Peripheral dopamine suppression and elevated cystatin C in early diabetic nephropathy in spontaneously diabetic rats.

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with renal-specific catechol-O-methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, although dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we orally administered 10 mg/kg benserazide, a peripheral decarboxylase inhibitor, to spontaneously diabetic Torii rats daily to investigate the activation of the renal dopaminergic system during the progression of diabetic nephropathy. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F2α and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance.NEW & NOTEWORTHY By administering a peripheral decarboxylase inhibitor, we revealed that peripheral dopamine inhibits both the increase in urinary 8-iso-prostaglandin F2α, an oxidative stress marker, and the increase in plasma cystatin C, an early renal dysfunction marker, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration. By visualizing renal dopamine precursor distribution, we highlighted the role of endogenous renal dopamine in oxidative stress and renal function following the onset of glomerular hyperfiltration.

Associations between urinary level of bisphenol A, phthalates, 8-iso-prostaglandin-F2α, and emotional and behavioral problems among Chinese adolescents.

BACKGROUND: Emotional and behavioral problems (EBPs) of adolescents is a worldwide public health problem. Bisphenol A (BPA) and phthalate (PAEs) are prevalent and potentially toxic to human health. Therefore, this study aimed to investigate the associations between urinary level of BPA, PAEs, 8-iso-prostaglandin-F2α (8-iso-PGF2α), and EBPs. METHODS: A total of 865 Chinese adolescents were included in this study and EBPs was assessed using the Strengths and Difficulties Questionnaire (SDQ). Urinary concentrations of BPA and seven PAEs metabolites in adolescents were determined by high performance liquid chromatography-tandem mass spectrometry. Urinary 8-iso-PGF2α concentration was detected by enzyme-linked immunosorbent assay (ELISA). Spearman rank correlation analysis, multivariate logistic regression analysis, restricted cubic spline functions were used to explore the relationship between the levels of BPA, PAEs, 8-iso-PGF2α and EBPs. RESULTS: BPA and PAEs metabolites were positively associated with EBPs in Chinese adolescents. And the 8-iso-PGF2α was significantly non-linearly correlated with emotional symptoms, conduct problems, peer problems and total difficulties. Furthermore, 8-iso-PGF2α may partially mediate the association between BPA and PAEs exposure and EBPs. LIMITATIONS: This study was a cross-sectional study, the cause-effect relationship between BPA, PAEs exposure and EBPs could not be determined. A single spot urine sample for BPA and PAEs exposure characterization maybe could not represent their long-term exposure level. CONCLUSIONS: High exposure of BPA and PAEs are associated with EBPs, which may be partly mediated by oxidative stress among adolescents. The results of this study could provide certain ideas for subsequent related research.

8-Iso-prostaglandin F2α as a biomarker of type 2 low airway inflammation and remodeling in adult asthma.

BACKGROUND: Although 8-iso-prostaglandin F2a has been proposed as a potential biomarker for oxidative stress in airway diseases, its specific role in asthma remains poorly understood. OBJECTIVE: To evaluate the diagnostic potential of 8-iso-prostaglandin F2a in assessing airway inflammation, airway remodeling, airway hyperresponsiveness, and oxidative stress in asthma. METHODS: Blood and urine concentrations of 8-iso-prostaglandin F2a were quantified using liquid chromatography-tandem mass spectrometry in 128 adults with asthma who had maintained antiasthma medications. Their correlations with clinical data, sputum cell counts, lung function parameters, and serum markers of epithelial/neutrophil activity and airway remodeling were then analyzed. RESULTS: The urinary 8-iso-prostaglandin F2a concentrations were significantly higher in patients with noneosinophilic asthma than in those with eosinophilic asthma (P < .05). The area under the curve was 0.678, indicating moderate diagnostic accuracy for noneosinophilic asthma. There were significant correlations with neutrophilic inflammation markers and airway remodeling markers (all P < .05). Negative correlations were observed with forced expiratory volume in 1 second (%), forced expiratory volume in 1 second/forced vital capacity, forced expiratory flow at 25% to 75% of forced vital capacity, and serum club cell protein 16 levels (all P < .05). High 8-iso-prostaglandin F2a concentrations were also noted in obese and smoking subgroups (all P < .05). However, the serum 8-iso-prostaglandin F2a concentrations were not correlated with these asthma-related parameters. CONCLUSION: Urinary 8-iso-prostaglandin F2a concentrations are a potential biomarker for phenotyping severe asthma, particularly noneosinophilic asthma, offering oxidative stress-induced epithelial inflammation/remodeling as an additional target in asthma management.

The influence of physical activity, body mass index and urinary levels of prostaglandin (PGF2α) with the incidence of primary dysmenorrhea in adolescents.

OBJECTIVE: This study aims to investigate the effect of physical activity, body mass index (BMI), and levels of prostaglandins (PGF2α) urine on the occurrence of dysmenorrhea in adolescents. METHODS: A total of 128 female students included in the study. The study was conducted from January to March 2023 using a cross-sectional design. This study utilized the Menstrual Symptom Questionnaire (MSQ) and gynecological examination with ultrasonography. The urinary prostaglandin (PGF2α) was measured using the enzyme linked immuno sorbent assay (ELISA). Data were analyzed using the chi-square test and logistic regression test. RESULTS: The age range of the participants included in the study was 14-17, with a mean age of 15.85 ± 0.65. There was an correlation between physical activity, BMI, and urinary prostaglandin (PGF2α) levels with the incidence of dysmenorrhea in adolescents (p < 0.001). In multivariate analysis, it revealed that underweight, and had a high urinary prostaglandin significant correlated to primary dysmenorrhea with odds ratio 4.78 (95% confidence interval [CI] 1.98-11.54) and 4.88 (95% CI 1.98-12.08), respectively. High physical activity and overweight was not associated with incidence of dysmenorrhea in adolescents. CONCLUSION: This study provides valuable insights into the correlation between physical activity, BMI, and levels of prostaglandins (PGF2α) in urine. A high level of urinary prostaglandin was found to be the most influential factor in the incidence of primary dysmenorrhea in adolescents. By addressing factors associated with dysmenorrhea in adolescents, healthcare professionals can potentially enhance well-being by reducing menstrual pain and encouraging a healthy lifestyle to prevent dysmenorrhea.

Lipid peroxidation mediates the association between iron overload and liver injury: cross-sectional and longitudinal analyses in general Chinese urban adults.

Iron overload has been associated with acute/chronic organ failure, but whether iron overload induces liver injury remains unclear. The objectives of this study were to assess the relationship between urinary iron and serum alanine aminotransferase (ALT, a biomarker for liver injury), and investigate the potential mediating roles of lipid peroxidation and oxidative DNA damage in such association. Levels of urinary iron, serum ALT, and urinary biomarkers of lipid peroxidation (8-iso-prostaglandin-F2α [8-iso-PGF2α]) and oxidative DNA damage (8-hydroxy-deoxyguano-sine [8-OHdG]) were measured among 5386 observations of 4220 participants from the Wuhan-Zhuhai cohort. The relationships of urinary iron with serum ALT and risk of hyperALT were evaluated by linear mixed model and logistic regression model, respectively. The mediating roles of 8-iso-PGF2α and 8-OHdG were assessed by mediation analyses. This cross-sectional analysis found that urinary iron was positively associated with ALT (ß = 0.032; 95% CI: 0.020, 0.044) and hyperALT prevalence (OR = 1.127; 95% CI: 1.065, 1.192). After 3 years of follow-up, participants with persistent high iron levels had increased risk of developing hyperALT (RR = 3.800; 95% CI: 1.464, 9.972) when compared with those with persistent low iron levels. In addition, each 1% increase in urinary iron was associated with a 0.146% (95% CI: 0.128%, 0.164%) increase and a 0.192% (95% CI: 0.154%, 0.229%) increase in 8-iso-PGF2α and 8-OHdG, respectively. Urinary 8-iso-PGF2α (ß = 0.056; 95% CI: 0.039, 0.074) was positively associated with ALT, while the association between 8-OHdG and ALT was insignificant. Furthermore, increased 8-iso-PGF2α significantly mediated 22.48% of the urinary iron-associated ALT increment. Our study demonstrated that iron overload was significantly associated with liver injury, which was partly mediated by lipid peroxidation. Controlling iron intake and regulating lipid peroxidation may help in preventing liver injury.

Urinary oxidative stress biomarkers are associated with preterm birth: an Environmental Influences on Child Health Outcomes program study.

BACKGROUND: Preterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States. OBJECTIVE: We leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin. STUDY DESIGN: This study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F2α, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F2α (F2-IsoP-M; the major 8-iso-prostaglandin-F2α metabolite), and prostaglandin-F2α were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models. RESULTS: Approximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11-1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16-1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F2α was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94-1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis. CONCLUSION: Here, oxidative stress, as measured by 8-iso-prostaglandin-F2α, F2-IsoP-M, and prostaglandin-F2α in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

Urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of colitis-associated colorectal cancer in mice.

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E2 metabolite tetranor-PGEM and PGD2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F2 isoprostanes (F2-IsoPs), 8-iso PGF2α and 2,3-dinor-8-iso PGF2α, were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22phox). These observations suggest that urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of CAC.

Estimated 24-hour urinary sodium excretion as a risk factor for oxidative stress in Zambian adults: A cross-sectional study.

INTRODUCTION: Persistent oxidative stress predisposes to various non-communicable diseases (NCDs), whose occurrence is increasing in sub-Saharan Africa. The aim of this study was to evaluate the link between markers of oxidative stress and some risk factors for NCDs in a Zambian cohort. METHODS: We assessed oxidative stress by measuring 8-isoprostane (lipid oxidative stress) and 8-hydroxydeoxyguanosine (DNA oxidative stress). In addition, we measured mycotoxins (aflatoxin M1 and ochratoxin A), salt intake estimated from 24-hour sodium excretion calculated using the Tanaka and Kawaski formulae, and 1-hydroxypyrene (a metabolite of polycyclic aromatic hydrocarbons). Data on lifestyle risk factors were collected using questionnaires. RESULTS: Included were 244 participants; 128 (52%) were female and the median age was 48 years (IQR 39-58). The median level of 8-isoprostane was 0.13 ng/mg creatinine (IQR 0.08-0.23) while that of 8-hydroxydeoxyguanosine (8-OHdG) was 4 ng/mg creatinine (IQR 2-10). The median 24-hour sodium excretion was 21 g (IQR 16-25 g), with none being less than the 5 g recommended by WHO. Unadjusted urinary levels of 8-isoprostane were moderately correlated with 1-hydroxypyrene (Spearman r = 0.30, p<0.001) and estimated 24-hour urine sodium (Spearman r = 0.38, p<0.001). Urinary levels of 8-OHdG were not correlated with 1-hydroxypyrene, estimated 24-hour urine sodium, aflatoxin M1 or ochratoxin A (all p-values >0.05). Using logistic regression, adjusted and unadjusted 8-isoprostanes levels were associated with 1-hydroxypyrene (p = 0.02 and p = 0.001 respectively) and estimated 24-hour urine sodium method (p = 0.003 and p<0.001 respectively). However, only unadjusted 8-OHdG was associated with 1-hydroxypyrene (p = 0.03) and age (p = 0.007). CONCLUSIONS: Estimated 24-hour urinary sodium is high among Zambians and it is associated with lipid but not DNA oxidative stress. High exposure to polycyclic aromatic hydrocarbons is also associated with oxidative stress.

Oxidative damage mediates the association between polycyclic aromatic hydrocarbon exposure and lung function.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) is related to decreased lung function. However, whether oxidative damage is involved in this relationship remains unclear. This study was aimed to explore the potential mediating role of oxidative DNA or lipid damage in the association between PAH exposure and lung function. METHODS: The urinary levels of monohydroxy polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and lung function parameters were measured among 3367 participants from the baseline of the Wuhan-Zhuhai cohort. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-iso-PGF2α) were determined to evaluate the individuals' oxidative DNA and lipid damage degrees, respectively. Linear mixed models were used to investigate the associations of urinary OH-PAHs, 8-OHdG and 8-iso-PGF2α with lung function parameters. Mediation analysis was further conducted to assess the potential role of oxidative damage in the association between urinary OH-PAHs and lung function. RESULTS: Each one-percentage increase in the sum of urinary OH-PAHs, high-molecular-weight or low-molecular-weight OH-PAHs (Æ©OH-PAHs, Æ©HMW OH-PAH or Æ©LMW OH-PAHs, respectively) was associated with a 0.2152-, 0.2076- or 0.1985- ml decrease in FEV1, and a 0.1891-, 0.2195- or 0.1634- ml decrease in FVC, respectively. Additionally, significantly positive dose-response relationships of Æ©OH-PAHs, Æ©HMW OH-PAH and Æ©LMW OH-PAHs with urinary 8-OHdG or 8-iso-PGF2α, as well as an inverse dose-response relationship between urinary 8-OHdG and FVC, were observed (all P for trend < 0.05). Mediation analysis indicated that urinary 8-OHdG mediated 14.22% of the association between Æ©HMW OH-PAH and FVC. CONCLUSION: Higher levels of oxidative DNA damage might be involved in the decreased levels of FVC caused by high-molecular-weight PAH exposure.

Effect of 1,5-anhydroglucitol levels on culprit plaque rupture in diabetic patients with acute coronary syndrome.

BACKGROUND: Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of short-term postprandial glucose (PPG) excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD. However, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with acute coronary syndrome (ACS). METHODS: A total of 144 diabetic patients with ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 49 patients with plaque rupture and 95 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBG), hemoglobin A1c (HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) level was measured and corrected by creatinine clearance. RESULTS: Patients with ruptured plaque had significantly lower serum 1,5-AG levels, longer duration of diabetes, higher HbA1c and FBG levels than patients without ruptured plaque in our study population. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.421; P = 0.005) in diabetic patients with ACS. The area under the receiver-operating characteristic curve for 1,5-AG (0.658, P = 0.002) to predict plaque rupture was superior to that for HbA1c (0.587, P = 0.087). Levels of 1,5-AG were significantly correlated with urinary 8-iso-prostaglandin F2α levels (r = - 0.234, P = 0.005). CONCLUSIONS: Serum 1,5-AG may identify high risk for coronary plaque rupture in diabetic patients with ACS, which suggests PPG excursions are related to the pathogenesis of plaque rupture in diabetes.

dLLME-µSPE extraction coupled to HPLC-ESI-MS/MS for the determination of F2α-IsoPs in human urine.

Oxidative stress is a pathological condition characterized by an imbalance between body's antioxidant defenses and oxidizing agents, resulting in damage of endogenous molecules. These products can be used as markers of oxidative conditions; in particular, isoprostanes (IsoPs) come from the reaction of arachidonic acid with reactive oxygen species (ROS) and are currently defined as gold markers of oxidative stress in urine. Our main goal was the development of a reliable analytical method for the determination and quantification of the IsoPs in human urine by dispersive Liquid-Liquid Micro Extraction (dLLME) coupled with micro Solid Phase Extraction (µSPE) clean-up and HPLC-MS/MS analysis. The selected compounds are present in very small concentration in urine, furthermore, due to relevant matrix effect, they are challenging for ESI-MS/MS analysis. This approach provided selectivity and sensitivity for 8-isoprotaglandine F2α (8-iso-PGF2α), the "gold" OS marker, together with the main isomers. dLLME extraction allowed a significant enrichment factor and µSPE clean-up provided the removal of ion-suppressing compounds from the sample resulting in low matrix effect. The chromatographic separation was also challenging as the target compounds possess very similar chemical characteristics, so experimental conditions were carefully tuned. The reported method represents a useful tool for the detection of IsoPs in urine taking advantage of the combination of dLLME extraction and µSPE clean-up; overall recoveries were above 50 % and matrix effects were ≤15 %, with LOQs ranging between 0.020 and 0.060 ng mL-1. The procedure is easy to use and rapid allowing the removal of interfering compounds and matrix effect maintaining a highly sensitive determination.

Bisphenols and Oxidative Stress Biomarkers-Associations Found in Human Studies, Evaluation of Methods Used, and Strengths and Weaknesses of the Biomarkers.

Bisphenols, particularly bisphenol A (4,4'-(hexafluoroisopropylidene)-diphenol) (BPA), are suspected of inducing oxidative stress in humans, which may be associated with adverse health outcomes. We investigated the associations between exposure to bisphenols and biomarkers of oxidative stress in human studies over the last 12 years (2008‒2019) related to six health endpoints and evaluated their suitability as effect biomarkers. PubMed database searches identified 27 relevant articles that were used for data extraction. In all studies, BPA exposure was reported, whereas some studies also reported other bisphenols. More than a dozen different biomarkers were measured. The most frequently measured biomarkers were 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoprostane) and malondialdehyde (MDA), which almost always were positively associated with BPA. Methodological issues were reported for MDA, mainly the need to handle samples with caution to avoid artefact formation and its measurements using a chromatographic step to distinguish it from similar aldehydes, making some of the MDA results less reliable. Urinary 8-OHdG and 8-isoprostane can be considered the most reliable biomarkers of oxidative stress associated with BPA exposure. Although none of the biomarkers are considered BPA- or organ-specific, the biomarkers can be assessed repeatedly and non-invasively in urine and could help to understand causal relationships.

Urinary 8-isoprostane as a biomarker for oxidative stress. A systematic review and meta-analysis.

Oxidative stress is defined as an imbalance between the production and elimination of reactive oxygen species (ROS) are associated with various inflammation-related human disease. ROS can oxidize lipids, which subsequently undergo fragmentation to produce F2-isoprostanes (F2-IsoPs). Eight-isoprostane is one of the most extensively studied F2-IsoPs and the most commonly used biomarker for the assessment of oxidative stress in human studies. This urinary biomarker is quantified using either chemical or immunological techniques. A "physiological" range for 8-isoprostanes is needed to use this biomarker as a measure of excess oxidative stress originating from occupational exposures. However, ranges reported in the literature are inconsistent. We designed a standardized protocol of a systematic review and meta-analysis to assess baseline values for 8-isoprostane concentrations in urine of healthy adults and identify determinants of their inter- and intra-individual variability. We searched PubMed from journal inception and up to April 2019, and screened articles for studies containing F2-IsoPs concentrations in urine for healthy adult participants. We grouped studies in three biomarker groups: "8-isoprostane", "Isoprostanes" "15- F2t-Isoprostane". We computed geometric mean (GM) and geometric standard deviation (GSD) as the basis for the meta-analysis. Of the initial 1849 articles retrieved, 63 studies were included and 107 subgroups within these study populations were identified. We stratified the subgroups analyzed with the chemical methods by body mass index (BMI) reported. We provide pooled GM values for urinary 8-isoprostane concentrations in healthy adults, separately for chemical and immunological analysis in this review. The interquartile range (IQR) in subgroups with a mean BMI below 25 measured using chemical methods was 0.18 to 0.40 µg/g creatinine. We show that there is a significant positive association between BMI and urinary 8-isoprostane concentrations. We recommend adjusting urinary 8-isoprostane concentrations in spot urine with creatinine, quantifying 8-isoprostane with chemical analytical methods, and reporting results as median and quartiles. This will help in comparing results across studies.

Formaldehyde, Oxidative Stress, and FeNO in Traffic Police Officers Working in Two Cities of Northern Italy.

Personal air formaldehyde (air-FA) was measured as risk factor of airways inflammation and oxidative stress (SO) induction. Overall, 154 police officers were enrolled from two differently urbanised Italian cities, Turin and Pavia. Urinary F2t-isoprostane (15-F2t-IsoP), a prostaglandin-like compound, was quantified as a biomarker of general OS in vivo and fractional exhaled nitric oxide (FeNO) was measured for monitoring local inflammatory processes. Urinary cotinine was quantified as a biomarker of tobacco smoking exposure. Traffic police officers living in Turin showed an increased level of log air-FA (p < 0.001), equal to +53.6% (p < 0.001). Log air-(FA) mean values were 3.38 (C.I. 95% 3.33-3.43) and 2.84 (C.I. 95% 2.77-2.92) in Turin and Pavia, respectively. Log (air-FA) was higher in "outdoor workers" (3.18, C.I. 95% 3.13-3.24, p = 0.035) compared to "indoor workers", showing an increase of +9.3%, even controlling for sex and city. The analyses on 15-F2t-IsoP and FeNO, both adjusted for log air-FA, highlighted that OS and inflammation were higher (+66.8%, p < 0.001 and +75%, p < 0.001, respectively) in Turin traffic police officers compared to those from Pavia. Our findings suggest that even low exposures to traffic-related emissions and urbanisation may influence both general oxidative stress levels and local inflammation.

2,4-D exposure and urinary markers of oxidative DNA damage and lipid peroxidation: a longitudinal study.

OBJECTIVE: 2,4-Dichlorophenoxyacetic acid (2,4-D) is a herbicide that is commonly used commercially, agriculturally and residentially worldwide. There is concern about its potential for carcinogenicity based on studies in laboratory animals demonstrating the potential for induction of oxidative stress. We conducted a longitudinal biomarker study of 31 pesticide applicators in Kansas who heavily applied 2,4-D and 34 non-applicator controls. METHODS: We used multivariable generalised linear mixed-effect models to evaluate the association between urinary 2,4-D and natural log-transformed 8-iso prostaglandin F2α (8-isoprostane) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), adjusting for urinary creatinine, age, tobacco use and concomitant use of the herbicide picloram. RESULTS: Compared with non-applicator controls, urinary 2,4-D in the third quartile of exposure was associated with elevated 8-isoprostane (eß=1.38, 95% CI 1.03 to 1.84). There was no association among the highest exposed and no exposure-response trend. 2,4-D exposure was not associated with 8-OHdG. Results were unchanged when restricted to participants who only applied 2,4-D (no picloram use). CONCLUSIONS: We did not find evidence that increasing 2,4-D exposure was associated with 8-isoprostane or 8-OHdG. Future work should carefully evaluate potential confounders of this association, such as diet and physical activity, as well as additional biological markers of oxidative stress and damage.

Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies.

OBJECTIVE: To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM). METHODS: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance. RESULTS: When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study. CONCLUSION: In ambulatory RYR1-RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane. CLINICALTRIALSGOV IDENTIFIER: NCT02362425.

Survey of Mast Cell Mediator Levels from Patients Presenting with Symptoms of Mast Cell Activation.

INTRODUCTION: Although 4 mast cell mediators can be routinely measured, the results of initial testing to evaluate symptoms of mast cell activation have not been widely reported. OBJECTIVE: We examined the results of mast cell mediator tests used to assess patients with mast cell activation symptoms during a 5-year time span. METHODS: After excluding patients with alternative diagnoses, records of 108 patients were reviewed for initial mediator test results. Mediators included serum tryptase plus urinary N-methyl histamine (N-MH), leukotriene (LT)E4, and 11ß-prostaglandin (PG) F2α or 2,3-dinor-11ß-PGF2α (BPG). RESULTS: Most commonly, either a single measured elevation of 1 mediator (48.1%) or elevations of 2 (33.3%) mediators was found at baseline, during symptoms or at both time points. Elevated levels of a single mediator in order of frequency were: BPG > tryptase > LTE4 > N-MH, and for two mediators: BPG + tryptase (n = 16 cases) > BPG + LTE4 (n = 9) > BPG + N-MH (n = 6). Elevations in 3 mediators (n = 8) or 4 mediators (n = 2) were much less frequent. Monoclonal mast cell activation syndrome (n = 6), and systemic and cutaneous mastocytosis (n = 4) were also infrequent. Baseline plus symptom-associated tryptase values were obtained in only 7 patients. CONCLUSIONS: This survey suggests that elevations of 1 or 2 mediators are the most common (total 81.4% of cases) findings from initial tests for mast cell activation. Elevated levels of BPG were most commonly found both singly and in combination with other mediators, followed by the finding of elevated levels of tryptase. Baseline plus symptom-associated tryptase levels were measured in only a minority of patients.

Oxidative stress, DNA stability and evoked inflammatory signaling in young celiac patients consuming a gluten-free diet.

PURPOSE: 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. METHODS: 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. RESULTS: No differences were found in oxidative stress between CD patients and controls; however, IFN-γ, IL-1α, IP-10 and TNF-ß were higher in the CD patients. VEGF was also higher than in the control group. CONCLUSION: 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.

Oxidatively Damaged DNA/RNA and 8-Isoprostane Levels Are Associated With the Development of Type 2 Diabetes at Older Age: Results From a Large Cohort Study.

OBJECTIVE: Oxidative stress is believed to play an important role in the pathophysiology of type 2 diabetes, but the few cohort studies that have assessed the association of oxidative stress biomarkers with type 2 diabetes incidence were small and reported inconclusive results. RESEARCH DESIGN AND METHODS: We examined the associations of urinary oxidized guanine/guanosine (OxGua) levels (a biomarker of DNA/RNA oxidation) and urinary 8-isoprostane levels (a biomarker of lipid peroxidation) with type 2 diabetes incidence in 7,828 individuals initially without diabetes from a population-based German cohort study with 14 years of follow-up. Hazard ratios (HRs) (95% CIs) per 1 SD were obtained using multivariable-adjusted Cox proportional hazards regression models. RESULTS: In the total population, weak but statistically significant associations with type 2 diabetes incidence were observed for OxGua levels (HR [95% CI] per 1 SD 1.05 [1.01; 1.09]) and 8-isoprostane levels (1.04 [1.00; 1.09]). Stratified analyses showed that associations of both biomarkers with type 2 diabetes incidence were absent in the youngest age-group (50-59 years) and strongest in the oldest age-group (65-75 years) of the cohort, with HR of OxGua levels 1.14 (1.05; 1.23) per 1 SD and of 8-isoprostane levels 1.22 (1.02; 1.45) per 1 SD. CONCLUSIONS: These results from a large cohort study support suggestions that an imbalanced redox system contributes to the development of type 2 diabetes but suggest that this association becomes clinically apparent at older ages only, possibly as a result of reduced cellular repair capacity.