Urinary F2-isoprostanes Research Articles

Evaluation of oxidative stress in dogs and cats with chronic kidney disease.

Oxidative stress is a potential contributor to chronic kidney disease (CKD) progression but has not been evaluated in dogs and cats with CKD. Oxidative stress is higher in animals with CKD compared with healthy controls and decreases with the advancing CKD stage. The aim of this study was to determine the presence and intensity of oxidative stress in dogs and cats at different CKD stages. Sixty dogs and 30 cats with naturally acquired CKD; 10 dogs and 14 cats, healthy controls. Analytical cross-sectional study. Oxidative stress was evaluated by measuring the urinary concentration of F2-isoprostane (uF2-IsoPs) normalized to urinary creatinine. Urinary F2-isoprostanes normalized to urinary creatinine of healthy dogs and of dogs with CKD Stages 1 to 4 was 3.3 ng/mg, 4.7 ng/mg (range, 1.0-73.4), 2.4 ng/mg (range, 0.4-7.8), 0.52 ng/mg (range, 0.01-2.9), and 0.37 ng/mg (range, 0.01-0.6), respectively. Urinary F2-isoprostanes differed among CKD stages (P < .001), but not compared with controls. uF2-IsoPs of healthy cats and cats with CKD Stages 1 to 4 was 0.68 ng/mg (range, 0.2-1.4), 0.97 ng/mg (range, 0.4-1.8), 0.6 ng/mg (range, 0.002-2.0), 0.94 ng/mg (range, 0.3-2.3), and 0.2 ng/mg (range, 0.01-0.4). Urinary F2-isoprostanes differed among stages (P = .05) but not compared with healthy controls. Oxidative stress might be present in dogs and cats with CKD. Its magnitude declines as the disease progresses, therefore, it should be considered a potential therapeutic target mostly at the early stages of the disease.

Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (β) = 0.15, 95% CI 0.02-0.29; FTL-by-sex βinteraction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (FTL: rho = -0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.

A phase II randomized, double-blind, placebo-controlled study of Nuvastatic (C50SEW505OESA), a standardized rosmarinic acid-rich polymolecular botanical extract formulation to reduce cancer-related fatigue in patients with solid tumors.

We evaluated the efficacy and safety of Nuvastatic™ (C5OSEW5050ESA)in improving cancer-related fatigue (CRF) among cancer patients. This multicenter randomized double-blind placebo-controlled phase 2 trial included 110 solid malignant tumor patients (stage II-IV) undergoing chemotherapy. They were randomly selected and provided oral Nuvastatic™ 1000mg (N = 56) or placebo (N = 54) thrice daily for 9weeks. The primary outcomes were fatigue (Brief Fatigue Inventory (BFI)) and Visual Analog Scale for Fatigue (VAS-F)) scores measured before and after intervention at baseline and weeks 3, 6, and 9. The secondary outcomes were mean group difference in the vitality subscale of the Medical Outcome Scale Short Form-36 (SF-36) and urinary F2-isoprostane concentration (an oxidative stress biomarker), Eastern Cooperative Oncology Group scores, adverse events, and biochemical and hematologic parameters. Analysis was performed by intention-to-treat (ITT). Primary and secondary outcomes were assessed by two-way repeated-measures analysis of variance (mixed ANOVA). The Nuvastatic™ group exhibited an overall decreased fatigue score compared with the placebo group. Compared with the placebo group, the Nuvastatic™ group significantly reduced BFI-fatigue (BFI fatigue score, F (1.4, 147) = 16.554, p < 0.001, partial η2 = 0.333). The Nuvastatic™ group significantly reduced VAS-F fatigue (F (2, 210) = 9.534, p < 0.001, partial η2 = 0.083), improved quality of life (QoL) (F (1.2, 127.48) = 34.07, p < 0.001, partial η2 = 0.243), and lowered urinary F2-IsoP concentrations (mean difference (95% CI) = 55.57 (24.84, 86.30)), t (55) = 3.624, p < 0.001, Cohen's d (95% CI) = 0.48 (0.20, 0.75)). Reported adverse events were vomiting (0.9%), fever (5.4%), and headache (2.7%). Nuvastatic™ is potentially an effective adjuvant for CRF management in solid tumor patients and worthy of further investigation in larger trials. ClinicalTrial.gov ID: NCT04546607. Study registration date (first submitted): 11-05-2020.

Temperature stability of urinary F2-isoprostane and 8-hydroxy-2′-deoxyguanosine

BackgroundClinical and epidemiological studies employ long-term temperature storage but the effect of temperature on the stability of oxidative stress (OS) markers is unknown. We investigated the effects of storage at −20 °C and −80 °C over 4–9 months on F2-isoprostanes (F2-IsoP) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in urine of children, a population group among whom the measurement of these markers is still limited. MethodsPaired spot urine samples from 87 children aged 8.9–16.9 years (52.9% boys) were analyzed. Samples were preserved with 0.005% (w/v) butylated hydroxytoluene, portioned and stored within 2.5 h (median) of collection. Samples were analyzed in duplicate or triplicate using commercial ELISA kits and their correlations were evaluated. ResultsF2-IsoP and 8-OHdG showed high correlations (Spearman rho of 0.90 and 0.97, respectively; P < 0.0001) with storage at −20 °C and −80 °C. There was a strong agreement among categories of values for F2-IsoP (Kappa = 0.76 ± 0.08, agreement = 83.9%, P < 0.0001) and 8-OHdG: (Kappa = 0.83 ± 0.08, agreement = 88.4%, P < 0.0001). The correlation between the temperatures for F2-IsoP concentrations was also high when stored for <4 (0.93), 4 (0.93), and 5 months (0.88), all P < 0.0001. For 8-OHdG, Spearman correlations at <8, 8, and 9 months of storage at −20 °C and −80 °C were 0.95, 0.98, and 0.96 (all P < 0.0001), respectively. ConclusionsUrine storage with BHT for up to nine months at a temperature of −20 °C to −80 °C yields highly comparable concentrations of F2-IsoP and 8-OHdG.

Predictors of upstream inflammation and oxidative stress pathways during early pregnancy

BackgroundInflammation and oxidative stress are critical to pregnancy, but most human study has focused on downstream, non-causal indicators. Oxylipins are lipid mediators of inflammation and oxidative stress that act through many biological pathways. Our aim was to characterize predictors of circulating oxylipin concentrations based on maternal characteristics. MethodsOur study was conducted among 901 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured a targeted panel of oxylipins in early pregnancy plasma and urine samples from several biosynthetic pathways, defined by the polyunsaturated fatty acid (PUFA) precursor and enzyme group. We evaluated levels across predictors, including characteristics of participants’ pregnancy, socioeconomic determinants, and obstetric and medical history. ResultsCurrent pregnancy and sociodemographic characteristics were the most important predictors of circulating oxylipins concentrations. Plasma oxylipins were lower and urinary oxylipins higher for participants with a later gestational age at sampling (13–23 weeks), higher prepregnancy BMI (obesity class I, II, or III), Black or Hispanic race and ethnicity, and lower socioeconomic status (younger age, lower education, and uninsured). For example, compared to those with normal or underweight prepregnancy BMI, participants with class III prepregnancy obesity had 45–46% lower plasma epoxy-eicosatrienoic acids, the anti-inflammatory oxylipins produced from arachidonic acid (AA) by cytochrome P450, and had 81% higher urinary 15-series F2-isoprostanes, an indicator of oxidative stress produced from non-enzymatic AA oxidation. Similarly, in urine, Black participants had 92% higher prostaglandin E2 metabolite, a pro-inflammatory oxylipin, and 41% higher 5-series F2-isoprostane, an oxidative stress indicator. ConclusionsIn this large pregnancy study, we found that circulating levels of oxylipins were different for participants of lower socioeconomic status or of a systematically marginalized racial and ethnic groups. Given associations differed along biosynthetic pathways, results provide insight into etiologic links between maternal predictors and inflammation and oxidative stress.

Association of non-daily hookah tobacco smoking and cardiovascular disease-related exposure biomarkers among U.S. users: The Population Assessment of Tobacco and Health Study

Hookah smoking has grown to become a global tobacco epidemic. While cigarette smoking is a well-established cardiovascular disease (CVD) risk factor, the CVD risks of hookah smoking are unknown, particularly among regular U.S. adult hookah users who are predominantly non-daily users. Herein, we examined the association between hookah smoking and biomarkers of CVD risk among regular exclusive hookah smokers (n = 75), compared to regular exclusive cigarette smokers (n = 1773), dual hookah and cigarette smokers (n = 43) and never tobacco users (n = 757), using data from a nationally representative sample of adults from the Population Assessment of Tobacco and Health Study (2013–2014). Whereas 84% of cigarette smokers reported daily use, only 8% of hookahsmokers reported daily use, with more than a third reporting monthly use. Adjusting for age and sex and as compared to exclusive cigarette smokers, exclusive hookah smokers had significantly lower geometric mean concentrations in serum sICAM-1 and urinary F2-isoprostane (p < 0.05). Although not statistically significant, a signal of increased oxidative stress was observed among hookah smokers as compared to never tobacco users (urinary F2-isoprostane). CVD-related harm biomarkers appear to be lower among hookah smokers than cigarette smokers. These findings represent patterns of hookah smoking predominantly shared among adult U.S. users who report non-daily occasional use and do not reflect solitary, daily use as is common in the Middle East. Future studies with longer exposure and longitudinal hookah use are warranted to explore the association between hookah smoking and CVD risk.

Association between lipid peroxidation biomarkers and microRNA expression profiles

BackgroundIn-vitro and animal studies demonstrate that epigenetic regulation may play an important role in lipid peroxidation. No human study to date has directly evaluated microRNAs (miRNAs), as epigenetic modulators, in relation to systemic levels of lipid peroxidation. ObjectivesTo evaluate associations between systemic levels of lipid peroxidation and miRNA expression profiles in women. MethodsIncluded in the analysis were 92 women aged 40–70 years, a subset of the Shanghai Women’s Health Study (SWHS). Lipid peroxidation was assessed by urinary markers F2-isoprostanes (F2-IsoPs), the products of free radical-catalyzed peroxidation of arachidonic acid, and its major metabolite after β-oxidation, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), with GC/NICI-MS assays. Expression levels of 798 miRNAs were quantified in peripheral plasma with NanoString nCounter assays. A multivariable linear regression model was used to examine the association between lipid peroxidation and miRNA expression. ResultsAfter adjusting for potential confounders, 29 miRNAs and 213 miRNAs were associated with F2-IsoPs and F2-IsoP-M, respectively. When further controlling for multiple comparisons, none of these nominally significant associations with F2-IsoPs was retained, whereas 71 of 213 miRNAs associated with F2-IsoP-M remained. The predicted targets of the F2-IsoP-M associated miRNAs were enriched for several lipid peroxidation-related processes such as PI3K/AKT, MAPK, FOXO and HIF-1 signaling pathways. Moreover, 10 miRNAs (miR-93-5p, miR-761, miR-301b-3p, miR-497-5p, miR-141-3p, miR-186-5p, miR-126-3p, miR-200b-3p, miR-520d-3p, and miR-363-3p) exhibited functional interactions with 50 unique mRNAs targets involved in the regulation of β-oxidation. ConclusionsTo our knowledge, this study, for the first time, provides human data suggesting that miRNA expression may be linked to lipid peroxidation products and their metabolism.

Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome

SummaryMilk fortifiers help meet the nutritional needs of preterm infants receiving their mother’s own milk (MOM) or donor human milk. We conducted a randomized clinical trial (NCT03214822) in 30 very low birth weight premature neonates comparing bovine-derived human milk fortifier (BHMF) versus human-derived fortifier (H2MF). We found that fortifier type does not affect the overall microbiome, although H2MF infants were less often colonized by an unclassified member of Clostridiales Family XI. Secondary analyses show that MOM intake is strongly associated with weight gain and microbiota composition, including Bifidobacterium, Veillonella, and Propionibacterium enrichment. Finally, we show that while oxidative stress (urinary F2-isoprostanes) is not affected by fortifier type or MOM intake, fecal calprotectin is higher in H2MF infants and lower in those consuming more MOM. Overall, the source of human milk (mother versus donor) appears more important than the type of milk fortifier (human versus bovine) in shaping preterm infant gut microbiota.

Association between lipid peroxidation and risk of type 2 diabetes in women

In-vitro and animal studies demonstrate that lipid peroxidation plays an important role in the pathogenesis of type 2 diabetes (T2D). However, human data from prospective studies are limited and contradictory. We used data originally collected in two nested case-control studies of cancer to prospectively evaluate whether systemic levels of lipid peroxidation were associated with incidence of T2D in 1917 women who were 40–70 years old and diabetes-free at baseline. Lipid peroxidation was measured by urinary F2-isoprostanes (F2-IsoPs) and its major metabolite 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M) with GC/NICI-MS assays. The Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident T2D. After a median follow-up of 10.1 years, 187 women were diagnosed with T2D. Urinary concentrations of both F2-IsoPs and F2-IsoP-M were significantly higher in T2D cases than in non-cases. Both biomarkers were positively associated with subsequent risk of T2D in multivariable-adjusted Cox models. When further adjusted for body mass index (BMI), the positive association with F2-IsoP-M was attenuated and no longer statistically significant, whereas the association with F2-IsoPs remained (P for overall significance < 0.001). HR for T2D was 1.68 (95% CI: 1.13, 2.51) for the highest vs the lowest quartile of F2-IsoPs. Moreover, this association appeared more pronounced among women with higher BMI. In summary, our study suggests that F2-IsoPs could be of significance in T2D risk prediction among middle-aged and elderly women.

The association between prenatal F2-isoprostanes and child wheeze/asthma and modification by maternal race

BackgroundChildhood wheeze, asthma, and allergic rhinitis are common and likely have prenatal origins. Oxidative stress is associated with respiratory disease, but the association of oxidative stress during the prenatal period with development of respiratory and atopic disease in childhood, particularly beyond the infancy period, is unknown. This study aims to investigate associations between prenatal oxidative stress, measured by maternal urinary F2-isoprostanes, and child respiratory outcomes, including effect modification by maternal race. MethodsWe prospectively studied Black (n = 717) and White (n = 363) mother-child dyads. We measured F2-isoprostanes in 2nd-trimester urine (ng/mg-creatinine). At approximately age 4, we obtained parent report of provider-diagnosed asthma (ever), current wheeze, current asthma (diagnosis, symptoms and/or medication), and current allergic rhinitis (current defined as previous 12 months). We used multivariable logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) per interquartile range (IQR) increase in F2-isoprostane concentration, controlling for confounders. We examined modification by maternal race using interaction terms. ResultsThe prevalence of provider-diagnosed asthma and current wheeze, asthma and allergic rhinitis was 14%, 19%, 15%, and 24%, respectively. Median (IQR) F2-isoprostane levels were 2.1 (1.6, 2.9) ng/mg-creatinine. Associations between prenatal F2-isoprostanes and provider-diagnosed asthma, current wheeze, and current asthma were modified by maternal race. Results were strongest for current wheeze (aOR [95%CI]: 1.55 [1.16, 2.06] for White; 0.98 [0.78, 1.22] for Black; p-interaction = 0.01). We observed no association between F2-isoprostanes and allergic rhinitis. ConclusionPrenatal urinary F2-isoprostanes may be a marker associated with childhood wheeze/asthma in certain populations. Research is needed to understand underlying mechanisms and racial differences.

Association Between Healthy Dietary Patterns and Markers of Oxidative Stress

ObjectivesOxidative stress is involved in chronic disease etiology and the aging process and is related to antioxidant intake. However, less is known about the relationship between dietary patterns and markers of oxidative stress. We assessed cross-sectionally the association between healthy dietary patterns [alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), alternative Healthy Eating Index (aHEI), and Healthy Eating Index 2015 (HEI-2015)] and urinary F2-isoprostanes (8-iso-PGF2α and 8-iso-PGF2α-M), which are established biomarkers of oxidative stress. MethodsData were obtained from 844 premenopausal and 454 postmenopausal women participating in the Sister Study who had urinary samples analyzed for F2-isoprostanes. Responses from a 110-item validated food frequency questionnaire (FFQ) at baseline were used to calculate dietary pattern scores. Concentrations of 8-iso-PGF2α and its metabolite (8-iso-PGF2α-M) were measured by GC/MS for samples from premenopausal women and LC/MS for samples from postmenopausal women. Multivariable linear regression models were used to estimate associations between aMED, DASH, aHEI, and HEI-2015 and urinary F2-isoprostanes among pre-menopausal and post-menopausal women separately. ResultsAmong premenopausal women, we observed significant inverse associations between the four dietary indices and mean 8-iso-PGF2α (aMED βQ4vsQ1: –0.15, 95% CI: –0.25, –0.05; DASH βQ4vsQ1: –0.15, 95% CI: –0.25, –0.25; aHEI βQ4vsQ1: –0.15, 95% CI: –0.25, –0.05; HEI-2015 βQ4vsQ1: –0.17, 95% CI: –0.27, –0.07). These associations were modified by age, education, income, and BMI, though there was no evidence of statistical interaction. In a sensitivity analysis, estimates did not substantially differ by the presence or absence of chronic disease. Among postmenopausal women, aHEI was associated with mean 8-iso-PGF2α and 8-iso-PGF2α-M (β8-iso-PGF2α: –0.003, 95% CI: –0.01, –0.005, β8-iso-PGF2α-M: –0.003, 95% CI: –0.01, –0.005). No other significant findings were observed among postmenopausal women. ConclusionsHealthy dietary patterns may be associated with reduced oxidative stress, particularly among premenopausal women. Funding SourcesNational Institute of Environmental Health Sciences, NIH Office of Dietary Supplements, Avon Foundation, T32 from NIH-NIGMS.

Oxidative Balance Score during Pregnancy Is Associated with Oxidative Stress in the CANDLE Study.

The objective of this study was to calculate an oxidative balance score (OBS) utilizing diet and lifestyle information collected from 1322 women during the second trimester of pregnancy in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. An energy-adjusted OBS was calculated using nutrient information from a Food Frequency Questionnaire (FFQ), lifestyle measures, and plasma folate and vitamin D levels. Using the least absolute shrinkage and selection operator method, 91 food items from the FFQ were selected and they accounted for 82% of the variance in the OBS, with cruciferous vegetables, citrus fruits, fruit juice, and coffee being among the highest anti-oxidant predictors, and red meats and alcohol among the highest pro-oxidant contributors. Urinary F2-isoprostane, an objective indicator of oxidative stress, was lower with increasing OBS quintiles in a stairstep manner (p for trend = 0.0003), suggesting the possible utility of the OBS as an indicator of oxidative stress. The OBS was moderately correlated with the Healthy Eating Index (correlation coefficient = 0.6076), suggesting it provides a distinct measure of a healthy diet. In conclusion, the OBS may serve as a valid reflective indicator of urinary F2-isoprostanes and an epidemiological tool to inform intervention studies, in order to minimize oxidative stress during pregnancy.

Association of dietary and plasma carotenoids with urinary F2-isoprostanes.

Carotenoids may protect against chronic diseases including cancer and cardiometabolic disease by mitigating oxidative stress and/or inflammation. We cross-sectionally evaluated associations between carotenoids and biomarkers of oxidative stress or inflammation. From 2003 to 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35-74. Post-menopausal participants (n = 512) were randomly sampled to measure carotenoids and biomarkers of oxidative stress. Dietary carotenoid consumption was assessed using a validated 110-item Block 1998 food frequency questionnaire; use of β-carotene-containing supplements was also assessed. Plasma carotenoids were quantified, adjusting for batch. Urinary markers of lipid peroxidation, 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were also measured. Since the biomarker 8-iso-PGF2α can reflect both oxidative stress and inflammation, we used a modeled 8-iso-PGF2α to prostaglandin F2α ratio approach to distinguish effects reflecting oxidative stress versus inflammation. Multivariable linear regression was used to assess the associations of dietary and plasma carotenoids with the estimated biomarker concentrations. Total plasma carotenoids were inversely associated with 8-iso-PGF2α-M concentrations (P for trend across quartiles = 0.009). Inverse trends associations were also seen for α-carotene and β-carotene. In contrast, lutein/zeaxanthin showed associations with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations. The inverse association for total carotenoids appeared to be specific for oxidative stress (chemical 8-iso-PGF2α; Phighest vs. lowest quartile = 0.04 and P for trend across quartiles = 0.02). The pattern was similar for α-carotene. However, lutein/zeaxanthin tended to have a stronger association with enzymatic 8-iso-PGF2α, suggesting an additional anti-inflammatory effect. Supplemental β-carotene was inversely associated with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations, as well as with both chemical and enzymatic 8-iso-PGF2α. Dietary carotenoids were not associated with either biomarker. Plasma carotenoids and supplemental β-carotene were associated with lower concentrations of 8-iso-PGF2α metabolite. Plasma carotenoids associations may reflect antioxidant effects.

Mitochondria-targeted antioxidant supplementation does not affect muscle soreness or recovery of maximal voluntary isometric contraction force following muscle-damaging exercise in untrained men: a randomized clinical trial.

Unaccustomed exercise causes muscle damage resulting in loss of muscle function, which may be attributable to exercise-induced increases in skeletal muscle reactive oxygen species. This study examined the effect of mitochondria-targeted antioxidant supplementation on recovery of muscle function following exercise. Thirty-two untrained men received MitoQ (20mg/day) or a placebo for 14 days before performing 300 maximal eccentric contractions of the knee extensor muscles of 1 leg. Muscle function was assessed using isokinetic dynamometry before, immediately after, and 24, 48, 72, and 168 hours after exercise. Muscle soreness was assessed using a visual analogue scale 24, 48, 72, and 168 hours after exercise. Blood samples were collected before, immediately after, and 2, 24, 48, 72, and 168 hours after exercise and urine samples were collected before and during the 48 hours after exercise. The reduction in maximal voluntary isometric contraction force and peak concentric torque following exercise was unaffected by MitoQ while recovery of peak eccentric torque was delayed in the MitoQ group. Exercise-induced increases in urine F2-isoprostanes were unaffected by MitoQ. MitoQ augmented exercise-induced increases in plasma creatine kinase levels, while plasma IL-6 was similar between groups. Muscle soreness was not affected by MitoQ. These results indicate that MitoQ does not attenuate post-exercise muscle soreness and may delay recovery of muscle function following eccentric exercise. Trial registration number: ACTRN12620001089921. Novelty: Post-exercise recovery of maximal voluntary isometric contraction force and peak concentric torque were unaffected by MitoQ. MitoQ delayed post-exercise recovery of peak eccentric torque. Post-exercise muscle soreness was unaffected by MitoQ.

A randomised controlled trial of succinylated gelatin (4%) fluid on urinary acute kidney injury biomarkers in cardiac surgical patients

BackgroundFluid resuscitation is frequently required for cardiac surgical patients admitted to the intensive care unit. The ideal fluid of choice in regard to efficacy and safety remains uncertain. Compared with crystalloid fluid, colloid fluid may result in less positive fluid balance. However, some synthetic colloids are associated with increased risk of acute kidney injury (AKI). This study compared the effects of succinylated gelatin (4%) (GEL) with compound sodium lactate (CSL) on urinary AKI biomarkers in patients after cardiac surgery.MethodsCardiac surgical patients who required an intravenous fluid bolus of at least 500 mL postoperatively were randomly allocated to receive GEL or CSL as the resuscitation fluid of choice for the subsequent 24 h. Primary outcomes were serial urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C concentrations measured at baseline, 1 h, 5 h and 24 h after enrolment, with higher concentrations indicating greater kidney injury. Secondary biomarker outcomes included urinary clusterin, α1-microglobulin and F2-isoprostanes concentrations. Differences in change of biomarker concentration between the two groups over time were compared with mixed-effects regression models. Statistical significance was set at P < 0.05.ResultsForty cardiac surgical patients (n = 20 per group) with similar baseline characteristics were included. There was no significant difference in the median volume of fluid boluses administered over 24 h between the GEL (1250 mL, Q1–Q3 500–1750) and CSL group (1000 mL, Q1–Q3 500–1375) (P = 0.42). There was a significantly greater increase in urinary cystatin C (P < 0.001), clusterin (P < 0.001), α1-microglobulin (P < 0.001) and F2-isoprostanes (P = 0.020) concentrations over time in the GEL group, compared to the CSL group. Change in urinary NGAL concentration (P = 0.68) over time was not significantly different between the groups. The results were not modified by adjustment for either urinary osmolality or EuroSCORE II predicted risk of mortality.ConclusionsThis preliminary randomised controlled trial showed that use of succinylated gelatin (4%) for fluid resuscitation after cardiac surgery was associated with increased biomarker concentrations of renal tubular injury and dysfunction, compared to crystalloid fluid. These results generate concern that use of intravenous gelatin fluid may contribute to clinically relevant postoperative AKI.Trial registration ANZCTR.org.au, ACTRN12617001461381. Registered on 16th October, 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373619&isReview=true.

A Pilot Study of Associations Between Visceral Fat, IL-6, and Urinary F2-Isoprostanes in Older Adults Exposed to a Diet Intervention.

BackgroundShort-term markers of successful visceral adipose tissue (VAT) loss are needed. Urinary F2-isoprostanes might serve as a marker for intensified lipid metabolism, whereas circulating IL-6 might stimulate fat oxidation and enhance mobilization of VAT.ObjectivesThis pilot study was designed to explore the hypotheses that 1) reduction in VAT is associated with increase in IL-6, and 2) that increases in urinary F2-isoprostanes are associated with increases in IL-6 and reduction in VAT.MethodsEighteen participants (aged 60–75 y, BMI 30–40 kg/m2) were randomly assigned to either a very-low-carbohydrate diet (VLCD; <10:25:>65% energy from carbohydrate:protein:fat) or a low-fat diet (LFD; 55:25:20%) for 8 wk. Changes in fat distribution were assessed by MRI. Four urinary F2-isoprostane isomers were quantified in 24-h urine collection using LC-MS/MS analyses. Changes in 4 F2-isoprostane isomers were summarized using factor analysis (Δ-F2-isoprostane factor). Statistical significance was set at P < 0.1.ResultsWithin the VLCD group, change in VAT was inversely associated with change in IL-6 (r = −0.778, P = 0.069) and Δ-F2-isoprostane factor (r = −0.690, P = 0.086), demonstrating that participants who maintained higher concentrations of F2-isoprostane factor across the intervention showed greater decreases in VAT. A positive relation between Δ-F2-isoprostane factor and change in IL-6 was observed (r = 0.642, P = 0.062). In the LFD group, no significant associations between changes in VAT, F2-isoprostane factor, or IL-6 were observed.ConclusionsResults from this exploratory study in older adults with obesity suggest that, in the context of a VLCD, IL-6 could be involved in VAT mobilization, and urinary F2-isoprostanes could reflect intensified oxidation of mobilized fatty acids.Trial registration: This study is registered at clinicaltrials.gov as NCT02760641.

Biomarkers representing key aging-related biological pathways are associated with subclinical atherosclerosis and all-cause mortality: The Framingham Study.

Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality. We evaluated up to 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium [ln (CAC+1)] and carotid intima-media thickness (IMT). In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values (βADMA per 1-SD increase 0.25; 95% confidence interval [CI] [0.11, 0.39]). Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values (βLTL -0.08, 95%CI -0.14, -0.02, and βIGF-1 -0.04, 95%CI -0.08, -0.01, respectively). During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality (hazard ratios [HR] per SD increase in biomarker, 0.85, 95% CI 0.74-0.99, and 0.90, 95% CI 0.82-0.98 for LTL and IGF-1, respectively). F2-Isoprostanes and ADMA values were positively associated with all-cause mortality (HR per SD increase in biomarker, 1.15, 95% CI, 1.10-1.22, and 1.10, 95% CI, 1.02-1.20, respectively). In our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

The Role of Urine F2-ISOPROSTANE CONcentration in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Haemorrhage-A Poor Prognostic Factor.

Background: The pathophysiology of delayed cerebral ischemia (DCI) remains unclear. One of the hypotheses suggests that reactive oxygen species play a role in its onset. Thus, we studied F2-isoprostanes (F2-IsoPs)—oxidative stress biomarkers. Our goal was to improve the early diagnosis of DCI in a non-invasive way. Methods: We conducted a prospective single center analysis of 38 aneurysmal subarachnoid hemorrhage patients. We assessed urine F2-IsoP concentration using immunoenzymatic arrays between the first and fifth day after bleeding. A correlation between urine F2-IsoP concentration and DCI occurrence was examined regarding clinical conditions and outcomes. Results: The urine F2-IsoP concentrations were greater than those in the control groups (p < 0.001). The 3rd day urine F2-IsoPs concentrations were correlated with DCI occurrence (p < 0.001) and long term outcomes after 12 months (p < 0.001). Conclusions: High levels of urine F2-IsoPs on day 3 can herald DCI.

Serially assessed bisphenol A and phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: A longitudinal cohort study.

Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

A Randomized Controlled Trial of Long-Term (R)-α-Lipoic Acid Supplementation Promotes Weight Loss in Overweight or Obese Adults without Altering Baseline Elevated Plasma Triglyceride Concentrations

α-Lipoic acid (LA) is a dietary supplement for maintaining energy balance, but well-controlled clinical trials in otherwise healthy, overweight adults using LA supplementation are lacking. The primary objective was to evaluate whether LA supplementation decreases elevated plasma triglycerides in overweight or obese adults. Secondary aims examined if LA promotes weight loss and improves oxidative stress and inflammation. Overweight adults [n=81; 57% women; 21-60 y old; BMI (in kg/m2)≥25] with elevated plasma triglycerides ≥100mg/dL were enrolled in a 24-wk, randomized, double-blind, controlled trial, assigned to either (R)-α-lipoic acid (R-LA; 600mg/d) or matching placebo, and advised not to change their diet or physical activity. Linear models were used to evaluate treatment effects from baseline for primary and secondary endpoints. R-LA did not decrease triglyceride concentrations, but individuals on R-LA had a greater reduction in BMI at 24 wk than the placebo group (-0.8; P=0.04). The effect of R-LA on BMI was correlated to changes in plasma triglycerides (r = +0.50, P=0.004). Improvement in body weight was greater at 24 wk in R-LA subgroups than in placebo subgroups. Women and obese participants (BMI≥35) showed greater weight loss (-5.0% and -4.8%, respectively; both P<0.001) and loss of body fat (-9.4% and -8.6%, respectively; both P<0.005). Antioxidant gene expression in mononuclear cells at 24 wk was greater in the R-LA group (Heme oxygenase 1 [HMOX1] : +22%; P=0.02) than in placebo. Less urinary F2-isoprostanes (-25%; P=0.005), blood leukocytes (-10.1%; P=0.01), blood thrombocytes (-5.1%; P=0.03), and ICAM-1 (-7.4%; P=0.04) at 24 wk were also observed in the R-LA group than in placebo. Long-term LA supplementation results in BMI loss, greater antioxidant enzyme synthesis, and less potential for inflammation in overweight adults. Improved cellular bioenergetics is also evident in some individuals given R-LA.This trial was registered at clinicaltrials.gov as NCT00765310.