0.016) in patients with congenital hypothyroidism.. It is concluded that inflammatory and oxidative markers were slightly altered in well-controlled congenital hypothyroidism. The levels of urinary 8-OHdG and albumin excretion were not significantly different.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Biomarkers; C-Reactive Protein; Case-Control Studies; Child, Preschool; Congenital Hypothyroidism; Deoxyguanosine; Female; Follow-Up Studies; Humans; Inflammation; Inflammation Mediators; Male; Oxidative Stress; Prognosis

Although iron is an essential element for maintaining physiological function, excess iron leads to tissue damage caused by oxidative stress and inflammation. Oxidative stress and inflammation play critical roles for the development of abdominal aortic aneurysm (AAA). However, it has not been investigated whether iron plays a role in AAA formation through oxidative stress and inflammation. We, therefore, examined whether iron is involved in the pathophysiology of AAA formation using human AAA walls and murine AAA models.. Human aortic walls were collected from 53 patients who underwent cardiovascular surgery (non-AAA=34; AAA=19). Murine AAA was induced by infusion of angiotensin II to apolipoprotein E knockout mice. Iron was accumulated in human and murine AAA walls compared with non-AAA walls. Immunohistochemistry showed that both 8-hydroxy-2'-deoxyguanosine and CD68-positive areas were increased in AAA walls compared with non-AAA walls. The extent of iron accumulated area positively correlated with that of 8-hydroxy-2'-deoxyguanosine expression area and macrophage infiltration area in human and murine AAA walls. We next investigated the effects of dietary iron restriction on AAA formation in mice. Iron restriction reduced the incidence of AAA formation with attenuation of oxidative stress and inflammation. Aortic expression of transferrin receptor 1, intracellular iron transport protein, was increased in human and murine AAA walls, and transferrin receptor 1-positive area was similar to areas where iron accumulated and F4/80 were positive.. Iron is involved in the pathophysiology of AAA formation with oxidative stress and inflammation. Dietary iron restriction could be a new therapeutic strategy for AAA progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Aortic Aneurysm, Abdominal; Deoxyguanosine; Female; Fibrosis; Humans; Inflammation; Iron Overload; JNK Mitogen-Activated Protein Kinases; Macrophages; Male; Matrix Metalloproteinases; Mice, Knockout; Oxidative Stress; Phosphorylation; Receptors, Transferrin

Inflammation and oxidative stress play a crucial role in the pathogenesis of cardiac sarcoidosis (SAR). We investigated whether urinary (U) 8-hydroxy-2'-deoxyguanosine (8-OHdG)--an oxidative DNA damage marker--was related to SAR inflammatory activity.. U-8-OHdG levels were measured in 31 SAR patients, classified as active (n=17) or non-active (n=14) based on (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG-PET/CT), 28 dilated cardiomyopathy (DCM) patients, and 30 controls. In active SAR patients, U-8-OHdG levels were reexamined and compared with (18)F-FDG-PET/CT results at 6 months after corticosteroid treatment to assess therapeutic response.. Immunohistochemical examination of left ventricle (LV) autopsy samples from SAR patients revealed positive 8-OHdG staining in cardiomyocyte nuclei from LV sections showing (18)F-FDG accumulation on PET/CT, while serum 8-OHdG levels were significantly higher in the coronary sinus than in the aortic root only in active SAR patients. U-8-OHdG levels in SAR patients were higher than those in controls, and significantly higher in active SAR patients than in non-active SAR and DCM patients. U-8-OHdG was a powerful predictor of active SAR in receiver operating characteristic curve analysis (AUC, 0.98; 95% CI, 0.94-1.02; optimal cutoff value, 13.1 ng/mg creatinine), with a sensitivity of 88.2% and a specificity of 92.9%. U-8-OHdG levels in responders significantly decreased at 6 months after corticosteroid treatment initiation, in proportion with the decrease in the focal cardiac uptake of (18)F-FDG.. U-8-OHdG is a potentially clinically useful biomarker for evaluating inflammatory activity and monitoring the effectiveness of corticosteroid therapy in SAR patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Cardiomyopathies; Cohort Studies; Deoxyguanosine; Female; Humans; Inflammation; Male; Middle Aged; Radionuclide Imaging; Sarcoidosis

Restless legs syndrome (RLS) is a common comorbidity in patients undergoing hemodialysis, but clinical factors predictive of RLS risk and severity have not been identified. The aims of this multicenter cross-sectional study were to document RLS prevalence and severity in patients undergoing hemodialysis and to identify associated risk factors.. One-hundred and fifty-nine stable patients on maintenance hemodialysis were enrolled (113 men, 46 women; mean age: 68 ± 11 years; mean duration of dialysis: 54 ± 60 months). Diagnosis of RLS was based on the criteria proposed by the International Restless Legs Syndrome Study Group (IRLSSG), and RLS severity was assessed using the IRLSSG Severity Scale. Potential factors associated with RLS and IRLSSG Severity Scale score were assessed by univariate and multivariate regression analyses.. RLS affected 22% of the study population. The RLS subgroup had a significantly longer duration of hemodialysis and higher cardiothoracic ratio compared to the non-RLS subgroup. The RLS subgroup also had significantly higher serum levels of high-sensitivity C-reactive protein, interleukin-6, ferritin, N-terminal pro-B-type natriuretic peptide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and a significantly lower transferrin saturation level compared to the non-RLS subgroup, suggesting a chronic inflammatory state and associated oxidative stress in comorbid patients. Serum 8-OHdG level was an independent risk factor for high IRLSSG Severity Scale score.. This study confirms the high prevalence of RLS among hemodialysis patients and identifies the oxidative stress marker serum 8-OHdG as a significant independent predictor of RLS severity. Further studies are needed to identify detailed risk factors and the pathophysiological role of oxidative stress in RLS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Deoxyguanosine; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Prevalence; Renal Dialysis; Restless Legs Syndrome; Risk Factors; Severity of Illness Index

Since high sensitivity C-reactive protein (hsCRP) is predictive of cardiovascular events, it is important to examine the relationship between hsCRP and other inflammatory and oxidative stress markers linked to cardiovascular disease (CVD) etiology. Previously, we reported that hsCRP induces the oxidative stress adduct 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG) and that these markers are significantly associated in women. Recent data indicates that brain-derived neurotrophic factor (BDNF) may have a role in CVD.. We examined BDNF levels in 3 groups of women that were age- and race-matched with low (<3 mg/L), mid (>3-20 mg/L), and high (>20 mg/L) hsCRP (n = 39 per group) and found a significant association between hsCRP, BDNF, and 8-oxodG. In African American females with high hsCRP, increases in BDNF were associated with decreased serum 8-oxodG. This was not the case in white women where high hsCRP was associated with high levels of BDNF and high levels of 8-oxodG. BDNF treatment of cells reduced CRP levels and inhibited CRP-induced DNA damage.. We discovered an important relationship between hsCRP, 8-oxodG, and BDNF in women at hsCRP levels >3 mg/L. These data suggest that BDNF may have a protective role in counteracting the inflammatory effects of hsCRP.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Blood Pressure; Brain-Derived Neurotrophic Factor; C-Reactive Protein; Cells, Cultured; Deoxyguanosine; Female; Humans; Inflammation; Middle Aged

To evaluate the relationship between folate, cobalamin (Cbl), and homocysteine (Hcy), and markers of inflammation and oxidative stress within the periphery and central nervous system (CNS) of a healthy human cohort.. Thirty-five matched cerebrospinal fluid (CSF) and plasma samples were collected from consenting participants who required a spinal tap for the administration of anaesthetic. Plasma concentrations of Hcy and both plasma and CSF levels of folate, Cbl, nicotinamide adenine dinucleotide (NAD(H)) and markers of inflammation (interleukin-6, IL-6), and oxidative stress (F2-isoprostanes, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and total antioxidant capacity (TAC)) were quantified.. In the peripheral circulation, positive associations were observed between plasma folate and Cbl, and plasma TAC (P ≤ 0.01; P ≤ 0.01) and plasma NAD(H) (P ≤ 0.05; P ≤ 0.05) levels, respectively. Plasma folate was inversely associated with plasma Hcy concentrations (P ≤ 0.05); however, no statistically significant relationships were observed between plasma Hcy and plasma markers of inflammation, oxidative stress, or [NAD(H)]. Within the CNS plasma Hcy correlated positively with CSF IL-6 (P ≤ 0.01) and negatively with CSF NAD(H) (P ≤ 0.05) concentrations. An inverse association was observed between CSF folate and CSF levels of IL-6 (P ≤ 0.05). Unexpectedly, a positive association between CSF Cbl and CSF 8-OHdG levels was also found (P ≤ 0.01).. These results indicate that folate and Cbl concentrations may influence the levels of oxidative damage, inflammation, and NAD(H), both systemically and within the CNS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antioxidants; Biomarkers; Central Nervous System; Deoxyguanosine; F2-Isoprostanes; Female; Folic Acid; Homocysteine; Humans; Inflammation; Interleukin-6; Linear Models; Male; Middle Aged; NAD; Oxidative Stress; Vitamin B 12

Recent studies suggest that early life trauma is associated with elevations in circulating markers of inflammation in human subjects. History of aggression as a behavior, or aggression as a personality trait, is also associated with elevations of these inflammatory markers. Since early life trauma is associated with the development and maintenance of aggression in later life we examined the relationship of early life adversity, plasma inflammation markers (IL-6 and CRP) and oxidative stress markers (8-OH-DG and 8-ISO), and aggression in adult subjects with (n=79) and without (n=55) personality disorder. We used a series of mediated and moderated path models to test whether the effects of early adversity on later aggression may be mediated through markers of inflammation. Childhood abuse and parental control were associated with basal IL-6 and CRP concentrations. Path modeling suggested that childhood abuse was associated with aggression indirectly through CRP while parental control influenced aggression indirectly through IL-6 and CRP. Furthermore, these effects were independent of the effect of current depression. The results suggest that disruption of inflammatory processes represent one pathway by which early adversity influences aggression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Adult Survivors of Child Abuse; Aggression; Biomarkers; C-Reactive Protein; Deoxyguanosine; Female; Humans; Inflammation; Interleukin-6; Male; Oxidative Stress; Parent-Child Relations; Parenting; Personality Disorders; Risk Factors; Young Adult

Aiming to gain a detailed insight into the physiological mechanisms involved under extreme conditions, a group of experienced ultra-marathon runners, performing the mountain Tor des Géants® ultra-marathon: 330 km trail-run in Valle d'Aosta, 24000 m of positive and negative elevation changes, was monitored. ROS production rate, antioxidant capacity, oxidative damage and inflammation markers were assessed, adopting micro-invasive analytic techniques.. Forty-six male athletes (45.04±8.75 yr, 72.6±8.4 kg, 1.76±0.05 m) were tested. Capillary blood and urine were collected before (Pre-), in the middle (Middle-) and immediately after (Post-) Race. Samples were analyzed for: Reactive Oxygen Species (ROS) production by Electron Paramagnetic Resonance; Antioxidant Capacity by Electrochemistry; oxidative damage (8-hydroxy-2-deoxy Guanosine: 8-OH-dG; 8-isoprostane: 8-isoPGF2α) and nitric oxide metabolites by enzymatic assays; inflammatory biomarkers (plasma and urine interleukin-6: IL-6-P and IL-6-U) by enzyme-linked immunosorbent assays (ELISA); Creatinine and Neopterin by HPLC, hematologic (lactate, glucose and hematocrit) and urine parameters by standard analyses.. Twenty-five athletes finished the race, while twenty-one dropped out of it. A significant increase (Post-Race vs Pre) of the ROS production rate (2.20±0.27 vs 1.65±0.22 μmol.min-1), oxidative damage biomarkers (8-OH-dG: 6.32±2.38 vs 4.16±1.25 ng.mg-1 Creatinine and 8-isoPGF2α: 1404.0±518.30 vs 822.51±448.91 pg.mg-1Creatinine), inflammatory state (IL-6-P: 66.42±36.92 vs 1.29±0.54 pg.mL-1 and IL-6-U: 1.33±0.56 vs 0.71±0.17 pg.mL1) and lactate production (+190%), associated with a decrease of both antioxidant capacity (-7%) and renal function (i.e. Creatinine level +76%) was found.. The used micro-invasive analytic methods allowed us to perform most of them before, during and immediately after the race directly in the field, by passing the need of storing and transporting samples for further analysis. Considered altogether the investigated variables showed up that exhaustive and prolonged exercise not only promotes the generation of ROS but also induces oxidative stress, transient renal impairment and inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Athletes; Biomarkers; Deoxyguanosine; Dinoprost; Exercise; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Physical Endurance; Reactive Oxygen Species; Running

To investigate the effects of rhubarb enema treatment using a 5/6 nephrectomized rat model and study its mechanisms.. Twenty-eight Sprague Dawley rats were divided into three groups: sham operation group (n = 8), 5/6 nephrectomized (5/6Nx) (n = 10), and 5/6Nx with rhubarb enema treatment (n = 10). The rhubarb enema was continuous for 1.0 month. Serum creatinine, serum indoxyl sulfate (IS) level, renal pathology, tubulointerstitial fibrosis, and renal oxidative stress were assessed.. 5/6Nx rats showed increasing levels of serum creatinine and severe pathological lesions. Their serum creatinine levels obviously decreased after rhubarb enema treatment (P < 0.05 vs 5/6Nx group). The administration of rhubarb enema attenuated the histopathological changes in 5/6Nx rats. In addition, 5/6Nx rats showed an enhanced extent of tubulointerstitial fibrosis compared with sham rats, and administration of rhubarb enema to 5/6Nx rats ameliorated tubulointerstitial fibrosis. 5/6Nx rats showed increased serum levels of IS, renal oxidative stress, and NF-κB compared with sham rats, whereas administration of rhubarb enema to 5/6Nx rats decreased serum levels of IS, renal oxidative stress, and NF-κB levels.. Rhubarb enema treatment ameliorates tubulointerstitial fibrosis in the kidneys of 5/6Nx rats, most likely by alleviating IS overload and reducing kidney oxidative stress and inflammatory injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; C-Reactive Protein; Collagen Type I; Deoxyguanosine; Enema; Indican; Inflammation; Kidney; Male; Nephrectomy; NF-kappa B; Occludin; Oxidative Stress; Rats, Sprague-Dawley; Rheum; Superoxide Dismutase

The 1918 influenza pandemic caused over 40 million deaths worldwide, with 675,000 deaths in the United States alone. Studies in several experimental animal models showed that 1918 influenza virus infection resulted in severe lung pathology associated with dysregulated immune and cell death responses. To determine if reactive oxygen species produced by host inflammatory responses play a central role in promoting severity of lung pathology, we treated 1918 influenza virus-infected mice with the catalytic catalase/superoxide dismutase mimetic, salen-manganese complex EUK-207 beginning 3 days postinfection. Postexposure treatment of mice infected with a lethal dose of the 1918 influenza virus with EUK-207 resulted in significantly increased survival and reduced lung pathology without a reduction in viral titers. In vitro studies also showed that EUK-207 treatment did not affect 1918 influenza viral replication. Immunohistochemical analysis showed a reduction in the detection of the apoptosis marker cleaved caspase-3 and the oxidative stress marker 8-oxo-2'-deoxyguanosine in lungs of EUK-207-treated animals compared to vehicle controls. High-throughput sequencing and RNA expression microarray analysis revealed that treatment resulted in decreased expression of inflammatory response genes and increased lung metabolic and repair responses. These results directly demonstrate that 1918 influenza virus infection leads to an immunopathogenic immune response with excessive inflammatory and cell death responses that can be limited by treatment with the catalytic antioxidant EUK-207.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Caspase 3; Deoxyguanosine; DNA Repair; Dogs; Female; Free Radical Scavengers; Gene Expression; Humans; Inflammation; Influenza A Virus, H1N1 Subtype; Influenza Pandemic, 1918-1919; Lung; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred BALB C; Organometallic Compounds; Orthomyxoviridae Infections; Reactive Oxygen Species; Survival Analysis; Viral Load; Virus Replication

Ischemia-reperfusion injury (IRI) has been considered as the major cause of acute kidney injury and can result in poor long-term graft function. Functional recovery after IRI is impaired in the elderly. In the present study, we aimed to compare kidney morphology, function, oxidative stress, inflammation, and development of renal fibrosis in young and aged rats after renal IRI.. Rat models of warm renal IRI were established by clamping left pedicles for 45 min after right nephrectomy, then the clamp was removed, and kidneys were reperfused for up to 12 wk. Biochemical and histologic renal damage were assessed at 12 wk after reperfusion. The immunohistochemical staining of monocyte macrophage antigen-1 (ED-1) and transforming growth factor beta 1 (TGF-β1) and messenger RNA level of TGF-β1 in the kidney were analyzed.. Renal IRI caused significant increases of malondialdehyde and 8-hydroxydeoxyguanosine levels and a decrease of superoxide dismutase activity in young and aged IRI rats; however, these changes were more obvious in the aged rats. IRI resulted in severe inflammation and tubulointerstitial fibrosis with decreased creatinine (Cr) clearance and increased histologic damage in aged rats compared with young rats. Moreover, we measured the ratio of Cr clearance between young and aged IRI rats. It demonstrated that aged IRI rats did have poor Cr clearance compared with the young IRI rats. ED-1 and TGF-β1 expression levels in the kidney were significantly higher in aged rats than in young rats after IRI.. Aged rats are more susceptible to IRI-induced renal failure, which may associate with the increased oxidative stress, increased histologic damage, and increased inflammation and tubulointerstitial fibrosis. Targeting oxidative stress and inflammatory response should improve the kidney recovery after IRI.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Age Factors; Aging; Animals; Deoxyguanosine; Disease Models, Animal; Fibrosis; Inflammation; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Severity of Illness Index; Time

Transplantation of bone marrow mononuclear cells (BMMCs) exerts neuroprotection against cerebral ischemia. We examined the therapeutic timepoint of allogeneic BMMC transplantation in a rat model of focal cerebral ischemia, and determined the effects of repeated transplantation outside the therapeutic window.. Male Sprague-Dawley rats were subjected to 90 minute focal cerebral ischemia, followed by intravenous administration of 1 × 10(7) allogeneic BMMCs or vehicle at 0, 3 or 6 h after reperfusion or 2 × 10(7) BMMCs 6 h after reperfusion. Other rats administered 1 × 10(7) BMMCs at 6 h after reperfusion received additional BMMC transplantation or vehicle 9 h after reperfusion. Infarct volumes, neurological deficit scores and immunohistochemistry were evaluated 24 or 72 h after reperfusion.. Infarct volumes at 24 h were significantly decreased in transplantation rats at 0 and 3 h, but not at 6 h, after reperfusion, compared to vehicle-treatment. Even high dose BMMC transplantation at 6h after reperfusion was ineffective. Repeated BMMC transplantation at 6 and 9h after reperfusion reduced infarct volumes and significantly improved neurological deficit scores at 24 and 72 h. Immunohistochemistry showed repeated BMMC transplantation reduced ionized calcium-binding adapter molecule 1, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine expression at 24 and 72 h after reperfusion.. Intravenous allogeneic BMMCs were neuroprotective following transient focal cerebral ischemia, and the therapeutic time window of BMMC transplantation was >3 h and <6 h after reperfusion in this model. Repeated transplantation at 6 and 9 h after reperfusion suppressed inflammation and oxidative stress in ischemic brains, resulting in improved neuroprotection.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Bone Marrow Transplantation; Brain Injuries; Calcium-Binding Proteins; Deoxyguanosine; Disease Models, Animal; Immunohistochemistry; Inflammation; Ischemic Attack, Transient; Leukocytes, Mononuclear; Male; Microfilament Proteins; Oxidative Stress; Rats; Rats, Sprague-Dawley; Time Factors; Transplantation, Homologous

We aimed to evaluate oxidative stress [8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA)] endothelial damage [asymmetric dimethylarginine (ADMA)] and markers of cellular inflammation [interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), neopterin (NP) and high-sensitivity C-reactive protein (hsCRP)] in patients with diabetic nephropathy (DN) and non-diabetic nephropathy who were being administered hemodialysis treatment because of chronic renal failure.. In determining 8-OHdG, IL-6 and TNF-α levels, Enzyme-Linked Immuno-Sorbent Assay method was used. Serum MDA, ADMA and NP levels were determined by using high performance liquid chromatography (HPLC). And hs-CRP values were measured with nephelometric method.. Serum 8-OHdG and MDA levels were found statistically to have increased when compared with those of the control group in patients groups after dialysis. However, serum ADMA and neopterin levels were observed statistically to have decreased when compared with those of the control group in patients groups after dialysis. But, decreases on ADMA and neopterin levels are still much higher than those of control. IL-6 and TNF-α levels were found to have increased when compared with those of control group in patients groups before dialysis.. The oxidative stress in patients with DN, who were being treated with hemodialysis due to chronic renal failure, was higher than that of non-DN patients who were being treated with hemodialysis. In contrast with this, inflammation occurring in non-DN patients was found to have been higher than that of in patients with DN.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Arginine; Biomarkers; C-Reactive Protein; Case-Control Studies; Deoxyguanosine; Diabetic Nephropathies; Female; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Neopterin; Oxidative Stress; Tumor Necrosis Factor-alpha

The implication of lipid peroxidation in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) derive from high abundance of peroxidation-prone polyunsaturated fatty acids in central nervous system and its relatively low antioxidant content. In the present work, we evaluated the effect of dietary changes aimed to modify fatty acid tissular composition in survival, disease onset, protein, and DNA oxidative modifications in the hSODG93A transgenic mice, a model of this motor neuron disease. Both survival and clinical evolution is dependent on dietary fatty acid unsaturation and gender, with high unsaturated diet, leading to loss of the disease-sparing effect of feminine gender. This was associated with significant increases in protein carbonyl and glycoxidative modifications as well as non-nuclear 8-oxo-dG, a marker of mitochondrial DNA oxidation. Comparison of these data with γH2AX immunostaining, a marker of DNA damage response, suggests that the highly unsaturated diet-blunted mitochondrial-nuclear free radical dependent crosstalk, since increased 8-oxo-dG was not correlated with increased DNA damage response. Paradoxically, the highly unsaturated diet led to lower peroxidizability but higher anti-inflammatory indexes. To sum up, our results demonstrate that high polyunsaturated fatty acid content in diets may accelerate the disease in this model. Further, these results reinforce the need for adequately defining gender as a relevant factor in ALS models, as well as to use structurally characterized markers for oxidative damage assessment in neurodegeneration.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amyotrophic Lateral Sclerosis; Animals; Biomarkers; Deoxyguanosine; Dietary Fats; Disease Models, Animal; DNA Damage; DNA Repair; DNA, Mitochondrial; Fats, Unsaturated; Fatty Acids, Unsaturated; Female; Free Radicals; Glycosylation; Histones; Inflammation; Lipid Peroxidation; Male; Mice; Mice, Transgenic; Nerve Degeneration; Oxidative Stress; Point Mutation; Protein Carbonylation; Protein Processing, Post-Translational; Recombinant Fusion Proteins; Sex Characteristics; Superoxide Dismutase; Superoxide Dismutase-1

Oxidative stress is a key factor regulating the systemic pathophysiological effects associated with periodontitis. Resveratrol is a phytochemical with antioxidant and anti-inflammatory properties that can reduce oxidative stress and inflammation. We hypothesized that resveratrol may prevent the progression of periodontitis and reduce systemic oxidative stress through the activation of the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) and the nuclear factor E2-related factor 2 (Nrf2)/antioxidant defense pathways. Three groups of male Wistar rats (periodontitis treated with melinjo resveratrol, periodontitis without resveratrol, and control rats with no periodontitis or resveratrol treatment) were examined. A ligature was placed around the maxillary molars for 3 weeks to induce periodontitis, and the rats were then given drinking water with or without melinjo resveratrol. In rats with periodontitis, ligature placement induced alveolar bone resorption, quantified using three-dimensional images taken by micro-CT, and increased proinflammatory cytokine levels in gingival tissue. Melinjo resveratrol intake relieved alveolar bone resorption and activated the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in inflamed gingival tissues. Further, melinjo resveratrol improved the systemic levels of 8-hydroxydeoxyguanosine, dityrosine, nitric oxide metabolism, nitrotyrosine, and proinflammatory cytokines. We conclude that oral administration of melinjo resveratrol may prevent the progression of ligature-induced periodontitis and improve systemic oxidative and nitrosative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Bone Resorption; Cytokines; Deoxyguanosine; Disease Models, Animal; Gingiva; Inflammation; Male; NF-E2-Related Factor 2; Nitric Oxide; Oxidative Stress; Periodontitis; Random Allocation; Rats; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes; Tyrosine

We evaluated the neuroprotective effects of an anti-oxidative nutrient rich enteral diet (AO diet) that contained rich polyphenols (catechins and proanthocyanidins) and many other anti-oxidative ingredients. Wistar rats were treated with either vehicle, normal AO diet (containing 100kcal/100mL, catechin 38.75mg/100mL and proanthocyanidin 19mg/100mL, 1mL/day), or high AO diet (containing 10 times the polyphenols of the normal AO diet) for 14 days, and were subjected to 90min of transient middle cerebral artery occlusion. The AO diet improved motor function, reduced cerebral infarction volume, and decreased both peroxidative markers such as 4-hydroxynonenal, advanced glycation end products, 8-hydroxy-2-deoxyguanosine and inflammatory markers such as monocyte chemotactic protein-1, ionized calcium-binding adapter molecule-1, and tumor necrosis factor-α. Our study has shown that an AO diet has neuroprotective effects through both anti-oxidative and anti-inflammatory mechanisms, indicating that nutritional control with polyphenols could be useful for patients with acute ischemic stroke.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Aldehydes; Animals; Antioxidants; Biomarkers; Brain Chemistry; Brain Damage, Chronic; Brain Ischemia; Cerebral Infarction; Deoxyguanosine; Diet; Glycation End Products, Advanced; Infarction, Middle Cerebral Artery; Inflammation; Male; Oxidative Stress; Proanthocyanidins; Rats; Rats, Wistar

Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl salt-sensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone. All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1(+) cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antihypertensive Agents; Arterial Pressure; Atrasentan; Cell Adhesion Molecules; Chlorthalidone; Deoxyguanosine; Disease Models, Animal; Diuretics; Drug Combinations; Endothelin A Receptor Antagonists; Endothelins; Hypertension; Inflammation; Kidney Diseases; Male; Membrane Proteins; Metabolic Syndrome; Oxidative Stress; Proteinuria; Pyrrolidines; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium Chloride, Dietary

Patients with chronic kidney disease (CKD) have signs of genomic instability and, as a consequence, extensive genetic damage, possibly due to accumulation of uraemic toxins, oxidative stress mediators and other endogenous substances with genotoxic properties. We explored factors associated with the presence and background levels of genetic damage in CKD. A cross-sectional study was performed in 91 CKD patients including pre-dialysis (CKD patients; n = 23) and patients undergoing peritoneal dialysis (PD; n = 33) or haemodialysis (HD; n = 35) and with 61 healthy subjects, divided into two subgroups with the older group being in the age range of the patients, serving as controls. Alkaline comet assay and cytokinesis-block micronucleus assay in peripheral blood lymphocytes were used to determine DNA and chromosome damage, respectively, present in CKD. Markers of oxidative stress [malondialdehyde (MDA), advanced glycation end products (AGEs), thiols, advanced oxidation protein products and 8-hydroxy-2'-deoxyguanosine] and markers of inflammation (C-reactive protein, interleukin-6 and tumour necrosis factor alpha) were also measured. Micronucleus (MN) frequency was significantly higher (P < 0.05) in the CKD group (46±4‰) when compared with the older control (oC) group (27.7±14). A significant increase in MN frequency (P < 0.05) was also seen in PD patients (41.9±14‰) versus the oC group. There was no statistically significant difference for the HD group (29.7±15.6‰; P = NS) versus the oC group. Comet assay data showed a significant increase (P < 0.001) of tail DNA intensity in cells of patients with CKD (15.6±7%) with respect to the total control (TC) group (11±1%). PD patients (14.8±7%) also have a significant increase (P < 0.001) versus the TC group. Again, there was no statistically significant difference for the HD group (12.5±3%) compared with the TC group. Patients with MN values in the upper quartile had increased cholesterol, triglycerides, AGEs and MDA levels and lower albumin levels. Multiple logistic regression analysis showed that male gender, diabetes and treatment modality were independently associated with higher levels of DNA damage. Our results suggest that oxidative stress, diabetes, gender and dialysis modality in CKD patients increased DNA and chromosome damage. To confirm these data, prospective clinical trials need to be performed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; C-Reactive Protein; Chromosomal Instability; Comet Assay; Cross-Sectional Studies; Deoxyguanosine; DNA Damage; Female; Glycation End Products, Advanced; Humans; Inflammation; Interleukin-6; Logistic Models; Lymphocytes; Male; Malondialdehyde; Micronucleus Tests; Middle Aged; Oxidative Stress; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic; Serum Albumin; Triglycerides; Tumor Necrosis Factor-alpha

Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Azoxymethane; Carcinogenesis; Colitis; Colonic Neoplasms; Deoxyguanosine; Dextran Sulfate; Diet; DNA Damage; Epidermal Growth Factor; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Selenium; Signal Transduction; Transforming Growth Factor beta; Weight Loss

Nitrative and oxidative DNA damage plays an important role in inflammation-related carcinogenesis. Chronic inflammation such as parasite infection and primary sclerosing cholangitis can be an etiological factor of cholangiocarcinoma. Using a proteomic approach and double-fluorescent staining, we identified high expression and colocalization of albumin and cytokeratin-19 in liver fluke-associated cholangiocarcinoma tissues, compared with normal livers from cholangiocarcinoma patients and cadaveric donors, respectively. Albumin was detected not only in cells of hyperplastic bile ducts and cholangiocarcinoma, but also in liver stem/progenitor cell origin, such as canal of Hering, ductules, and ductular reactions, suggesting the involvement of stem/progenitor cells in cholangiocarcinoma development. To clarify the involvement of liver stem/progenitor cells in cholangiocarcinoma, we examined several stem/progenitor cell markers (CD133, CD44, OV6, and Oct3/4) in cholangiocarcinoma tissues analyzed by immunohistochemical staining, and measured 8-oxodG levels by using HPLC-ECD as an inflammation-related DNA lesion. In addition, a stem/progenitor cell factor Bmi1, 8-nitroguanine (formed during nitrative DNA damage), DNA damage response (DDR) proteins (phosphorylated ATM and γ-H2AX), and manganese-SOD (Mn-SOD) were analyzed by immunohistochemistry. Stem/progenitor cell markers (CD133, OV6, CD44, and Oct3/4) were positively stained in 56, 38, 47, and 56% of 34 cholangiocarcinoma cases, respectively. Quantitative analysis of 8-oxodG revealed significantly increased levels in CD133- and/or Oct3/4-positive tumor tissues compared to negative tumor tissues, as well as 8-nitroguanine formation detected by immunohistochemistry. In the cases of CD44- and/or OV6-positive tissue, no significant difference was observed. Cholangiocarcinoma patients with CD133- and/or Oct3/4-positive tumor tissues showed significantly lower expression of Mn-SOD and higher DDR protein, γ-H2AX. Moreover, CD133- and/or Oct3/4-positive cholangiocarcinoma patients had significant associations with tumor histology types, tumor stage, and poor prognoses. Our results suggest that CD133 and Oct3/4 in cholangiocarcinoma are associated with increased formation of DNA lesions and the DDR protein, which may be involved in genetic instability and lead to cholangiocarcinoma development with aggressive clinical features.

Topics: 8-Hydroxy-2'-Deoxyguanosine; AC133 Antigen; Albumins; Antigens, CD; Antigens, Differentiation; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Transformation, Neoplastic; Cholangiocarcinoma; Cholangitis, Sclerosing; Deoxyguanosine; DNA Damage; DNA Repair; Female; Genomic Instability; Glycoproteins; Guanine; Histones; Humans; Hyaluronan Receptors; Inflammation; Keratin-19; Liver; Male; Middle Aged; Octamer Transcription Factor-3; Oxidation-Reduction; Peptides; Polycomb Repressive Complex 1; Prognosis; Stem Cells; Superoxide Dismutase

(-)-Epigallocatechin-3-gallate (EGCG), which is largely found in green tea, is known to eliminate reactive oxygen species and associated inflammatory responses in vitro and in cells. However, the in vivo mechanisms underlying the effects of EGCG on the amelioration of metabolic disorders are not fully understood. In this study, we examined whether dietary supplementation with EGCG reduces inflammatory responses in peripheral leukocytes of a non-obese type 2 diabetes animal model, Goto-Kakizaki (GK) rats. GK rats at 9 wk of age were fed a control high-fat diet (46 energy % from lard and corn oil) or a high-fat diet containing 0.1%, 0.2%, or 0.5% EGCG (w/w) for 25 wk. The oxidative stress markers 8-hydroxydeoxyguanosine (OHdG) and total malondialdehyde (MDA) were reduced by supplementation with EGCG at 0.1%, but not at 0.2% or more. Significant reductions in the mRNA levels of genes related to inflammatory responses (TNF-α, IFN-γ, IL-1β, IL-6, IL-18, MCP-1, CD11b, and S100a6), 8-OHdG, and total MDA were induced in peripheral leukocytes of GK rats by EGCG supplementation at 0.1%, but not at 0.2% or more, compared with rats fed the control diet. The present results suggest that supplementation with a low dose of EGCG reduces oxidative stress and the expressions of genes involved in inflammation in peripheral leukocytes of GK rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Analysis of Variance; Animals; Catechin; Chemokines; Corn Oil; Cytokines; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Dietary Fats; Dietary Supplements; Disease Models, Animal; Inflammation; Leukocytes; Male; Malondialdehyde; Oxidative Stress; Polymerase Chain Reaction; Rats; Rats, Wistar

Exhausting exercise induces muscle damage associated with high production of free radicals and pro-inflammatory mediators.. The objective of this study was to determine for the first time and simultaneously whether oral coenzyme Q(10) (CoQ(10)) supplementation can prevent over-expression of inflammatory mediators and oxidative stress associated with strenuous exercise.. The participants were classified in two groups: CoQ(10) group (CG) and placebo group (PG). The physical test consisted in a constant run (50 km) that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing.. Exercise was associated with an increase in TNF-α, IL-6, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and isoprostane levels, revealing the degree of inflammation and oxidative stress induced. Oral supplementation of CoQ(10) during exercise was efficient reducing oxidative stress (decreased membrane hydroperoxides, 8-OHdG and isoprostanes generation, increased catalase, and total antioxidant status), which would lead to the maintenance of the cell integrity. Data obtained also indicate that CoQ(10) prevents over-expression of TNF-α after exercise, together with an increase in sTNF-RII that limits the pro-inflammatory actions of TNF. Moreover, CoQ(10) supplementation reduced creatinine production.. CoQ(10) supplementation before strenuous exercise decreases the oxidative stress and modulates the inflammatory signaling, reducing the subsequent muscle damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Adult; Antioxidants; Athletes; Catalase; Deoxyguanosine; Dietary Supplements; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Isoprostanes; Male; Oxidative Stress; Running; Signal Transduction; Tumor Necrosis Factor-alpha; Ubiquinone

The urinary concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG) reflect the oxidation status of hypertensive subjects and it can be used for monitoring oxidative stress changes. However, the influence of cardiovascular risk factors and inflammation on the urinary levels of this marker in hypertension (HT) has never evaluated. The purpose of this study was to analyze the impact of cardiovascular risk factors, and established inflammatory markers on 8-OHdG in essential HT.. We studied 149 asymptomatic hypertensive patients (61 ± 14 years). A routine physical examination, laboratory analyses, and echo-Doppler study were performed. Urinary 8-OHdG and plasma tumor necrosis factor-α (TNF-α), soluble TNF receptor 1 (sTNF-R1), soluble TNF receptor 2 (sTNF-R2), and interleukin-6 (IL-6) were determined.. 8-OHdG/creatinine levels were higher in hypertrophic patients (P = 0.022) and correlated with left ventricular mass index (P < 0.01). When 8-OHdG/creatinine was compared according to obesity and diabetes in our hypertensive subjects, no significant differences were found. 8-OHdG/creatinine was increased in hypertensive smokers (P = 0.032) and women (P = 0.006). Furthermore, 8-OHdG/creatinine correlated with TNF-α, sTNF-R1, sTNF-R2 (P < 0.0001), and with IL-6 (P < 0.05). A multivariate linear regression analysis showed that gender, smoking, and TNF-α were independent factors of 8-OHdG/creatinine.. Urinary 8-OHdG was increased in hypertensive patients with hypertrophy even under medical treatment. The presence of other cardiovascular risk factors on top of HT do not alter the concentrations of this oxidative stress marker, only smoking increasing its levels. TNF-α is an independent factor of 8-OHdG. These data suggest that this urinary marker gives specific additional information, further than blood pressure control alone, when evaluating hypertensive patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Blood Pressure; Cardiovascular Diseases; Deoxyguanosine; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Interleukin-6; Male; Middle Aged; Obesity; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Risk Factors; Tumor Necrosis Factor-alpha

The present study investigated the antioxidant and anti-inflammatory actions of tocopherols in mice and determined whether the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is involved in these activities. A mixture of tocopherols (γ-TmT) that is rich in γ-tocopherol was used. Nrf2 knockout (Nrf2 -/-) and wild-type mice were maintained on 0.03, 0.1, or 0.3% γ-TmT-enriched diet starting 2 weeks before the administration of dextran sulfate sodium (DSS) in drinking water (for 1 week, to induce colonic inflammation), until the termination of the experiment at 3 days after the DSS treatment. Dietary γ-TmT dose dependently lowered the levels of 8-oxo-deoxyguanosine, nitrotyrosine, inflammation index, and leukocyte infiltration in colon tissues, as well as 8-isoprostane and prostaglandin E2 in the serum, in both Nrf2 (-/-) and wild-type mice. No significant difference on the inhibitory actions of γ-TmT between the Nrf2 (-/-) and the wild-type mice was observed. The γ-TmT treatment significantly increased the serum levels of γ- and δ-tocopherols. Interestingly, the serum levels of tocopherol metabolites, specifically the γ- and δ-forms of carboxymethylbutyl hydroxychroman and carboxyethyl hydroxychroman, in Nrf2 (-/-) mice were significantly higher than those in wild-type mice. These findings suggest that the antioxidant and anti-inflammatory activities of γ-TmT in the colon are mostly due to the direct action of tocopherols in trapping reactive oxygen and nitrogen species, independent of the antioxidant enzymes and anti-inflammatory proteins that are regulated by Nrf2; however, Nrf2 knockout appears to affect the serum levels of tocopherol metabolites.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Chromatography, High Pressure Liquid; Colon; Deoxyguanosine; Dinoprost; Drinking Water; Female; gamma-Tocopherol; Immunoenzyme Techniques; Inflammation; Leukocyte Common Antigens; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Tyrosine

Heparin and low molecular weight heparins have been demonstrated to reduce myocardial ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhagic and thrombotic complications. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility of producing heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of regional myocardial I/R, we investigated the effects of an epimerized N-,O-sulphated K5 polysaccharide derivative, K5-N,OSepi, on infarct size and histological signs of myocardial injury caused by 30 min. ligature of the left anterior descending coronary artery followed by 1 or 24 h reperfusion. K5-N,OSepi (0.1-1 mg/kg given i.v. 15 min. before reperfusion) significantly reduced the extent of myocardial damage in a dose-dependent manner. Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by K5-N,OSepi. In left ventricular samples, I/R induced mast cell degranulation and a robust increase in lipid peroxidation, free radical-induced DNA damage and calcium overload. Markers of neutrophil infiltration and activation were also induced by I/R in rat hearts, specifically myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, prostaglandin-E(2) and tumour-necrosis-factor-α production. The robust increase in oxidative stress and inflammatory markers was blunted by K5-N,OSepi, in a dose-dependent manner, with maximum at 1 mg/kg. Furthermore, K5-N,OSepi administration attenuated the increase in caspase 3 activity, Bid and Bax activation and ameliorated the decrease in expression of Bcl-2 within the ischaemic myocardium. In conclusion, we demonstrate that the cardioprotective effect of the non-anticoagulant K5 derivative K5-N,OSepi is secondary to a combination of anti-apoptotic and anti-inflammatory effects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Anticoagulants; Apoptosis; Bacterial Capsules; Calcium; Caspase 3; Deoxyguanosine; Diagnosis, Computer-Assisted; Dinoprostone; Heparin; Inflammation; Male; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Cyclooxygenase (COX)-inhibiting nitric oxide (NO) donors (CINODs) are designed to inhibit COX-1 and COX-2 while releasing NO. COX inhibition is responsible for anti-inflammatory and pain-relieving effects, whereas NO donation can improve microcirculation and exert anti-inflammatory and antioxidant actions. In an in vivo mouse model of bleomycin-induced lung fibrosis, we evaluated whether a prototype CINOD compound, (S)-(5S)-5,6-bis(nitrooxy)hexyl)2-(6-methoxynaphthalen-2-yl)propanoate (NCX 466), may show an advantage over naproxen, its congener drug not releasing NO. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated orally with vehicle, NCX 466 (1.9 or 19 mg/kg), or an equimolar dose of naproxen (1 or 10 mg/kg) once daily for 14 days. Afterward, airway resistance, assumed as lung stiffness index, was assayed, and lung specimens were collected for analysis of lung inflammation and fibrosis. NCX 466 and naproxen dose-dependently prevented bleomycin-induced airway stiffness and collagen accumulation. NCX 466, at the highest dose, was significantly more effective than naproxen in reducing the levels of the profibrotic cytokine transforming growth factor-β and the oxidative stress markers thiobarbituric acid reactive substance and 8-hydroxy-2'-deoxyguanosine. NCX 466 also decreased myeloperoxidase activity, a leukocyte recruitment index, to a greater extent than naproxen. A similar inhibition of prostaglandin E₂ was achieved by both compounds. In conclusion, NCX 466 has shown a significantly higher efficacy than naproxen in reducing lung inflammation and preventing collagen accumulation. These findings suggest that COX inhibition along with NO donation may possess a therapeutic potential in lung inflammatory diseases with fibrotic outcome.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Bleomycin; Collagen; Cyclooxygenase Inhibitors; Deoxyguanosine; Dinoprostone; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Naproxen; Nitrates; Nitric Oxide; Nitric Oxide Donors; Oxidative Stress; Peroxidase; Propionates; Prostaglandin-Endoperoxide Synthases; Pulmonary Fibrosis; Thiobarbiturates; Transforming Growth Factor beta

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of a metabolic syndrome characterized by accumulation of hepatic fat, inflammation and varying degrees of fibrosis. Angiotensin (AT)-II has been reported to play a role in the establishment of NASH. This study examined the effects of an AT-II receptor blocker, irbesartan, on NASH using fatty liver Shionogi (FLS)-ob/ob male mice as the closest animal model of human metabolic syndrome-related NASH. Irbesartan (30 mg/kg/day) was orally administered to FLS-ob/ob mice for 12 weeks (irbesartan group). The effects of irbesartan on steatohepatitis were examined using factors including steatosis, fibrosis, inflammation and oxidative stress. The areas of hepatic fibrosis and hepatic hydroxyproline content were significantly lower in the irbesartan group compared to controls. The areas of α-smooth muscle actin-positivity and F4/80-positive cells were significantly decreased in the irbesartan group. The percentage of 8-hydroxy-2-deoxyguanosine (8-OHdG)-positive cells and 8-OHdG DNA content were significantly decreased in the irbesartan group compared to controls. Levels of RNA expression for procollagen I, transforming growth factor β1, tumor necrosis factor-α, sterol regulatory element-binding protein 1c and fatty acid synthase were significantly lower in the irbesartan group compared to controls. In contrast, the gene expression of peroxisome proliferator activated receptor-α was significantly higher in the irbesartan group compared to controls. Irbesartan administration improved hepatic steatosis and attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Kupffer cells and reducing oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Actins; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Collagen Type I; Deoxyguanosine; Fatty Acid Synthases; Fatty Liver; Hepatic Stellate Cells; Inflammation; Irbesartan; Liver Cirrhosis; Male; Mice; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; PPAR alpha; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Tetrazoles; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Oxidative stress contributes to liver fibrosis through the activation of hepatic stellate cells. In a cell-based screening study, a class of imidazolium salts demonstrates anti-fibrogenic properties. Little is known on imidazolium salt mechanistic effects. We investigated the anti-fibrogenic effect of one of the imidazolium salts, 1,3-bisbenzylimidazoliumbromide (DBZIM), in a chronic mouse model of liver fibrosis and evaluated the mechanism of this treatment.. Liver fibrosis was induced in mice by oral feeding of thioacetamide for 16 weeks. DBZIM was administered weekly, starting on the first day or 12 weeks from the day of thioacetamide administration. Hepatic function, histology and oxidative stress were examined. Expression of key inflammatory molecules and the molecular mechanism of DBZIM were assessed in hepatic stellate cells.. DBZIM decreased the fibrogenic response in thioacetamide-mice as measured by collagen deposition and α-smooth muscle actin expression (P<0.01). DBZIM improved liver function and reduced both oxidative damage and inflammation (P<0.01). Most importantly, our findings report the discovery that astrocyte elevated gene-1, involved in tumour progression, was up-regulated in thioacetamide-mice and DBZIM modulated astrocyte elevated gene-1 and NF-κB expression.. These findings indicate DBZIM is a potent therapeutic agent for the treatment of liver fibrosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Actins; Analysis of Variance; Animals; Cell Movement; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Cyclooxygenase 2; Deoxyguanosine; Gene Expression; Hepatic Stellate Cells; Imidazoles; Inflammation; Liver Cirrhosis; Male; Membrane Proteins; Mice; Nerve Tissue Proteins; NF-kappa B; Oxidative Stress; RNA-Binding Proteins; Superoxide Dismutase; Thioacetamide; Up-Regulation

Ozone is a pulmonary irritant known to cause oxidative stress, inflammation and tissue injury. Evidence suggests that macrophages play a role in the pathogenic response; however, their contribution depends on the mediators they encounter in the lung which dictate their function. In these studies we analyzed the effects of ozone-induced oxidative stress on the phenotype of alveolar macrophages (AM). Exposure of rats to ozone (2 ppm, 3h) resulted in increased expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), as well as heme oxygenase-1 (HO-1) in AM. Whereas 8-OHdG was maximum at 24h, expression of HO-1 was biphasic increasing after 3h and 48-72 h. Cleaved caspase-9 and beclin-1, markers of apoptosis and autophagy, were also induced in AM 24h post-ozone. This was associated with increased bronchoalveolar lavage protein and cells, as well as matrix metalloproteinase (MMP)-2 and MMP-9, demonstrating alveolar epithelial injury. Ozone intoxication resulted in biphasic activation of the transcription factor, NFκB. This correlated with expression of monocyte chemotactic protein-1, inducible nitric oxide synthase and cyclooxygenase-2, markers of proinflammatory macrophages. Increases in arginase-1, Ym1 and galectin-3 positive anti-inflammatory/wound repair macrophages were also observed in the lung after ozone inhalation, beginning at 24h (arginase-1, Ym1), and persisting for 72 h (galectin-3). This was associated with increased expression of pro-surfactant protein-C, a marker of Type II cell proliferation and activation, important steps in wound repair. These data suggest that both proinflammatory/cytotoxic and anti-inflammatory/wound repair macrophages are activated early in the response to ozone-induced oxidative stress and tissue injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Autophagy; Cell Proliferation; Deoxyguanosine; Female; Gene Expression Regulation; Heme Oxygenase-1; Inflammation; Lung; Macrophages, Alveolar; Oxidative Stress; Ozone; Protein C; Rats; Rats, Wistar; Time Factors

We determined the in vivo efficacy of apigenin, as an anti-oxidant and anti-inflammatory agent, given to mice after irradiation. Various concentrations of apigenin (0, 10, 20, and 40mg/kg body weight) were administered to mice by a single intraperitoneal injection 3hr after receiving 0 or 3Gy of (137)Cs gamma rays. Mice receiving vehicle only (no radiation and no apigenin) served as sham controls. We assessed the anti-oxidative activity of apigenin in vivo by measuring levels of 8-hydroxy-2-deoxy guanosine (8-OH-dG) in bone marrow (BM) cells, collected at days 3 and 10 after irradiation, from groups of mice (5 mice per treatment group) with or without apigenin treatment. Simultaneously, we evaluated the ability of apigenin to diminish radiation-induced inflammatory responses in bone-marrow-derived macrophages (BMDMs) from the same individual mice used for measuring the level of 8-OH-dG. To do this, the levels of activated nuclear factor-kappa B (NF-kappa B) and NF-kappa B-regulated pro-inflammatory cytokines [i.e. interleukin 1-beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha)] were measured in BMDMs. Our results indicated significant reductions (p<0.01 or <0.05) in the levels of 8-OH-dG in BM cells collected at both harvest times from irradiated mice receiving apigenin treatment, at all apigenin concentrations tested. Likewise, activation of NF-kappa B in BMDMs collected from gamma-irradiated mice that received apigenin was suppressed at both harvest times. Further, the levels of pro-inflammatory cytokines in gamma-irradiated mice treated with 20 or 40mg/kg body weight apigenin were significantly lower than those in mice receiving radiation only (p<0.01 or <0.05) even at day 10 post-irradiation. Additionally, the ratio of neutrophils to lymphocytes indicated that apigenin ameliorated radiation-induced hematological toxicity. Our study is the first to demonstrate the mitigative/therapeutic effects of apigenin given to mice after irradiation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antioxidants; Apigenin; Bone Marrow Cells; Deoxyguanosine; DNA Damage; Gamma Rays; Inflammation; Macrophages; Mice; NF-kappa B; Oxidative Stress

Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antidotes; Apoptosis; Cells, Cultured; Chemical Warfare Agents; Cyclooxygenase 2; Deoxyguanosine; DNA Damage; Female; Gene Expression Regulation; Humans; Inflammation; Matrix Metalloproteinase 9; Mice; Mice, Hairless; Mustard Gas; Nitric Oxide Synthase Type II; Oxidative Stress; Signal Transduction; Silybin; Silymarin; Skin

To correlate changes between VEGF expression with systemic and retinal oxidative stress and inflammation in rodent models of obesity induced insulin resistance and diabetes.. Retinal VEGF mRNA and protein levels were assessed by RT-PCR and VEGF ELISA, respectively. Urinary 8-hydroxydeoxyguanosine (8-OHdG), blood levels of C-reactive protein (CRP), malondialdehyde (MDA), and CD11b/c positive cell ratio were used as systemic inflammatory markers. Retinal expression of Nox2, Nox4, and p47phox mRNA levels were measured as oxidative stress markers. TNF-α, inter-cellular adhesion molecule-1 (ICAM-1), IL1β, and activation of nuclear factor κB (NF-κB) were used as retinal inflammatory markers.. Retinal VEGF mRNA and protein expression increased in Zucker diabetic fatty (ZDF(fa/fa)) rats and streptozotosin (STZ) induced diabetic Sprague-Dawley rats, after two months of disease, but not in Zucker fatty (ZF) rats. Systemic markers of oxidative stress and inflammation were elevated in insulin resistant and diabetic rats. Some oxidative stress and inflammatory markers (TNF-α, IL-6, ICAM-1, and IL1-β) were upregulated in the retina of ZDF(fa/fa) and STZ diabetic rats after 4 months of disease. In contrast, activation of NF-κB in the retina was observed in high fat fed nondiabetic and diabetic cis-NF-κB(EGFP) mice, ZF, ZDF(fa/fa), and STZ-induced diabetic rats.. Only persistent hyperglycemia and diabetes increased retinal VEGF expression. Some markers of inflammation and oxidative stress were elevated in the retina and systemic circulation of obese and insulin resistant rodents with and without diabetes. Induction of VEGF and its associated retinal pathologies by diabetes requires chronic hyperglycemia and factors in addition to inflammation and oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; C-Reactive Protein; CD11b Antigen; CD11c Antigen; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Inflammation; Insulin Resistance; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; NF-kappa B; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rats, Zucker; Retina; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stress, Physiological; Vascular Endothelial Growth Factor A

Lignophenols (LP) are the derivatives of native lignin, which is an abundant organic polymer in the plant kingdom. This study investigated whether LP can attenuate vascular oxidative stress and inflammation in streptozotocin (STZ)-induced diabetic rats. The diabetic rats induced by a single intravenous injection of STZ were randomly divided into two groups fed either 0 or 1.0% LP-containing diet. After 5 weeks of treatment, the superoxide (O(2)(-)) production, mRNA expression levels of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase subunits, monocyte chemoattractant protein-1 (MCP-1) and its receptor C-C chemokine receptor 2 (CCR2), and protein expression level of inducible nitric oxide synthase (iNOS) were examined in the aorta of vehicle-injected control and diabetic rats treated with or without LP. The increased O(2)(-) production and mRNA expression levels of NAD(P)H oxidase subunits Nox4 and p47phox were found to be significantly reduced in the aorta of diabetic rats treated with LP. The mRNA expression of MCP-1 and CCR2, and the protein expression of iNOS were found to be increased in the aorta of untreated diabetic rats, whereas these levels were significantly lower in the LP-treated group. These findings suggest that LP could attenuate vascular oxidative stress and/or inflammation via inhibition of NAD(P)H oxidase. This may lead to an improvement in the vascular impairment of diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Blood Glucose; Body Weight; Chemokine CCL2; Deoxyguanosine; Diabetes Mellitus, Experimental; Fagus; Inflammation; Lignin; Lipids; Male; Malondialdehyde; NADPH Oxidase 4; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Phenols; Rats; Rats, Wistar; Receptors, CCR2; RNA, Messenger; Superoxides; Time Factors

We previously reported that 8-oxo-2'-deoxyguanosine (8-oxo-dG) suppressed airway hyperresponsiveness and allergy-associated immune responses in ovalbumin-induced allergic mice by inactivating Rac. In the present study, 8-oxo-dG was investigated for its suppression of inflammation and remodeling in lung tissues induced by allergic reaction in mice. Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG. The mice without 8-oxo-dG administration showed the following inflammatory and airway remodeling signs: infiltration of inflammatory cells into peribronchial area, hyperplasia of mucus-secreting goblet cells in bronchial walls, increase of expressions of Muc5ac and vascular cell adhesion molecule (VCAM)-1, collagen deposition and protein expression, and matrix metalloproteinase (MMP)-2/-9 expressions. We also observed an increase of various inflammation-mediating proteins, namely IL-4, IL-5, IL-8, IL-13, TNF-α and IFN-γ, and activation of STAT1 and NF-κB. Production of reactive oxygen species and nitric oxide (NO(.)) was increased as indicated by a dramatic increase in formation of nitro-tyrosine. Importantly, Rac1 and 2 were also markedly activated. However, 8-oxo-dG suppressed all these inflammatory and tissue remodeling signs as well as activation of Rac1 and 2. These results indicate that 8-oxo-dG can inhibit allergy-induced inflammation and remodeling in airway and lung tissues through Rac inactivation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Airway Remodeling; Animals; Collagen; Cytokines; Deoxyguanosine; Enzyme Activation; Female; Gene Expression Regulation; Goblet Cells; Hyperplasia; Hypersensitivity; Immunosuppressive Agents; Inflammation; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mucin 5AC; NF-kappa B; rac GTP-Binding Proteins; RNA, Messenger; STAT1 Transcription Factor; Tyrosine; Vascular Cell Adhesion Molecule-1

This study applied a case-control approach to investigate the association between low-grade inflammation, defined by high values within the normal range of C-reactive protein (CRP) and interleukin-6 (IL-6), and urinary markers of nucleic acid oxidation. No differences in excretion of urinary markers of nucleic acid oxidation between cases and controls were found and multivariable linear regression analysis showed no association between urinary markers of nucleic acid oxidation and inflammatory markers. Post-hoc multivariable linear regression analysis showed significant associations between nucleic acid oxidation and various iron status markers and especially a close relationship between nucleic acid oxidation and ferritin. This study shows no association between low-grade inflammation and urinary markers of nucleic acid oxidation in a population of elderly Italian people. The results suggest that low-grade inflammation only has a negligible impact on whole body nucleic acid oxidation, whereas iron status seems to be of great importance.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Deoxyguanosine; Female; Ferritins; Guanosine; Humans; Inflammation; Interleukin-6; Iron; Iron, Dietary; Italy; Male; Nucleic Acids; Oxidation-Reduction; Reference Values; Regression Analysis

This study was conducted to evaluate blood concentrations of inflammatory cytokines and oxidative stress-related biomarkers as risk factors of breast cancer and to determine the relation between these markers and antioxidant nutrient intake.. Study subjects were 134 patients with breast cancer and 149 controls. Total antioxidant capacity and concentrations of 8-isoprostane, 8-hydroxy-2'-deoxyguanosine, interleukin (IL)-1β, IL-6, and IL-8 of blood samples were determined. A food-frequency questionnaire was used to assess nutrient intake.. Patients with breast cancer had significantly higher blood levels of oxidative stress markers compared with control subjects. Plasma concentrations of IL-1β and IL-6 were significantly higher in patients with breast cancer compared with those of control subjects. In the pooled analysis, total antioxidant capacity was significantly decreased with increasing quartiles of carbohydrate intake but was increased with increasing quartiles of total vitamin A intake and vitamin C intake. In addition, 8-hydroxy-2'-deoxyguanosine concentration was decreased with increasing quartiles of vitamin A and β-carotene. No significant association was found between nutrient intake and cytokine concentrations.. These results suggest that oxidative stress and inflammation may be associated with the risk of breast cancer. Total vitamin A intake was negatively related to oxidative stresses, possibly modifying the risk of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Ascorbic Acid; beta Carotene; Biomarkers; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Diet; Diet Surveys; Dietary Carbohydrates; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Middle Aged; Oxidative Stress; Risk Factors; Surveys and Questionnaires; Vitamin A; Vitamins

Currently, bronchopulmonary dysplasia (BPD) occurs almost exclusively in pre-term infants. In addition to prematurity, other factors like oxygen toxicity and inflammation can contribute to the pathogenesis. This study aimed to compare urinary inflammatory and oxidative stress markers between the no/mild BPD group and moderate/severe BPD group and between BPD cases with significant early lung disease like respiratory distress syndrome (RDS) ('classic' BPD) and with minimal early lung disease ('atypical' BPD). A total of 60 patients who were a gestational age < 30 weeks or a birth weight < 1250 g were included. Urine samples were obtained on the 1(st), 3(rd) and 7(th) day of life and measured the levels of leukotriene E(4) (LTE(4)) and 8-hydroxydeoxyguanosine (8-OHdG). The 8-OHdG values on the 3(rd) day showed significant correlation to duration of mechanical ventilation. The 8-OHdG levels on the 7(th) day were the independent risk factor for developing moderate/severe BPD. In 'classic' BPD, the 8-OHdG values on the 3(rd) day were higher than those of 'atypical' BPD. In 'atypical' BPD, the LTE(4) values on the 7(th) day were higher than the values in 'classic' BPD. These results suggest that oxidative DNA damage could be the crucial mechanism in the pathogenesis of current BPD and the ongoing inflammatory process could be an important mechanism in 'atypical' BPD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Bronchopulmonary Dysplasia; Deoxyguanosine; Female; Humans; Infant; Infant, Newborn; Infant, Very Low Birth Weight; Inflammation; Leukotriene E4; Male; Oxidative Stress; Statistics as Topic

Colitis-associated cancer (CAC) is one of clear examples of inflammation-carcinogenesis sequence, by which the strict control of colitis with potent anti-inflammatory or antioxidative agent offers the chance of cancer prevention. Supported with the facts that Rac1 binds and activates STAT3, which are significantly upregulated in inflammatory bowel disease (IBD) as well as CAC, but 8-hydroxydeoxyguanosine (8-oxo-7,8-dihydrodeoxyguanosine or 8-OHdG) paradoxically can block Rac1 activation and subsequent NADPH oxidase (NOX) inactivation in various inflammation models, we hypothesized that attenuated Rac1-STAT3 and COX-NF-κB pathway by exogenous 8-OHdG administration may ameliorate inflammatory signaling in dextran sodium sulfate (DSS)-induced colitis and can prevent CAC. Before commencing carcinogenesis model, we checked whether exogenous 8-OHdG can alleviate IBD, for which interleukin (IL)-10 knockout mice were designed to ingest 5% DSS for 1 week, and 8-OHdG is given through intraperitoneal route daily. 8-OHdG treatment groups significantly reduced pathologic grade of DSS-induced colitis as well as various inflammatory mediators such as TNF-α, IL-6, COX-2, and iNOS in a dose-dependent manner. To document the cancer prevention effects of 8-OHdG, mice were injected azoxymethane followed by drinking 2.5% DSS for 1 week, after which 8-OHdG-containing diets were given for 20 weeks. As results, mice that consumed 8-OHdG-containing diet significantly reduced both tumor incidence and multiplicity. Rac1 activity and phosphorylated STAT3 level were significantly attenuated in the 8-OHdG-treated group. Significantly decreased levels of malondialdehyde, monocyte chemotactic protein-1, matrix metalloproteinasess, COX-2, NOX4, and β-catenin nuclear accumulation were responsible for cancer prevention effects of exogenous 8-OHdG. In conclusion, we clearly showed cancer-preventive effect of exogenous 8-OHdG against CAC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anticarcinogenic Agents; Azoxymethane; Colitis; Colorectal Neoplasms; Deoxyguanosine; Dextrans; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; STAT3 Transcription Factor; Sulfates

DNA fragmentation is one of the typical features of apoptosis, frequently induced by oxidative stress. Increased oxidative stress is known to be related to several pathological processes. In this study, we assessed oxidative damage in the early follow-up period after kidney transplantation measuring DNA oxidation and fragmentation of mononuclear cells and the circulating levels of inflammatory cytokines.. Blood samples from 30 kidney transplant recipients were collected before transplantation and after 2 days, 1 month and 6 months. Oxidative DNA fragmentation was measured by Comet Assay, whereas DNA oxidation was evaluated measuring 8-OHdG leukocyte levels. Serum IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ and TNF-α were assayed using a multiplex ELISA analysis.. At 6 months after transplantation, a significant reduction in DNA fragmentation and IL-6 plasma levels was observed; DNA oxidation was higher in patients with a worse outcome, with delayed graft function and low nutritional status. We also found a correlation of IL-6 and IL-10 levels with DNA fragmentation and of IL-10 levels with DNA oxidation.. Low levels of oxidation and apoptosis at 6 months after transplantation correlate with a better recovery of renal function in kidney allografts. The measurement of cytokine levels confirmed a reduction of inflammatory parameters within 6 months of follow-up.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Comet Assay; Deoxyguanosine; DNA; DNA Fragmentation; Enzyme-Linked Immunosorbent Assay; Female; Graft Survival; Humans; Inflammation; Interleukin-10; Kidney Transplantation; Male; Middle Aged; Oxidative Stress; Oxygen; Time Factors; Treatment Outcome

Chronic inflammation has been recognized as a contributing factor in the pathogenesis of lung cancer. In this process, reactive oxygen species released by neutrophils may play an important role. The aim of the present study was to investigate the capacity of the major neutrophilic oxidant hypochlorous acid (HOCl), which is formed by myeloperoxidase (MPO), to induce DNA damage and mutagenicity in lung cells. HOCl was mutagenic in lung epithelial A549 cells in vitro, showing at physiological concentrations a significant induction of mutations in the HPRT gene. We studied three major types of DNA lesions that could be relevant for this HOCl-induced mutagenicity. Single strand DNA breakage and 8-oxo-7,8-dihydro-2'-deoxyguanosine were not found to be increased following HOCl treatment. On the other hand, HOCl caused a significant increase in the formation of 3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one (M(1)dG), which can be formed by either malondialdehyde (MDA) or base propenals. We observed an increased MDA formation upon exposure of A549 cells to HOCl, but a role of base propenals cannot be excluded. In line with this, we observed 4-fold increased M(1)dG adduct levels in mice that were intratracheally instilled with lipopolysaccharide to induce a pulmonary inflammation with neutrophil influx. Depletion of circulating neutrophils significantly reduced pulmonary MPO activity as well as M(1)dG adducts levels, thereby providing a causal link between neutrophils/HOCl and pulmonary genotoxicity in vivo. Taken together, these data indicate that MPO catalysed formation of HOCl during lung inflammation should be considered as a significant source of neutrophil-induced genotoxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenoma; Animals; Cells, Cultured; Colony-Forming Units Assay; Deoxyguanosine; DNA Adducts; DNA Breaks, Single-Stranded; DNA Damage; Humans; Hypochlorous Acid; Hypoxanthine Phosphoribosyltransferase; Inflammation; Lipid Peroxidation; Lipopolysaccharides; Lung; Lung Neoplasms; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mutation; Neutrophils; Oxidants; Peroxidase; Purine Nucleosides

Low vitamin B-6 status has been linked to an increased risk of cardiovascular diseases. The cardioprotective effects of vitamin B-6 independent of homocysteine suggest that additional mechanisms may be involved.. Our objective was to examine the cross-sectional association of vitamin B-6 status with markers of inflammation and oxidative stress.. We measured plasma pyridoxal-5'-phosphate (PLP), C-reactive protein (CRP), and an oxidative DNA damage marker, urinary 8-hydroxydeoxyguanosine (8-OHdG), in Puerto Rican adults who were living in Massachusetts (n = 1205, aged 45-75 y).. There was a strong dose-response relation of plasma PLP concentration with plasma CRP. Increasing quartiles of PLP were significantly associated with lower CRP concentrations (geometric means: 4.7, 3.6, 3.1, and 2.5 mg/L; P for trend < 0.0001) and with lower urinary 8-OHdG concentrations (geometric means: 124, 124, 117, and 108 ng/mg creatinine; P for trend: 0.025) after multivariate adjustment. These negative associations persisted after plasma homocysteine was controlled for. Plasma PLP concentrations were significantly correlated with plasma fasting glucose (r = -0.1, P = 0.0006), glycated hemoglobin (r = -0.08, P = 0.006), and homeostasis model assessment of beta cell function (r = 0.082, P = 0.005). Metabolic syndrome, obesity, and diabetes were also significantly associated with low plasma PLP concentrations (P = 0.011, 0.0007, and 0.004, respectively).. Low vitamin B-6 concentrations are associated with inflammation, higher oxidative stress, and metabolic conditions in older Puerto Rican adults. Our data suggest that vitamin B-6 may influence cardiovascular disease risk through mechanisms other than homocysteine and support the notion that nutritional status may influence the health disparities present in this population.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Boston; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Deoxyguanosine; Female; Hispanic or Latino; Humans; Inflammation; Male; Metabolic Syndrome; Middle Aged; Oxidative Stress; Pyridoxal Phosphate; Statistics, Nonparametric; Vitamin B 6

The purpose of this study was to explore the bioavailability, efficacy and molecular mechanisms of green tea polyphenols (GTP) related to preventing bone loss in rats with chronic inflammation. A 2 [placebo vs. lipopolysaccharide (LPS)]×2 (no GTP vs. 0.5% GTP in drinking water) factorial design enabled the evaluation of effects of LPS administration, GTP levels, and LPS×GTP interaction. Urinary GTP components and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were determined by high-pressure liquid chromatography for bioavailability and molecular mechanism, respectively. Efficacy was evaluated by examining changes in femoral mineral content (BMC) and density (BMD) using dual-energy X-ray absorptiometry, and bone turnover biomarkers [osteocalcin (OC) and tartrate-resistant acid phosphatase (TRAP)] using respective ELISA kits. The mRNA expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) in spleen was determined by real-time RT-PCR. Neither LPS administration nor GTP levels affected body weight and femoral bone area throughout the study period. Only GTP supplementation resulted in increased urinary epigallocatechin and epicatechin concentrations. LPS administration led to a decrease in femur BMC and BMD, and serum OC levels, but an increase in serum TRAP, urinary 8-OHdG and spleen mRNA expression of TNF-α and COX-2 levels. GTP supplementation resulted in higher values for femur BMC, BMD and serum OC, but lower values for serum TRAP, urinary 8-OHdG and spleen mRNA expression of TNF-α and COX-2 levels. We conclude that GTP mitigates bone loss in a chronic inflammation-induced bone loss model by reducing oxidative stress-induced damage and inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Base Sequence; Biological Availability; Body Weight; Bone Diseases, Metabolic; Bone Remodeling; Chromatography, High Pressure Liquid; Chronic Disease; Cyclooxygenase 2; Deoxyguanosine; Disease Models, Animal; DNA Primers; Drinking Behavior; Enzyme-Linked Immunosorbent Assay; Female; Flavonoids; Inflammation; Phenols; Polyphenols; Rats; RNA, Messenger; Tea; Tumor Necrosis Factor-alpha

Purpose. To investigate the status of oxidative stress and histopathologic alterations in patients with conjunctivochalasis and compare the findings with those in healthy control subjects. Methods. Eleven patients (n = 20 eyes) with Yokoi grade 3 conjunctivochalasis and 11 health control subjects (n = 22 eyes) were prospectively recruited. ELISA for tear hexanoyl-lysine (HEL) and inflammatory cytokines, tear film break-up time tests, Schirmer test measurements, and fluorescein and rose bengal vital staining were performed. Conjunctival specimens obtained during surgery for conjunctivochalasis and cataract underwent immunohistochemical staining for HEL+8-OHdG, MMP-3, and MMP-9, and positively stained cells were counted. Transmission electron microscopy was also performed, with staining for elastic fibers in the conjunctival stroma. Results. The mean tear stability and vital staining scores were significantly worse in the conjunctivochalasis patients than in the control subjects. The tear HEL and tear cytokine levels showed significantly higher values in eyes with conjunctivochalasis. IL-1beta and IL-6 levels showed a significant correlation with corneal epithelial damage. IL-1beta and TNFalpha showed a significant correlation with 8-OHdG-stained cell counts. Specimens from patients with conjunctivochalasis revealed a significantly higher number of cells positively stained for HEL, 8-OHdG, MMP-3, and MMP-9 than did specimens from age- and sex-matched control subjects. Transmission electron microscopy showed decreased intercellular cohesiveness, with the conjunctival stroma showing an accumulation of elastic fibers. Conclusions. Lipid and DNA oxidative stress were present in the conjunctiva. Increased tear inflammation seemed to coexist with loss of conjunctival epithelial cohesiveness and increased collagenolytic activity, which may explain the conjunctival laxity observed in patients with conjunctivochalasis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Conjunctival Diseases; Cytokines; Deoxyguanosine; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoenzyme Techniques; Inflammation; Lipid Peroxidation; Lysine; Male; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Oxidative Stress; Prospective Studies; Tears

Studies suggest that green tea polyphenols (GTP) or alphacalcidol is promising agent for preventing bone loss. Findings that GTP supplementation plus alphacalcidol administration increased bone mass via a decrease of oxidative stress and inflammation suggest a significant role of GTP plus alphacalcidol in bone health of patients with chronic inflammation.. Studies have suggested that green tea polyphenols (GTP) or alphacalcidol are promising dietary supplements for preventing bone loss in women. However, the mechanism(s) related to the possible osteo-protective role of GTP plus D(3) in chronic inflammation-induced bone loss is not well understood.. This study evaluated bioavailability, efficacy, and related mechanisms of GTP in combination with alphacalcidol in conserving bone loss in rats with chronic inflammation. A 12-week study of 2 (no GTP vs. 0.5% GTP in drinking water) × 2 (no alphacalcidol vs. 0.05 μg/kg alphacalcidol, 5×/week) factorial design in lipopolysaccharide-administered female rats was performed. In addition, a group receiving placebo administration was used to compare with a group receiving lipopolysaccharide administration only to evaluate the effect of lipopolysaccharide.. Lipopolysaccharide administration resulted in lower values for bone mass, but higher values for serum tartrate-resistant acid phosphatase (TRAP), urinary 8-hydroxy-2'-deoxyguanosine, and mRNA expression of tumor necrosis factor-α and cyclooxygenase-2 in spleen. GTP supplementation increased urinary epigallocatechin and epicatechin concentrations. Both GTP supplementation and alphacalcidol administration resulted in a significant increase in bone mass, but a significant decrease in serum TRAP levels, urinary 8-hydroxydeoxyguanosine levels, and mRNA expression of tumor necrosis factor-α and cyclooxygenase-2 in spleen. A synergistic effect of GTP and alphacalcidol was observed in these parameters. Neither GTP nor alphacalcidol affected femoral bone area or serum osteocalcin.. We conclude that a bone-protective role of GTP plus alphacalcidol during chronic inflammation bone loss may be due to a reduction of oxidative stress damage and inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Body Weight; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Cyclooxygenase 2; Deoxyguanosine; Drinking; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Female; Flavonoids; Gene Expression; Hydroxycholecalciferols; Inflammation; Lipopolysaccharides; Phenols; Phytotherapy; Plant Extracts; Polyphenols; Rats; RNA, Messenger; Spleen; Tea; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) generates reactive halogenating species that can modify DNA. The aim of this study was to investigate the formation of 8-halogenated 2'-deoxyguanosines (8- halo-dGs) during inflammatory events. 8-Bromo-2'-dG (8-BrdG) and 8-chloro-2'-dG (8-CldG) were generated by treatment of MPO with hydrogen peroxide at physiological concentrations of Cl(-) and Br(-). The formation of 8-halo-dGs with other oxidative stress biomarkers in lipopolysaccharide-treated rats was assessed by liquid chromatography tandem mass spectrometry and immunohistochemistry using a novel monoclonal antibody (mAb8B3) to 8-BrdG-conjugated keyhole limpet hemocyanin. The antibody recognized both 8-BrdG and 8-CldG. In the liver of lipopolysaccharide-treated rats, immunostaining for 8-halo-dGs, halogenated tyrosines, and MPO were increased at 8 h, whereas those of 8-oxo-2'-dG (8-OxodG) and 3-nitrotyrosine were increased at 24 h. Urinary excretion of both 8-CldG and 8-BrdG was also observed earlier than those of 8-OxodG and modified tyrosines (3-nitrotyrosine, 3-chlorotyrosine, and 3- bromotyrosine). Moreover, the levels of the 8-halo-dGs in urine from human diabetic patients were 8-fold higher than in healthy subjects (n = 10, healthy and diabetic, p < 0.0001), whereas there was a moderate difference in 8-OxodG between the two groups (p < 0.001). Interestingly, positive mAb8B3 antibody staining was observed in liver tissue from hepatocellular carcinoma patients but not in liver tissue from human cirrhosis patients. These data suggest that 8-halo-dGs may be potential biomarkers of early inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antibodies, Monoclonal; Chromatography, Liquid; Deoxyguanosine; Female; Halogens; Inflammation; Lipopolysaccharides; Liver; Mass Spectrometry; Mice; Mice, Inbred C57BL; Peroxidase; Rats; Rats, Wistar; Time Factors; Tyrosine

In obesity, the combined effects of enhanced food consumption, enhanced oxidative stress and microinflammation could augment the advanced glycation end products (AGEs) accumulation in plasma. We compared the plasma concentrations of AGEs and the soluble receptor for AGEs (sRAGE) in relation to markers of oxidative stress, microinflammation and renal function in obese and lean children/adolescents.. In 18 apparently healthy obese children/adolescents (7 females/11 males; age: 5-18 years; body mass index, BMI: 27.3+/-3.3 kg/m2) and 18 healthy lean controls (10 females/8 males; age: 4-17 years, BMI: 22.4+/-2.1 kg/m2) the plasma concentration of N(epsilon)-carboxymethyllysine (CML), fructoselysine (FL), AGE-associated fluorescence, sRAGE, high sensitive-C-reactive protein (hsCRP), interleukin-6 (IL-6) and urinary 8-hydroxy-2-deoxyguanosine (U-8-OHdG) excretion, plasma advanced oxidation protein products (AOPPs), renal function, and the HOMA index of insulin resistance were determined.. Obese children/adolescents had significantly lower concentrations of plasma FL (6.8+/-0.3 mmol/mol lysine vs. 7.7+/-0.3, p<0.02), CML (0.14+/-0.03 mmol/mol lysine vs. 0.22+/-0.04, p<0.001), and fluorescent AGEs (223+/-37 arbitrary units (AU) vs. 318+/-64, p<0.01) than their lean counterparts. Plasma sRAGE concentration did not differ (2.3+/-0.6 ng/ml vs. 2.6+/-0.6). Obese children/adolescents were more insulin-resistant (HOMA index: p<0.01), exhibited higher levels of markers of inflammation (hs-CRP: p<0.03; IL-6: p<0.02), of oxidative stress (AOPPs: p<0.05; 8-OHdG: p<0.04) and had a higher creatinine clearance (p<0.01) and proteinuria (p<0.01).. We present the first evidence that childhood/adolescent obesity is characterized by lower plasma AGE levels, despite lower insulin sensitivity, enhanced oxidative stress and microinflammation. An enhanced removal of AGE peptides via hyperfiltration may partially contribute to the lower plasma AGE levels.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Biomarkers; Blood Glucose; C-Reactive Protein; Case-Control Studies; Child; Child, Preschool; Deoxyguanosine; Female; Fluorescence; Glycation End Products, Advanced; Humans; Inflammation; Insulin; Kidney; Lysine; Male; Overweight; Oxidative Stress; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Resveratrol is known as one of the antioxidant polyphenols contained in red wine and grape skin. The purpose of the present study was to investigate the role of resveratrol in ocular inflammation in endotoxin-induced uveitis (EIU).. EIU was induced in male C57/B6 mice at the age of 6 weeks by a single intraperitoneal injection of lipopolysaccharide (LPS). Animals had received oral supplementation of resveratrol at the doses of 5, 50, 100, or 200 mg/kg for 5 days until LPS injection. Twenty-four hours after LPS administration, leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. Retinal and retinal pigment epithelium (RPE)-choroidal levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear translocation of nuclear factor (NF)-kappaB p65 were evaluated by enzyme-linked immunosorbent assay. Retinal and RPE-choroidal activities of silent information regulator two ortholog (SIRT) 1 were measured by deacetylase fluorometric assay.. Resveratrol pretreatment led to significant and dose-dependent suppression of leukocyte adhesion to retinal vessels of EIU mice compared with vehicle application. Protein levels of MCP-1 and ICAM-1 in the retina and the RPE-choroid of EIU animals were significantly reduced by resveratrol administration. Importantly, resveratrol-treated animals showed significant decline of retinal 8-OHdG generation and nuclear NF-kappaB P65 translocation, both of which were upregulated after EIU induction. RPE-choroidal SIRT1 activity, reduced in EIU animals, was significantly augmented by treatment with resveratrol.. Resveratrol prevented EIU-associated cellular and molecular inflammatory responses by inhibiting oxidative damage and redox-sensitive NF-kappaB activation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Blotting, Western; Chemokine CCL2; Deoxyguanosine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Fluorescent Antibody Technique, Indirect; Inflammation; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Leukocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Resveratrol; Retina; Retinal Pigment Epithelium; Retinal Vessels; Sirtuin 1; Sirtuins; Stilbenes; Transcription Factor RelA; Uveitis

The aim of this study was to investigate high molecular weight hyaluronan (HMW-HA) protection on human corneal epithelial (HCE) cells against ultraviolet B (UVB) radiation-induced toxic effects.. The HCE cell line was incubated with HMW-HA or phosphate-buffered salt solution (PBS), rinsed, and exposed to UVB radiation. Cell viability, reactive oxygen species (ROS) and glutathione (GSH) levels, 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) release, p53 phosphorylation, caspase-3, -8, -9 activation, and interleukin (IL)-6 and -8 production were assessed to evaluate and to compare UVB-induced toxicity between cells treated with HMW-HA and cells treated with PBS.. Data indicate that HMW-HA had significant protective effects against UVB radiation. HMW-HA increased HCE cell viability, decreased IL-6 and -8 production, and decreased caspase-3 and -8 activation. However, HMW-HA had no significant effect on ROS and GSH levels, 8-oxo-dG release, and p53 phosphorylation.. To our knowledge, we report for the first time the ability of HMW-HA to protect cells against UV irradiation. According to our results, HMW-HA provides anti-inflammatory and anti-apoptotic signals to cells exposed to UVB.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adjuvants, Immunologic; Apoptosis; Caspase 3; Caspase 8; Caspase 9; Cell Line; Cytoprotection; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Radiation; Epithelium, Corneal; Glutathione; Humans; Hyaluronic Acid; Inflammation; Interleukin-6; Interleukin-8; Oxidative Stress; Reactive Oxygen Species; Tumor Suppressor Protein p53; Ultraviolet Rays

Chronic inflammation is induced by various infectious/infected agents and by many physical, chemical and immunological factors. Many malignancies arise from areas of infection and inflammation. Reactive oxygen species and reactive nitrogen species are considered to play the key role in inflammation-associated carcinogenesis by causing oxidative and nitrative DNA damage. 8-Nitroguanine is a mutagenic nitrative DNA lesion formed during inflammation. Development of a detection method for 8-nitroguanine would provide an insight into the mechanism of inflammation-associated carcinogenesis and the assessment of carcinogenic risk in patients with inflammatory diseases. We established the method to produce highly sensitive and specific anti-8-nitroguanine rabbit polyclonal antibody, and detect 8-nitroguanine formation in biopsy specimens and animal tissues by immunohistochemistry. We have found that 8-nitroguanine is formed at the sites of carcinogenesis regardless of etiology, and proposed the possibility that 8-nitroguanine is a potential biomarker to evaluate the risk of inflammation-associated carcinogenesis. In this paper, we describe the procedures of these experiments and the application to clinical specimens and animal tissues.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers, Tumor; Deoxyguanosine; DNA Damage; Fluorescent Antibody Technique, Indirect; Guanine; Humans; Inflammation; Neoplasms; Rabbits; Reactive Nitrogen Species

Genetic instability is a hallmark of human cancers. It is the driving force for tumor development as it facilitates the accumulation of mutations in genes that regulate cell death and proliferation and therefore promotes malignant transformation. Chronic inflammation is a common underlying condition for human tumor development, accounting for approximately 20% of human cancers. TNFalpha is an important inflammation cytokine and is crucial to the development of inflammation-associated cancers. We have shown that TNFalpha can cause DNA damages through reactive oxygen species (ROS). TNFalpha treatment in cultured cells resulted in increased gene mutations, gene amplification, micronuclei formation and chromosomal instability. Antioxidants significantly reduced TNFalpha-induced genetic damage. In addition, TNFalpha treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. Therefore, genetic instability plays an important role in inflammation-associated cancers.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cell Transformation, Neoplastic; Cells, Cultured; Chromosomal Instability; Chromosome Aberrations; Chronic Disease; Colonic Neoplasms; Deoxyguanosine; Embryo, Mammalian; Fibroblasts; Humans; In Situ Hybridization, Fluorescence; Inflammation; Mice; Mice, Inbred BALB C; Mice, Nude; Micronucleus Tests; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

The aim of the present observational study was to investigate the relationships between glycaemic status and levels of oxidative stress and inflammation in well-controlled type 2 diabetes subjects. Metabolic variables (weight, BMI, waist circumference (waist), blood glucose, glycated Hb (HbA(1c)), insulin, blood lipids), biomarkers of oxidative stress (8-iso-PGF(2alpha), malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, formamido pyrimidine glycosylase-sites, frequency of micronucleated erythrocytes, nitrotyrosine) and inflammatory markers (high sensitivity C-reactive protein (hsCRP), IL-6, cyclo-oxygenase-catalyzed PGF(2alpha)-metabolite) were measured. Fifty-six patients (thirty women and twenty-six men, age 62.3 (SD 7.0) years, HbA(1c) 6.1 (SD 0.9) %, BMI 28.3 (SD 3.8) kg/m(2), waist 99.6 (SD 11.1) cm) were included in the study. HbA(1c) (r 0.29, P=0.03) and blood glucose (r 0.33, P=0.01) correlated positively with 8-iso-PGF(2alpha). Positive correlations were also observed between HbA(1c) and nitrotyrosine (r 0.42, P=0.01), waist and hsCRP (r 0.37, P=0.005), hsCRP and IL-6 (r 0.61, P<0.0001) and between PGF(2alpha)-metabolite and 8-iso-PGF(2alpha) (r 0.27, P=0.048). The present study indicates that glycaemic status is associated with oxidative stress even in subjects with well-controlled type 2 diabetes. Furthermore, inflammation was more related to abdominal obesity than to glycaemic control. A large number of biomarkers of oxidative stress and inflammation were investigated, but only a few associations were found between the markers. This could be due to the fact that none of these biomarkers biosynthesises via similar pathways or simultaneously owing to their diverse nature and origin.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Interleukin-6; Lipids; Male; Malondialdehyde; Middle Aged; Obesity; Oxidative Stress; Probability; Statistics, Nonparametric; Tyrosine; Waist Circumference

We have shown that direct reaction of catechol with nitric oxide (NO) results in generation of reactive oxygen and nitrogen species (RNS) through semiquinone radical formation, leading to oxidative DNA damage in rat forestomach. In the present study, we investigated whether dietary catechol systemically exerts the same effects under NO-rich circumstances, when given before and during induction of inflammatory lesions. Male ICR mice were treated with or without 0.8% catechol in the diet for 2 weeks followed by acetaminophen (APAP) administration at a dose of 300mg/kg by single i.p. injection. Along with several indicators of APAP-induced hepatitis, 8-hydroxydeoxyguanosine (8-OHdG) levels and immunohistochemistry for 3-nitrotyrosine (NO(2)Tyr) in the livers were examined at 1.5, 4 and 24h after APAP injection. 8-OHdG was significantly increased at 24h in the co-treatment group, but not with either catechol or APAP alone. Elevation of serum ALT and AST activities, decrease of reduced glutathione levels and histopathological liver changes were observed to the same extents in both APAP-treated groups. In view of the finding of positive hepatocytes for NO(2)Tyr prior to generation of 8-OHdG, the process of oxidative DNA damage might involve RNS formation. Precise quantitative analysis of NO(2)Tyr by means of liquid chromatography with tandem mass spectrometry (LC-MS/MS) in an additional study with the same experimental protocol confirmed increase of RNS due to the reaction of catechol with NO produced after APAP-induced hepatitis. The overall data imply that antioxidants with a catechol structure can cause oxidative DNA damage under inflammatory conditions.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetaminophen; Alanine Transaminase; Animals; Catechols; Chemical and Drug Induced Liver Injury; Deoxyguanosine; Diet; DNA Damage; Glutathione; Immunohistochemistry; Inflammation; Liver; Male; Mice; Mice, Inbred ICR; Nitric Oxide; Oxidation-Reduction; Time Factors; Transaminases; Tyrosine

Vascular endothelial growth factor (VEGF), which is associated with the stimulation of angiogenesis and collateral vessel synthase, is one of the crucial factors involved in cardiac remodeling in type 2 diabetes.. We investigated VEGF inhibition by dRK6 on the heart in an animal model of type 2 diabetes. Male db/db and db/m mice either were treated with dRK6 starting at 7 weeks of age for 12 weeks (db/db-dRK6 and db/m-dRK6) or were untreated.. Cardiac dysfunction and hypertrophy were noted by echocardiogram and molecular markers in the db/db-dRK6 mice. The presence of diabetes significantly suppressed the expression of VEGF receptor (VEGFR)-1 and VEGFR-2, phospho-Akt, and phospho-endothelial nitric oxide synthase (eNOS) in the heart. In db/db-dRK6 mice, dRK6 completely inhibited VEGFR-2, phospho-Akt, and phospho-eNOS expression, whereas no effect on VEGFR-1 was observed. Cardiac fibrosis, microvascular scarcity associated with an increase in apoptotic endothelial cells, and inflammation were prominent, as well as increase in antiangiogenic growth factors. Cardiac 8-hydroxy-deoxyguanine and hypoxia-inducible factor-1alpha expression were significantly increased. No such changes were found in the other groups, including the db/m-dRK6 mice. The number of apoptotic human umbilical vein endothelial cells was increased by dRK6 in a dose-dependent manner only at high glucose concentrations, and this was associated with a decrease in phospho-Akt and phospho-eNOS related to oxidative stress.. Our results demonstrated that systemic blockade of VEGF by dRK6 had deleterious effects on the heart in an animal model of type 2 diabetes; dRK6 induced downregulation of the VEGFR-2 and Akt-eNOS axis and enhancement of oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cardiomegaly; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Echocardiography; Endothelium, Vascular; Fibrosis; Heart Diseases; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred Strains; Nitric Oxide Synthase Type III; Oligopeptides; Proto-Oncogene Proteins c-akt; Thrombospondin 1; Vascular Endothelial Growth Factor A

UV-irradiated skin and UV-induced tumors overexpress the inducible isoform of cyclooxygenase-2 (Cox-2), and Cox-2 inhibition reduces photocarcinogenesis. To evaluate photoprotective effects of Polypodium leucotomos extract (PL), hairless Xpc(+/-) mice were fed for 10 days with PL (300 mg/kg) or vehicle then UV-irradiated, once. By 24 hours, UV-induced Cox-2 levels were increased in vehicle-fed and PL-fed mice, whereas by 48 and 72 hours, Cox-2 levels were four- to fivefold lower in PL-fed mice (P < 0.05). p53 expression/activity was increased in PL-fed versus vehicle-fed then UV-irradiated mice. UV-induced inflammation was decreased in PL-fed mice, as shown by approximately 60% decrease (P < 0.001) in neutrophil infiltration at 24 hours, and macrophages by approximately 50% (<0.02) at 24 and 48 hours. By 72 hours, 54 +/- 5% cyclobutane pyrimidine dimers remained in vehicle-fed versus 31 +/- 5% in PL-fed skin (P < 0.003). The number of 8-hydroxy-2'-deoxyguanosine-positive cells were decreased before UV irradiation by approximately 36% (P < 0.01), suggesting that PL reduces constitutive oxidative DNA damage. By 6 and 24 hours, the number of 8-hydroxy-2'-deoxyguanosine-positive cells were approximately 59% (P < 0.01) and approximately 79% (P < 0.03) lower in PL-fed versus vehicle-fed mice. Finally, UV-induced mutations in PL-fed-mice were decreased by approximately 25% when assessed 2 weeks after the single UV exposure. These data demonstrate that PL extract supplementation affords the following photoprotective effects: p53 activation and reduction of acute inflammation via Cox-2 enzyme inhibition, increased cyclobutane pyrimidine dimer removal, and reduction of oxidative DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cyclooxygenase 2; Deoxyguanosine; Dietary Supplements; DNA Mutational Analysis; DNA Repair; Humans; Inflammation; Macrophages; Male; Mice; Mice, Hairless; Mutagenesis; Plant Extracts; Polypodium; Pyrimidine Dimers; Skin; Tumor Suppressor Protein p53; Ultraviolet Rays

Metabolic syndrome (MetS) is a group of cardiovascular risk factors, including visceral obesity, glucose intolerance, hypertension, and dyslipidemia. Increased oxidative and nitrative stress and inflammation and decreased endothelial function occur in an animal model of metabolic syndrome, SHR/NDmcr-cp (SHR/cp) rats. The present study investigated the effects of coenzyme Q10 (CoQ10), one of the important antioxidants, on the abnormal oxidative condition and characteristic components of metabolic syndrome in SHR/cp rats by maintaining them on a diet supplemented with 0.07% - 0.7% CoQ10 for 26 weeks. We determined serum levels of oxidatively modified low-density lipoprotein (Ox-LDL) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as oxidative stress markers, 3-nitrotyrosine as a nitrative stress marker, 3-chlorotyrosine as a marker of myeloperoxidase (MPO)-catalyzed oxidation and high-sensitivity C-reactive protein (hsCRP) as an inflammatory marker. The administration of CoQ10 significantly attenuated the increase of oxidative and nitrative stress markers and inflammatory markers in a dose-dependent manner. CoQ10 prevented the elevated serum insulin levels, although it did not affect the elevated glucose level and dyslipidemia. CoQ10 also reduced elevated blood pressure, but did not affect body weight gain. In addition, CoQ10 improved endothelial dysfunction in the mesenteric arteries. These findings suggest that the antioxidant properties of CoQ10 can be effective for ameliorating cardiovascular risk in MetS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Body Weight; Deoxyguanosine; Disease Models, Animal; Inflammation; Insulin; Lipids; Lipoproteins, LDL; Metabolic Syndrome; Oxidative Stress; Peroxidase; Rats; Rats, Inbred SHR; Tyrosine; Ubiquinone

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Cell Movement; Deoxyguanosine; DNA Glycosylases; DNA Repair Enzymes; Female; Gastric Mucosa; Humans; Inflammation; Male; Mutation; Phosphoric Monoester Hydrolases; Polymorphism, Single Nucleotide; Stomach Neoplasms

Tissue accumulation of advanced glycation end products (AGEs) is associated with ageing, both in diabetics and nondiabetic subjects.. The purpose of this study was to assess immunostaining for AGEs, specifically carboxymethyl-lysine (CML) and receptor for AGEs (RAGE), in muscle tissue of healthy male subjects differing in age and weight stability.. Muscle tissue was obtained during hernia surgery in middle-aged men reporting weight maintenance (WM, n = 10) or weight gain (WG, n = 7), and also in 4 elderly men. Tissue inmunostaining for CML and RAGE was performed.. Intensity of CML and RAGE staining were highly correlated (r = 0.84) and also significantly associated with weight change and age. Muscle AGEs accretion was statistically associated with muscle expression of oxidative injury (8-hydroxy-deoxyguanosine and 4-hydroxy-2-nonenal) and inflammatory markers (tumor necrosis factor-alpha).. The increase of skeletal muscle AGEs/RAGE and markers of inflammation and oxidative injury in association with weight gain and old age suggest a pathogenic role of AGEs in weight gain and in sarcopenia of aging.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Biomarkers; Deoxyguanosine; Glycation End Products, Advanced; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Tumor Necrosis Factor-alpha; Weight Gain

This study evaluated the relationship between inflammation, intra-hepatic oxidative stress, oxidative DNA damage and the progression of liver carcinogenesis in hepatitis C virus (HCV)-infected humans.. Non-cancerous liver tissues were collected from 30 patients with an HCV-associated solitary hepatocellular carcinoma (HCC) who received curative tumor removal. After surgery, the patients were followed at monthly intervals at the outpatient clinic. Distribution of the inflammatory cells (CD68+), the number of 8-hydroxydeoxyguanosine (8-OHdG) DNA adducts and 4-hydroxynonenal (HNE) protein adducts and the expression of apurinic/apyrimidinic endonuclease (APE) were determined by immunohistochemical analysis in serial liver sections from tumor-free parenchyma at the surgical margin around the tumor.. Significant positive correlations were observed between the number of CD68+ cells, the amount of HNE protein adducts, and the number of 8-OHdG adducts in liver tissue of patients with HCC and HCV. The cumulative disease-free survival was significantly shorter in patients with the highest percentage of 8-OHdG-positive hepatocytes. Using a Cox proportional hazard model, 8-OHdG, HNE and CD68 were determined to be good biomarkers for predicting disease-free survival in patients with HCC and HCV.. These results support the hypothesis that HCV-induced inflammation causes oxidative DNA damage and promotes hepatocarcinogenesis which directly affects the clinical outcome. Since patients with greater intra-hepatic oxidative stress had a higher incidence of HCC recurrence, we suggest that oxidative stress biomarkers could potentially be used as a useful clinical diagnostic tool to predict the duration of disease-free survival in patients with HCV-associated HCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Alanine Transaminase; Aldehydes; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Carcinoma, Hepatocellular; Deoxyguanosine; DNA Adducts; DNA Damage; Female; Follow-Up Studies; Hepacivirus; Hepatectomy; Hepatitis C; Humans; Inflammation; Lipid Peroxidation; Liver Neoplasms; Male; Microfilament Proteins; Middle Aged; Neoplasm Recurrence, Local; Oxidative Stress; Prognosis; Reactive Oxygen Species; Risk Factors; Survival Rate; Vesicular Transport Proteins

In an effort to define the prevalent DNA damage chemistry-associated chronic inflammation, we have quantified 12 DNA damage products in tissues from the SJL mouse model of nitric oxide (NO) overproduction. Using liquid chromatography-mass spectrometry/MS and immunoblot techniques, we analyzed spleen, liver and kidney from RcsX-stimulated and control mice for the level of the following adducts: the DNA oxidation products 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), guanidinohydantoin (Gh), oxazolone (Ox); 5-guanidino-4-nitroimidazole (NitroIm); spiroiminodihydantoin (Sp) and M(1)dG; the nitrosative deamination products 2'-deoxyxanthosine, 2'-deoxyoxanosine (dO), 2'-deoxyinosine and 2'-deoxyuridine and the lipid peroxidation-derived adducts 1,N(6)-etheno-deoxyadenosine and 1,N(2)-etheno-deoxyguanosine. The levels of dO, Gh, Ox, NitroIm and Sp were all below a detection limit of approximately 1 lesion per 10(7) bases. Whereas there were only modest increases in the spleens of RcsX-treated compared with control mice for the nucleobase deamination products (10-30%) and the DNA oxidation products 8-oxodG (10%) and M(1)dG (50%), there were large (3- to 4-fold) increases in the levels of 1,N(6)-etheno-deoxyadenosine and 1,N(2)-etheno-deoxyguanosine. Similar results were obtained with the liver and with an organ not considered to be a target for inflammation in the SJL mouse, the kidney. This latter observation suggests that oxidative and nitrosative stresses associated with inflammation can affect tissues at a distance from the activated macrophages responsible for NO overproduction during chronic inflammation. These results reveal the complexity of NO chemistry in vivo and support an important role for lipids in the pathophysiology of inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cell Line; Deoxyguanosine; Disease Models, Animal; DNA Adducts; DNA Damage; Inflammation; Lipid Peroxidation; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred Strains; Nitric Oxide

The biological mechanisms linking air pollution to cardiovascular events still remain largely unclear.. To investigate whether biological mechanisms linking air pollution to cardiovascular events occurred concurrently in human subjects exposed to urban air pollutants.. We recruited a panel of 76 young, healthy students from a university in Taipei. Between April and June of 2004 or 2005, three measurements were made in each participant of high-sensitivity C-reactive protein (hs-CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasminogen activator fibrinogen inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA) in plasma, and heart rate variability (HRV). Gaseous air pollutants were measured at one air-monitoring station inside their campus, and particulate air pollutants were measured at one particulate matter supersite monitoring station 1 km from their campus. We used linear mixed-effects models to associate biological endpoints with individual air pollutants averaged over 1- to 3-day periods before measurements were performed.. We found that increases in hs-CRP, 8-OHdG, fibrinogen, and PAI-1, and decreases in HRV indices were associated with increases in levels of particles with aerodynamic diameters less than 10 microm and 2.5 microm, sulfate, nitrate, and ozone (O(3)) in single-pollutant models. The increase in 8-OHdG, fibrinogen, and PAI-1, and the reduction in HRV remained significantly associated with 3-day averaged sulfate and O(3) levels in two-pollutant models. There were moderate correlations (r = -0.3) between blood markers of hs-CRP, fibrinogen, PAI-1, and HRV indices.. Urban air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction simultaneously in healthy young humans, with sulfate and O(3) as two major traffic-related pollutants contributing to such effects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Air Pollutants; Air Pollution; Biomarkers; Blood Coagulation; C-Reactive Protein; Deoxyguanosine; Environmental Monitoring; Female; Fibrinogen; Heart Rate; Humans; Inflammation; Male; Oxidative Stress; Particle Size; Plasminogen Activator Inhibitor 1; Taiwan; Tissue Plasminogen Activator; Urban Health; Urban Population

Di(2-ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPARalpha). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPARalpha, we compared DEHP-induced tumorigenesis in wild-type and Pparalpha-null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Pparalpha-null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild-type mice (10.0%). These results suggest the existence of pathways for DEHP-induced hepatic tumorigenesis that are independent of PPARalpha. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Pparalpha-null than in wild-type mice. NFkappaB levels also significantly increased in a dose-dependent manner in Pparalpha-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Pparalpha-null mice fed a 0.05% DEHP-containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Pparalpha-null mice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Animals; Base Sequence; Deoxyguanosine; Inflammation; Japan; Liver Neoplasms; Male; Mice; NF-kappa B p50 Subunit; Oxidative Stress; Phthalic Acids; Polymerase Chain Reaction; PPAR alpha

Recently, we observed that 8-hydroxyguanosine triphosphate and 8-hydroxy-2'-deoxyguanosine (oh(8)dG) inactivate Rac and consequently down-regulate the Rac-linked NADPH oxidase, iNOS, and Cox2. Based on these observations, we tested whether oh(8)dG has anti-inflammatory activity in vivo in lipopolysaccharide (LPS)-treated mice. LPS (1 mg/kg, ip)-treated mice exhibit marked inflammatory responses, including increases in proinflammatory cytokines (TNF-alpha, IL-6, IL-18, and IL-12p70) in serum and infiltration of neutrophils, increased translocation of NF-kappaB p50 from the cytosol to the nucleus, and phosphorylation of c-Jun in lung tissues. Mice were pretreated with oh(8)dG (up to 60 mg/kg, ip) 4 h before LPS injection, and this pretreatment dose-dependently inhibited the inflammatory responses; the inhibitions observed with 60 mg/kg oh(8)dG were statistically significant. At the same time, oh(8)dG pretreatment inactivated Rac in lung tissues. Oh(8)dG pretreatment (50 mg/kg, ip) also significantly protected against LPS-induced septic death. Furthermore, oh(8)dG was more effective than acetyl salicylic acid in inhibiting these inflammatory responses. 8-Hydroxyguanosine also had some effect but was much weaker than oh(8)dG. The effects of normal nucleosides (dG, G, and A) were negligible or not significant. These results support an anti-inflammatory activity for oh(8)dG, which could be ascribed to its Rac-inactivating action.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Deoxyguanosine; Free Radicals; Inflammation; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B p50 Subunit; Peroxidase; rac GTP-Binding Proteins

Weight maintenance within normal standards is recommended for prevention of conditions associated with oxidative injury. To compare oxidative damage in a post mitotic tissue, between adults differing in long-term energy balance.. During hernia surgery, a sample of skeletal muscle was obtained in 17 non-obese adults. Subjects were divided into two groups according to their self-reported weight change: weight maintainers (WM) reported <4kg increase, and weight gainers (WG) reported >5kg increment. Muscle immunohistochemistry for 8-hydroxy-deoxyguanosine (8OHdG), 4-Hydroxy-2-nonenal (4HNE), and TNF-alpha, as markers of oxidative injury and inflammation, were performed. As known positive controls for oxidative injury, we included 10 elderly subjects (66-101yr). Anthropometric measures and blood samples for clinical laboratory and serum cytokines (TNF-alpha and IL-6) were obtained.. 8OHdG was higher in WG compared with WM (149.1+/-16.2 versus 117.8+/-29.5, P=0.03), and was associated with anthropometric indicators of fat accumulation. 4HNE was similar in WG compared with WM (10.9+/-7.6 versus 9.8+/-6.3) but noticeably higher in elderly subjects (21.5+/-15.3, P=0.059). TNF-alpha protein in WG was higher compared with WM (114.0+/-41.7 versus 70.1+/-23.3, P=0.025), and was associated with weight increase.. Moderate self-reported weight increase, and body fat accumulation, suggesting long-term positive energy balance is associated with muscle DNA oxidative injury and inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Aging; Aldehydes; Case-Control Studies; Deoxyguanosine; DNA Damage; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Muscle, Skeletal; Obesity; Tumor Necrosis Factor-alpha; Weight Gain

Corosolic acid (CRA), a constituent of banaba leaves, has been reported to have anti-inflammatory and hypoglycemic activities. The aim of this study was to determine the effects of CRA on metabolic risk factors including obesity, hypertension, hyperinsulinemia, hyperglycemia, and hyperlipidemia together with oxidative stress and inflammation, all of which are characteristic of the SHR/NDmcr-cp (cp/cp) (SHR-cp) rat, an animal model of metabolic syndrome. Six-week-old male SHR-cp rats were fed a high fat diet containing 0.072% CRA for 14 weeks. Treatment with CRA lowered blood pressure, which was elevated in control animals, by 10% after 8 weeks, and serum free fatty acids by 21% after 2 weeks. CRA treatment resulted in decreases in the levels of the oxidative stress markers thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine by 27% and 59%, respectively, after 2 weeks. CRA treatment also reduced the levels of myeloperoxidase markers, 3-nitrotyrosine and 3-chlorotyrosine by 38% and 39%, respectively, after 10 weeks, and tended to decrease the levels of high sensitivity C-reactive protein, a marker of inflammation, after 6 weeks. However, CRA had no effect on weight gain or hyperglycemia. These results demonstrate that CRA can ameliorate hypertension, abnormal lipid metabolism, and oxidative stress as well as the inflammatory state in SHR-cp rats. This implies that CRA can be beneficial for preventing atherosclerosis-related diseases that are an increasing health care problem worldwide.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Deoxyguanosine; Disease Models, Animal; Fatty Acids, Nonesterified; Hypertension; Inflammation; Insulin; Male; Metabolic Syndrome; Molecular Structure; Musa; Oxidative Stress; Phytotherapy; Plant Extracts; Rats; Rats, Inbred SHR; Thiobarbituric Acid Reactive Substances; Triglycerides; Triterpenes; Tyrosine

Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mm to cells differentiated at 25 mm glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mm glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by co-infusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.

Topics: 3T3-L1 Cells; 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Adenoviridae; Adipocytes; Animals; Blotting, Northern; Cell Differentiation; Deoxyguanosine; Diabetes Mellitus, Experimental; Dicarboxylic Acid Transporters; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glucose; Hyperglycemia; Immunoblotting; Inflammation; Insulin; Interleukin-6; Membrane Potentials; Mice; Mitochondria; Oxidative Stress; Oxygen; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Streptozocin; Time Factors; Transcription, Genetic; Up-Regulation

TGF-beta1, which is one of the profibrogenic cytokines, is considered essential for both the tubulointerstitial fibrosis found in chronic kidney diseases and the repair of tissue damage in acute renal injury. Iron plays an important part in inflammatory damage since it supplies cytotoxic hydroxyl radicals. The aim of the present study was to examine the direct effects of iron on TGF-beta1 production and the expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, by human renal proximal tubular epithelial cells (RPTEC).. Using human RPTEC, TGF-beta1 expression was studied by immunohistochemical staining, ELISA and RNase protection assays. 8-OHdG expression was evaluated by immunohistochemical staining.. Ferric iron suppressed both TGF-beta1 secretion and mRNA expression, and enhanced 8-OHdG expression in RPTEC in a dose-dependent manner. Desferrioxamine, an iron chelator, eliminated the suppressive effect of ferric citrate on TGF-beta1 production.. The results suggest that iron may delay the repair of kidney injury during the acute inflammatory phase via a reduction in TGF-beta1 production by RPTEC. Iron chelation may therefore be a useful strategy in the treatment of inflammatory kidney diseases.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Cell Culture Techniques; Deoxyguanosine; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Fibrosis; Humans; Hydroxyl Radical; Immunohistochemistry; Inflammation; Iron; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Oxidants; Oxidative Stress; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Oxidative stress caused by chronic lung inflammation in patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa is characterized by the reactive oxygen species (ROS) liberated by polymorphonuclear leukocytes (PMNs). We formulated the hypothesis that oxidation of the bacterial DNA by ROS presents an increased risk for the occurrence of hypermutable P. aeruginosa. The occurrence of hypermutable P. aeruginosa isolates was investigated directly in the sputum of 79 CF patients and among 141 isolates collected from 11 CF patients (10 to 15 isolates/patient) collected from the 1st and up to the 25th year of their chronic lung infection. The level of oxidized guanine moiety 8-oxo-2'-deoxyguanosine (8-oxodG), which is a frequently investigated DNA oxidative lesion, was measured. Hypermutable P. aeruginosa isolates were found in the sputum bacterial population of 54.4% of the CF patients. The earliest mutator P. aeruginosa isolates were found after 5 years from the onset of the chronic lung infection, and once they were present in the CF lung, the prevalence increased with time. The hypermutable isolates were significantly more resistant to antipseudomonal antibiotics than nonhypermutable isolates (P

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Anti-Bacterial Agents; Chronic Disease; Cross-Sectional Studies; Cystic Fibrosis; Deoxyguanosine; Drug Resistance, Bacterial; Humans; Inflammation; Lung Diseases; Mutation; Oxidative Stress; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum

Nucleic acid damage by reactive nitrogen and oxygen species may contribute to inflammation-related carcinogenesis. To investigate the extent of nucleic acid damage in hepatitis C virus infection and its change after interferon treatment, we measured 8-nitroguanine and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the liver of patients with chronic hepatitis C (CHC) before and after interferon therapy.. Hepatic accumulation of 8-nitroguanine and 8-OHdG was immunohistochemically evaluated in 20 CHC patients and 7 control patients with non-alcoholic fatty liver.. Immunoreactivities of 8-nitroguanine and 8-OHdG were strongly detected in the liver from patients with CHC, but not in control livers. 8-Nitroguanine accumulation was found not only in infiltrating inflammatory cells, but also hepatocytes particularly in the periportal area. The accumulation of 8-nitroguanine and 8-OHdG increased with inflammatory grade (8-nitroguanine; P = 0.0019, 8-OHdG; P = 0.0009). In the sustained virological responder group after interferon therapy, 8-nitroguanine and 8-OHdG accumulation were markedly decreased in the liver (8-nitroguanine; P = 0.018, 8-OHdG; P = 0.018).. In this study, we demonstrated for the first time that 8-nitroguanine accumulated in the liver of patients with CHC. 8-Nitroguanine is a useful biomarker to evaluate the severity of HCV-induced chronic inflammation in relation to hepatocellular carcinoma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Carcinoma, Hepatocellular; Deoxyguanosine; DNA Damage; Female; Guanine; Hepatitis C, Chronic; Humans; Inflammation; Liver; Liver Neoplasms; Male; Middle Aged; Reactive Oxygen Species

Oxidative stress contributes to ischemia/reperfusion neuronal damage in a consecutive 2-phase pattern: an immediate direct cytotoxic effect and subsequent redox-mediated inflammatory insult. The present study was designed to assess the neuroprotective mechanisms of edaravone, a novel free radical scavenger, through antioxidative and anti-inflammatory pathways, from the early period to up to 7 days after ischemia/reperfusion in mice.. Mice were subjected to 60-minute ischemia followed by reperfusion. They were divided into the edaravone group (n=72; with different schedules for first administration) and the vehicle (control) group (n=36). Infarct volume and neurological deficit scores were evaluated at several time points after ischemia. Immunohistochemical analysis for 4-hydroxy-2-nonenal (HNE), 8-hydroxy-deoxyguanosine (8-OHdG), ionized calcium-binding adapter molecule 1 (Iba-1), inducible NO synthase (iNOS), and nitrotyrosine were performed at 24 hours, 72 hours, or 7 days after reperfusion.. Edaravone, even when administrated 6 hours after onset of ischemia/reperfusion, significantly reduced the infarct volume (68.10+/-6.24%; P<0.05) and improved the neurological deficit scores (P<0.05) at 24 hours after reperfusion. Edaravone markedly suppressed the accumulation of HNE-modified protein and 8-OHdG at the penumbra area during the early period after reperfusion (P<0.05) and reduced microglial activation, iNOS expression, and nitrotyrosine formation at the late period.. Our results indicated that edaravone exerts an early neuroprotective effect through the early free radicals scavenging pathway and a late anti-inflammatory effect and suggested that edaravone is important for expansion of the therapeutic time window in stroke patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Anti-Inflammatory Agents; Antioxidants; Antipyrine; Brain; Brain Ischemia; Deoxyguanosine; DNA Damage; Edaravone; Electrophoresis, Polyacrylamide Gel; Free Radical Scavengers; Immunoblotting; Immunohistochemistry; Inflammation; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Reperfusion Injury; Time Factors; Tyrosine

Inflammation has been postulated as a risk factor for several cancers. 3-Nitrotyrosine is a biochemical marker for inflammation. We investigated the ability of nitrotyrosine and nitrotyrosine-containing peptides (nitroY-peptide) to induce DNA damage by the experiments using 32P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and an HPLC-electrochemical detector. Nitrotyrosine and nitroY-peptide caused Cu(II)-dependent DNA damage in the presence of P450 reductase, which is considered to yield nitroreduction. Catalase inhibited DNA damage, suggesting the involvement of H2O2. Nitrotyrosine and nitroY-peptide increased 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, an indicator of oxidative DNA damage. Nitrotyrosine-containing peptides of histone induced 8-oxodG formation more efficiently than free nitrotyrosine. We propose the possibility that nitrotyrosine-induced H2O2 formation and DNA damage contribute to inflammation-associated carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Copper; Deoxyguanosine; DNA; DNA Damage; Free Radical Scavengers; Humans; Inflammation; NADP; NADPH-Ferrihemoprotein Reductase; Oxidative Stress; Phenanthrolines; Tyrosine

Both Helicobacter pylori (Hp) and bile acids are gastric carcinogens. An experimental model of duodenogastric reflux in Mongolian gerbils was developed and was used to study the effects of Hp infection and duodenogastric reflux on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced glandular stomach tumorigenesis independently and synergistically. Male Mongolian gerbils underwent both inoculation with Hp, and had duodenogastric reflux (DR) induced, or neither, followed by MNNG administration. Animals were sacrificed at week 40, and histopathological examination of their excised stomachs and serological investigation were performed. Glandular stomach adenocarcinomas were observed in animals that underwent Hp inoculation and/or induction of DR after MNNG administration, and glandular stomach adenomas were found in animals inoculated with Hp after MNNG administration. The incidence of glandular stomach tumors was significantly higher in animals inoculated with Hp after MNNG administration and in animals undergoing combined Hp inoculation, DR induction and MNNG administration than in animals only administered MNNG. These findings indicate that Hp infection has a stronger tumorigenic effect than the exposure to duodenal contents, and duodenal contents may attenuate the effect of Hp on glandular stomach tumorigenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Deoxyguanosine; Duodenogastric Reflux; Gastrointestinal Contents; Gerbillinae; Helicobacter Infections; Inflammation; Male; Methylnitronitrosoguanidine; Mongolia; Neoplasms, Glandular and Epithelial; Stomach Neoplasms

Reactive oxygen species are generated in many types of inflammation; it is unclear, however, if inflammation leads to oxidative damage of DNA, proteins and lipids within the inflamed tissues. In this study, we used mice that are homozygous for the alymphoplasia (aly) mutation as a model to determine if inflammation induces oxidative damage in liver and pancreas. We found that 8-hydroxy-2'-deoxyguanosine (8OHdG), which is a product of oxidative DNA damage, increases with age in livers and pancreata of C57BL/6aly/aly (aly/aly) and C57BL/6 wild type (WT) mice. The 8OHdG levels in liver, but not in pancreas, of aged aly/aly mice were significantly higher than those in age-matched WT mice. We showed that aging enhances oxidative protein damage, as measured by carbonylated protein contents, in the pancreata of WT but not aly/aly mice. In contrast, neither aging nor inflammation was associated with lipid damage, as measured by thiobarbituric acid-reactive substances (TBARS), in aly/aly or WT mice. Our results indicate that chronic inflammation in liver but not pancreas leads to increased oxidative damage to DNA, but not to lipids and proteins in aly/aly mouse model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Autoimmune Diseases; Deoxyguanosine; Disease Models, Animal; DNA Damage; Inflammation; Liver; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Oxidative Stress; Placenta; Proteins

Inflammation mediated by infection is an important factor causing carcinogenesis. Opisthorchis viverrini (OV) infection is a risk factor of cholangiocarcinoma (CHCA), probably through chronic inflammation. Formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) were assessed in the liver of hamsters infected with OV. We newly produced specific anti-8-nitroguanine antibody without cross-reaction. Double immunofluorescence staining revealed that 8-oxodG and 8-nitroguanine were formed mainly in the same inflammatory cells and epithelium of bile ducts from day 7 and showed the strongest immunoreactivity on days 21 and 30, respectively. It is noteworthy that 8-oxodG and 8-nitroguanine still remained in epithelium of bile ducts on day 180, although amount of alanine aminotransferase activity returned to normal level. A time course of 8-nitroguanine was associated with iNOS expression. Furthermore, this study demonstrated that HO-1 expression and subsequent iron accumulation may be involved in enhancement of oxidative DNA damage in epithelium of small bile ducts. In conclusion, nitrative and oxidative DNA damage via iNOS expression in hamsters infected with OV may participate in CHCA carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cholangiocarcinoma; Cricetinae; Deoxyguanosine; Disease Models, Animal; DNA Damage; Gene Expression Regulation; Guanine; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Inflammation; Liver; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Opisthorchiasis; Opisthorchis; Oxidation-Reduction

Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells--predominantly endothelial and type II epithelial cells--as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Apoptosis; Bronchoalveolar Lavage; Deoxyguanosine; DNA-Binding Proteins; Emphysema; Epithelial Cells; Genetic Predisposition to Disease; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Lung; Mice; Mice, Inbred ICR; Mice, Transgenic; Microscopy, Fluorescence; NF-E2-Related Factor 2; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Phenotype; Pulmonary Alveoli; Smoking; Time Factors; Trans-Activators; Transcription, Genetic; Up-Regulation

QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day -2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin beta(2) knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2'-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antibodies, Monoclonal; Blood Cells; CD18 Antigens; Cell Line, Tumor; Complement System Proteins; Cytotoxicity, Immunologic; Deoxyguanosine; Disease Progression; Drug Administration Schedule; Fibrosarcoma; Granulocytes; Immunohistochemistry; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Neutrophil Infiltration; Neutrophils; Phenotype; Time Factors; Tyrosine

Hypohalites (OCl-, OBr-) are formed at inflammation sites as antimicrobial agents. OCl- is also used for the disinfection of water supplies and the association of drinking chlorinated water with cancer risk is pointed out. In this study, OCl- itself induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, while OBr- damaged DNA only when glutathione (GSH) was added. OCl- caused oxidative DNA damage more efficiently than OBr-/GSH. In experiment with 32P-labeled DNA fragments, OCl- strongly caused piperidine-labile sites at guanine residues than piperidine-inert 8-oxodG, whereas OBr-/GSH caused no piperidine-labile sites. Endogenous OCl- may play a role in genotoxicity close to the site of inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bromates; Carcinogens; Cattle; Cell Line; Deoxyguanosine; Dimethyl Sulfoxide; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Genes, p53; Genes, ras; Genes, Tumor Suppressor; Glutathione; Humans; Inflammation; Neoplasms; Oxidation-Reduction; Phosphorus Isotopes; Piperidines; Sodium Hypochlorite

Reperfusion injury is considered primarily an inflammatory response to oxidative stress. In vitro, oxygen free radicals induce the formation of oxidized phospholipids with platelet-activating factor (PAF) activity (PAF-like lipids). We examined the following: 1) whether PAF and PAF-like lipids are released during reperfusion; 2) the relationship between these phospholipids and oxidative damage on the one hand, and leukocyte recruitment in renal tissue on the other; and 3) whether antioxidant treatment influences the behavior of these phospholipids, the renal inflammatory response, and the outcome of postischemic acute renal failure. After 60 min of warm renal ischemia in rabbits, a release of PAF and, particularly, PAF-like lipids was seen in the first 15 min of reperfusion. In addition, the release of those phospholipids was associated with intense tissue DNA oxidation and with an increase in myeloperoxidase activity. Vitamin C was able to attenuate these postischemic oxidative changes, decrease PAF and PAF-like lipid levels, and, consequently, reduce myeloperoxidase activity. After 40 min of warm renal ischemia in rats, vitamin C treatment ameliorated renal function and structure. This is the first in vivo demonstration of the release of phospholipid oxidation products as part of an oxidative-inflammatory response after renal ischemia-reperfusion, with the release of phospholipid oxidation products significantly reduced by antioxidant treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Ascorbic Acid; Creatinine; Deoxyguanosine; DNA Damage; Inflammation; Ischemia; Kidney; Lipoproteins, LDL; Oxidative Stress; Platelet Activating Factor; Rabbits; Rats

The present study investigated the interaction between inflammatory reactions and benzene in vitro and in vivo with respect to oxidative DNA damage. In the in vitro models the oxidative burst of cells was induced by the pretreatment with phorbol myristate acetate (PMA) and in the in vivo models of inflammation mice were pretreated with lipopolysaccharide (LPS). The oxidative DNA damage was indicated by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and strand breaks as assessed by alkaline single cell gel electrophoresis (SCGE, Comet assay). The results showed that combination of PMA and benzene enhanced the level of 8-oxodG in DNA from mouse bone marrow cells by 197%, from human lymphocytes by 188% and from human neutrophils by 205% (p < .05). Pretreatment of mice with LPS and benzene resulted in an enhanced Comet score formation in bone marrow cells by 98% and in lymphocytes by 39% in Comet score (p < .05) and in an enhanced 8-oxodG level in bone marrow cells by 290%. The effects of the combined treatment with PMA/LPS and benzene exceeded the sum of the effects induced by PMA/LPS or benzene alone. The production of nitrate/nitrite showed a two fold increase in the supernatant from incubation of benzene and PMA-pretreated neutrophils. The increase in the 8-oxodG level in the human neutrophil incubation system demonstrated a correlation with nitrate/nitrite production, indicating a possible relationship with the generation of reactive nitrogen species.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Benzene; Bone Marrow Cells; Cells, Cultured; Deoxyguanosine; DNA Damage; Humans; Inflammation; Lipopolysaccharides; Lymphocytes; Mice; Neutrophils; Nitrates; Nitrites; Reactive Oxygen Species

The effect of metabolic activation of the food additive 3-tert-butyl-4-hydroxyanisole (BHA) by prostaglandin H synthase on the gastro-intestinal cell proliferation was determined by studies of the nature and the time dependency of early lesions in the forestomach, glandular stomach and colon/rectum of rats given BHA with and without co-administration of acetylsalicyclic acid (ASA: an inhibitor of prostaglandin H synthase), in combination with the formation of oxidative DNA damage in the epithelial cells of glandular stomach and colon/rectum as well as in the liver. BHA appeared to be a strong inducer of oxidative DNA damage in the epithelial cells of the glandular stomach, increasing the level of 7-hydro-8-oxo-2'deoxyguanosine (8-oxodG) with increasing duration of BHA administration. Similar observations were made in colorectal DNA although levels of oxidative DNA damage tend to be smaller. In liver DNA, BHA appeared to be capable of increasing background 8-oxodG levels only after 14 days of treatment. This relatively slow response may be related to very low prostaglandin H synthase activity of liver cells. The severity of hyperplasia and inflammation in both forestomach and glandular stomach appeared to increase gradually with continued BHA administration. The hyperplasia induced by BHA was paralleled by inflammatory changes. In colorectal tissue, however, no tissue abnormalities were observed. This indicates that oxidative DNA damage induced by BHA is not a consequence of early lesions in gastro-intestinal epithelium, but might be the initial step in the stimulation of gastro-intestinal cell proliferation which, as shown previously, also occurs in colon epithelium. Co-administration of the prostaglandin H synthase inhibitor ASA resulted in a significant decrease of both epithelial oxidative DNA damage and the incidence of lesions, which indicates that this enzyme system is involved in the enhancement of cellular proliferation induced by BHA. Co-oxidation by prostaglandin H synthase of the BHA-metabolite tert-butylhydroquinone into tert-butylquinone, yielding active oxygen species, might therefore be responsible for the carcinogenic effects of this food antioxidant.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Aspirin; Biotransformation; Butylated Hydroxyanisole; Cell Division; Colon; Cyclooxygenase Inhibitors; Deoxyguanosine; Digestive System; DNA Damage; Dose-Response Relationship, Drug; Drug Interactions; Epithelium; Food Additives; Hyperplasia; Inflammation; Liver; Male; Oxidation-Reduction; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Reactive Oxygen Species; Rectum; Stomach