ChapterLiterature Review

Measurement of F2-isoprostanes as an index of oxidative stress in vivo

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Abstract

In 1990 we discovered the formation of prostaglandin F(2)-like compounds, F(2)-isoprostanes (F(2)-IsoPs), in vivo by nonenzymatic free radical-induced peroxidation of arachidonic acid. F(2)-IsoPs are initially formed esterified to phospholipids and then released in free form. There are several favorable attributes that make measurement of F(2)-IsoPs attractive as a reliable indicator of oxidative stress in vivo: (i) F(2)-IsoPs are specific products of lipid peroxidation; (ii) they are stable compounds; (iii) levels are present in detectable quantities in all normal biological fluids and tissues, allowing the definition of a normal range; (iv) their formation increases dramatically in vivo in a number of animal models of oxidant injury; (v) their formation is modulated by antioxidant status; and (vi) their levels are not effected by lipid content of the diet. Measurement of F(2)-IsoPs in plasma can be utilized to assess total endogenous production of F(2)-IsoPs whereas measurement of levels esterified in phospholipids can be used to determine the extent of lipid peroxidation in target sites of interest. Recently, we developed an assay for a urinary metabolite of F(2)-IsoPs, which should provide a valuable noninvasive integrated approach to assess total endogenous production of F(2)-IsoPs in large clinical studies.

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... The coefficient of variation for samples analyzed in multiple batches was 7.2% and the assay accuracy was 93% (n = 4 separate experiments [29] ). F2-isoprostane measurement provides a measure of in vivo lipid peroxidation as an estimate of systemic oxidative stress [30, 31]. To avoid concern that unmetabolized isoprostanes may be artificially generated in vitro in biological fluids by autoxidation or that the level may be significantly affected by the renal isoprostane production, we also measured the F2-isopros- tane metabolite (2,3-dinor-5,6-dihydro-15-F 2t -IsoP or F2iP-M)[30][31][32]. F2iP and F2iP-M were measured by gas chromatography/negative ion chemical ionization mass spectrometry (GC/ NICI MS) [30, 31]. ...
... F2-isoprostane measurement provides a measure of in vivo lipid peroxidation as an estimate of systemic oxidative stress [30, 31]. To avoid concern that unmetabolized isoprostanes may be artificially generated in vitro in biological fluids by autoxidation or that the level may be significantly affected by the renal isoprostane production, we also measured the F2-isopros- tane metabolite (2,3-dinor-5,6-dihydro-15-F 2t -IsoP or F2iP-M)[30][31][32]. F2iP and F2iP-M were measured by gas chromatography/negative ion chemical ionization mass spectrometry (GC/ NICI MS) [30, 31]. ...
... F2-isoprostane measurement provides a measure of in vivo lipid peroxidation as an estimate of systemic oxidative stress [30, 31]. To avoid concern that unmetabolized isoprostanes may be artificially generated in vitro in biological fluids by autoxidation or that the level may be significantly affected by the renal isoprostane production, we also measured the F2-isopros- tane metabolite (2,3-dinor-5,6-dihydro-15-F 2t -IsoP or F2iP-M)[30][31][32]. F2iP and F2iP-M were measured by gas chromatography/negative ion chemical ionization mass spectrometry (GC/ NICI MS) [30, 31]. Urinary markers were standardized to urinary creatinine prior to analysis to control for differences in urine volume. ...
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Background: BPH is a common disease associated with age and obesity. However, the biological pathways between obesity and BPH are unknown. Our objective was to investigate biomarkers of systemic and prostate tissue inflammation as potential mediators of the obesity and BPH association. Methods: Participants included 191 men without prostate cancer at prostate biopsy. Trained staff measured weight, height, waist and hip circumferences, and body composition by bioelectric impedance analysis. Systemic inflammation was estimated by serum IL-6, IL-1β, IL-8, and TNF-α; and by urinary prostaglandin E2 metabolite (PGE-M), F2-isoprostane (F2iP), and F2-isoprostane metabolite (F2iP-M) levels. Prostate tissue was scored for grade, aggressiveness, extent, and location of inflammatory regions, and also stained for CD3 and CD20 positive lymphocytes. Analyses investigated the association between multiple body composition scales, systemic inflammation, and prostate tissue inflammation against BPH outcomes, including prostate size at ultrasound and LUTS severity by the AUA-symptom index (AUA-SI). Results: Prostate size was significantly associated with all obesity measures. For example, prostate volume was 5.5 to 9.0 mls larger comparing men in the 25th vs. 75th percentile of % body fat, fat mass (kg) or lean mass (kg). However, prostate size was not associated with proinflammatory cytokines, PGE-M, F2iP, F2iP-M, prostate tissue inflammation scores or immune cell infiltration. In contrast, the severity of prostate tissue inflammation was significantly associated with LUTS, such that there was a 7 point difference in AUA-SI between men with mild vs. severe inflammation (p = 0.004). Additionally, men with a greater waist-hip ratio (WHR) were significantly more likely to have severe prostate tissue inflammation (p = 0.02), and a high WHR was significantly associated with moderate/severe LUTS (OR = 2.56, p = 0.03) among those participants with prostate tissue inflammation. Conclusion: The WHR, an estimate of centralized obesity, was associated with the severity of inflammatory regions in prostate tissue and with LUTS severity among men with inflammation. Our results suggest centralized obesity advances prostate tissue inflammation to increase LUTS severity. Clinically targeting centralized fat deposition may reduce LUTS severity. Mechanistically, the lack of a clear relationship between systemic inflammatory or oxidative stress markers in blood or urine with prostate size or LUTS suggests pathways other than systemic inflammatory signaling may link body adiposity to BPH outcomes.
... 20,21 The GC-NICI-MS and ELISA methods were found to have poor agreement when comparing urinary 15-F 2 -isoprostane concentrations in people, dogs, and cats. [25][26][27] Currently, gas chromatography/mass spectroscopy is the recommended method for quantification of urinary 15-F 2 -isoprostanes in people and domestic species, which is the method used in our study. [25][26][27] It is acknowledged that, in our study, the method of urine collection in the dogs with lower urinary tract signs varied from case to case. ...
... [25][26][27] Currently, gas chromatography/mass spectroscopy is the recommended method for quantification of urinary 15-F 2 -isoprostanes in people and domestic species, which is the method used in our study. [25][26][27] It is acknowledged that, in our study, the method of urine collection in the dogs with lower urinary tract signs varied from case to case. It was considered unsafe to collect urine by cystocentesis if mass lesions were present or UC was suspected. ...
... Although the effects of urine collection method have not been studied in dogs, in other species the method of urine collection has not altered the results of the 15-F 2 -isoprostane assay. 25,27 Inflammation of the lower urinary tract has been studied in people and dogs, and biomarkers of inflammation including cyclooxygenase (COX-1 and COX-2) expression, PGE 2 concentrations, and cytokine profiles have been used to measure the impact of diseases such as urinary tract infections and urinary neoplasia. 14,15,29 In people, activity of the arachidonic acid pathway is increased in the presence of urinary tract neoplasia. ...
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Background: The 15-F2 -isoprostanes are by-products of oxidative stress and are increased in the urine of people with lower urinary tract diseases (LUTD), especially urinary neoplasia. Urothelial carcinoma (UC) is the most common urinary neoplasm in dogs. Earlier detection of UC by noninvasive means could lead to improved outcomes. Urinary 15-F2 -isoprostanes potentially could provide this means, but have not been evaluated in dogs with UC. Objective: The objective of this study was to measure urinary 15-F2 -isoprostanes in dogs with UC and dogs with other LUTD. Animals: One hundred seventeen dogs: 46 dogs with UC, 30 dogs with LUTD, and 25 control dogs. Methods: Any dog that was presented with dysuria was eligible for inclusion. Diagnosis of UC was confirmed histologically. Urinalysis was performed in each case, and 15-F2 -isoprostanes quantified by gas chromatography-negative ion chemical ionization-mass spectrometry (GC-NICI-MS) and normalized to urinary creatinine concentration. Results: Dogs with urinary diseases (UC + LUTD) had higher median urinary 15-F2 -isoprostanes when compared to control dogs (5.92 ng/mg [range, 0.46-31.03] vs 3.73 [range, 1.8-7.98]; P = .02). Urinary 15-F2 -isoprostanes were similar in dogs with UC (5.33 ng/mg [range, 0.46-31.03]) compared to dogs with LUTD (6.29 ng/mg [range, 0.54-18.93]; P = .47) and control dogs (P = .06). Dogs with UC had higher qualitative measures of proteinuria (P = .004), hematuria (P = .01), and epithelial cells on urinalysis (P = .002) compared to the other groups. Conclusions and clinical importance: Urinary F2 -isoprostanes are not useful for the detection of UC in dogs. Future research could evaluate urinary 15-F2 -isoprostanes as a marker of inflammation in disease progression and prognosis.
... Isoprostanes are excellent biomarkers and have numerous advantages over other biomarkers of oxidative stress; they are chemically stable markers and are formed in vivo. They are specific to lipid peroxidation and are not affected by the dietary lipid content [27]. Since they are detectable in biological fluids, they have the significant advantage over other oxidative stress markers due to the ease of measuring them since they can be measured by noninvasive methods extracellularly in the urine, plasma, and tissue [27, 28]. ...
... They are specific to lipid peroxidation and are not affected by the dietary lipid content [27]. Since they are detectable in biological fluids, they have the significant advantage over other oxidative stress markers due to the ease of measuring them since they can be measured by noninvasive methods extracellularly in the urine, plasma, and tissue [27, 28]. High levels of F2?isoprostanes are found in many human diseases such as coronary heart disease [29], obesity, cancer, and even genetic disorders [30]. ...
... They are also observed in bypass [35] and angioplasty. The extent of lipid peroxidation can be measured by calculating the level of F2?IsoPs which is esterified in phospholipids due to them being initially formed esterified and subsequently gain their free form [27]. In humans, the two major metabolites of isoprostane which are detectable in the urine are 2,3?dinor?15?F2t?IsoP and 2,3 dinor?5,6?dihydro?15?F2t?IsoP [36]. ...
Chapter
Biomarkers of reactive oxygen species serve as indicators of oxidative stress in the pathology of cardiovascular diseases. This chapter presents an overview of the various biomarkers available to quantify oxidative stress to advance the understanding of the pathophysiology of cardiovascular diseases as well as to serve as an adjunct in their diagnosis and prognosis. The plasma levels of reactive oxygen species themselves are unstable and unreliable markers of oxidative stress. The commonly used stable biomarkers are derivatives of oxygen radicals such as products of lipid peroxidation and protein oxidation, with isoprostanes and malondialdehyde (MDA) being the most widely used biomarkers due to higher specificity and ease of measurement. Recently, micro‐RNA is emerging as stable and specific biomarkers for detection of heart failure. Other biomarkers have a role in certain conditions; for example, advanced oxidation protein products indicate acute inflammation, whereas advanced glycation end products serve as indicators of chronic disease.
... Such markers as TAS (total antioxidative status), TBARS (thiobarbituric acid reactive substances), and MDA (malonyldialdehyde) are not, however, specific for the rat and do not provide an unambiguous answer as to the antioxidative defense potential of the body. The extent of oxidative stress in that species of animals can be explicitly indicated by the plasma concentration of 8-iPF2α-III or the level of its urinary excretion (Roberts and Morrow, 2000). Increased concentrations/excretion of isoprostanes was demonstrated in many model studies conducted on animals with induced oxidative stress (Nanji et al., 1994), and the assay of isoprostane concentrations in tissues and/ or body fluids provides a biochemical basis for potential therapeutic intervention (Halliwell, 2000). ...
... Peroxidation of lipids (Saito and Kubo, 2003), among others of polyunsaturated fatty acids (PUFA) built into membrane phospholipids, refers mainly to arachidonic acid, which as a free fatty acid is a precursor of eicosanoids, prostaglandins, tromboxanes and leukotrienes, synthesized in enzymatic pathways. When this acid is subjected to the non-enzymatic free radical mechanism of peroxidation, however, it is a precursor of the synthesis of isoprostanes, chemically stable isomers of prostaglandins that are released into the circulation through the action of A2 phospholipase and circulate therein in the free form or as esters in phospholipids of blood plasma (Roberts and Morrow, 2000). Isoprostane 8-iPF2α-III may also be formed in lipoprotein fractions (of LDL-cholesterol) in vivo and modified in vitro by the action of free radicals. ...
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The purpose of this research was to assess the amount of isoprostane 8-iPF2α-III, a marker of oxidation stress, in excreted urine. The study was conducted on 40 male rats aged 5 months. Group 1 received the basic diet, groups 2-4, the modified diet in which whole cereal grains were partly substituted with wheat flour and sucrose. Groups 1-2 received water to drink, groups 3 and 4 were given aqueous solutions of B group vitamins at different doses. On the fifth week of the experiment, a 24-h urine collection was conducted. The concentrations of creatinine and 8-iPGF2a-III were determined in urine samples. Modification of diet composition caused increased excretion of isoprostane, which may indicate enhancement of free-radical reactions in the examined animal. The provided supplementation decreased the value of this parameter expressed as a creatinine ratio, but not, however, to the values observed in the animals fed the basic diet. A stronger effect was observed with excess supplementation.
... GSH also acts as a cofactor for glutathione peroxidases enzyme which is involved in protecting cells against reactive oxygen species (ROS) (Becker et al., 2003 ). F2- IsoPs are markers of lipid peroxidation that are generated when free radicals attack cell membranes catalyzing the peroxidation of esterified arachidonic acid (an omega-6 fatty acid found in the phospholipids of cell membranes) which are then cleaved and released into the circulation by phospholipases (Roberts and Morrow, 2000 ). Available data indicate that quantification of F2- IsoPs in plasma gives a highly precise and accurate index of oxidative stress (Morrow, 2005). ...
... In agreement with this compensation theory, Marin et al. (2011) found that GSH concentration was reduced immediately after a handball game. In addition to GSH/GSSG ratio, F2-Isoprostanes are considered to be the best available chemically stable biomarkers of oxidative stress induced lipid peroxidation in vivo (Roberts and Morrow 2000), that also present in detectable amounts in plasma and are unaffected by lipid content in the diet (Gopaul et al., 2000). Consistent with a previous report (Schmitz et al., 2008), the present study found that the free F2-Isoprostanes in plasma were significantly lower following 8 weeks of exercise in obese and leptin responder normal-weight participants. ...
... 8-isoprostane-prostaglandin-F2α (8-iso-PGF2α), the major 8-isoprostane-prostaglandin-F2α metabolite, and prostaglandin-F2α (PGF2α) were included as biomarkers of oxidative stress. 8-iso-PGF2α is widely studied and considered one of the best biomarkers of oxidative stress because because it is relatively stable, including in human pregnancy, unaffected by dietary lipid intake unlike other oxidative stress measures, and readily detectable in urine (Ferguson et al., 2017;Roberts & Morrow, 2000). The 8-iso-PGF2α metabolite is generated in the lungs rather than the kidneys and may be a particularly sensitive biomarker of oxidative stress throughout the entire body (Dorjgochoo et al., 2012). ...
... Despite these limitations, this study has many strengths. The oxidative stress measure 8-iso-PGF2α is one of the best biomarkers of oxidative stress, including during human pregnancy (Ferguson et al., 2017;Roberts & Morrow, 2000). 8-iso-PGF2α concentration is not significantly affected by differences in dietary lipid intake of participants (Gopaul, Halliwell, & Änggård, 2000;Richelle et al., 1999). ...
... Levels of F 2 -isoprostanes in cortex were determined by a previously described method with minor modifications [40]. Briefly, 200 mg of cortex was homogenized in 10 ml of icecold Folch solution (CHCl 3 :MeOH, 2:1) containing butylated hydroxytoluene (BHT). ...
... We found no difference in GSH, GSSG, or GSSG ratio between the groups (Supplemental Table 1). F 2isoprostanes are a reliable marker of lipid peroxidation, which is formed by free radical reaction with arachidonic acid [40]. We found a significant increase in F 2 -isoprostanes in 24-month LID eWAT compared with eWAT from aged GFP (Fig. 3i, Supplemental Table 1). ...
Article
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Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.
... This may be a result of excessive accumulation of ROS from oxidation or the decrease in reduction potential resulting from a decrease in antioxidant defenses. This study utilized two markers of oxidative stress:Roberts & Morrow, 2000) that can be detected in biological fluids such as CSF (Bayir et al., 2002; Morrow, Minton, & Roberts, 1992 ). In this study, F 2 - Isoprostane was measured using a commercially available enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI), with a detection threshold of 5 pg/ml. ...
Article
Preliminary evidence suggests that PbtO2 values of ¡Ü 15 mm Hg may be suggestive of brain tissue hypoxia. Accordingly, many neurotrauma intensive care units attempt to maintain the PbtO2 ¡Ý 20 mm Hg based on the belief that this intervention will increase availability of oxygen in the brain for metabolism, and will avoid periods of brain tissue hypoxia with a 5 mm Hg buffer range. In clinical practice, one approach to managing a low PbtO2 (< 20 torr) is to increase the delivered fraction of inspired oxygen (FiO2). It remains unclear whether this therapy has risks as it also has the potential to increase oxidative stress. To determine if short periods of normobaric hyperoxia (2h) affect oxidative stress markers and antioxidant defenses, cerebrospinal fluid (CSF) was assessed in adults [n=11, (9 male, 2 female), mean age 26¡À1.8 yrs], with severe TBI (Glasgow Coma Scale score 6¡À1.4) before, during, and after a FiO2=1.0 challenge. Markers of oxidative stress including lipid peroxidation (F2-isoprostane [ELISA]) and protein oxidation (protein sulfhydryls [fluorescence]) and markers of antioxidant defenses including total antioxidant reserve (AOR) [chemiluminescence] and glutathione [fluorescence] were evaluated in CSF. Physiological parameters, [intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), PbtO2, arterial oxygen content (pO2)] were assessed at the same time points, using a 30 minute average prior to each FiO2 change. Mean (¡ÀSD) PbtO2 and PaO2 levels significantly changed for each time point, [before 27.3¡À7.4, 173.1¡À51.4; during 93.9¡À58.1, 385.5¡À108.3; and after 29.3¡À13.0, 171.8¡À45.1] a FiO2 challenge, (p=.04; .01), respectively. Oxidative stress markers, antioxidant reserve defenses and physiological parameters did not significantly change for any time period. These preliminary findings suggest that brief periods of normobaric hyperoxia improve oxygen levels without producing local oxidative stress in brain tissue. Additional studies are required to examine extended periods of normobaric hyperoxia and application of treatment during periods of critical PbtO2 levels.
... A common mechanism of lipid peroxidation is oxidative damage to cellular membranes. 8-iso-Prostaglandin F 2 (8-iso-PGF 2 ) has been recognized as a gold standard biomarker for the quantification of oxidative stress and oxidative damage [22][23][24] . Several analytical methods such as enzyme-linked immunosorbent assay (ELISA) and gas chromatography–mass spectrometry (GC–MS), have been used for quantification of 8-iso-PGF 2 in various biological samples . ...
Article
Prediabetes is the preclinical stage of type 2 diabetes mellitus (T2DM) with intermediate state of hyperglycemia. Hyperglycemia results in a state of oxidative stress, which may contribute to the production of insulin resistance, β-cell dysfunction and long-term complications of diabetes. Novel approaches are required for prevention and treatment of diabetes. New biomarkers that can be used in risk stratification and therapy control as supplementary to current parameters are needed. These biomarkers may facilitate a more individualized and sufficient treatment of diabetes. Therefore, the aim of this study was to investigate the levels of oxidatively induced DNA damage products, 8-oxo-2′-deoxyguanosine (8-oxo-dG) (also known as 8-OH-dG), (5′R)- and (5′S)-8,5′-cyclo-2′-deoxyadenosines (R-cdA and S-cdA), and the lipid peroxidation product 8-iso-prostaglandin F2α (8-iso-PGF2α) as reliable oxidative stress markers in patients with prediabetes or T2DM in comparison with healthy volunteers. Urine samples were collected from these subjects. Absolute quantification of 8-oxo-dG, R-cdA, S-cdA and 8-iso-PGF2α was achieved by liquid chromatography-isotope dilution tandem mass spectrometry. The levels of 8-oxo-dG, S-cdA and 8-iso-PGF2α were significantly greater in prediabetes patients than those in healthy volunteers. T2DM patients also had higher levels of 8-oxo-dG than healthy volunteers. No statistically significant difference was observed for R-cdA levels. 8-oxo-dG levels positively correlated with R-cdA and S-cdA levels for prediabetes and newly diagnosed T2DM. S-cdA levels and HbA1c were found negatively correlated in prediabetes patients. Also 8-iso-PGF2α levels and HbA1c were found negatively correlated in prediabetes patients. These results indicate that oxidatively induced macromolecular damage appears before the establishment of T2DM. Thus, our data suggest that oxidatively induced DNA damage and lipid peroxidation products that were found to be elevated in prediabetic stage may be used as early disease markers in patients at risk for T2DM.
... It remains controversial which anthropometric measurements and inflammatory biomarkers are the most appropriate to describe the association of obesity and inflammation or oxidative stress. The measurement of urinary F 2 -isoprostanes (F 2 - IsoPs) is now well accepted as the most accurate and reliable biomarker of oxidative stress in vivo [14, 15] . Urine is considered an ideal biological material for the measurement of F 2 -IsoPs because, unlike plasma, urine does not have a high lipid content; therefore , there is less concern about artifactual generation of isoprostanes by lipid autoxidation during sampling and storage [16] . ...
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Objectives: This study evaluated associations of various anthropometric measures of adiposity with a panel of inflammatory and oxidative stress markers in a relatively lean population of Chinese women. Methods: This analysis included 1,005 Chinese women aged 40–70 years. Plasma concentrations of inflammatory and oxidative stress markers were measured. Anthropometric measurements were taken by trained interviewers. Results: Body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) were all positively and linearly associated with the inflammatory markers, CRP, TNF-α, soluble TNF-receptor 1 (sTNF-R1), and IL-6. A significant positive association of these measures of adiposity with the oxidative stress marker F 2 -IsoP-M, a metabolite of F 2 -IsoPs, but with not F 2 -IsoPs was found. Differences in biomarkers between extreme quartiles of anthropometric measurements varied widely, ranging from 9.7% for sTNF-R1 to 162.0% for CRP. For each specific biomarker, various anthropometric measurements exhibited similar ability to explain variations in the biomarker, with the biggest partial r ² (11%) observed for CRP. Conclusions: This study suggests that both general adiposity (measured by BMI) and central adiposity (measured by WC and WHtR) are positively and similarly associated with various markers of inflammation and oxidative stress in relatively lean Chinese women. The metabolite F 2 -IsoP-M of F 2 -IsoPs may be a better marker of in vivo oxidative stress than its parent compounds.
... 371 Plasma measures of endothelial oxidative stress include indices of lipid peroxidation (F 2 -IsoPs and TBARS) and nitrotyrosine levels, reflecting peroxynitrite generation, although these measurements are not specific for endothelial ROS production. 372 Lipid peroxidation is increased in diseases associated with endothelial dysfunction, and there is a strong negative correlation between oxidative stress and endothelial function as assessed by forearm blood flow responses to acetylcholine in the presence of the antioxidant vitamin C. 373,374 ...
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Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. These guidelines are intended to help investigators and clinical researchers avoid experimental error and ensure high-quality measurements of these important biological species.
... Hyperglycaemia substantially stimulates methylglyoxal and ROS production (predominantly by mitochondria and cellular NADPH oxidases) and activates several metabolic pathways that are directly responsible for cellular damage (such as polyol pathway, advanced glycation endproduct (AGE) formation, activation of protein kinase C and hexosamine pathway)[8]. Clinical studies commonly use 24-h urinary excretion rate of free 8-iso-prostaglandin F2a (PGF2a) to estimate the intensity of oxidative stress [9]. The first study reporting the relationship between GV and oxidative stress measured as 24-h PGF2a in type 2 diabetes patients (T2DM) found a strong positive correlation between PGF2a and GV [10], however, subsequent studies of the same authors and others using PGF2a to evaluate oxidative damage in T1DM [11,12] and T2DM patients [13] failed to replicate previous findings. ...
... This finding supports current evidence that exposure to environmental factors is a risk factor for atherosclerosis in addition to other known risk factors. state systemic oxidative stress levels (Roberts and Morrow, 2000;Kadiiska et al., 2005;Milne et al., 2007). Isoprostanes are stable prostaglandin-like molecules formed in situ during free radical peroxidation of arachidonic acid, a component of low-density lipoprotein Materials-Analytical standards and [ 2 H]-stable isotope labeled standards of 8-isoprostaglandin F 2α were purchased from Cayman Chemicals (Ann Arbor, MI). ...
Article
Recent epidemiological studies suggest a strong association between exposure to environmental contaminants, including organochlorine (OC) insecticides or their metabolites, and development of pathologies, such as atherosclerosis, in which oxidative stress plays a significant etiological role. Biomarkers of systemic oxidative stress have the potential to link production of reactive oxygen species (ROS), which are formed as a result of exposure to xenobiotic toxicants, and underlying pathophysiological states. Measurement of F2-isoprostane concentrations in body fluids is the most accurate and sensitive method currently available for assessing in vivo steady-state oxidative stress levels. In the current study, urinary concentrations of F2-isoprostanes and serum levels of persistent OC compounds p,p'-dichlorodiphenyldichloroethene (DDE), trans-nonachlor (a component of the technical chlordane mixture), and oxychlordane (a chlordane metabolite) were quantified in a cross-sectional study sample and the association of these factors with a clinical diagnosis of atherosclerosis determined. Urinary isoprostane levels were not associated with atherosclerosis or serum concentrations of OC compounds in this study sample. However, occurrence of atherosclerosis was found to be associated with serum trans-nonachlor levels. DDE and oxychlordane were not associated with atherosclerosis. This finding supports current evidence that exposure to environmental factors is a risk factor for atherosclerosis, in addition to other known risk factors.
... Elevated levels of F2-isoPs, IsoFs, F4-NeuroPs and NeuroFs have been observed under different conditions related to increase of reactive oxygen species [4]. Therefore, the measurement of their concentrations in biological samples is an important tool to evaluate the role of oxidative stress in the pathogenesis of several human diseases [5,6]. In the perinatal field, the oxidative stress associated with physiopathological changes in several neonatal diseases (bronchopulmonary dysplasia, retinopathy of prematurity, hypoxic/ischemic encephalopathy) has been widely studied [7]. ...
Article
This paper describes a reliable analytical method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry to determine F2-isoprostanes and other total byproducts (isoprostanes, isofurans, neuroprostanes, neurofurans) as lipid peroxidation biomarkers in newborn plasma samples. The proposed procedure is characterized by a simple sample treatment employing a reduced sample volume (100 µL). Also, it shows a high throughput and high selectivity to determine simultaneously different isoprostane isomers in a large number of samples. The reliability of the described method was demonstrated by analysis of spiked plasma samples, obtaining recoveries between 70 and 130% for most of the analytes. Taking into account the implementation of further clinical studies, it was demonstrated the proper sensitivity of the method by means of the analysis of few human newborn plasma samples.
... Furthermore, the values of TBARS, which serve as a proxy to measure the products of lipid peroxidation, were unaffected by age in this study, which contradicts earlier studies [62, 64, 66]. However, the reliability of TBARS is criticized for low sensitivity and specificity, and the use of F2-isoprostanes is recommended as the most reliable approach to assess oxidative stress in vivo [67, 68] . The time courses of F2-iso- prostanes were significantly decreased in all calves; thus, we support the theory that exposure to an oxygen-rich environment following hypoxia during birth results in severe oxidative stress in the newborn [5]. ...
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Immaturity of the neonatal immune system is causative for high morbidity in calves and colostrum intake is crucial for acquiring passive immunity. Pathogenesis is promoted by reactive oxygen species accumulating at birth if counter-regulation is inadequate. The flavonol quercetin exerts antioxidative and anti-inflammatory effects that may enhance neonatal health. The aim of this work was to study effects of quercetin feeding on metabolic, antioxidative and inflammatory parameters in neonatal calves to investigate whether quercetin could compensate for insufficient colostrum supply. Twenty-eight newborn calves were assigned to two dietary groups fed colostrum or milk-based formula on day 1 and 2 and milk replacer thereafter. From day 2 onwards, 7 calves per diet group were additionally fed quercetin aglycone (50 mg/(kg body weight × day)). Blood samples were taken repeatedly to measure plasma concentrations of flavonols, glucose, lactate, total protein, albumin, urea, non-esterified fatty acids, triglycerides, cholesterol, insulin, glucagon, cortisol, immunoglobulins, fibrinogen, haptoglobin and serum amyloid A. Trolox equivalent antioxidative capacity, ferric reducing ability of plasma, thiobarbituric acid reactive species and F2-isoprostanes were analyzed to evaluate plasma antioxidative status. Expression of tumor necrosis factor, interleukin-1α, interleukin-1β, serum amyloid A, haptoglobin, fibrinogen, C-reactive protein, catalase, glutathione peroxidase and superoxide dismutase mRNA were measured in liver tissue on day 8. Plasma flavonol concentrations were detectable only after quercetin-feeding without differences between colostrum and formula feeding. Plasma glucose, lactate, total protein, immunoglobulins, triglycerides, cholesterol, trolox equivalent antioxidative capacity and thiobarbituric acid reactive species were higher after colostrum feeding. Body temperature, fecal fluidity and plasma concentrations of cortisol and haptoglobin were higher in formula- than in colostrum-fed groups. Hepatic mRNA expression of tumor necrosis factor was higher after quercetin feeding and expression of C-reactive protein was higher after formula feeding. Data confirm that colostrum improves neonatal health and indicate that quercetin feeding cannot compensate for insufficient colostrum supply.
... The antioxidant defenses act as a coordinated system when deficiencies in one component may affect the efficiency of the other (4). The most representative product that may reflect oxidative damage to the cells are F 2isoprostanes, which are specific products of lipid peroxidation and stable compounds present in detectable volumes in all normal biological fluids and tissues (5,6). The measurement of F 2 α Isoprostanes may represent an important development in the assessment of free radical generation and oxidative stress in vivo (7). ...
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Accumulative reports documented that oxidative stress is implicated in many human and animal diseases. However, the reports concerning the effect of oxidative stress on pregnancy outcome are limited and scarce. The objective of this study was to determine the impact of oxidative stress on pregnancy outcome and to assess the antioxidant effect of vitamin C and E on oxidative stress parameters in blood and placental tissue samples in experimental pregnant animals model exposed to oxidative stress. Wister Albino rats were used in this work to investigate the effects of oxidative stress exposure (addition of H2O2 to the drinking water) on pregnancy outcome. Rats were divided into 5 groups, as follows: Group I (included 7 normal pregnant rats which served as control group). Group II (exposed to 1% H2O2) included 7 pregnant rats, the rats were allowed to become pregnant and received (1% H2O2) in drinking water from day 7th till the day 19th of pregnancy. Group III (exposed to 3% H2O2) included 8 pregnant rats. Same as group 2, but the rats were exposed to a higher concentration of H2O2 (3%) in drinking water. Group IV (included 8 pregnant rats). Pregnant rats received vitamins C and E without induction of oxidative stress. Group V (included 8 pregnant rats).induction of oxidative stress by 1% H2O2 with vitamins supplementation in the pregnant rats. Serum total antioxidants capacity (TAC), serum and placental tissue oxidative stress biomarker; 8-iso prostaglandin F2α (8-Isoprostane) were measured using specific ELISA kits. Also placental tissues of pregnant rats were isolated and put directly in 10% formalin prepared for histopathological examination. Results revealed a significant decrease in the median values of the body weight and total serum antioxidants capacity (TAC) in groups II and III of rats compared with the control group. A significant higher median value of TAC obtained in the groups IV and V when compared with the control group. Significant higher levels of serum and tissue Isoprostane observed in both groups II and III compared with control group. Histopathological, oxidative stress induced macroscopically degenerative with microscopical appearance of vasculitis and hemorrhage within decidua. Data of the present study demonstrated that imbalance oxidative stress status in pregnant rats occurred due to exposure to oxidant, which played an important role in the pathogenesis of abnormal pregnancy outcome. In addition antioxidants supplementation (vitamins E and C) were valuable in reducing this stress.
... They may also act as vasoconstrictors and promote platelet activation resulting in thrombus formation [56,57]. Measurement of F2-isoprostanes is widely considered the most accurate method to measure oxidant stress in vivo [58,59]. Although it is not clear why F2-IsoP/Cr did not decrease with rosuvastatin in our study, this is consistent with prior studies evaluating the effect of statins on this oxidative stress marker outside of HIV [29,60]. ...
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Background: Oxidative stress plays a significant role in atherosclerosis development. HIV infection has been linked with heightened cardiovascular disease risk. HMG-CoA reductase inhibitors may reduce oxidative stress and subsequently subclinical vascular disease in HIV. Design/methods: This is a randomized, placebo-controlled trial to evaluate the effect of rosuvastatin in HIV-infected adults on stable antiretroviral therapy with low-density lipoprotein less than 130 mg/dl and increased inflammation or T-cell activation on subclinical vascular disease. Changes over 48 weeks in oxidative stress markers, oxidized low-density lipoprotein (oxLDL) and F2-isoprostane/creatinine ratio (F2-IsoP/Cr), were compared between groups. Spearman correlation and multivariable linear regression were used to evaluate relationships between changes in markers of oxidative stress, inflammation and monocyte activation and carotid intima media thickness (CIMT). Results: One hundred and forty-seven adults enrolled (72 to rosuvastatin and 75 to placebo). In the rosuvastatin group, oxLDL decreased significantly over 24 weeks compared to placebo [mean absolute change in log-oxLDL for rosuvastatin -0.2 ± 0.468 log U/l (P < 0.001 within-group) vs. placebo -0.018 ± 0.456 log U/l (P = 0.83 within-group); P = 0.004 between groups] and this change was linked with changes in soluble CD14 and proportion of patrolling monocytes (CD14dimCD16). Although oxLDL levels increased after initially declining and were not different from placebo at week 48, the early improvement in oxLDL was associated with improved CIMT at week 48. Changes in F2-IsoP/Cr were not significant between groups. Conclusion: Rosuvastatin decreases oxLDL levels early after initiation and is associated with decreased monocyte activation. Early improvement in oxLDL is linked with improved CIMT in treated HIV infection.
... It was reported that the formation of prostaglandin F2 compounds and F2-isoprostanes F2-IsoPs by free radicals in vivo induces the peroxidation of arachidonic acid. The F2-IsoPs are initially formed esterified to phospholipids and then released in free forms (27). Isoprostanes are prostaglandin (PG)-like substances that are formed in vivo independently from cyclooxygenase (COX) enzymes, mainly by free radical-induced peroxidation of arachidonic acid. ...
Article
Context: This study was a systematic review that aimed to extract published articles regarding oxidant and antioxidants status in opium addiction by searching in PubMed, Google Scholar engine, SID, and Magiran databases. Evidence Acquisition: Sixty-six published articles were investigated in this review, which were selected from studies among the Iranian society and other societies from 1976 to 2015. All articles published in different fields of descriptive-analytical, experimental, and interventional studies were considered. Results: Several studies have shown that with increased production of free radicals and reactive oxygen species (ROS), the enzymatic and non-enzymatic antioxidants such as glutathione (GSH) and glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activities, and also the concentration of vitamins A, E, C and total antioxidant capacity (TAC) decrease in opium addiction. Increased atherogenic indexes such as Low density lipoprotein/high density lipoprotein (LDL/HDL) ratio and malondialdehyde (MDA)maycontribute to the increased risk of cardiovascular disease. However, it has also increased other markers of oxidative stress including: isoprostanes, 8-oxoguanine and protein carbonyl. Conclusions: Oxidative stress increases in opium-addicted people. It seems that opium is capable of provoking oxidative stress and also, has harmful effects on lipid profile and antioxidant enzyme. Drug addicts were found to have antioxidant vitamin deficiency.
... In the present study, CDDP and MTX treatment resulted in significant increases in the F2-IsoPs production. Previous study have been reported that depletion of renal GSH, which is one the primary reasons for the resulting lipid peroxidation, may cause increases in F2-IsoPs levels (Roberts et al., 2000). As with the current findings, our data indicates that the generation of free radicals and subsequent lipid peroxidation may play a role in cisplatin and methotrexate nephrotoxicity (Abraham et al., 2010). ...
... Arachidonic acid peroxidation generates F2-isoprostanes by a cyclo-oxygenase independent pathway [260][261][262]. Part of these isoprostanes is unesterified but a great majority remains esterified. ...
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Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity.
... 8-iso-PGF-2α is a specific isoprostane formed from free radical oxidation of arachidonic acid and is an excellent reflection of activating oxidative stress throughout the body (10). ...
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Objective: The purpose of this study was to investigate the heterogeneity of the association between glycemic variability and oxidative stress markers in T1DM patients under daily life insulin treatment. Methods: We studied, in a cross-sectional analysis, 76 T1DM patients without clinical chronic diabetes complications and 22 healthy individuals. Were evaluated the short-term glycemic variability (STGV), long-term glycemic variability (LTGV), oxidative stress markers [8-isoprostaglandin-F2α (Ur-8-iso-PGF2α), nitric oxide (NO), thiobarbituric acid reactive substances (TBARS) and erythrocytes reduced/oxidized glutathione (GSH/GSSG)] and biochemical dosages (glycaemia, HbA1c, lipidogram, albuminuria). Results: Plasmatic NO was positively associated with LTGV (last year average of HbA1c) (8.7 ± 1.6% or 71 ± 18 mmol) (rS: 0.278; p: 0.042). Plasmatic TBARS, erythrocytes GSH/GSSH and Ur-8-iso-PGF-2α didn't show correlation with glycemic variability. GSH/GSSG was inversely correlated with LDL-cholesterol (rS: - 0.417; p: 0.047) and triglycerides (rS: -0.521; p: 0.013). Albuminuria was positive correlated with age (rS: 0.340; p: 0.002), plasmatic NO (rS: 0.267; p 0.049) and TBARS (rS: 0.327; p: 0.015). Conclusion: In daily life insulin treatment, young T1DM patients have higher plasmatic NO than healthy subjects. However, the correlation between glycemic variability and oxidative stress markers is heterogeneous. Lipid profile and albuminuria are associated with different oxidative stress markers. These data collaborate to explain the controversial results in this issue.
... Circulating biomarkers of endothelial health included asymmetric dimethylarginine (ADMA), 13,14 F2-isoprostanes, 15 growth differentiation factor-15 (GDF-15), 16 and von Willebrand factor (vWF). 17 ADMA and GDF-15 were quantitated via commercially available enzyme-linked immunosorbent assay (ELISA) kits (Immundiagnostik and R&D Systems respectively). F2-isoprostanes were measured using Enzo-Life competitive assays. ...
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Aims: Cardiorenal syndrome (CRS) is a common problem of great morbidity and mortality. Hydralazine-isosorbide dinitrate (H-ISDN) may be used in renal failure and may improve exercise capacity in heart failure (HF). Our proof-of-concept study aimed to evaluate early evidence of efficacy, safety, and feasibility of H-ISDN compared with standard of care in CRS. Methods and results: This multi-centre, single-blind, randomized trial in Singapore enrolled CRS patients, defined as chronic HF with concomitant renal failure [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 ]. The primary outcome was 6 min walk test (6MWT) distance measured at 6 months. Secondary outcomes included study feasibility; efficacy outcomes which included renal, cardiac, and endothelial functions, health-related quality of life using Short Form-36, clinical outcomes; and adverse events. Forty-four patients [71 ± 10 years; 75% male; median (inter-quartile range) N-terminal prohormone brain natriuretic peptide 1346 (481-2272) pg/mL] with CRS (left ventricular ejection fraction 42 ± 12% and eGFR 46 ± 15 ml/min/1.73 m2 ) were randomized into two equal groups. Of these, 39 (89%) had hypertension, 27 (61%) had diabetes mellitus, and 17 (39%) had atrial fibrillation. Six (27%) discontinued H-ISDN owing to intolerance and poor compliance. There was a trend towards improved 6MWT distance with H-ISDN compared with standard of care at 6 months (mean difference 27 m; 95% CI, -12 to 66), with little differences in secondary efficacy outcomes. Giddiness and hypotension occurred more frequently with H-ISDN, but HF hospitalizations and mortality were less. Conclusions: Our pilot study does not support the addition of H-ISDN on top of standard medical therapy to improve exercise capacity in patients with CRS.
... L'HA induit une réduction importante des teneurs des isoprostanes sériques et urinaires chez le groupe traité comparé au non traité suggérant une réduction du stress oxydant chez ce groupe. Leur taux est augmenté dans les modèles animaux ou cliniques en réponse à un stress oxydant, modulés en fonction du statut antioxydant, mais insensibles aux variations courantes de la quantité de lipides contenue dans l'alimentation [31]. Les antioxydants sont des molécules capables de ralentir ou d'empêcher l'oxydation d'autres molécules, protégeant ainsi les cellules contre les dommages de l'oxydation, les antioxydants peuvent retirer des intermédiaires radicaux libres et inhiber d'autres réactions d'oxydation en étant eux-mêmes oxydés. ...
Chapter
Reactive species provoke amplification of inflammatory response in the airways and lung parenchyma causing inhibition of mitochondrial respiration, and lipid, protein, and DNA damage causing oxidative stress. Long-term persistence of oxidative stress may contribute to progressive deterioration of pulmonary functions leading to respiratory failure. Recent reports, suggesting protein nitration as dynamic and reversible (denitration) mechanism, open new horizons in the treatment of chronic respiratory disease affected by deleterious action of nitrosative stress. Reduced antioxidants in the body overwhelm the system with oxidants and promote cellular oxidative stress. Different species of ROS activate various transcription factors altering signaling pathways, and lead to divergent cellular response. Therapeutic interventions which increase endogenous lung antioxidants, or with administration of exogenous antioxidants which reduce effects of environmental exposure to oxidants may prove to be beneficial as adjunct therapies in respiratory disorders. Hundreds of antioxidant supplements are readily available in the market which require regulation for efficacy and side effects.
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Age-related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle-specific overexpression of the mitochondrial H2 O2 scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2 O2 can prevent or delay the redox-dependent sarcopenia. Basal rates of H2 O2 generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross-sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild-type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle-specific PRDX3 overexpression reduces mitochondrial H2 O2 generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox-dependent sarcopenia.
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Cardiovascular disease is the major cause of morbidity and mortality globally. As such better approaches for early detection and mechanism-targeted therapies are key priorities in cardiovascular research. Growing evidence indicates that vascular inflammation and oxidative stress may play an important role in the genesis and progression of cardiovascular disease. Accordingly identification of markers reflecting these processes may be useful early predictors of vascular damage and could provide insights into mechanisms, risk and targeted treatment. The present chapter provides a brief overview of vascular damage in cardiovascular disease and discusses recently identified novel biomarkers of vascular inflammation and oxidative stress. The potential clinical relevance is also highlighted.
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Significance: Oxidized phospholipids are now well recognized as markers of biological oxidative stress and bioactive molecules with both pro-inflammatory and anti-inflammatory effects. While analytical methods continue to be developed for studies of generic lipid oxidation, mass spectrometry (MS) has underpinned the advances in knowledge of specific oxidized phospholipids by allowing their identification and characterization, and it is responsible for the expansion of oxidative lipidomics. Recent Advances: Studies of oxidized phos-pholipids in biological samples, from both animal models and clinical samples, have been facilitated by the recent improvements in MS, especially targeted routines that depend on the fragmentation pattern of the parent molecular ion and improved resolution and mass accuracy.
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The presence of various bioactive markers in the human body reflects its health condition, physical endurance, and also the intake of some valuable compounds from food. Analytical methods for their determination are becoming a useful tool for gaining information on the levels of these physiologically essential substances. Antioxidants that can prevent or slow the harmful action of free radicals belong to one of the most significant biomarkers. Reactive oxygen species/reactive nitrogen species produced under oxidative stress act together and cause damage to all cellular biomolecules. Therefore excessive levels of such reactive species pose a threat to human organisms contributing to inflammatory responses. For measurements of oxidative stress or damage indicators, both the reactive species are analyzed, and also different markers considered useful indexes of the level of the phenomenon are determined. Biological samples usually include whole blood derivatives (serum and plasma), urine, and saliva. The fluorescence methods are most commonly applied for the determination of oxygen radicals. At the same time, markers of cellular oxidative damage are most often tested in body fluids and tissue homogenates using enzyme-linked immunoassay kits, high-pressure liquid chromatography, or even gas chromatography, both combined with mass spectrometry. For the assay of protein carbonyls in biological matrices, the derivatization of the carbonyl group, usually with 2,4-dinitrophenylhydrazine, is performed and followed by the detection of various types, for example, using anti-DNP antibodies in immunoblotting.
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Introduction Cancer has been associated with increased oxidative stress and deregulation of bioactive oxylipins derived from long-chain polyunsaturated fatty acids (LC-PUFA) like arachidonic acid (AA). There is a debate whether ω-3 LC-PUFA could promote or prevent prostate tumor growth through immune modulation and reduction of oxidative stress. Our aim was to study the association between enzymatically or non-enzymatically produced oxidized-LC-PUFA metabolites and tumor growth in an immune-competent eugonadal and castrated C57BL/6 male mice injected with TRAMP-C2 prostate tumor cells, fed with ω-3 or ω-6 LC-PUFA-rich diets. Materials and methods Tumor fatty acids were profiled by gas chromatography and 26 metabolites derived from either AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were assessed by liquid chromatography-mass spectrometry. Results The enriched ω-3 diet did not reduce oxidative stress overall in tumors but favored the formation of ω-3 rather than ω-6 derived isoprostanoids. We discovered that EPA and its oxidized-derivatives like F3-isoprostanes and prostaglandin (PG)F3α, were inversely correlated with tumor volume (spearman correlations and T-test, p<0.05). In contrast, F2-isoprostanes, adrenic acid, docosapentaenoic acid (DPAω-6) and PGE2 were positively correlated with tumor volume. Interestingly, F4-neuroprostanes, PGD2, PGF2α, and thromboxane were specifically increased in TRAMP-C2 tumors of castrated mice compared to those of eugonadal mice. Discussion Decreasing tumor growth under ω-3 diet could be attributed in part to increased levels of EPA and its oxidized-derivatives, a reduced level of pro-angiogenic PGE2 and increased levels of F4-neuroprostanes and resolvins content in tumors, suspected of having anti-proliferative and anti-inflammatory effects.
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Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F2-isoprostanes in brains and hearts of mice. The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning.
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Oxidized polyunsaturated fatty acids (PUFA) are associated to pathogenesis of diseases including cardiovascular and neurodegeneration. The novel products are not only biomarkers but also lipid mediators in gene regulation and signaling pathways. Herein, simultaneous quantitation of 28 products derived from nonenzymatic and enzymatic oxidation of PUFA i.e. 5-, 15-F2t -isoprostanes, 7-, 17-F2t -dihomo-isoprostanes, 7-, 17-F2t -dihomo-isofurans, 5-, 8-, 18-F3t -isoprostanes, 4-, 10-, 13-, 14-, 20-F4t -neuroprostanes, 5-, 8-, 9-, 11-,12-, 15-, 20-HETE, 4-, 7-, 11-, 14-, 17-HDHA, RvE1, and NPD1 using LC-(ESI)-QTOF-MS/MS was developed. These products were measurable in a single sample and the analytical time was relative short (~15 min). Furthermore, we showed that the use of internal standards is a requisite to normalize matrix effects and preparation loss for the quantitation. Validation assays indicated the method to be robust for plasma and mid-stream urine sample analysis in particular from those of age-related macular degeneration subjects, where the accuracy of quantitation displayed good repeatability.
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Objective: The objective of this study, in addition to confirming that therapy with131I causes oxidative stress, was to evaluate the effect of supplementation with vitamins C and E and selenium on this phenomenon by measuring plasma 8-epi-PGF2a, a marker of lipid peroxidation. Subjects and methods: Forty patients with thyroid cancer submitted to thyroidectomy, who received 3.7 GBq 131I after levothyroxine withdrawal, were selected; 20 patients did not receive (control group) and 20 patients received (intervention group) daily supplementation consisting of 2000 mg vitamin C, 1000 mg vitamin E and 400 µg selenium for 21 days before131I. Plasma 8-epi-PGF2a was measured immediately before and 2 and 7 days after 131I. Results: A significant increase in plasma 8-epi-PGF2a after 131I was observed in the two groups. The concentrations of 8-epi-PGF2α were significantly higher in the control group before and 2 and 7 days after131I. The percentage of patients with elevated 8-epi-PGF2α was also significantly higher in the control group before and after131I. Furthermore, the increase (percent) in 8-epi-PGF2α was significantly greater in the control group (average of 112.3%versus 56.3%). Only two patients (10%) reported side effects during supplementation. Conclusions: Ablation with 131I causes oxidative stress which can be minimized by the use of antioxidants.
Article
Objective: The cause of perioperative myocardial infarction (PMI) is postulated to involve hemodynamic stress or coronary plaque destabilization. We aimed to evaluate perioperative factors in patients with peripheral artery disease (PAD) undergoing major vascular surgery to determine the likely mechanisms and predictors of PMI. Methods: This was a prospective cohort study of 133 patients undergoing major vascular surgery including open abdominal aortic aneurysm (AAA) repair (n = 40) and major suprainguinal or infrainguinal arterial bypasses (non-AAA; n = 93). Preoperative assessment with history, physical examination, and peripheral artery tonometry was performed in addition to plasma sampling of biomarkers associated with inflammation and coronary plaque instability. The primary outcome was occurrence of a 30-day cardiovascular event (CVE; composite of PMI [troponin I elevation >99th percentile reference of ≥0.1 μg/L], stroke, or death). Results: Of 133 patients, 36 patients (27%) developed a 30-day CVE after vascular surgery, and all were PMI. Patients with 30-day CVE were older (75 ± 8 years vs 69 ± 10 years, mean ± standard deviation; P = .001), had higher prevalence of hypertension (94% vs 79%; P = .01) and preoperative beta-blocker therapy (50% vs 29%; P = .02), and had longer duration of surgery (5.1 ± 1.8 hours vs 4.0 ± 1.1 hours; P < .0001). Significant elevations in cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin I, high-sensitivity troponin T, matrix metalloproteinase 3, and osteoprotegerin occurred in those who developed 30-day CVE (all P < .05). Multivariate binary logistic regression identified AAA surgery and log-transformed NT-proBNP to be independent preoperative predictors of 30-day CVE (area under the receiver operating characteristic curve = 0.81). Conclusions: In patients with peripheral artery disease undergoing major vascular surgery, the likely mechanism of PMI appears to be the hemodynamic stress related to the type and duration of surgery. NT-proBNP was a useful independent predictor of CVE and thus may serve as an important biomarker of cardiovascular fitness for surgery.
Article
Introduction: Cutaneous leishmaniasis is a dermal disease caused by several species of the genus Leishmania. It is an endemic disease with 1.2 million new cases occurring annually and mostly in developing countries. Oxidative stress is a condition of an imbalance in oxidant/antioxidant which may play a role in many different pathologic conditions. For the first time in this study, we introduced isoprostane as a reliable index for oxidative stress in patients suffering from leishmaniasis. We also investigated the possible relation between quantitative CRP and this disease. Method and material: We collected 5 ml blood of 30 patients in addition to the same sample of the control healthy group. After applying appropriate methods, the plasma and serum specimens were extracted in order to conduct oxidant-antioxidant balance and CRP tests in serum as well as measuring isoprostane factor in plasma. Statistical analysis: We used T-student, ANOVA as well as linear regression to analyze the gathered data with a 0.05 confidence interval in SPSS environment. Results: The results showed a significant difference between the two groups in terms of the oxidant-antioxidant balance. Also, isoprostane and quantitative CRP levels were substantially higher in patients. There was no significant relationship between the mentioned factors and wound size and number. Conclusion: Leishmania Amastigotes plays an important role in disturbing the oxidant-antioxidant balance resulting in inflammation and stress in patients. Furthermore, isoprostane was confirmed as a reliable index for evaluating oxidative stress in patients.
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Background Short‐term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community‐based studies have assessed this association. Methods and Results Two thousand thirty‐five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998–2001) and urinary creatinine‐indexed 8‐epi‐prostaglandin F2α (8‐epi‐PGF 2α) at the seventh and eighth (2005–2008) examinations. We measured fine particulate matter (PM 2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1‐, 2‐, 3‐, 5‐, and 7‐day moving averages of each pollutant. Measured myeloperoxidase and 8‐epi‐PGF 2α were loge transformed. We used linear regression models and linear mixed‐effects models with random intercepts for myeloperoxidase and indexed 8‐epi‐PGF 2α, respectively. Models were adjusted for demographic variables, individual‐ and area‐level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM 2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2‐ to 7‐day moving averages of PM 2.5 and sulfate were consistently positively associated with 8‐epi‐PGF 2α. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. Conclusions Our community‐based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress.
Chapter
Pulmonary arterial hypertension (PAH) is a severe disease characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance (PVR), progressive arterial stiffening, and ultimately right ventricular (RV) failure and death. Despite state-of-the-art therapy and recent advances in our understanding of the molecular mechanisms and genetic determinants of disease, morbidity and mortality remain unacceptably high. Vascular remodeling in PAH is characterized by endothelial dysfunction with release of vasoactive mediators, growth factors, and cytokines; smooth muscle cell hyperplasia and hypertrophy with medial wall thickening; and adventitial fibroblast proliferation, extracellular matrix deposition, and myofibroblast differentiation. Growing evidence through animal and human studies suggests that oxidative stress plays a key role in the pathogenesis of PAH. Oxidative stress in PAH is associated with increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), decreased nitric oxide (NO) levels, and mitochondrial dysfunction. Dysregulation of ROS/RNS/NO homeostasis can impair vascular tone and lead to activation of antiapoptotic and pro-proliferative signaling pathways resulting in aberrant vascular remodeling in the lung. Increases in oxidative stress have been demonstrated in animal PH models and PAH patients, and therapies targeting oxidative stress have shown promise in animal models of PH. This chapter will examine the mechanisms of ROS generation in the pulmonary vasculature, review the available animal and human data on the role of oxidative stress in the pathobiology of PAH, and discuss potential therapies targeting oxidative stress for the treatment of patients with PAH.
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Wastewater analysis has been demonstrated to be a complementary approach for assessing the overall patterns of drug use by a population while the full potential of wastewater-based epidemiology has yet to be explored. F2-isoprostanes are a prototype wastewater biomarker to study the cumulative oxidative stress at a community level. In this work, 8-iso-prostaglandin F2α (8-iso-PGF2α) was analysed in raw 24 h-composite wastewater samples collected from 4 Norwegian and 7 other European cities in 2014 and 2015. Using the same samples, biomarkers of alcohol (ethyl sulfate) and tobacco (trans-3′-hydroxycotinine) use were also analysed to investigate any possible correlation between 8-iso-PGF2α and the consumption of the two drugs. The estimated per capita daily loads of 8-iso-PGF2α in the 11 cities ranged between 2.5 and 9.9 mg/day/1000 inhabitants with a population-weighted mean of 4.8 mg/day/1000 inhabitants. There were no temporal trends observed in the levels of 8-iso-PGF2α, however, spatial differences were found at the inter-city level correlating to the degree of urbanisation. The 8-iso-PGF2α mass load was found to be strongly associated with that of trans-3′-hydroxycotinine while it showed no correlation with ethyl sulfate. The present study shows the potential for 8-iso-PGF2α as a wastewater biomarker for the assessment of community public health.
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Schizophrenia is a complex and unique disorder with processes of neurodevelopment and neurodegeneration. This is one of the most severe and chronic forms of mental disorders, and it affects roughly 1 % of the world’s population. Despite the recent advances, the molecular mechanisms underlying schizophrenia remain unclear. There is accumulating evidence for oxidative stress mechanisms as common pathophysiological pathways in this disorder. Specific markers of oxidative stress as a sensor of oxidation associated with schizophrenia might provide a key link connecting mechanisms underlying numerous processes described in schizophrenia. Mitochondrial dysfunction triggers extensive generation of free radicals leading to oxidative/nitrative stress, abnormalities, and pathologic consequences. Patients with schizophrenia present an increase in oxidative damage to lipids, proteins, and DNA, in both central and peripheral tissues with deficits of antioxidant defense, especially deficit of glutathione. The chapter presents biomarkers of oxidative damage and the role of oxidative stress in numerous abnormalities in biochemical pathways including apoptosis in the pathophysiology of schizophrenia. At present, no single theory provides all aspects of abnormalities in the disease. The development of new investigative techniques, especially neuroimaging, and studies of apoptotic pathway seem to prove neurodegenerative and neurodevelopmental theories; oxidative/nitrative damage may integrate and support basic mechanisms of neurodevelopment and neurodegeneration processes in schizophrenia.
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Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications, including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans.
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Background & aims: Nonalcoholic fatty liver disease is an inflammatory condition that results in progressive liver disease. It is unknown if individuals with hepatic steatosis, but not known to have liver disease, have higher serum concentrations of markers of systemic inflammation and oxidative stress. Methods: We collected data from 2482 participants from the Framingham Heart Study (mean age, 51 ± 11 y; 51% women) who underwent computed tomography and measurement of 14 serum markers of systemic inflammation. Heavy alcohol users were excluded. The liver:phantom ratio (a continuous parameter of liver attenuation relative to a calibration phantom) was used to identify individuals with radiographic evidence of liver fat. Primary covariates included age, sex, smoking, alcohol, aspirin use, hypertension, dyslipidemia, diabetes, and cardiovascular disease. Body mass index and visceral fat were secondary covariates. We used multivariable linear regression models to assess the association between liver fat and systemic inflammatory markers. Results: In multivariable-adjusted models, liver fat was associated with the following inflammatory markers: high-sensitivity C-reactive protein (P < .001), urinary isoprostanes (P < .001), interleukin 6 (P < .001), intercellular adhesion molecule 1 (P < .001), and P-selectin (P = .002). Additional adjustment for body mass index or visceral fat attenuated the results slightly, although all associations remained statistically significant (P for all ≤ .01). Conclusions: In a community-based cohort, individuals with hepatic steatosis without known liver disease had higher mean serum concentrations of systemic markers of inflammation. Studies are needed to determine whether treatment of hepatic steatosis reduces systemic inflammation.
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Hypertension is a major cardiovascular risk factor. Of the many processes involved in the pathophysiology of hypertension, cardiac, vascular and renal damage due to oxidative stress (excess bioavailability of reactive oxygen species (ROS)) is important. Physiologically, ROS regulate cell function through redox-sensitive pathways. In hypertension, oxidative stress promotes endothelial dysfunction, vascular remodeling and inflammation, leading to vascular damage. While experimental evidence indicates a causative role for oxidative stress in hypertension, human data are less convincing. This may relate to sub-optimal approaches to accurately measure ROS in humans. Various methods have been developed to assess the extent and nature of oxidative stress, including markers of protein oxidation, lipid oxidation, and anti-oxidant status. These approaches are, in general, indirect and measure indices of redox state. While large clinical studies to establish whether biomarkers of oxidative stress accurately predict disease risk are still needed, oxidative biomarkers have provided important mechanistic insights regarding redox-sensitive processes of hypertension. Here we briefly describe the importance of ROS in redox signaling and hypertension and discuss biomarkers of oxidative stress in human hypertension.
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The malfunction of the finely tuned homeostatic systems that maintain oxidative balance is part of the pathology of almost every known human disease. There are scores of individual components and pathways which maintain oxidative balance. One or more of these maybe altered in disease, though it is difficult to determine what the triggering pathway or analyte is. In light of this, biomarkers are useful tools to evaluate oxidative imbalance or indicate the degree of oxidative stress. When selecting which biomarkers for oxidative stress, there are three categories of biomarkers to choose from. These depend on the target of oxidation and are isoprostanes, oxysterols, and hydroxyoctadecadienoic acid. Biomarkers of nucleic acid oxidation include nucleotides, single- and double-stranded breaks in DNA, and RNA oxidative products. Oxidative damage to proteins can be measured via protein carbonyls, glutathione levels, glycosylated hemoglobin, and erythrocyte oxidation from fluorescent heme degradation products. In isolation, each of these will give specific information on the target of oxidation, as well as providing tentative information regarding affected pathways. Here, we describe in detail the selective markers, protein carbonyls, oxysterols, isoprostanes, heme degradation products, HbA1C, and many more. All the above biomarkers are discussed in this review. As with ideal biomarkers, these have a mixed utility and can be measured in different tissues and compartments. In blood, each will provide a certain amount of information, which will vary between giving a systemic scope of oxidative stress (e.g., erythrocyte oxidation) to evaluating oxidative stress in specific diseases (e.g., glycosylated hemoglobin and diabetes). Ideally, it is better to select multiple biomarkers based on an in-depth knowledge of the condition at hand. © Springer Science+Business Media Dordrecht 2015. All rights reserved.
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Objective: This study aimed to investigate whether and how lipid peroxidation markers are associated with height and obesity measures. Methods: In two independent samples of women (Study 1: n = 1,005; Study 2: n = 1,158), systemic levels of lipid peroxidation were assessed by urinary markers F2 -isoprostanes (F2 -IsoPs) and its major metabolite (F2 -IsoP-M), with gas chromatography/negative ion chemical ionization mass spectrometry assays. Anthropometric parameters were directly measured and genetically estimated, and they were used in the primary analysis and in a Mendelian randomization analysis in relation to lipid peroxidation, respectively, with general linear models. Results: After adjusting for potential confounders, it was found that measured adult height was inversely associated with levels of F2 -IsoPs (β = -0.89, p < 0.001) and F2 -IsoP-M (β = -0.71, p = 0.003), whereas obesity measures were positively associated with F2 -IsoP-M (β = 1.81, p < 0.001 for BMI; and β = 0.77, p < 0.001 for waist circumference). Results were consistent between the two study samples. The opposite associations were further replicated when using genetically determined measures of height and obesity in the Mendelian randomization analysis. Moreover, analyses mutually adjusted for height and obesity measures suggested that these associations were independent of one another. Conclusions: This study, for the first time, to our knowledge, reveals that a shared biological process (lipid peroxidation) is associated with both height and obesity measures but in the opposite direction.
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BACKGROUND: Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association. METHODS AND RESULTS: Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine-indexed 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2-, 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF2alpha were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF2alpha, respectively. Models were adjusted for demographic variables, individual- and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2- to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF2alpha. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. CONCLUSIONS: Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress.
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Excess macronutrient intake leads to an increase in formation of reactive oxygen species (ROS). This causes an imbalance between ROS generation and the ability of the body to neutralize these radicals, a state known as oxidative stress. Previous research suggests the ability of dairy products to attenuate the postprandial response, which may reduce ROS formation. Therefore, this study aimed to elucidate the impact of low-fat yogurt consumption on fasting and postprandial oxidative stress in obese women. We hypothesized that co-consumption of low-fat yogurt and a high-calorie, high-fat meal would reduce postprandial elevations in oxidative stress in obese women. To test this hypothesis, healthy, lean and obese women co-consumed low-fat yogurt or soy pudding (control) and a high-calorie, high-fat meal on 2 occasions separated by 9-week daily yogurt or pudding consumption. Postprandial blood samples were collected for 4 h during meal challenges and fasting samples were collected at 3 week intervals throughout the duration of the intervention. Fasting and postprandial plasma samples were analyzed for malondialdehyde (MDA), total thiols (SH), and advanced glycation endproducts (AGEs). A secondary aim of this work was to classify changes in dietary intake associated with the intervention; data was based on 3-day self-reported dietary records. Low-fat yogurt consumption did not lead to changes in BMI, waist circumference, or blood pressure. Consumption of low-fat yogurt attenuated postprandial increases in MDA in obese women at both the initial and final meal challenges. However, 9-week yogurt consumption did not further attenuate the postprandial response and had no effect on fasting MDA concentrations in obese women. Yogurt and pudding prevented postprandial changes in SH and AGEs, while chronic plasma SH and AGEs were unaffected by 9-week yogurt or soy pudding intake. Daily consumption of low-fat yogurt and soy pudding increased calcium and vitamin D intake and yogurt increased dairy intake in lean and obese women. Therefore, the addition of low-fat yogurt to the diet may be a strategy to increase dairy, calcium, and vitamin D intake without inducing any unfavorable changes in body composition, blood pressure, and postprandial or chronic levels of oxidative stress.
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In Ghana, uncomplicated malaria and sickle cell disease (SCD) is common, hence comorbidity is not farfetched. However, the extent of oxidative stress and the array of clinical manifestations in this comorbidity (presence of both malaria and SCD) has not been fully explored. This study highlights the impact of uncomplicated malaria on SCD. The level of isoprostane, 8-iso-prostaglandin F2α (8-iso-PGF2α) was used to assess oxidative stress while plasma biochemistry and urinalysis was used to assess renal function. Hematological profiling was also done to assess the impact of comorbidity on the hematological cell lines. Of the 411 study participants with malaria, 45 (11%) had SCD. Mean body temperature was significantly higher in comorbidity compared to malaria and SCD cohorts, while a lower parasite density range was obtained in comorbidity compared to malaria cohorts. Furthermore, in comorbidity, the 8-iso-PGF2α oxidative stress biomarker was significantly elevated in all ages, parasite density ranges and gender groups. Comorbidity affected both leukocytic and erythrocytic cell lines with significant eosinophilia and monocytosis coexisting with erythrocytic parameters consistent with severe anemia. Biochemically, while plasma creatinine and bilirubin were significantly elevated in comorbidity, spot urinary creatinine was significantly reduced. Additionally, urine samples in the comorbid state were slightly acidic and hypersthenuric with significant hematuria, proteinuria, and bilirubinemia. Finally, 80% or more malaria-SCD presented with chills, fever, anorexia, headache, joint pains, lethargy, and vomiting. In conclusion, malaria could induce vaso-occlusive crisis in sickle cell disease, therefore, prompt management will alleviate the severity of this comorbidity.
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It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals. However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking. We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke. We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex. The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers. Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (242 +/- 147 and 574 +/- 217 pmol per liter, respectively) than in the nonsmokers (103 +/- 19 and 345 +/- 65 pmol per liter; P = 0.02 for free F2-isoprostanes and P = 0.03 for esterified F2-isoprostanes). Smoking had no short-term effects on the circulating levels of F2-isoprostanes. However, the levels of free and esterified F2-isoprostanes fell significantly after two weeks of abstinence from smoking (250 +/- 156 and 624 +/- 214 pmol per liter, respectively, before the cessation of smoking, as compared with 156 +/- 67 and 469 +/- 108 pmol per liter after two weeks' cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 for esterified F2-isoprostanes). The increased levels of F2-isoprostanes in the circulation of persons who smoke support the hypothesis that smoking can cause the oxidative modification of important biologic molecules in vivo.
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The question as to whether free radical reactions are a major cause of tissue injury in human disease, or merely an accompaniment to such injury, is very difficult to answer because of lack of adequate experimental techniques. New techniques that are becoming available are discussed, with specific reference to their use in humans.
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Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F2-like compounds, termed F2-isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress. As a measure of oxidative stress, we determined urinary concentrations of a tetranor-dicarboxylic acid metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects. F2IP-M concentrations were significantly higher in patients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease. The increased level of urinary F2IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.
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Postmortem studies have associated Alzheimer's disease (AD) with regionally increased oxidative damage to brain. Lacking, however, is a specific marker of oxidative damage to brain that may be measured during life. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of F2-isoprostanes (F2-IsoPs), stable products of arachidonate peroxidation, are increased in CSF of AD patients. CSF from lateral ventricles (VF) was analyzed from 11 AD patients and 11 control subjects who participated in a rapid autopsy program. VF F2-IsoP concentrations were significantly elevated in AD patients compared with control subjects (72 +/- 7 vs 46 +/- 4 pg/ml) and were significantly linearly correlated with brain weight (-0.3 pg/ml/g, r2 = 0.32). These results suggest that quantification of CSF F2-IsoP concentrations may provide a useful biomarker of central nervous system oxidative damage in AD.
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We previously reported the detection of a carbon-centered radical adduct of alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (POBN) in the bile of rats acutely poisoned with Cr(VI) utilizing an electron spin resonance spin-trapping technique. These former studies suggested that the free radical metabolite was derived from a polyunsaturated fatty acid. The present studies were undertaken to further characterize this radical adduct and to determine whether its formation is associated with enhanced lipid peroxidation in vivo. This report demonstrates that electron spin resonance (ESR) spectra with hyperfine coupling constants aN of 15.71 G and of 2.90 G were present in bile from Cr(VI)-poisoned rats. We found out that virtually identical ESR spectra were obtained when authentic POBN-pentyl radical adducts generated from the reaction of POBN with either pentylhydrazine or linoleic or arachidonic acid with lipoxygenase were added to bile. The hyperfine coupling constants for the POBN-pentyl radical adducts added to bile were as follows: aN = 15.85 G and = 2.60 G for the reaction between pentylhydrazine and POBN; aN = 15.72 G and = 2.61 G for the reaction between arachidonic acid, lipoxygenase, and POBN; and aN = 15.85 G and = 2. 85 G for the reaction between linoleic acid, lipoxygenase, and POBN. In addition, the formation of this radical adduct was associated with lipid peroxidation as quantified by increases in F2-isoprostane levels in bile. These studies, therefore, provide additional evidence that acute Cr(VI) poisoning is associated with enhanced generation of F2-isoprostanes in vivo and tentatively identify the radical species that is produced as the POBN-pentyl radical adduct.
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This study aims to determine if isoprostanes accurately reflect in vivo lipid peroxidation or whether they are influenced by the lipid content of the diet. Isoprostanes were measured in urine of healthy subjects under different conditions of lipid intake and under conditions of oxidative stress (fasting). We found that isoprostanes were not influenced by the lipid content of the diet: the urinary level remained constant over 24 h as well as over 4 consecutive days when switching from high to low lipid intake. Urinary isoprostane excretion was increased by 40% following a 24 h fast. We concluded that urinary isoprostane excretion reflects endogenous lipid peroxidation in vivo.