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Previous research indicates that ultramarathon exercise can result in blood oxidative stress. The purpose of this investigation was to examine the efficacy of oral supplementation with quercetin, a naturally occurring compound with known antioxidant properties, as a potential countermeasure against blood oxidative stress during an ultramarathon competition. In double-blind fashion, 63 participants received either oral quercetin (250 mg, 4×/day; 1,000 mg/day total) or quercetin-free supplements 3 weeks before and during the 160-km Western States Endurance Run. Blood drawn before and immediately after (quercetin finishers n = 18, quercetin-free finishers n = 21) the event was analyzed for changes in blood redox status and oxidative damage. Results show that quercetin supplementation did not affect race performance. In response to the ultramarathon challenge, aqueous-phase antioxidant capacity (ferric-reducing ability of plasma) was similarly elevated in athletes in both quercetin and quercetin-free treatments and likely reflects significant increases in plasma urate levels. Alternatively, trolox-equivalent antioxidant capacity was not altered by exercise or quercetin. Accordingly, neither F2-isoprostances nor protein carbonyls were influenced by either exercise or quercetin supplementation. In the absence of postrace blood oxidative damage, these findings suggest that oral quercetin supplementation does not alter blood plasma lipid or aqueous-phase antioxidant capacity or oxidative damage during an ultramarathon challenge. [ABSTRACT FROM AUTHOR]

This study compared effects of carbohydrate (CHO) and rest on oxidative stress during exercise. Cyclists (N = 12) completed 4 randomized trials at 64% Wattsmax under 2 conditions (continuous cycling for 2 h [C] and cycling with 3-min rest every 10 min for 2.6 h [R]). Subjects cycled under each condition while receiving 6% CHO and placebo (PLA). CHO and PLA were given preexercise (12 mL/kg) and during exercise (4 mL·kg-1·15 min-1). Blood was collected preexercise, postexercise, and 1 h postexercise and assayed for F2-isoprostanes, hydroperoxides (LH), nitrite, antioxidant capacity, glucose, insulin, cortisol, and epinephrine. F2-isoprostanes and LH were lower in CHO. Glucose, cortisol, and epinephrine exhibited significant effects, with postexercise levels of glucose higher and cortisol and epinephrine lower in CHO during the R condition. This pattern was identical in the C condition (21). Oxidative stress during cycling was unaffected by use of short rest intervals but was diminished by CHO. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2011) 119, 604-616. Abstract Fatty acids such as eicosapentaenoic acid (EPA) have been shown to be beneficial for neurological function and human health. It is widely thought that oxidation products of EPA are responsible for biological activity, although the specific EPA peroxidation product(s) which exert these responses have not yet been identified. In this work we provide the first evidence that the synthesized representative cyclopentenone IsoP, 15-A3t-IsoP, serves as a potent inhibitor of lipopolysaccharide-stimulated macrophage activation. The anti-inflammatory activities of 15-A3t-IsoP were observed in response not only to lipopolysaccharide, but also to tumor necrosis factor alpha and IL-1b stimulation. Subsequently, this response blocked the ability of these compounds to stimulate nuclear factor kappa b (NFκB) activation and production of proinflammatory cytokines. The bioactivity of 15-A3t-IsoP was shown to be dependent upon an unsaturated carbonyl residue which transiently adducts to free thiols. Site directed mutagenesis of the redox sensitive C179 site of the Ikappa kinase beta subunit, blocked the biological activity of 15-A3t-IsoP and NFκB activation. The vasoprotective potential of 15-A3t-IsoP was underscored by the ability of this compound to block oxidized lipid accumulation, a critical step in foam cell transformation and atherosclerotic plaque formation. Taken together, these are the first data identifying the biological activity of a specific product of EPA peroxidation, which is formed in abundance in vivo. The clear mechanism linking 15-A3t-IsoP to redox control of NFκB transcription, and the compound's ability to block foam cell transformation suggest that 15-A3t-IsoP provides a unique and potent tool to provide vaso- and cytoprotection under conditions of oxidative stress. [ABSTRACT FROM AUTHOR]

The mortality rate for acute lung injury (ALI) is reported to be between 35-40%, and there are very few treatment strategies that improve the death rate from this condition. Previous studies have suggested that signaling through the prostaglandin (PG) I2 receptor may protect against bleomycin-induced ALI in mice. We found that mice that overexpress PGI synthase (PGIS) in the airway epithelium were significantly protected against bleomycin-induced mortality and had reduced parenchymal consolidation, apoptosis of lung tissue, and generation of F2-isoprostanes compared with littermate wild-type controls. In addition, we show for the first time in both in vivo and in vitro experiments that PGI2 induced the expression of NADP (H): quinoneoxidoreductase 1 (Nqo 1), an enzyme that prevents the generation of reactive oxygen species. PGI2 induction of Nqo 1 provides a possible novel mechanism by which this prostanoid protects against bleomycin-induced mortality and identifies a potential therapeutic target for human ALI. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning is a phenomenon in which low-level stressful stimuli upregulate endogenous defensive programs, resulting in subsequent resistance to otherwise lethal injuries. We previously observed that signal transduction systems typically associated with neurodegeneration such as caspase activation are requisite events for the expression of tolerance and induction of HSP70. In this work, we sought to determine the extent and duration of oxidative and energetic dysfunction as well as the role of effector kinases on metabolic function in preconditioned cells. Using an in vitro neuronal culture model, we observed a robust increase in Raf and p66shc activation within 1h of preconditioning. Total ATP content decreased by 25%3 h after preconditioning but returned to baseline by 24 h. Use of a free radical spin trap or p66shc inhibitor increased ATP content whereas a Raf inhibitor had no effect. Phosphorylated p66shc rapidly relocalized to the mitochondria and in the absence of activated p66shc, autophagic processing increased. The constitutively expressed chaperone HSC70 relocalized to autophagosomes. Preconditioned cells experience significant total oxidative stress measured by F2-isoprostanes and neuronal stress evaluated by F4-neuroprostane measurement. Neuroprostane levels were enhanced in the presence of Shc inhibitors. Finally, we found that inhibiting either p66shc or Raf blocked neuroprotection afforded by preconditioning as well as upregulation of HSP70, suggesting both kinases are critical for preconditioning but function in fundamentally different ways. This is the first work to demonstrate the essential role of p66shc in mediating requisite mitochondrial and energetic compensation after preconditioning and suggests a mechanism by which protein and organelle damage mediated by ROS can increase HSP70. [ABSTRACT FROM AUTHOR]

Obesity is often associated with dyslipidemia, insulin resistance, and hypertension. Together, these metabolic perturbations greatly increase the risk of developing cardiovascular disease and diabetes. Although fish oil is a well- established hypolipidemic agent, the mechanisms by which it mediates its lipid-lowering effects are not clear. In addition, it has not been established whether dietary fish oil has different effects in lean and obese mice. LDL receptor deficient (LDLR-/-) and leptin deficient mice on a LDLR-/- background (ob/ob;LDLR-/-) were fed a high fat diet (39% total fat) supplemented with 6% olive oil or fish oil for 6 wk. Fish oil supplementation resulted in lower concentrations of plasma total cholesterol (P< 0.01), triglycerides (P< 0.01), and free fatty acids (P< 0.001) in lean LDLR-/- mice, but not in obi ob;LDLR-/- mice. In contrast, a fish oil diet did not modulate insulin sensitivity in lean LDLR-/- mice, but it improved insulin sensitivity in ob/ob;LDLR-/- mice IP < 0.05) compared with olive oil fed ob/ob;LDLR-/-- mice. Interestingly, plasma adiponectin concentrations were significantly higher and hepatic steatosis was reduced in both mouse models upon fish oil feeding. Finally, fish oil fed LDLR-/- mice exhibited higher hepatic AMP activated protein kinase (AMPK) phosphorylation (P< 0.05), whereas AMPK phosphorylation was not elevated by fish oil feeding in ob/ob;LDLR-/- mice. Taken together, our data suggest that fish oil reduces hepatic steatosis in both lean and obese mice, has potent plasma lipid lowering effects in lean mice, and exerts insulin sensitizing effects in obese mice. [ABSTRACT FROM AUTHOR]

Oxidative stress is a potentially important aetiological factor for many chronic diseases, including cardiovascular disease, neurodegenerative disease and cancer, yet studies often find inconsistent results. The associations between three of the most widely used biomarkers of oxidative stress, i.e. F2-isoprostanes for lipid peroxidation and 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxo-dG) and the comet assay with FPG for oxidative DNA damage, were compared in a sample of 135 healthy African-American and white adults. Modest associations were observed between F2-isoprostanes and the comet assay ( r = 0.22, p = 0.01), but there were no significant correlations between 8-oxo-dG and the comet assay ( r = −0.09) or F2-IsoP ( r = −0.04). These results are informative for researchers seeking to compare results pertaining to oxidative stress across studies and/or assessment methods in healthy disease-free populations. The development and use of oxidative stress biomarkers is a promising field; however, additional validation studies are necessary to establish accuracy and comparability across oxidative stress biomarkers. [ABSTRACT FROM AUTHOR]

The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F2-Isoprostanes, 8-hydroxy-2- deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease. [ABSTRACT FROM AUTHOR]

Oxidative stress is thought to play a role in the pathogenesis of fibromyalgia. We examined the hypothesis that oxidative stress was increased in patients with fibromyalgia and related to the severity of symptoms. Urinary F2-isoprostane excretion was measured in 48 patients with fibromyalgia and compared to those of 96 control subjects. In patients, we examined the association between oxidative stress and symptoms. Patients with fibromyalgia were significantly more symptomatic than control subjects, but urinary F2-isoprostane excretion did not differ significantly (2.3 ± 1.9 vs. 2.8 ± 2.2 ng/mg creatinine, p = 0.16). In patients with fibromyalgia, F2-isoprostane excretion was associated with fatigue visual analog scale (rho = 0.30, p = 0.04) but not with pain, quality of life, functional capacity, depression, number of tender points, or overall impact of fibromyalgia. Oxidative stress is not increased in patients with fibromyalgia, but as was previously found in patients with systemic lupus erythematosus, oxidative stress was associated with fatigue. [ABSTRACT FROM AUTHOR]

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 < 0·008 and P < 0·002, respectively). No significant differences were measured for IL-6 and the endothelial activation markers von Willebrand factor, tissue-plasminogen activator and plasmin activator inhibitor-1. Vitamin E supplementation had no significant effects on the various markers. We observed no significant interaction between juice and vitamin E. In this study, orange and blackcurrant juice reduced markers of inflammation, but not markers of endothelial activation, in patients with peripheral arterial disease, relative to sugar drinks. [ABSTRACT FROM PUBLISHER]

Background: The precise pathway by which alcohol causes the characteristic features of fetal alcohol spectrum disorders is unknown. Proposed mechanisms for fetal injury from maternal alcohol use include cellular damage from oxidative stress and impaired fetal oxygenation related to maternal systemic vasoconstriction. Our objective was to compare the levels of urinary markers of oxidative stress and systemic vasoconstriction between women consuming large amounts of alcohol during pregnancy and women who did not drink alcohol during pregnancy. Methods: Pregnant women consuming ≥48 g alcohol per day ( n = 29) on average and pregnant women who abstained from alcohol use ( n = 39) were identified using detailed interviews and home visits. Random maternal urine specimens were collected. Urinary levels of the oxidative stress marker, 8-isoprostane F2α, and of the vasoactive prostaglandin metabolites, 2,3-dinor-6-keto-prostaglandin F1α (a vasodilator) and 11-dehydro-thromboxane B2 (a vasoconstrictor), were measured using mass spectrometric methods. All analyte levels were corrected for urinary creatinine. Results: In crude analyses, there was no significant difference in 8-isoprostane F2α between pregnant drinkers and nondrinkers (2.16 vs. 2.08 ng/mg creatinine, respectively, p = 0.87). There were no significant differences between the drinking and nondrinking groups in levels of 2,3-dinor-6-keto-prostaglandin F1α (1.03 vs. 1.17 ng/mg creatinine, repectively, p = 0.50), 11-dehydro-thromboxane B2 (0.72 vs. 0.59 ng/mg creatinine, respectively, p = 0.21), or the ratio of vasodilatory metabolite to vasoconstrictive metabolite (1.73 vs. 2.72, respectively, p = 0.14). Adjusting for maternal age, marital status, smoking, and gestational age at sampling did not substantially alter the results. Conclusion: Our results show no difference in levels of urinary eicosanoid markers of oxidative stress and systemic vasoconstriction between pregnant women who drink heavily and pregnant women who abstain. These findings speak against a role for maternal oxidative stress or systemic vasoconstriction in the pathogenesis of alcohol damage to the fetus. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives. Cardiovascular risk is increased in patients with systemic lupus erythematosus (SLE). Drugs used to treat SLE can modify traditional cardiovascular risk factors. We examined the effect of selected drugs used in the treatment of SLE on cardiovascular risk factors. Methods. We compared systolic and diastolic blood pressure, serum lipid concentrations, glucose, homocysteine, and urinary F2-isoprostane concentrations in 99 patients with lupus who were either current users or non-users of systemic corticosteroids, antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, azathioprine, and methotrexate. Multivariable adjustment was done with linear regression modeling using sex, age and disease activity (SLEDAI) as controlling variables. Results. Serum triglyceride concentrations were higher (135.1 ± 61.4 vs. 95.3 ± 47.5 mg/dL, adjusted P = 0.003) in patients receiving corticosteroids. Homocysteine concentrations were marginally higher in patients receiving methotrexate (adjusted P = 0.08). Current use of either NSAIDs or COX-2 inhibitors was not associated with increased cardiovascular risk factors. Current hydroxychloroquine use was not associated with significant alterations in lipid profiles. Conclusions. In a non-random sample of patients with SLE, current corticosteroid use was associated with increased triglyceride concentrations, but other drugs had little effect on traditional cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg-1 day-1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR. [ABSTRACT FROM AUTHOR]

Lipid peroxidation of docosahexaenoic (22:6; n-3) acid (DHA) is elevated in the CNS in patients with Alzheimer’s disease and in animal models of seizure and ethanol withdrawal. One product of DHA oxidation is trans-4-hydroxy-2-hexenal (HHE), a six carbon analog of the n-6 fatty acid derived trans-4-hydroxy-2-nonenal (HNE). In this work, we studied the neurotoxic potential of HHE. HHE and HNE were toxic to primary cultures of cerebral cortical neurons with LD50’s of 23 and 18 μmol/L, respectively. Toxicity was prevented by the addition of thiol scavengers. HHE and HNE depleted neuronal GSH content identically with depletion observed with 10 μmol/L of either compound. Using an antibody raised against HHE–protein adducts, we show that HHE modified specific proteins of 75, 50, and 45 kDa in concentration- and time-dependent manners. The time-dependent formation of HHE differed from that of F4-neuroprostanes following in vitro DHA oxidation likely as a result of the different oxidation pathways involved. Using purified mitochondrial aldehyde dehydrogenase ALDH5A, we found that HHE was oxidized 6.5-fold less efficiently than HNE. Our data demonstrate that HHE and HNE have similarities but also differences in their neurotoxic mechanisms and metabolism. [ABSTRACT FROM AUTHOR]

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As evidence of the involvement of inflammation and oxidative damage in pathogenesis of age-related chronic diseases is growing, epidemiologists need to develop measures of both conditions to study their relationships in human populations. One way of searching for appropriate biomarkers is to examine correlations between different inflammatory markers and oxidative indices. We examined cross-sectional correlations between two inflammatory markers, serum C-reactive protein (CRP) and interleukin (IL)-6, and three oxidative indices, plasma levels of α-tocopherol and β-carotene, and urinary levels of 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoP), in 60 individuals at high risk of cardiovascular disease. Correlations between the biomarkers were examined graphically and using the Pearson correlation coefficient. No correlation was found between plasma levels of α-tocopherol and either of the inflammatory markers. Plasma β-carotene inversely correlated with IL-6 (r=-0.46, p=0.0002) and CRP (r=-0.41, p=0.001). Although urinary F2-IsoP did not correlate with IL-6, this biomarker positively correlated with CRP (r=0.31, p=0.002). As only urinary F2-IsoP levels have been validated against known oxidative assaults, their positive association with CRP levels is interpreted as evidence of an interconnection between low-level inflammation and oxidative status. Urinary levels of F2-IsoP and serum levels of CRP represent appropriate biomarkers for future studies of inflammation and oxidative status in humans. [ABSTRACT FROM AUTHOR]

Incomplete suppression of thromboxane biosynthesis during aspirin therapy is associated with increased cardiovascular risk. Since systemic lupus erythematosus (SLE) is associated with platelet activation and increased cardiovascular mortality, we compared thromboxane and prostacyclin biosynthesis in patients with SLE and control subjects, and measured inhibition of thromboxane excretion in aspirin-treated subjects. We measured the urinary excretion of 11-dehydro thromboxane B2 (TXB2) and 2,3-dinor 6-ketoPGF1α (PGI-M), the stable metabolites of thromboxane A2 and prostacyclin, respectively, in 74 patients with SLE and 70 controls. In subjects who were not receiving aspirin, TXB2 excretion was higher in patients with SLE [0.40 ng/mg creatinine (0.26-0.64), median (interquartile range)] than controls [0.31 ng/mg creatinine (0.23-0.44)] (P = 0.04), and in these patients, TXB2 excretion correlated with disease activity (rho = 0.28, P = 0.03) and tumor necrosis factor alpha (rho = 0.48, P = 0.001). Aspirin therapy resulted in significantly lower TXB2 excretion in controls (P = 0.01), but not in patients with SLE (P = 0.10), compared with subjects not receiving aspirin. Prostacyclin biosynthesis did not differ among patients and controls, and was not affected by aspirin (P all =0.35). Thromboxane biosynthesis is increased in SLE and is associated with disease activity. Additionally, response to aspirin may be attenuated in some patients with SLE. [ABSTRACT FROM AUTHOR]

Although fish oil has hypolipidemic and antiatherosclerotic properties, the potential for white adipose tissue (WAT) to mediate these effects has not been studied. LDL-receptor deficient (LDLR-/-) mice were fed high fat, olive oil-containing diets supplemented with additional olive oil or with fish oil for 12 wk. Fish oil feeding significantly reduced plasma lipid levels. In contrast, lipid storage in WAT was increased in fish oil-fed mice as evidenced by increased total fat (P < 0.05) and perigonadal WAT mass (P < 0.05), increased cholesterol storage (P < 0.001), and adipocyte hypertrophy. Despite increased adipose tissue mass, WAT-specific inflammation and insulin sensitivity were improved (P < 0.05), concomitant with reduced macrophage infiltration. Furthermore, fish oil increased WAT and plasma levels of adiponectin. In addition, fish oil feeding decreased the formation of proinflammatory F2- isoprostanes, markers of oxidative stress (P < 0.05). The increased WAT lipid storage in fish oil-fed mice was associated with reduced lipid accumulation in liver (P < 0.05) and decreased atherosclerotic lesion area (P < 0.05). Taken together, these data highlight the specific role of WAT in regulating dietary fish oil-mediated improvement in systemic lipid homeostasis and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Recent data suggest that acute hyperglycemia may increase in vivo free radical production. This increased production has been implicated in many disease processes. Objective: The objective was to investigate whether a diet with a high glycemic index (GI) or glycemic load (GL) is associated with greater oxidative stress as measured by 2 lipid peroxidation markers, malondialdehyde (MDA) and F2-isoprostanes (IsoPs). Design: Plasma MDA and IsoP concentrations were measured in 292 healthy adults, and dietary GI and GL were assessed by using a validated food-frequency questionnaire. Cross-sectional associations between GI, GL, and the 2 markers were examined by using multiple regression techniques with adjustment for potential confounding variables. Results: Dietary GI was positively associated with both plasma MDA and IsoPs. The mean multivariate-adjusted MDA concentrations increased from 0.55 to 0.73 μmol/L as GI increased from the lowest to the highest quartile (P for trend=0.02); the corresponding IsoP concentrations increased from 0.034 to 0.040 ng/mL (P for trend = 0.03). GL was positively associated with both MDA and IsoPs, but the linear relation was significant only for MDA. In addition, a marginally significant interaction between overall GI and body mass index (BMI; in kg/m2) for plasma MDA was observed (P = 0.09). The positive association between overall GI and MDA was stronger in those with a BMI < 26.5 than for those with a BMI ⩾ 26.5. Conclusions: Chronic consumption of high-GI foods may lead to chronically high oxidative stress. A low-GI diet, not a low-carbohydrate diet, appears to be beneficial in reducing oxidative stress. [ABSTRACT FROM AUTHOR]

Oxidative stress and subsequent lipid peroxidation are involved in the pathogenesis of numerous neurodegenerative conditions, including stroke. Cyclopentenone isoprostanes (IsoPs) are novel electrophilic lipid peroxidation products formed under conditions of oxidative stress via the isoprostane pathway. These cyclopentenone IsoPs are isomeric to highly bioactive cyclopentenone prostaglandins, yet it has not been determined if these products are biologically active or are formed in the brain. Here we demonstrate that the major cyclopentenone IsoP isomer 15-A2t-IsoP potently induces apoptosis in neuronal cultures at submicromolar concentrations. We present a model in which 15-A2t-IsoP induced neuronal apoptosis involves initial depletion of glutathione and enhanced production of reactive oxygen species, followed by 12-lipoxygenase activation and phosphorylation of extracellular signal-regulated kinase 1/2 and the redox sensitive adaptor protein p66shc, which results in caspase-3 cleavage. 15-A2t-IsoP application also dramatically potentiates oxidative glutamate toxicity at concentrations as low as 100 nm, demonstrating the functional importance of these molecules in neurodegeneration. Finally, we employ novel mass spectrometric methods to show that cyclopentenone IsoPs are formed abundantly in brain tissue under conditions of oxidative stress. Together these findings suggest that cyclopentenone IsoPs may contribute to neuronal death caused by oxidative insults, and that their activity should perhaps be addressed when designing neuroprotective therapies. [ABSTRACT FROM AUTHOR]

Electrophilic lipids, such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-Δ12.14-prostaglandin J2 (15d-PGJ2) and 15-J2-isoprostane induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses, such as heme oxygenase-1 (HO-1) and glutathione (GSH). When we compared the ability of these distinct electrophiles to stimulate GSH and HO-1 production, the cyclopentenone electrophiles were somewhat more potent than HNE. Over the concentration range required to observe equivalent induction of GSH, dichlorofluorescein fluorescence was used to determine both the location and amounts of electrophilic lipid-dependent ROS formation in endothelial cells. The origin of the ROS on exposure to these compounds was largely mitochondrial. To investigate the possibility that the increased ROS formation was due to mitochondrial localization of the lipids, we prepared a novel fluorescently labeled form of the electrophilic lipid 15d-PGJ2. The lipid demonstrated strong colocalization with the mitochondria, an effect which was not observed by using a fluorescently labeled nonelectrophilic lipid. The role of mitochondria was confirmed by using cells deficient in functional mitochondria. On the basis of these data, we propose that ROS formation in endothelial cells is due to the direct interaction of these lipids with the organelle. [ABSTRACT FROM AUTHOR]

In the spontaneously hypertensive rat (SHR) and aging Wistar–Kyoto rats (WKY), acetylcholine releases an endothelium-derived contracting factor (EDCF) produced by endothelial cyclooxygenase-1, which stimulates thromboxane A2 receptors (TP receptors) on vascular smooth muscle. The purpose of the present study was to identify this EDCF by measuring changes in isometric tension and the release of various prostaglandins by acetylcholine.In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H2, PGF2α, PGE2, PGD2, prostacyclin (PGI2) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619≫8-isoprostane=PGF2α=PGH2>PGE2=PGD2>PGI2). The contractions produced by PGH2 and PGI2 were fast and transient, mimicking endothelium-dependent contractions. PGI2 did not relax isolated aortic rings of WKY and SHR.Acetylcholine evoked the endothelium-dependent release of thromboxane A2, PGF2α, PGE2, PGI2 and most likely PGH2 (PGI2≫PGF2αPGE2>TXA2>8-isoprostane, PGD2). Dazoxiben abolished the production of thromboxane A2, but did not influence the endothelium-dependent contractions to acetylcholine.The release of PGI2 was significantly larger in the aorta of SHR than in WKY, and the former was more sensitive to the contractile effect of PGI2 than the latter. The inhibition of PGI-synthase was associated with an increase in PGH2 spillover and the enhancement of acetylcholine-induced endothelium-dependent contractions.Thus, in the aorta of SHR and aging WKY, the endothelium-dependent contractions elicited by acetylcholine most likely involve the release of PGI2 with a concomitant contribution of PGH2.British Journal of Pharmacology (2005) 146, 834–845. doi:10.1038/sj.bjp.0706390; published online 12 September 2005 [ABSTRACT FROM AUTHOR]

The isoprostanes are a unique series of prostaglandin-like compounds formed in vivo via a non-enzymatic mechanism involving the free radical-initiated peroxidation of arachidonic acid. This article summarizes selected aspects regarding current knowledge of these compounds and their value as markers of oxidative injury. Novel aspects related to the biochemistry of isoprostane formation are discussed and methods by which these compounds can be analysed and quantified are summarized. A considerable portion of this article examines the utility of F 2 -isoprostanes as markers of oxidant injury in vivo . Numerous studies carried out over the past decade have shown that these compounds are extremely accurate measures of lipid peroxidation and have illuminated the role of oxidant injury in a number of human diseases including atherosclerosis, Alzheimer's disease and pulmonary disorders. [ABSTRACT FROM AUTHOR]

Lipid peroxidation and the accompanying translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the lipid bilayer have recently been identified as key components of a signaling pathway for phagocytosis of apoptotic cells by macrophages. Drug-induced hemolytic anemia has long been known to be caused by an accelerated uptake of damaged (but intact) erythrocytes by macrophages in the spleen, and this process has been associated with enhanced formation of reactive oxygen species (ROS). However, the role of lipid peroxidation in hemolytic injury has remained unclear, and the effect of hemolytic agents on the distribution of PS in the erythrocyte membrane is unknown. The present studies were undertaken to determine whether lipid peroxidation and PS translocation could be detected in rat and human erythrocytes by three types of direct-acting hemolytic agents—dapsone hydroxylamine, divicine hydroquinone, and phenylhydrazine. 2′,7′-Dichlorodihydrofluorescein diacetate was employed as a probe for intracellular ROS formation; lipid peroxidation was assessed by GC/MS analysis of F2-isoprostanes; and PS externalization was measured by annexin V labeling and the prothrombinase assay. The data confirmed that all three hemolytic agents generate ROS within erythrocytes under hemolytic conditions; however, no evidence for lipid peroxidation or PS translocation was detected. Instead, ROS production by these hemolytic agents was associated with extensive binding of oxidized and denatured hemoglobin to the membrane cytoskeleton. The data suggest that the transmembrane signal for macrophage recognition of hemolytic injury may be derived from oxidative alterations to erythrocyte proteins rather than to membrane lipids. [ABSTRACT FROM AUTHOR]

Objective: This study examined whether, daily fruit (blueberries) consumption (250 g) for three weeks or acute fruit ingestion (250 g) would attenuate angiotensin converting enzyme (ACE) activity and reduce oxidative stress in chronic cigarette smokers. Methods: Twenty subjects were recruited and randomized into fruit or control groups. Blood samples and blood pressure were obtained at baseline and then pre and one hour post when subjects returned to the lab three weeks later. To examine acute effects, the fruit group immediately ingested 250 g of blueberries after returning and at least one hour prior to the post blood draw. Plasma samples were analyzed for ACE activity, F 2 - isoprostanes and lipid hydroperoxides (LH) as measures of oxidative stress, and ferric reducing ability of plasma (FRAP) as a measure of antioxidant potential. A 2 (treatment) × 3 (time) repeated measures ANOVA was used for statistical analysis. If interaction was significant, then Student's t -tests were used to further examine this relationship. For these comparisons, a Bonferroni adjustment was made with statistical significance set at P < 0.025. Results: The pattern of change between treatments was not significant for any variable except LH ( P < 0.001). Conclusion: This study indicates that LH are significantly reduced by daily fruit consumption, but not affected by acute ingestion. This finding could be one way in which fruit consumption contributes to prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Some research studies have produced data indicating that resistance exercise induces oxidative stress, despite minimal increases in VO 2 . These studies have primarily relied on oxidative stress markers with low sensitivity and debatable reliability. However, F 2 -isoprostanes as measured by gas chromatography mass spectrometry are considered to be a reliable and precise indicator of oxidative stress. Carbohydrate ingestion during exercise is associated with reduced levels of stress hormones, which may influence oxidative stress and plasma antioxidant potential. Therefore, the purpose of this study was to investigate the influence of carbohydrate ingestion during resistance training on F 2 -isoprostanes and plasma antioxidant potential. Thirty strength-trained subjects were randomized to carbohydrate (CHO) or placebo (PLA) groups that lifted weights for 2 h. Subjects received 10 ml kg - 1 h - 1 CHO (6%) or PLA beverages during the exercise. Blood and vastus lateralis muscle biopsy samples were collected before and after exercise and analyzed for cortisol as a marker of general stress, F 2 -isoprostanes as a measure of oxidative stress, and ferric reducing ability of plasma (FRAP) as a measure of antioxidant potential, and for muscle glycogen, respectively. Decreases in muscle glycogen content did not differ between CHO and PLA. Cortisol and FRAP increased significantly in CHO and PLA ( P = 0.008 and 0.044, respectively), but the pattern of change was not different between groups. F 2 -isoprostanes were unaffected by exercise. These results indicate that exhaustive resistance exercise and carbohydrate ingestion have no effect on oxidative stress or plasma antioxidant potential in trained subjects. [ABSTRACT FROM AUTHOR]

The article discusses the position of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) concerning issues about dietary supplement safety and regulation. ASCPT has established the ASCPT Task Force on Dietary Supplements, under the U.S. Committee on Government Affairs, to examine the issue and provide recommendations for changes in Dietary Supplement Health and Education Act (DSHEA). Its goal is to increase the safety of the dietary supplements for the consumers.

Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases. [ABSTRACT FROM AUTHOR]

We investigated the effect of long-term vitamin E deficiency (38 weeks) on free radical (superoxide) production and free radical products (neuroprostanes and isoprostanes) and on mitochondrial function (oxygraph and electron transport chain activities) in C57B6J mice. We found that after 38 weeks, while liver was approximately 95% deficient, the brain had retained approximately 50% of its α-tocopherol. We also found that superoxide production was lowered in multiple brain regions of male vitamin E-deficient mice, as were neuroprostanes. Oxygraph studies showed higher respiratory control ratios (RCRs) in liver and lower RCRs in brain, which did not appear to be due to changes in electron transport chain activities. We conclude that vitamin E can function in vivo in both its traditional role as a lipid-soluble antioxidant as well as in non-traditional roles in the mitochondria. [ABSTRACT FROM AUTHOR]

To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5 months old), middle-aged (15 months old), and old (25 months old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 hours after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P <.01). Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate early genes found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart. [ABSTRACT FROM AUTHOR]

Patients with the metabolic syndrome have three or more of five cardiovascular risk factors and increased oxidative stress, arterial stiffness and pressor responses to exercise, which may contribute to their threefold greater risk for coronary heart disease. In addition to lowering basal blood pressure (BP), angiotensin receptor blockers (ARBs) may benefit metabolic syndrome patients by reducing oxidative stress, arterial stiffness, and pressor responses to exercise. Twelve patients, 7 women and 5 men, with the metabolic syndrome (aged 45 ± 2 years, BP 145 ± 5/85 ± 2 mm Hg, waist girth 110 ± 3 cm, triglycerides 186 ± 23 mg/dL, HDL cholesterol 44 ± 2 mg/dL, glucose 99 ± 3 mg/dL) were studied off medications, while on modest sodium restriction (∼100 mmol/d). Patients were randomized to the ARB losartan or placebo for 3 weeks then crossed over to the complement for 3 weeks. Studies were performed at the end of each phase following an overnight fast. Serum lipids and biomarkers of oxidative stress (F2-isoprostanes, thiobarbituric acid reacting substances) were unchanged by losartan, whereas large artery elasticity at rest, measured with the HDI PulseWave, increased from 13.6 ± 0.7 on placebo to 16.2 ± 1.1 mL/mm Hg on losartan, P < .05. Losartan lowered systolic BP pre-exercise from 142 ± 3 to 131 plusmn; 3 mm Hg (P < .001) and systolic BP after 6 min of treadmill exercise from 192 ± 6 to 169 ± 5 mm Hg (P < .001). Losartan lowered systolic BP (-23 ± 3 v -11 ± 2 mm Hg, P < .05) and pulse pressure (-4 ± 1 v -15 ± 2 mm Hg, P < .05) more during exercise than rest. Losartan reduces the pressor response to exercise, perhaps by enhancing arterial compliance. In addition to lowering basal BP, angiotensin receptor blockade in patients with metabolic syndrome improves arterial compliance and reduces pressor reactivity to exercise. [Copyright &y& Elsevier]

We report the first longitudinal analysis of cerebrospinal fluid (CSF) F2-isoprostanes (IsoPs), quantitative in vivo biomarkers of lipid peroxidation, in patients with mild Alzheimer's disease (AD). CSF F2-IsoPs (i) were significantly increased in patients followed over one year, (ii) correlated with some clinical indices of dementia following correction for variation in ventricular enlargement, and (iii) were significantly lower in patients who used both alpha-tocopherol and vitamin C. [ABSTRACT FROM AUTHOR]

We report the first longitudinal analysis of cerebrospinal fluid (CSF) _2-isoprostanes (IsoPs), quantitative in vivo biomarkers of lipid peroxidation, in patients with mild Alzheimer's disease (AD). CSF_2-IsoPs (i) were significantly increased in patients followed over one year, (ii) correlated with some clinical indices of dementia following correction for variation in ventricular enlargement, and (iii) were significantly lower in patients who used both α-tocopherol and vitamin C. [ABSTRACT FROM AUTHOR]

This randomized study measured the influence of vitamin C ( N=15) compared to placebo ( N=13) supplementation on oxidative and salivary immunoglobulin A (sIgA) changes in runners competing in an ultramarathon race. Seven days prior to the race, subjects ingested in randomized, double-blind fashion three 500-mg tablets of vitamin C or placebo each day. On race day, blood and saliva samples were collected 1 h pre-race, after 32 km of running, and then again immediately post-race. During the race, runners received 1 l/h carbohydrate beverages (60 g/l) with vitamin C (150 mg/l) or without in a double-blinded fashion. The runners also ingested two to three carbohydrate gel packs per hour (25 g each). Subjects in both groups ran a mean of 69 km (range 48-80 km) in 9.8 h (range 5-12 h) and maintained an intensity of approximately 75% maximal heart rate (HR(max)) throughout the ultramarathon race. Plasma ascorbic acid was higher in the vitamin C compared to placebo group pre-race, and increased significantly in the vitamin C group during the race [post-race, 3.21 (0.29) and 1.28 (0.12) microg/100 microl, respectively, P<0.001]. No significant group or interaction effects were measured for lipid hydroperoxide and F(2)-isoprostane, but both oxidative measures rose significantly during the ultramarathon race. Saliva volume, sIgA concentration, sIgA secretion and sIgA:saliva protein ratio all decreased significantly (P<0.001) during the race, but the pattern of change in all saliva measures did not differ significantly between groups. No significant correlations were found between post-race plasma vitamin C, oxidative, and saliva measures, except for a positive correlation between post-race serum cortisol and serum vitamin C (r=0.50, P=0.006). These data indicate that vitamin C supplementation in carbohydrate-fed runners does not serve as a countermeasure to oxidative and sIgA changes during or following a competitive ultramarathon race. [ABSTRACT FROM AUTHOR]

Exposure to environmental tobacco smoke (ETS) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers. Current research suggests that some of these diseases are associated with elevated oxidative stress. We investigated the effect of antioxidant (AO) intervention on the lipid peroxidation biomarker F[SUB2]-isoprostanes (F[SUB2]-IsoPs), an index of oxidative stress, in plasma of nonsmokers exposed to ETS (passive smokers). We measured free F[SUB2]-IsoP concentrations in plasma of 67 passive smokers at baseline and after 2 mo of daily intervention with AOs or placebo. The study subjects (47 females, 20 males; mean age 46 ± 15) were randomized into one of three treatment groups: vitamin C, "mixture" (vitamin C, vitamin E, and α-lipoic-acid), and placebo. Investigated confounders included plasma baseline AO levels, lipid and total cholesterol profiles, transferrin saturation, and C-reactive protein. Plasma F[SUB2] IsoP concentrations of subjects in the vitamin C and mixture groups decreased significantly by 17.2 pmol/l (P = 0.0105) and 19.2 pmol/l (P = 0.0083) when compared with the placebo group (11.4% and 12.7%, respectively). Daily AO supplementation (especially with vitamin C) decreases this oxidative stress biomarker in passive smokers. This finding might be of importance for the prevention of ETS-associated adverse health effects in nonsmokers. [ABSTRACT FROM AUTHOR]

To better understand the pathogenesis of herpes simplex virus type 1 (HSV-1) infections of the nervous system, concentrations of F 4 -neuroprostanes (F 4 -NP) and F 2 -isoprostanes (F 2 -IP) in the murine brain were determined following intracerebral inoculation of HSV-1 or normal saline. F 4 -NP are highly selective, quantitative markers of neuronal oxidative damage, while F 2 -IP are markers of oxidative damage to brain tissue not limited to a certain cell type. In contrast to saline-treated control animals, HSV-1-infected animals developed encephalitic symptoms associated with severe inflammation, widespread HSV-1 protein expression, and significantly elevated F 4 -NP and F 2 -IP levels in the brain. Survivors of acute HSV-1 infection showed no encephalitic symptoms 2 to 3 weeks following virus inoculation. Brain tissue derived from mice euthanized 2 month after virus inoculation demonstrated expression of HSV-1 latency-associated transcripts without detectable HSV-1 protein expression. However, brain tissue from these animals showed focal chronic inflammation, moderately elevated F 2 -IP levels, and normal levels of F 4 -NP. These observations provide novel biochemical evidence that oxidant tissue injury is a mechanism underlying neuronal damage during acute HSV-1 encephalitis and suggest that oxidative damage to tissue may continue in the mammalian brain until at least several weeks after recovery from the symptomatic phase of HSV-1 infection. Journal of NeuroVirology (2002) 8, 295-305. [ABSTRACT FROM AUTHOR]

Oxidation of biomolecules may play a role in susceptibility to a number of diseases. However, there are few large-scale survey data describing oxidative damage that occurs in humans and the demographic, physical, or nutritional factors that may be associated with it. Such information is essential for the design and analysis of studies investigating the role of oxidative stress in health and disease. This paper presents data on levels of two biomarkers of lipid peroxidation, malondialdehyde and F2-isoprostanes, in 298 healthy adults aged 19–78 years. The study was conducted in Berkeley and Oakland, California, in 1998–1999. Sex was the strongest predictor of lipid peroxidation as measured by both biomarkers (p < 0.0001); it was stronger than smoking. C-reactive protein was positively associated with lipid peroxidation (p = 0.004), as was plasma cholesterol. Plasma ascorbic acid had a strong inverse relation (p < 0.001) with both biomarkers. Plasma β-carotene was also associated with F2-isoprostanes. Other plasma antioxidants were not associated with lipid peroxidation biomarkers, once ascorbic acid was included in the multivariate model. Future surveys and epidemiologic studies should measure at least one marker of oxidative damage, as well as plasma ascorbic acid. These data would permit a better understanding of the role that oxidants and antioxidants play in the health of human populations. Am J Epidemiol 2002;156:274–85. [ABSTRACT FROM PUBLISHER]