Isoprostanes and isofurans as non-traditional risk factors for cardiovascular disease among Canadian Inuit

Abstract Objectives: The aim of the present study was to investigate the potential importance of oxidative stress, measured by isoprostanes-related compounds, as non-traditional risk factor for cardiovascular disease. We planned to examine the relationship between concentrations of plasma F(2)-isoprostanes (F(2)-IsoPs), isofurans (IsoFs), measures of obesity and various cardiometabolic risk factors. Materials and methods: Cross-sectional study using a sub-sample from the population of a survey conducted in the summer and fall 2007 and 2008 by Canadian Coastguard Ship Amundsen in 36 Canadian Arctic Inuit communities. Subjects included a subset (n =?233) of a total study population (n =?2595) with a mean age 42.56 ± 15.39 years and body mass index 27.78 ± 5.65 kg/m(2). Plasma levels of F(2)-IsoPs and IsoFs was determined by gas chromatography/negative ion chemical ionization/mass spectrometry (GC/NICI/MS) method; and their relationships to waist circumference (WC), blood pressure C reactive proteins (CRP), blood lipids and fasting glucose were assessed by multivariate analyses. Results: Plasma F(2)-IsoPs correlated positively with CRP (r =.132, P =.048) and systolic blood pressure (SBP) (r =.157, P =.024) after adjustment for age, sex and body mass index. IsoFs correlated with WC (r =.190, P =.005) and SBP (r =.137, P =.048). F2-IsoPs were not found elevated in smokers (P =.034), whereas IsoFs were decreased in smokers (P =.001). WC, SBP and sex were found to be major correlates of oxidative stress in Canadian Inuit. Conclusions: Plasma measures of F(2)-IsoPs and IsoFs increase with increased obesity and associated cardiometabolic risk factors, including CRP and blood pressure. Simultaneous measurement of IsoFs provides an advantageous mechanistic insight into oxidative stress not captured by F(2)-IsoPs alone.     

New insights regarding tissue Se and Hg interactions on oxidative stress from plasma IsoP and IsoF measures in the Canadian Inuit population

Despite animal and in vitro studies demonstrating pro-oxidative effects of Hg, previous human work showed no relationship between tissue Hg and plasma levels of F₂-isoprostanes (IsoPs), a whole-body oxidative stress marker. We hypothesized that another IsoP species, isofurans (IsoFs), was a more sensitive indicator of Hg-mediated oxidative stress, which can be modified by tissue Se status. A cross-sectional study was carried out involving individuals from a random subset (n = 233) of Inuit adults from a population-based survey (n = 2,595) of 36 Canadian Arctic Inuit communities to assess the relationships of plasma IsoPs to Se and Hg status indicators. F₂-IsoPs were inversely correlated with blood Se (r = −0.186, P = 0.005) and toenail Se (r = −0.146, P = 0.044), but not correlated with Hg. IsoFs were inversely correlated with blood Se (r = −0.164, P = 0.014) and positively correlated with Hg (r = 0.228, P < 0.001) and Hg:Se (r = 0.340, P < 0.001). The strength of the correlations remained unchanged after multivariate adjustments. Multivariate analysis showed that F₂-IsoPs were not positively associated with Hg but with Hg:Se (β = 0.148, P = 0.021). We conclude that Se and Hg status and their interactions are important factors modulating F₂-IsoP and IsoF levels such that the Inuit may be protected from Hg-induced oxidative stress because of their high Se status.     

Does radiotherapy increase oxidative stress? A study with nasopharyngeal cancer patients revealing anomalies in isoprostanes measurements

Abstract

This study aimed to examine if exposure to ionizing radiation during clinical radiotherapy (RT) causes increased oxidative damage. Seven patients with nasopharyngeal cancer (NPC) who underwent RT took part in this controlled-trial study. Blood and urine samples were obtained for F₂-isoprostanes (F₂-IsoPs) measurement. Urinary F₂-IsoPs levels were elevated pre-treatment and remained high (but did not increase) during treatment, but decreased to the normal range after treatment. Plasma F₂-IsoPs decreased significantly after the start of treatment before rising midway through treatment. Levels decreased significantly to below baseline following treatment. However, the patients were observed to have substantially lower levels of plasma esterified arachidonic acid (AA) residues than controls. The data shows that NPC is associated with elevated F₂-isoprostanes in urine and in plasma after correction for decreased AA levels. RT did not increase these levels and, indeed, was associated with falls in F₂-IsoPs. The validity and usefulness of correction of plasma F₂-IsoPs for lowered AA levels is discussed.     

F2-Isoprostanes in HDL are bound to neutral lipids and phospholipids

Low HDL cholesterol (HDL-C) is a risk factor for coronary artery disease (CAD). However, interventions that raise HDL-C have failed to reduce cardiovascular events. We previously reported that HDL is the main carrier of plasma F₂-isoprostanes (F₂-IsoPs) that are markers of oxidative stress formed upon oxidation of arachidonic acid. F₂-IsoPs are predominantly associated with phospholipids. However, there is evidence that F₂-IsoPs in the liver of rats treated with carbon tetrachloride associate with the neutral lipids. To date it is not known whether F₂-IsoPs are found in the neutral lipids in HDL in humans. Possible candidate neutral lipids include cholesteryl esters, triglycerides, diglycerides, and monoglycerides. This study aimed to identify the lipid classes within native and oxidized HDL that contain F₂-IsoPs. We showed that F₂-IsoPs in HDL are bound to neutral lipids as well as phospholipids. HDL-3 contained the highest concentration of F₂-IsoPs in all lipid classes before and after in vitro oxidation. Using targeted LC/MS and high resolution MS, we were unable to provide conclusive evidence for the presence of the synthesized standards 15(R)-15-F_2t-isoP cholesterol and 1-ent-15(RS)-15-F_2t-isoprostanoyl-sn-glycerol in the neutral lipids of HDL. Our findings show that oxidized lipids such as F₂-IsoPs are found in the core and surface of HDL. However, the exact molecular species remain to be definitively characterized. Future studies are required to determine whether the presence of F₂-IsoPs in neutral lipids alters HDL function.     

Isofurans,but not F2-isoprostanes,are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

F2-isoprostanes (F2-IsoPs) are well-established sensitive and specific markers of oxidative stress in vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F2-IsoPs, their formation is favored when oxygen tension is increased in vitro or in vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F2-IsoPs and IsoFs. In this study, we attempted to compare the levels of F2-IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age-matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F2-IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F2-IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age-matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.     

Oxidative stress,erythrocyte ageing and plasma non-protein-bound iron in diabetic patients

Increased oxidative stress and decreased life span of erythrocytes (RBCs) are repeatedly reported in diabetes. In the aim to elucidate the mechanism of the latter, i.e. the events leading to erythrocyte ageing, this study determined in RBCs from diabetic patients iron release in a free desferrioxamine-chelatable form (DCI), methemoglobin (MetHb) formation, binding of autologous IgG to membrane proteins and in plasma non-protein-bound iron (NPBI), F₂-Isoprostanes (F₂-IsoPs) and advanced oxidation protein products (AOPP). DCI and MetHb were higher in diabetic RBCs than in controls and autologous IgG binding occurred in a much higher percentage of diabetic patients than controls. A significant correlation between DCI and IgG binding was found in diabetic RBCs. Plasma NPBI, esterified F₂-IsoPs and AOPP were higher in diabetic patients and a significant correlation was found between plasma NPBI and intra-erythrocyte DCI. The increased DCI and autologous IgG binding appear to be important factors in the accelerated removal of RBCs from the blood stream in diabetes and the increase in plasma NPBI could play an important role in the increased oxidative stress.     

Levels of F2-isoprostanes,F4-neuroprostanes,and total nitrate/nitrite in plasma and cerebrospinal fluid of patients with traumatic brain injury

Several events occurring during the secondary damage of traumatic brain injury (TBI) can cause oxidative stress. F₂-isoprostanes (F₂-IsoPs) and F₄-neuroprostanes (F₄-NPs) are specific lipid peroxidation markers generated from arachidonic acid and docosahexaenoic acid, respectively. In this study, we evaluated oxidative stress in patients with moderate and severe TBI. Since sedatives are routinely used to treat TBI patients and propofol has been considered an antioxidant, TBI patients were randomly treated with propofol or midazolam for 72 h postoperation. We postoperatively collected cerebrospinal fluid (CSF) and plasma from 15 TBI patients for 6–10 d and a single specimen of CSF or plasma from 11 controls. Compared with the controls, the TBI patients exhibited elevated levels of F₂-IsoPs and F₄-NPs in CSF throughout the postsurgery period regardless of the sedative used. Compared with the group of patients who received midazolam, those who received propofol exhibited markedly augmented levels of plasma F₂-IsoPs, which were associated with higher F₄-NPs levels and lower total nitrate/nitrite levels in CSF early in the postsurgery period. Furthermore, the higher CSF F₂-IsoPs levels correlated with 6-month and 12-month worse outcomes, which were graded according to the Glasgow Outcome Scale. The results demonstrate enhanced oxidative damage in the brain of TBI patients and the association of higher CSF levels of F₂-IsoPs with a poor outcome. Moreover, propofol treatment might promote lipid peroxidation in the circulation, despite possibly suppressing nitric oxide or peroxynitrite levels in CSF, because of the increased loading of the lipid components from the propofol infusion.     

Oxidative stress in Rett syndrome: Natural history,genotype, and variants

Abstract

Objectives

Rett syndrome (RTT) is an X-linked autism spectrum disorder caused by mutations in the MeCP2 gene in the great majority of cases. Evidence suggests a potential role of oxidative stress (OS) in its pathogenesis. Here, we investigated the potential value of OS markers (non-protein-bound iron (NPBI) and F₂-isoprostanes (F₂-IsoPs)) in explaining natural history, genotype-phenotype correlation, and clinical heterogeneity of RTT, and gauging the response to omega-3 polyunsaturated fatty acids (ω-3 PUFAs).

Methods

RTT patients (n = 113) and healthy controls were assayed for plasma NPBI and F₂-IsoPs, and intraerythrocyte NPBI. Forty-two patients with typical RTT were randomly assigned to ω-3 PUFAs supplementation for 12 months. NPBI was measured by HPLC and F₂-IsoPs using a gas chromatography/negative ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) technique.

Results

F₂-IsoPs were significantly higher in the early stages as compared with the late natural progression of classic RTT. MeCP2 mutations related to more severe phenotypes exhibited higher OS marker levels than those of milder phenotypes. Higher OS markers were observed in typical RTT and early seizure variant as compared with the preserved speech and congenital variants. Significant reduction in OS markers levels and improvement of severity scores were observed after ω-3 PUFAs supplementation.

Discussion

OS is a key modulator of disease expression in RTT.     

Oxidative Stress Predicts All-Cause Mortality in HIV-Infected Patients

ObjectiveWe aimed to assess whether oxidative stress is a predictor of mortality in HIV-infected patients.MethodsWe conducted a nested case-control study in CoRIS, a contemporary, multicentre cohort of HIV-infected patients, antiretroviral-naïve at entry, launched in 2004. Cases were patients who died with available stored plasma samples collected. Two age and sex-matched controls for each case were selected. We measured F2-isoprostanes (F₂-IsoPs) and malondialdehyde (MDA) plasma levels in the first blood sample obtained after cohort engagement.Results54 cases and 93 controls were included. Median F₂-IsoPs and MDA levels were significantly higher in cases than in controls. When adjustment was performed for age, HIV-transmission category, CD4 cell count and HIV viral load at cohort entry, and subclinical inflammation measured with highly-sensitive C-reactive protein (hsCRP), the association of F₂-IsoPs with mortality remained significant (adjusted OR per 1 log₁₀ increase, 2.34 [1.23–4.47], P = 0.009). The association of MDA with mortality was attenuated after adjustment: adjusted OR (95% CI) per 1 log₁₀ increase, 2.05 [0.91–4.59], P = 0.080. Median hsCRP was also higher in cases, and it also proved to be an independent predictor of mortality in the adjusted analysis: OR (95% CI) per 1 log₁₀ increase, 1.39 (1.01–1.91), P = 0.043; and OR (95% CI) per 1 log₁₀ increase, 1.46 (1.07–1.99), P = 0.014, respectively, when adjustment included F₂-IsoPs and MDA.ConclusionOxidative stress is a predictor of all-cause mortality in HIV-infected patients. For plasma F₂-IsoPs, this association is independent of HIV-related factors and subclinical inflammation.     

Correlation of F4-neuroprostanes levels in cerebrospinal fluid with outcome of aneurysmal subarachnoid hemorrhage in humans

Aneurysmal subarachnoid hemorrhage (aSAH) is one type of hemorrhagic stroke in humans. F₂-isoprostanes (F₂-IsoPs) and F₄-neuroprostanes (F₄-NPs), derived from arachidonic acid and docosahexaenoic acid (DHA), respectively, are specific markers of lipid peroxidation. We previously demonstrated that F₂-IsoPs levels in cerebrospinal fluid (CSF) of aSAH patients positively correlated with poor clinical conditions. In this work, we refined F₄-NPs analysis and investigated the role of potential oxidative damage to neurons in aSAH patients by detecting F₄-NPs in CSF. [²H₄]-15-F_2t-IsoP, rather than [¹⁸O₂]-17-F_4c-NP or [²H₄]-PGF_2α, was used as the internal standard for F₄-NPs analysis. One problem of the use of [¹⁸O₂]-17-F_4c-NP was the potential interference resulting from F₂-dihomo-IsoPs in CSF. CSF specimens of 15 aSAH patients for up to 10 days and those of 12 non-aSAH controls were analyzed. First day, mean, and peak levels of F₄-NPs were all significantly higher in aSAH patients than in controls and correlated with the Fisher Scale and 3-month Glasgow Outcome Scale, but only mean levels of F₄-NPs correlated with Hunt and Hess Grade. The results first demonstrate oxidative damage to DHA in brain tissue following aSAH and suggest that F₄-NPs in CSF could be a better predictor for outcome of aSAH than F₂-IsoPs at early time points.     

How do Different Indices of Obesity Correlate with Cardiometabolic Disease Risk Factors in Multiethnic Youths?

ObjectiveTo investigate the relationship between cardiometabolic disease risk factors (CDRFs) among ethnic minorities and anthropometric factors including body mass index z score, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHTR) in Hispanic and non-Hispanic black youths originating primarily from Central America, South America, and the Caribbean.MethodsClinical data of 167 young persons 2 to 19 years of age encountered in an outpatient pediatric endocrinology clinic were analyzed. The CDRFs included fasting insulin and glucose, homeostasis model assessment of insulin resistance (HOMA-IR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), high-density lipoprotein cholesterol, triglycerides, cardiac C-reactive protein (CRP), and apolipoproteins.ResultsFor both the non-Hispanic black and the Hispanic youths, WC was significantly correlated with SBP (r = 0.63; P < .001 and r = 0.50; P < .001, respectively), DBP (r = 0.61; P < .001 and r = 0.47; P < .001, respectively), and cardiac CRP (r = 0.76; P < .001 and r = 0.26; P = .026, respectively). Similarly, WHTR was significantly correlated with SBP, DBP, and cardiac CRP for the non-Hispanic black study subjects, whereas SBP (r = 0.22; P = .01), DBP ( r = 0.34; P < .001), fasting insulin ( r = 0.43; P < .001), HOMA-IR (r = 0.38; P < .001), apolipoprotein A-I (r = 0.30; P = .01), and CRP (r = 0.44; P < .001) were significantly correlated for the Hispanic group. For both groups, body mass index z score was not consistently correlated with CDRFs, and waist-to-hip ratio was not significantly correlated with any CDRFs, except for apolipoprotein B in non-Hispanic black youths.ConclusionOur study shows that WC and WHTR may be useful anthropometric factors for better identification of ethnic minority youths at risk for adult-onset cardiometabolic disease. (Endocr Pract. 2009;15:403-409)     

Uric acid correlates to oxidation and inflammation in opposite directions in women

Abstract

Objective: To evaluate the association of uric acid (UA) levels with a panel of markers of oxidative stress and inflammation.

Methods: Plasma UA levels, along with a panel of oxidative stress and inflammatory markers, were measured in 755 Chinese women.

Results: Plasma UA levels were inversely associated with urinary levels of the oxidative stress marker F₂-isoprostanes and positively correlated to levels of inflammatory markers, such as C-reactive protein and some proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) in blood as well as prostaglandin E₂ metabolites in urine.

Conclusions: Plasma UA levels correlate to oxidation and inflammation biomarkers in opposite directions in women.     

Pericardial Fat Volume Correlates With Inflammatory Markers: The Framingham Heart Study

The objective of this study was to determine whether systemic inflammatory and oxidative stress marker concentrations correlate with pericardial and intrathoracic fat volumes. Participants of the Framingham Offspring Study (n = 1,175, 53% women, mean age 59 ± 9 years) had pericardial and intrathoracic fat volumes assessed by multidetector computed tomography (MDCT) scans, and provided fasting blood and urine samples to measure concentrations of 14 inflammatory markers: C‐reactive protein (CRP), interleukin‐6, monocyte chemoattractant protein‐1 (MCP‐1), CD40 ligand, fibrinogen, intracellular adhesion molecule‐1, lipoprotein‐associated phospholipase A₂ activity and mass, myeloperoxidase, osteoprotegerin, P‐selectin, tumor necrosis factor‐α, tumor necrosis factor receptor‐2, and urinary isoprostanes. Multivariable linear regression models were used to determine the association of log‐transformed inflammatory marker concentrations with fat volumes, using fat volume as the dependent variable. Due to smaller sample sizes, models were rerun after adding urinary isoprostanes (n = 961) and tumor necrosis factor‐α (n = 813) to the marker panel. Upon backward elimination, four of the biomarkers correlated positively with each fat depot: CRP (P < 0.0001 for each fat depot), interleukin‐6 (P < 0.05 for each fat depot), MCP‐1 (P < 0.01 for each fat depot), and urinary isoprostanes (P < 0.01 for pericardial fat; P < 0.001 for intrathoracic fat). Even after adjusting for BMI, waist circumference (WC), and abdominal visceral fat, CRP (P = 0.0001) and urinary isoprostanes (P = 0.02) demonstrated significant positive associations with intrathoracic fat, but not with pericardial fat. Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress.     

Insulin Resistance is the Best Predictor of the Metabolic Syndrome in Subjects With a First‐Degree Relative With Type 2 Diabetes

Although obesity is associated with insulin resistance and the metabolic syndrome (MetS), some obese individuals are metabolically healthy. Conversely, some lean individuals are insulin resistant (IR) and at increased cardiometabolic risk. To determine the relative importance of insulin sensitivity, BMI and waist circumference (WC) in predicting MetS, we studied these two extreme groups in a high‐risk population. One thousand seven hundred and sixty six subjects with a first‐degree relative with type 2 diabetes were stratified by BMI and homeostasis model assessment of insulin resistance (HOMA_IR) into groups. IR groups had higher triglycerides, fasting glucose, and more diabetes than their BMI‐group insulin sensitive (IS) counterparts. Within both IS and IR groups, obesity was associated with higher HOMA_IR and diastolic blood pressure (BP), but no difference in other metabolic variables. MetS (Adult Treatment Panel III (ATPIII)) prevalence was higher in IR groups (P < 0.001) and more subjects met each MetS criterion (P < 0.001). Within each BMI category, HOMA_IR independently predicted MetS (P < 0.001) whereas WC did not. Within IS and IR groups, age and WC, but not BMI, were independent determinants of MetS (P < 0.001). WC was a less meaningful predictor of MetS at higher values of HOMA_IR. HOMA_IR was a better predictor of MetS than WC or BMI (receiver operating characteristic (ROC) area under the curve 0.76 vs. 0.65 vs. 0.59, P < 0.001). In conclusion, insulin sensitivity rather than obesity is the major predictor of MetS and is better than WC at identifying obese individuals with a healthier metabolic profile. Further, as many lean individuals with a first‐degree relative with type 2 diabetes are IR and metabolically unhealthy, they may all benefit from metabolic testing.     

Ethnic Differences in Cardiometabolic Risk Profile at Age 5-6 Years: The ABCD Study

Background

To examine ethnic differences in cardiometabolic risk profile in early age, and explore whether such differences can be explained by differences in body mass index (BMI) or waist circumference (WC).

Method

Anthropometric measurements, blood pressure and (in a subsample) fasting blood were collected during a health check of 2,509 children aged 5–6 years. Four ethnic groups were distinguished: Dutch (n = 2,008; blood n = 1,300), African descent (n = 199; blood n = 105), Turkish (n = 108; blood n = 57) and Moroccan (n = 194; blood n = 94). Ethnic differences in diastolic and systolic blood pressure (DBP/SBP), fasting glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were determined and the explanatory role of BMI and WC was examined with regression analysis.

Results

After adjustment for confounders, African descent children showed higher DBP (β2.22 mmHg; 95%CI:1.09–3.36) and HDL levels (β:0.09 mmol/l; 95%CI:0.03–0.16) compared to Dutch children (reference group). Turkish children showed higher SBP (β:1.89 mmHg; 95%CI:0.25–3.54), DBP (β:2.62 mmHg; 95%CI:1.11–4.13), glucose (β:0.12 mmol/L; 95%CI:0.00–0.25) and triglyceride levels (β:0.13 mmol/L; 95%CI:0.02–0.25). Higher BMI values were found in all non–Dutch groups (differences ranged from 0.53–1.03 kg/m²) and higher WC in Turkish (β:1.68 cm; 95%CI:0.99–2.38) and Moroccan (β:1.65 cm; 95%CI:1.11–2.19) children. BMI and WC partly explained the higher SBP/DBP and triglyceride levels in Turkish children.

Conclusion

Ethnic differences in cardiometabolic profile exist early in life and are partly explained by differences in BMI and WC. African children showed favourable HDL levels and Turkish children the most unfavourable overall profile, whereas their Moroccan peers have less increased cardiometabolic risk in spite of their high BMI and WC.     

Oxidative damage in Parkinson disease: Measurement using accurate biomarkers

Oxidative damage has been implicated in the pathogenesis of Parkinson disease (PD) but the literature data are confusing. Using products of lipid and DNA oxidation measured by accurate methods, we assessed the extent of oxidative damage in PD patients. The levels of plasma F₂-isoprostanes (F₂-IsoPs), hydroxyeicosatetraenoic acid products (HETEs), cholesterol oxidation products, neuroprostanes (F₄-NPs), phospholipase A₂ (PLA₂) and platelet activating factor–acetylhydrolase (PAF-AH) activities, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), and serum high-sensitivity C-reactive protein were compared in 61 PD patients and 61 age-matched controls. The levels of plasma F₂-IsoPs, HETEs, 7β-and 27-hydroxycholesterol, 7-ketocholesterol, F₄-NPs, and urinary 8-OHdG were elevated, whereas the levels of plasma PLA₂ and PAF-AH activities were lower, in PD patients compared to controls (p <  0.05). The levels of plasma F₂-IsoPs, HETEs, and urinary 8-OHdG were higher in the early stages of PD (p trend <  0.05). There was a significant negative correlation between the cumulative intake of levodopa and urinary 8-OHdG (r =  ?0.305, p =  0.023) and plasma total HETEs (r =  ?0.285, p =  0.043). Oxidative damage markers are systemically elevated in PD, which may give clues about the relation of oxidative damage to the onset and progression of PD.     

The isoprostanes: Unique bioactive products of lipid peroxidation

The development of a specific, reliable and noninvasive method for measuring oxidative stress in humans is essential for establishing the role of free radicals in human diseases. Currently, accurate techniques to assess oxidant injury in vivo are extremely limited although a number of approaches are being investigated. Of these, the measurement of specific products of nonenzymatic lipid peroxidation, the F₂-isoprostanes (F₂-IsoPs), appears to be a more accurate marker of oxidative stress in vivo in humans than other available methods. The purpose of this brief review is to acquaint the reader with the IsoPs from a biochemical perspective and to provide information regarding the utility of quantifying these compounds as indicators of oxidant stress.     

Enrichment of Elevated Plasma F2t-Isoprostane Levels in Individuals with Autism Who Are Stratified by Presence of Gastrointestinal Dysfunction

Etiology is unknown in the majority of individuals with autism spectrum disorder (ASD). One strategy to investigate pathogenesis is to stratify this heterogeneous disorder based on a prominent phenotypic feature that enriches for homogeneity within population strata. Co-occurring gastrointestinal dysfunction (GID) characterizes a subset of children with ASD. Our current objective was to investigate a potential pathophysiological measure to test the hypothesis that children with both ASD and GID have a more severe metabolic dysfunction than children with ASD-only, given that the highly metabolically active brain and gastrointestinal system may additively contribute measurable impairment. Plasma levels of F_2t-Isoprostanes (F₂-IsoPs), a gold standard biomarker of oxidative stress, were measured in 87 children in four groups: ASD-GID, ASD-only, GID-only and Unaffected. F₂-IsoP levels were elevated in all 3 clinical groups compared to the Unaffected group, with the ASD-GID group significantly elevated above the ASD-only group (mean, SD in pg/mg: ASD-GID 53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007). Adjusting for age, sex, and triglyceride levels, F₂-IsoP levels remained significantly different between study groups, with a moderate effect size of η_p ² = 0.187 (p = 0.001). Elevation in peripheral oxidative stress is consistent with, and may contribute to, the more severe functional impairments in the ASD-GID group. With unique medical, metabolic, and behavioral features in children with ASD-GID, the present findings serve as a compelling rationale for both individualized approaches to clinical care and integrated studies of biomarker enrichment in ASD subgroups that may better address the complex etiology of ASD.     

31P nuclear magnetic resonance study on changes in phosphocreatine and the intracellular pH in rat skeletal muscle during exercise at various inspired oxygen contents

We measured ATP, phosphocreatine (PCr), inorganic phosphate (P_i), and the intracellular pH in rat hindlimb muscles during submaximal isometric exercise with various O₂ deliveries using³¹P nuclear magnetic resonance spectroscopy (³¹P NMR) to evaluate changes in energy metabolism in relation to O₂ availability. Delivery of O₂ to muscles was altered by controlling the fractional concentration of inspired oxygen (F _IO₂) at 0.50, 0.28, 0.21, 0.11 and 0.08 with monitoring partial pressure of oxygen and carbon dioxide, and bicarbonate at the femoral artery. The steady-state ratio of PCr : (PCr + P_i) during exercise decreased as a function ofF _IO₂ even at 0.21. Significant acidification of the intracellular pH during exercise occurred at 0.08F _IO₂. Change in the PCr : (PCr + P_i) ratio demonstrated that the oxidative capacity, i.e. the maximal rate of the oxidative phosphorylation reaction, in muscle was not limited by O₂ delivery at 0.50F _IO₂, but was significantly limited at 0.21F _IO₂ or below. Change in the intracellular pH at 0.08F _IO₂ could be interpreted as an increase in lactate, suggesting activation of glycolysis. Correlation between the PCr : (PCr + P_i) ratio and the intracellular pH revealed the existence of a critical PCr : (PCr + P_i) ratio and pH for glycolysis activation at around 0.4 and 6.7, respectively.     

Lack of effect of acute oral ingestion of vitamin C on oxidative stress,arterial stiffness or blood pressure in healthy subjects

Vitamin C is a potent antioxidant in vitro and has been reported to act as a vasodilator, possibly by increasing nitric oxide bioavailability. This study examined the antioxidant and vascular effects of a single large oral dose of vitamin C in 26 healthy human volunteers. Haemodynamic and oxidative DNA and lipid damage markers were measured for 8 h following an oral dose of 2 g vitamin C or placebo. Vitamin C had no effect on vasodilation (measured by augmentation index (mean change=0.04%, 90% CI=? 2.20% to 2.28%) or forearm blood flow (?0.19%/min (?0.68, 0.30)), in comparison to placebo) or on several markers of oxidative stress including DNA base oxidation products in blood cells, 8-hydroxy-2’-deoxyguanosine (8O HdG) in urine (0.068 (?0.009, 0.144)) or urinary or plasma total F₂-isoprostanes (?0.005 ng/ml (?0.021, 0.010), ?0.153 ng/mg (?0.319, 0.014), respectively).