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Oxidative stress generated nucleoside damage seems to represent key pathophysiological mechanisms of bipolar disorder (BD). Likewise, mood and activity are core features of BD and can be reliably monitored using smartphone-based applications. The aim was to investigate whether oxidative stress generated nucleoside damage could reflect psychopathology in BD using easily available and non-invasive patient-reported smartphone-based symptoms. We included 223 patients newly diagnosed with BD and employed linear mixed-effect regression models to associate baseline measurements of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels with patient-reported smartphone measures of mood, activity, anxiety, stress and sleep duration monitored three days prior to and 30 days after the baseline visit in the longitudinal Bipolar Illness Onset Study. In patients newly diagnosed with BD higher 8-oxoGuo levels were inversely associated with the patient-reported activity level (B = 0.953, 95%CI = 0.909;0.99, p = 0.043) and positively associated with patient-reported anxiety (B = 1.104, 95%CI = 1.022;1.161, p=0.012), perceived stress (B = 1.092, 95%CI = 1.009;1.183, p = 0.014) and sleep duration (B = 1.000, 95%CI = 1.000;1.001, p = 0.001), respectively, in analyses, adjusted for sex and age. The associations between 8-oxoGuo levels and anxiety, perceived stress and sleep duration, respectively, withstood adjustment for sex, age, smoking, BMI and alcohol intake. No associations between 8-oxodG levels and patient-reported smartphone-based data were found and mood was not associated with 8-oxoGuo. Oxidative stress was associated with patient-reported smartphone-based data on activity, anxiety, stress and sleep duration pointing towards that oxidative stress generated nucleoside damage may reflect ongoing psychopathology in BD.

Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders.To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum.The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed.Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility.The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses.The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids.Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis.The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes. Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes.

Enhanced oxidative stress-generated nucleoside damage may contribute to the increased cardiovascular disease mortality in patients with bipolar disorder (BD) but the association has never been investigated. We investigated the associations between oxidative stress-generated damage to DNA (8-oxodG) and RNA (8-oxoGuo), respectively, and three measures reflecting cardiovascular risk; namely, the Framingham 30-year risk score of cardiovascular diseases, the metabolic syndrome, and the insulin resistance index in 360 patients newly diagnosed with BD, 102 of their unaffected relatives (UR) and 197 healthy control individuals (HC). In sex- and age-adjusted models, the 30-year cardiovascular risk score increased by 20.8% (CI = 7.4–35.9%, p = 0.002) for every one nM/mM creatinine increase in 8-oxoGuo and by 15.6% (95% CI = 5.8–26.4%, p = 0.001) for every one nM/mM creatinine increase in 8-oxodG, respectively. Further, insulin resistance index increased by 24.1% (95% CI = 6.7–43%, p = 0.005) when 8-oxoGuo increased one nM/mM creatinine. The associations between cardiovascular measures and oxidative nucleoside damage were more pronounced in patients with BD compared with UR, and HC. Metabolic syndrome was not associated with nucleoside damage. Overall, higher oxidative stress-generated nucleoside damage was associated with a higher cardiovascular risk score and a higher degree of insulin resistance index, and having BD impacted the associations. Further, within patients, treatment with psychotropics seemed to enhance the associations between 30-year CVD risk score and insulin resistance index, respectively, and oxidatively stress-generated nucleoside damage. Our findings support enhanced oxidative stress-generated nucleoside damage as a putative pathophysiological mechanism that may mediate the higher cardiovascular risk observed in patients with BD already at the time of diagnosis.

Accumulating evidence supports the popular notion that psychological stress states may accelerate aging. Stress has been shown to influence cellular systems known to be involved in the aging process. Furthermore, stress is associated with an increased risk of various age-related medical disorders. These effects are likely mediated by the secretion of stress hormones. In this short review we focus on biochemical and epidemiological evidence for a link between stress and aging.

Of the DNA-derived biomarkers of oxidative stress, urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the most frequently measured. However, there is significant discrepancy between chromatographic and immunoassay approaches, and intratechnique agreement among all available chromatography-based assays and ELISAs is yet to be established. This is a significant obstacle to their use in large molecular epidemiological studies. To evaluate the accuracy of intra/intertechnique and interlaboratory measurements, samples of phosphate buffered saline and urine, spiked with different concentrations of 8-oxoG, together with a series of urine samples from healthy individuals were distributed to ESCULA members. All laboratories received identical samples, including 2 negative controls that contained no added 8-oxodG. Data were returned from 17 laboratories, representing 20 methods, broadly classified as mass spectrometric (MS), electrochemical detection (EC), or enzyme-linked immunosorbant assay (ELISA). Overall, there was good within-technique agreement, with the majority of laboratories' results lying within 1 sd of their consensus mean. However, ELISA showed more within-technique variation than did the chromatographic techniques and, for the urine samples, reported higher values. Bland-Altman plots revealed good agreement between MS and EC methods but concentration-dependent deviation for ELISA. All methods ranked urine samples according to concentration similarly. Creatinine levels are routinely used as a correction factor for urine concentration, and therefore we also conducted an interlaboratory comparison of methods for urinary creatinine determination, in which the vast majority of values lay within 1 sd of the consensus value, irrespective of the analysis procedure. This study reveals greater consensus than previously expected, although concern remains over ELISA.-ESCULA [European Standards Committee on Urinary (DNA) Lesion Analysis], Evans, M. D., Olinski, R., Loft, S., Cooke, M. S. Toward consensus in the analysis of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine as a noninvasive biomarker of oxidative stress. Some of the authors of this paper are partners in, and this work was partly supported by, ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a Network of Excellence operating within the European Union 6th Framework Program, Priority 5: Food Quality and Safety (contract 513943)

Inflammation and endothelial activation are associated with an increased risk of CVD and epidemiological evidence suggests an association between levels of markers of inflammation or endothelial activation and the intake of fruit. Also, vitamin E, a fat-soluble antioxidant, has anti-inflammatory properties. We performed a randomised 2 × 2 factorial, crossover trial to determine the effect of orange and blackcurrant juice (500 ml/d) and vitamin E (15 mg RRR-α-tocopherol/d) supplementation on markers of inflammation and endothelial activation in forty-eight patients with peripheral arterial disease. Patients were randomly allocated to two dietary supplements from the four possible combinations of juice and vitamin E: juice+vitamin E; juice+placebo; reference beverage (sugar drink)+vitamin E; and reference beverage+placebo. The supplementations were given for 28 d, separated by a 4-week wash-out period. Analysis of main effects showed that juice decreased C-reactive protein (CRP) by 11 % and fibrinogen by 3 % while the reference drink increased CRP by 13 % and fibrinogen by 2 % (P P

Restriction of energy intake (ER), without malnutrition of essential nutrients, has repeatedly been demonstrated to increase longevity in rodents. In the antioxidant theory of aging the lack of balance between the generation of free radicals and free radical scavenging was thought to be a main causal agent, in the aging process. From this point of view the antiaging effect induced by ER might be due to the lower rate of free-radical production and related damage induced by a lower metabolic rate. The antiaging effects of ER might also occur in humans. This study explored the effects of a 10-week moderately energy-restricted diet (80% of habitual) in 24 non-obese middle-aged men (16 ER subjects, 8 controls) on resting metabolic rate (RMR) and indicators of the primary antioxidant defense system, oxidative stress and genotoxicity. RMR decreased significantly in both groups, even when adjustments were made for the change in body composition. The increase in blood vitamin C concentration correlated with the increase in urinary 8-hydroxydeoxyguanosine (80HdG) excretion. The change in urinary 80HdG excretion also correlated with the change in RMR per kg fat-free mass. No differences between groups were found for changes in indicators of genotoxicity, erythrocyte catalase, glutathione peroxidase and superoxide dismutase activity and in plasma vitamin E, A or beta-carotene concentrations. We conclude that 10 weeks of moderate ER did not affect indicators of antioxidative capacity, oxidative stress and genotoxicity of humans. Since subjects were not in energy balance at the end of the study, no conclusions can be made with respect to long-term effects.

The cancer-preventive effect of energy restriction in rodents has been related to a decrease in oxidative damage to DNA. We have investigated the effect of energy restriction on the rate of oxidative DNA modification estimated from the urinary excretion of the repair product, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), in healthy, normal weight men. Before and after 10 weeks on a diet containing 80 (n = 16) or 100% (n = 8) of the estimated weight-maintaining energy, resting metabolic rate (RMR) was measured and 24-h urine was collected for 8-oxodG determination by HPLC. During the study, the weight loss was 10 and 2.5% of the initial weight, mostly in terms of fat, and the RMR decreased by 13 and 8% in the energy-restricted and control groups, respectively. With the use of t tests there was no significant difference within or between groups with respect to 8-oxodG excretion. However, if RMR was included as a covariate in multifactorial ANOVA, an average relative 17% (2-31%; 95% confidence interval) increase in 8-oxodG excretion in the energy-restricted group was significantly different from the corresponding value of the control group (P0.02). In the energy-restricted group the change in 8-oxodG excretion was correlated closely with the decrease in RMR (r = 0.63; P = 0.013). In the present study, 20% energy restriction for 10 weeks did not reduce oxidative DNA damage; we question a beneficial effect on cancer risk in normal weight humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactive oxygen species (ROS) are generated from incomplete reduction in the respiratory chain. On one hand they pose a serious threat of deleterious effects on important macromolecules, among which DNA is considered most important since it carries the genetic information and changes will be carried on to future generations, or will fundamentally change the behaviour of the cells. On the other hand, it is becoming evident that there are important changes in the cells in response to redox changes. This review summarises the genes, the intracellular signalling elements and molecules that presently are known to be regulated by oxidative stress. It is now clear that both oxidants and antioxidants can regulate a multitude of different cellular functions, signal transduction pathways and gene expression. However, the quantitative importance is unknown and as of yet there are no examples of regulation exclusively by oxidative stress. Also the response to oxidative stress is variable, can be up-regulation as well as down-regulation, and different responses to dose or magnitude of the oxidative stress can be demonstrated. The effect from supplementation with an antioxidant is difficult to predict, and ultimately must be assessed in clinical trials.

Normal aerobic metabolism produces huge amounts of potentially dangerous oxidants, controlled by a variety of antioxidant systems. An imbalance between the generated and exogenously inflicted oxidants and the oxidant system is termed oxidative stress. Even without oxidative stress, i.e. under normal physiological conditions, the damage to vital cellular micromolecules, such as DNA, is extensive, amounting to hundreds of hits per cell per day. More than one hundred different oxidative modifications in DNA have been described. The hydroxylation of guanine in the 8-position is the most frequent and most mutagenic lesion described. The 8-hydroxylation of guanine leads to lack of base pairing specifically and misreading of the modified base and adjacent residues. The modifications to DNA are so frequent that extensive and specific repair is needed for survival. Indeed, multiple repair enzyme systems to mediate and remove/repair oxidative DNA modification are described. Within DNA, hot-spots of oxidative modification and subsequent mutation have been described, and some specificity appears as compared to other agents that can lead to modification of DNA, i.e. aflatoxin and benzo[a]pyrene. Numerous publications from epidemiology and intervention studies with antioxidants point at oxidative modification as an important factor in cancer development at certain sites. Yet, direct evidence linking oxidative DNA modification to cancer has not been published. With regard to antoxidant prevention of cancer no effective single substance has so far been identified.