Plasma F2-isoprostane Concentrations Research Articles

Carotenoids and Markers of Oxidative Stress in Human Observational Studies and Intervention Trials: Implications for Chronic Diseases.

Carotenoids include C30, C40 and C50 terpenoid-based molecules, many of which constitute coloured pigments. However, >1100 of these are known to occur in nature and only about a dozen are known to play a role in our daily diet. Carotenoids have received much attention due to their proposed health benefits, including reducing the incidence of chronic diseases, such as cardiovascular disease and diabetes. Many of these diseases are characterized by chronic inflammation co-occurring with oxidative stress, characterized by, for example, enhanced plasma F2-isoprostane concentrations, malondialdehyde, and 8-hydroxyguanosine. Though carotenoids can act as direct antioxidants, quenching, for example, singlet oxygen and peroxide radicals, an important biological function appears to rest also in the activation of the body’s own antioxidant defence system, related to superoxide-dismutase, catalase, and glutathione-peroxidase expression, likely due to the interaction with transcription factors, such as nuclear-factor erythroid 2-related factor 2 (Nrf-2). Though mostly based on small-scale and observational studies which do not allow for drawing conclusions regarding causality, several supplementation trials with isolated carotenoids or food items suggest positive health effects. However, negative effects have also been reported, especially regarding beta-carotene for smokers. This review is aimed at summarizing the results from human observational studies/intervention trials targeting carotenoids in relation to chronic diseases characterized by oxidative stress and markers thereof.

Higher plasma levels of F2-isoprostanes are associated with slower psychomotor speed in healthy older adults

Oxidative stress has been identified as a process which is detrimental to brain health, and associated with age-related cognitive declines. Few studies to-date have examined the relationship between in vivo oxidative stress biomarkers and cognitive performance within healthy elderly populations. The current study investigated the relationship between reaction time and oxidative stress, as measured by blood plasma concentrations of F2-isoprostanes using a sample of 251 healthy, non-demented, elderly volunteers (Male; 111: Female 140) aged 60–75 years from the Australian Research Council Longevity Intervention (ARCLI) study cohort. A Jensen Box was used in conjunction with the Hick paradigm in order to differentiate simple from choice reaction time (two, four and eight-choice conditions) as well as movement (MT) and decision times (DT). MT, but not DT, was found to be significantly slower for participants in the high F2-isoprostane group compared to the low F2-isoprostane group, across all stimulus choices. F2-isoprostanes, age and Wechsler Abbreviated Scale of Intelligence (WASI) full scale intelligence quotient (IQ) were found to be significant predictors of average MT in the sample as a whole. These findings provide preliminary evidence to suggest that higher levels of oxidative stress may be associated with impaired psychomotor speed in the healthy elderly population.

Prevalence of Thiamin Deficiency in Ambulatory Patients with Heart Failure

BackgroundThiamin is a required coenzyme in energy production reactions that fuel myocardial contraction. Therefore, thiamin deficiency (TD) may aggravate cardiac dysfunction in patients with systolic heart failure (HF). ObjectiveTo determine the prevalence of TD in ambulatory participants with HF as well as the relationships between thiamin status and HF severity, dietary thiamin intake, diuretic use, and circulating neurohormones. DesignA cross-sectional study comparing the prevalence of TD in ambulatory patients with HF with that of controls. Demographic, anthropometric, nutrition, medication use, and heart function data were collected from direct interviewing, questionnaires, and medical records. Blood samples were obtained to measure levels of neurohormones and assess TD. Participants/settingFifty age-matched control participants without HF and 100 outpatients with HF and reduced left ventricular function were recruited from clinics at St Michael’s Hospital, University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada, between September 2009 and February 2011. Main outcome measuresTo assess TD, erythrocyte thiamin pyrophosphate (TPP) was measured using high-performance liquid chromatography. TD was defined as TPP<6.07 μg/dL (180 nmol/L). Statistical analyses performedPrevalence rates were analyzed using χ2 test. Nonparametric statistics (Jonckheere-Terpstra, Kruskal-Wallis, Spearman’s correlation) were used to assess TPP levels in relation to HF severity, medication use and plasma concentrations of F2-isoprostanes, norepinephrine, and N-terminal pro-brain natriuretic peptide (NT-proBNP). ResultsThere was no significant difference in the prevalence of TD in outpatients with HF (6%) and controls (6%) (P=0.99). No relationship was found between heart function, thiamin intake, use or dose of diuretics, and TD. A positive relationship was observed between erythrocyte TPP and F2-isoprostane levels (rs=0.22, P=0.03) but not between erythrocyte TPP and norepinephrine (P=0.45) and NT-proBNP (P=0.58). ConclusionThe prevalence of TD was low in ambulatory HF participants suggesting that, unlike hospitalized patients, ambulatory patients may be at a low risk for TD.

Metabolic Effects of Diet and Exercise in Patients with Moderate to Severe CKD: A Randomized Clinical Trial.

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F2-isoprostane concentrations, and peak oxygen uptake (VO2 peak). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F2-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO2 peak, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

The Risk of Oxygen during Cardiac Surgery (ROCS) trial: study protocol for a randomized clinical trial

BackgroundAnesthesiologists administer excess supplemental oxygen (hyper-oxygenation) to patients during surgery to avoid hypoxia. Hyper-oxygenation, however, may increase the generation of reactive oxygen species and cause oxidative damage. In cardiac surgery, increased oxidative damage has been associated with postoperative kidney and brain injury. We hypothesize that maintenance of normoxia during cardiac surgery (physiologic oxygenation) decreases kidney injury and oxidative damage compared to hyper-oxygenation.Methods/designThe Risk of Oxygen during Cardiac Surgery (ROCS) trial will randomly assign 200 cardiac surgery patients to receive physiologic oxygenation, defined as the lowest fraction of inspired oxygen (FIO2) necessary to maintain an arterial hemoglobin saturation of 95 to 97%, or hyper-oxygenation (FIO2 = 1.0) during surgery. The primary clinical endpoint is serum creatinine change from baseline to postoperative day 2, and the primary mechanism endpoint is change in plasma concentrations of F2-isoprostanes and isofurans. Secondary endpoints include superoxide production, clinical delirium, myocardial injury, and length of stay. An endothelial function substudy will examine the effects of oxygen treatment and oxidative stress on endothelial function, measured using flow mediated dilation, peripheral arterial tonometry, and wire tension myography of epicardial fat arterioles.DiscussionThe ROCS trial will test the hypothesis that intraoperative physiologic oxygenation decreases oxidative damage and organ injury compared to hyper-oxygenation in patients undergoing cardiac surgery.Trial registrationClinicalTrials.gov, ID: NCT02361944. Registered on the 30th of January 2015.

Effect of Coenzyme Q10 on Biomarkers of Oxidative Stress and Cardiac Function in Hemodialysis Patients: The CoQ10 Biomarker Trial

Oxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis. Placebo-controlled, 3-arm, double-blind, randomized, clinical trial. 65 patients undergoing thrice-weekly maintenance hemodialysis. Patients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10; 600 or 1,200mg) or matching placebo for 4 months. The primary outcome was plasma oxidative stress, defined as plasma concentration of F2-isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability. F2-isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro-brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months. Of 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200mg, but not 600mg, of CoQ10 significantly reduced plasma F2-isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of-10.7 [95% CI,-7.1 to-14.3] pg/mL [P<0.001] and-8.3 [95% CI,-5.5 to-11.0] pg/mL [P=0.1], respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures. Study not powered to detect small treatment effects; difference in baseline characteristics among randomized groups. In patients undergoing maintenance hemodialysis, daily supplementation with 1,200mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2-isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.

Absence of systemic oxidative stress and increased CSF prostaglandin F2α in progressive MS.

Objective:We aimed to investigate the role of oxidative stress in the progression of multiple sclerosis (MS).Methods:We determined by liquid chromatography–tandem mass spectrometry nonenzymatic (F2-isoprostanes) and enzymatic oxidation products of arachidonic acid (prostaglandin F2α [PGF2α]) in plasma and CSF of 45 controls (other neurologic disease [OND] with no signs of inflammation) and 62 patients with MS. Oxidation products were correlated with disease severity and validated biomarkers of inflammation (chemokine ligand 13; matrix metalloproteinase-9; osteopontin) and axonal damage (neurofilament light protein).Results:Compared with OND controls, plasma concentrations of F2-isoprostanes and PGF2α were significantly lower in patients with progressive disease, and decreased with increasing disability score (Expanded Disability Status Scale). In contrast, CSF concentrations of PGF2α, but not F2-isoprostanes, were significantly higher in patients with progressive disease than OND controls (p < 0.01). The content of PGF2α in CSF increased with disease severity (p = 0.044) and patient age (p = 0.022), although this increase could not be explained by age. CSF PGF2α decreased with natalizumab and methylprednisolone treatment and was unaffected by the use of nonsteroidal anti-inflammatory drug in secondary progressive MS. CSF PGF2α did not associate with validated CSF markers of inflammation and axonal damage that themselves did not associate with the Expanded Disability Status Scale.Conclusions:Our data suggest that MS progression is associated with low systemic oxidative activity. This may contribute to immune dysregulation with CNS inflammation accompanied by increased local cyclooxygenase-dependent lipid oxidation.

Paleolithic and Mediterranean Diet Pattern Scores Are Inversely Associated with Biomarkers of Inflammation and Oxidative Balance in Adults

Background:Chronic inflammation and oxidative balance are associated with poor diet quality and risk of cancer and other chronic diseases. A diet–inflammation/oxidative balance association may relate to evolutionary discordance.Objective:We investigated associations between 2 diet pattern scores, the Paleolithic and the Mediterranean, and circulating concentrations of 2 related biomarkers, high-sensitivity C-reactive protein (hsCRP), an acute inflammatory protein, and F2-isoprostane, a reliable marker of in vivo lipid peroxidation.Methods:In a pooled cross-sectional study of 30- to 74-y-old men and women in an elective outpatient colonoscopy population (n = 646), we created diet scores from responses on Willett food-frequency questionnaires and measured plasma hsCRP and F2-isoprostane concentrations by ELISA and gas chromatography–mass spectrometry, respectively. Both diet scores were calculated and categorized into quintiles, and their associations with biomarker concentrations were estimated with the use of general linear models to calculate and compare adjusted geometric means, and via unconditional ordinal logistic regression.Results:There were statistically significant trends for decreasing geometric mean plasma hsCRP and F2-isoprostane concentrations with increasing quintiles of the Paleolithic and Mediterranean diet scores. The multivariable-adjusted ORs comparing those in the highest with those in the lowest quintiles of the Paleolithic and Mediterranean diet scores were 0.61 (95% CI: 0.36, 1.05; P-trend = 0.06) and 0.71 (95% CI: 0.42, 1.20; P-trend = 0.01), respectively, for a higher hsCRP concentration, and 0.51 (95% CI: 0.27, 0.95; P-trend 0.01) and 0.39 (95% CI: 0.21, 0.73; P-trend = 0.01), respectively, for a higher F2-isoprostane concentration.Conclusion: These findings suggest that diets that are more Paleolithic- or Mediterranean-like may be associated with lower levels of systemic inflammation and oxidative stress in humans.

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BackgroundCoenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress.MethodsWe performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships.ResultsFifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study.ConclusionsCoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis.Trial RegistrationThis clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009.

Endogenously elevated bilirubin modulates kidney function and protects from circulating oxidative stress in a rat model of adenine-induced kidney failure.

Mildly elevated bilirubin is associated with a reduction in the presence and progression of chronic kidney disease and related mortality, which may be attributed to bilirubin’s antioxidant properties. This study investigated whether endogenously elevated bilirubin would protect against adenine-induced kidney damage in male hyperbilirubinaemic Gunn rats and littermate controls. Animals were orally administered adenine or methylcellulose solvent (vehicle) daily for 10 days and were then monitored for 28 days. Serum and urine were assessed throughout the protocol for parameters of kidney function and antioxidant/oxidative stress status and kidneys were harvested for histological examination upon completion of the study. Adenine-treated animals experienced weight-loss, polyuria and polydipsia; however, these effects were significantly attenuated in adenine-treated Gunn rats. No difference in the presence of dihydroadenine crystals, lymphocytic infiltration and fibrosis were noted in Gunn rat kidneys versus controls. However, plasma protein carbonyl and F2-isoprostane concentrations were significantly decreased in Gunn rats versus controls, with no change in urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine or kidney tissue F2-isoprostane concentrations. These data indicated that endogenously elevated bilirubin specifically protects from systemic oxidative stress in the vascular compartment. These data may help to clarify the protective relationship between bilirubin, kidney function and cardiovascular mortality in clinical investigations.

A Pilot Randomized Crossover Trial Assessing the Safety and Short-Term Effects of Pomegranate Supplementation in Hemodialysis Patients

Oxidative stress and systemic inflammation are highly prevalent in patients undergoing maintenance hemodialysis (MHD) and are linked to excess cardiovascular risk. This study examined whether short-term supplementation with pomegranate juice and extract is safe and well tolerated by MHD patients. The secondary aim was to assess the effect of pomegranate supplementation on oxidative stress, systemic inflammation, monocyte function, and blood pressure. Prospective, randomized, crossover, pilot clinical trial (NCT01562340). The study was conducted from March to October 2012 in outpatient dialysis facilities in the Seattle metropolitan area. Twenty-four patients undergoing MHD (men, 64%; mean age, 61±14years) were randomly assigned to receive pomegranate juice or extract during a 4-week intervention period. After a washout period, all patients received the alternative treatment during a second 4-week intervention period. Patients assigned to receive pomegranate juice received 100mL of juice before each dialysis session. Patients assigned to receive pomegranate extract were given 1,050mg of extract daily. The main outcome measures were safety and tolerability of pomegranate juice and extract. Additional secondary outcomes assessed included serum lipids, laboratory biomarkers of inflammation (C-reactive protein and interleukin 6) and oxidative stress (plasma F2 isoprostanes and isofurans), monocyte cytokine production, and predialysis blood pressure. Both pomegranate juice and extract were safe and well tolerated by study participants. Over the study period, neither treatment had a significant effect on lipid profiles, plasma C-reactive protein, interleukin 6, F2-isoprostane or isofuran concentrations, predialysis systolic or diastolic blood pressure nor changed the levels of monocyte cytokine production. Both pomegranate juice and extract are safe and well tolerated by patients undergoing MHD but do not influence markers of inflammation or oxidative stress nor affect predialysis blood pressure.

Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass.

Hemolysis, occurring during cardiopulmonary bypass, is associated with lipid peroxidation and postoperative acute kidney injury. Acetaminophen inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced acute kidney injury. This pilot study tests the hypothesis that acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass. Single-center prospective randomized double-blinded study. University-affiliated pediatric hospital. Thirty children undergoing elective surgical correction of a congenital heart defect. Patients were randomized to acetaminophen (OFIRMEV [acetaminophen] injection; Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for four doses starting before the onset of cardiopulmonary bypass. Markers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes), and acute kidney injury were measured throughout the perioperative period. Cardiopulmonary bypass was associated with a significant increase in free hemoglobin (from a prebypass level of 9.8 ± 6.2 mg/dL to a peak of 201.5 ± 42.6 mg/dL postbypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. Acetaminophen attenuated the increase in plasma isofurans compared with placebo (p = 0.02 for effect of study drug). There was no significant effect of acetaminophen on plasma F2-isoprostanes or urinary makers of lipid peroxidation. Acetaminophen did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin, or prevalence of acute kidney injury. Cardiopulmonary bypass in children is associated with hemolysis and lipid peroxidation. Acetaminophen attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients undergoing cardiopulmonary bypass.

Lowering of oxidative stress improves endothelial function in healthy subjects with habitually low intake of fruit and vegetables: A randomized controlled trial of antioxidant- and polyphenol-rich blackcurrant juice

Inadequate intake of the recommended five-a-day fruit and vegetable portions might contribute to increased cardiovascular disease risk. We assessed the effects of dietary intake of a blackcurrant juice drink, rich in vitamin C and polyphenols, on oxidative stress and vascular function. This was a double-blind, placebo-controlled, parallel group study of 66 healthy adults who habitually consume <2 portions of fruit and vegetables per day. Participants were randomly allocated to consume 250ml of placebo (flavored water) or low or high blackcurrant juice drink four times a day for 6 weeks. Flow-mediated dilation (FMD) and plasma concentrations of F2-isoprostanes and vitamin C were measured. In the high blackcurrant juice drink group FMD increased significantly (5.8±3.1 to 6.9±3.1%, P=0.022) compared with the placebo group (6.0±2.2 to 5.1±2.4%). Plasma vitamin C concentration increased significantly in the low (38.6±17.6 to 49.4±21.0µmol/L, P<0.001) and high (34.6±20.4 to 73.8±23.3µmol/L, P<0.001) blackcurrant juice drink groups compared with the placebo group (38.1±21.0 to 29.0±17.6µmol/L). F2-isoprostane concentrations were significantly lower in the high blackcurrant juice drink group (225±64pg/ml) compared with the low blackcurrant juice drink (257±69pg/ml, P=0.002) and placebo group (254±59pg/ml, P=0.003). At follow-up, changes in plasma vitamin C correlated significantly with changes in FMD (r=0.308, P=0.044). Consumption of blackcurrant juice drink high in vitamin C and polyphenols can decrease oxidative stress and improve vascular health in individuals with habitually low dietary fruit and vegetable intake.

Provision of Antioxidant Therapy in Hemodialysis (PATH)

Increased markers of oxidative stress and acute-phase inflammation are prevalent in patients undergoing maintenance hemodialysis therapy (MHD), and are associated with increased mortality and hospitalization rates and decreased erythropoietin responsiveness. No adequately powered studies have examined the efficacy of antioxidant therapies on markers of inflammation and oxidative stress. We tested the hypothesis that oral antioxidant therapy over 6 months would decrease selected biomarkers of acute-phase inflammation and oxidative stress and improve erythropoietic response in prevalent MHD patients. In total, 353 patients were enrolled in a prospective, placebo-controlled, double-blind clinical trial and randomly assigned to receive a combination of mixed tocopherols (666 IU/d) plus α-lipoic acid (ALA; 600 mg/d) or matching placebos for 6 months (NCT00237718); 238 patients completed the study. High-sensitivity C-reactive protein (hsCRP) and IL-6 concentration were measured as biomarkers of systemic inflammation, and F2 isoprostanes and isofurans were measured as biomarkers of oxidative stress. The groups did not significantly differ at baseline. At 3 and 6 months, the treatment had no significant effect on plasma hsCRP, IL-6, F2 isoprostane, or isofuran concentrations and did not improve the erythropoietic response. No major adverse events were related to the study drug, and both groups had similar mortality and hospitalization rates during the study. In conclusion, the administration of mixed tocopherols and ALA was generally safe and well tolerated, but did not influence biomarkers of inflammation and oxidative stress or the erythropoietic response.

Effects of low-fat or full-fat fermented and non-fermented dairy foods on selected cardiovascular biomarkers in overweight adults

The association between consumption of full-fat dairy foods and CVD may depend partly on the nature of products and may not apply to low-fat dairy foods. Increased circulating levels of inflammatory biomarkers after consumption of dairy product-rich meals suggest an association with CVD. In the present study, we tested the effects of low-fat and full-fat dairy diets on biomarkers associated with inflammation, oxidative stress or atherogenesis and on plasma lipid classes. Within full-fat dairy diets, we also compared fermented v. non-fermented products. In a randomised cross-over study, twelve overweight/obese subjects consumed during two 3-week periods two full-fat dairy diets containing either yogurt plus cheese (fermented) or butter, cream and ice cream (non-fermented) or a low-fat milk plus yogurt diet, with the latter being consumed between and at the end of the full-fat dairy dietary periods. The concentrations of six inflammatory and two atherogenic biomarkers known to be raised in CVD were measured as well as those of plasma F2-isoprostanes and lipid classes. The concentrations of six of the eight biomarkers tended to be higher on consumption of the low-fat dairy diet than on that of the fermented dairy diet and the concentrations of two plasmalogen lipid classes reported to be associated with increased oxidisability were also higher on consumption of the low-fat dairy diet than on that of the fermented dairy diet (P< 0.001), although plasma F2-isoprostane concentrations did not differ on consumption of any of the diets. On the other hand, the concentrations of plasma sphingomyelin and IL-6 were significantly higher on consumption of the non-fermented dairy diet than on that of the low-fat dairy diet (P< 0.02). In conclusion, short-term diets containing low-fat dairy products did not lead to a more favourable biomarker profile associated with CVD risk compared with the full-fat dairy products, suggesting that full-fat fermented dairy products may be the more favourable.

Effect of intravenous vitamin C on cytokine activation and oxidative stress in end-stage renal disease patients receiving intravenous iron sucrose

Reticuloendothelial blockade in hemodialysis patients prevents optimal intravenous (IV) iron utilization. Vitamin C has emerged as a potential therapy to improve anemia treatment by enhancing iron mobilization. However, Vitamin C can act as a pro-oxidant in the presence of iron. This was a prospective, open-label, crossover study. Thirteen patients with end-stage renal disease on hemodialysis and four healthy controls were assigned to receive 100mg of IV iron sucrose (IS) or 100mg of IV IS co-administered with 300mg of IV Vitamin C (IS+C) in random sequence. Serum samples for IL-1, IL-6, TNF-α and IL-10 and non-transferrin bound iron were obtained at baseline, 45min and 105min post study medication administration. Peripheral blood mononuclear cells were isolated at the same time points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential (Δψm) by flow cytometry. Lipid peroxidation was assessed by plasma F2-isoprosatane concentration. Both IS and IS+C were associated with increased plasma F2-isoprostanes concentrations post-infusion. Maximal plasma F2-isoprostane concentrations after IS+C were significantly elevated from baseline (234±0.04 vs. 0.198±0.028ng/mL, p=0.02). After IS+C, IL-1, IL-6, IL-10, and TNF-alpha were significantly elevated compared to baseline. After IS alone only IL-6 was noted to be elevated. Intracellular production of H(2)O(2) and loss of mitochondrial membrane potential (Δψm) was observed after IS while IS+C was associated with increased O (2) (·-) production. Both IS and IS+C induced serum cytokine activation accompanied by lipid peroxidation, however, IS+C induced higher plasma concentrations of F2-isoprostanes, IL-1, IL-10, and TNF-α post-infusion. Long-term safety studies of IV iron co-administered with Vitamin C are warranted.

Antioxidant Micronutrients and Biomarkers of Oxidative Stress and Inflammation in Colorectal Adenoma Patients: Results from a Randomized, Controlled Clinical Trial

Previous epidemiologic observational and experimental studies investigated the potential of antioxidant micronutrients to modulate cancer risk, but these studies produced inconsistent results. In this pilot, randomized, double-blind, placebo-controlled clinical trial (n = 47), we assessed the effects of an antioxidant micronutrient combination (800 mg dl-alpha-tocopherol acetate, 24 mg beta-carotene, 1.0 g vitamin C, 200 microg l-selenomethionine, 7.2 mg riboflavin, 80 mg niacin, 60 mg zinc, 5 mg manganese) given daily over 4 months on oxidative and inflammatory biomarkers in patients with a history of sporadic colorectal adenoma. Plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and F2-isoprostane concentrations were measured using ELISAs, and cystine (CySS) was measured using high-performance liquid chromatography. Plasma TNF-alpha concentration decreased in the active treatment group by 37% relative to the placebo group (P = 0.002), and CySS decreased by 19% (P = 0.03); however, interleukin-6 and F2-isoprostane concentrations decreased in antioxidant-treated nonsmokers but increased in smokers, although these findings were not statistically significant. The decreases of TNF-alpha and CySS were more pronounced in nonsmokers. These data suggest that (a) an antioxidant micronutrient cocktail can modulate biomarkers of oxidative stress and inflammation in humans and (b) the effects of antioxidant micronutrient supplementation on biomarkers of inflammation and oxidative stress may differ according to smoking status.

Obesity-Asthma Association: Is It Explained by Systemic Oxidant Stress?

The mechanism for the obesity-asthma association is unknown. This study evaluated the hypothesis that systemic oxidant stress explains this association. This cross-sectional study used year-20 follow-up evaluation data of 2,865 eligible participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Current asthma was self-reported. Oxidant stress primarily was assessed by plasma F2-isoprostane concentrations. Obesity measures included categories of BMI and dual-energy x-ray absorptiometry-assessed fat mass index (FMI) and lean mass index (LMI). Logistic and linear regressions were used for analyses. Asthma was associated with higher plasma F2-isoprostane concentrations (p = 0.049); however, this association was not significant when adjusted for either gender or BMI. The BMI-asthma association was seen only among women (p = 0.03; gender-specific interaction, p = 0.01), and this association was not explained by plasma F2-isoprostane levels. Similarly, both FMI and LMI were positively associated with asthma in women (p = 0.20 and 0.01, respectively). These associations also were not explained by plasma F2-isoprostane levels. Similar results were obtained when plasma levels of oxidized low-density lipoprotein were used instead of F2-isoprostane levels to study the BMI-asthma association at the year-15 evaluation. Systemic oxidant stress, primarily assessed by plasma F2-isoprostane concentrations, was not independently associated with asthma and, therefore, may not explain the obesity-asthma association in women. The asthma-oxidant stress association is confounded by gender and obesity. This study is limited by the inability to measure airway oxidant stress. It is possible that another (as yet undetermined) measure of systemic oxidant stress may be more relevant in asthma.

Antioxidant supplementation lowers circulating IGF-1 but not F2-isoprostanes immediately following anterior cruciate ligament surgery

Interleukin (IL)-10 is an anti-inflammatory cytokine that suppresses pro-inflammatory cytokines. We previously demonstrated that supplementation with vitamins E and C ameliorated the increase in IL-10 immediately following anterior cruciate ligament (ACL) surgery in the absence of other cytokine perturbations. Since both oxidative stress and insulin-like growth factor-1 (IGF-1) can modulate IL-10 concentrations, the mechanisms for these changes warranted further investigation. Our objective was to evaluate the mechanism for the IL-10 decrease following ACL surgery. This study consisted of randomized, double-blind, placebo-controlled experimental design. Subjects were randomly assigned to daily supplementation with either: (i) antioxidants (AO; vitamins E [α-tocopherol] and C [ascorbic acid]; n = 10); or (ii) matching placebos (PL; n = 10). Supplementation started ∼2 weeks prior to surgery (baseline) and concluded 3 months after surgery. Subjects provided six fasting blood samples at: (i) baseline; (ii) immediately pre-surgery (Pre); (iii) 90 min; (iv) 72 h; (v) 7 days; and (vi) 3 months post-surgery. α-Tocopherol, ascorbic acid, F2-isoprostane and IGF-1 concentrations were measured in each blood sample. At 90 min relative to other times, plasma F2-isoprostane concentrations were significantly (P < 0.05) elevated in both groups, while at 90 min IGF-1 was significantly (P < 0.05) lower in the AO compared to the PL group. The changes in IGF-1 at 90 min relative to baseline were correlated (P < 0.0001) with the changes in IL-10. The decrease in IL-10 observed in the AO group is likely dependent on the decrease IGF-1 since lipid peroxidation was unchanged between the two groups.

Flaxseed Oil Supplementation Increases Plasma F1-Phytoprostanes in Healthy Men ,

Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been reported to reduce lipid peroxidation products formed from arachidonic acid (F2-isoprostanes) in healthy humans, as well as in those under oxidative stress. α-Linolenic acid (ALA) is a precursor to EPA and DHA; however, its conversion in humans is thought to be inefficient. ALA can also undergo free radical oxidation, forming compounds known as F1-phytoprostanes, which are found in all plants and are in high concentrations in plant pollens. In this study, we examined the effect of ALA supplementation on plasma and urine F1-phytoprostane and F2-isoprostane concentrations in men. Thirty-six nonsmoking men, aged 20–65 y, were recruited from the general population and randomly allocated to consume 9 g/d of either flaxseed oil (62% ALA, 5.4 g/d) or olive oil (placebo) for 4 wk in a parallel design. At baseline and after 4 wk of supplementation, blood samples and a 24-h urine sample were collected for measurement of plasma and urinary F1-phytoprostanes and F2-isoprostanes and plasma fatty acids. Compared with the olive oil group, plasma phospholipid ALA was greater (P < 0.0001), as were F1-phytoprostanes in plasma (P = 0.049) and urine (P = 0.06) in the flaxseed oil group after 4 wk supplementation. Flaxseed oil did not affect plasma or urinary F2-isoprostanes. The greater plasma F1-phytoprostane concentration in the flaxseed oil group most likely resulted from the increased plasma concentration of the ALA substrate and/or the F1-phytoprostane content of the flaxseed oil. Future studies are needed to determine the physiological importance of increased plasma and urine F1-phytoprostanes and their relevance to heart disease prevention.