Non-transferrin bound iron,cytokine activation and intracellular reactive oxygen species generation in hemodialysis patients receiving intravenous iron dextran or iron sucrose

Intravenous (IV) iron supplementation is widely used to support erythropoeisis in hemodialysis patients. IV iron products are associated with oxidative stress that has been measured principally by circulating biomarkers such as products of lipid peroxidation. The pro-oxidant effects of IV iron are presumed to be due at least in part, by free or non-transferrin bound iron (NTBI). However, the effects of IV iron on intracellular redox status and downstream effectors is not known. This prospective, crossover study compared cytokine activation, reactive oxygen species generation and oxidative stress after single IV doses of iron sucrose and iron dextran. This was a prospective, open-label, crossover study. Ten patients with end-stage renal disease (ESRD) on hemodialysis and four age and sex-matched healthy were assigned to receive 100 mg of each IV iron product over 5 min in random sequence with a 2 week washout between products. Subjects were fasted and fed a low iron diet in the General Clinical Research Center at the University of New Mexico. Serum and plasma samples for IL-1, IL-6, TNF-α and IL-10 and NTBI were obtained at baseline, 60 and 240 min after iron infusion. Peripheral blood mononuclear cells (PBMC) were isolated at the same time points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential (Δψm) by flow cytometry. Lipid peroxidation was assessed by plasma F₂ isoprostane concentration. Mean ± SEM maximum serum NTBI values were significantly higher among patients receiving IS compared to ID (2.59 ± 0.31 and 1.0 ± 0.36 μM, respectively, P = 0.005 IS vs. ID) Mean ± SEM NTBI area under the serum concentration–time curve (AUC) was 3-fold higher after IS versus ID (202 ± 53 vs. 74 ± 23 μM*min/l, P = 0.04) in ESRD patients, indicating increased exposure to NTBI. IV iron administration was associated with increased pro-inflammatory cytokines. Serum IL-6 concentrations increased most profoundly, with a 2.6 and 2.1 fold increase from baseline in ESRD patients given IS and ID, respectively (P < 0.05 compared to baseline). In healthy controls, serum IL-6 was undetectable at baseline and after IV iron administration. Most ESRD patients had increased intracellular ROS generation, however, there was no difference between ID and IS. Only one healthy control had increased ROS generation post IV iron. All healthy controls experienced a loss of Δψm (100% with IS and 50% with ID). ESRD patients also had loss of Δψm with a nadir at 240 min. IS administration was associated with higher maximum serum NTBI concentrations compared to ID, however, the both compounds produced similar ROS generation and cytokine activation that was more pronounced among ESRD patients. The effect of IV iron-induced ROS production on pivotal signaling pathways needs to be explored.     

The effect of vitamins C and E on biomarkers of oxidative stress depends on baseline level

Oxidative stress is elevated in obesity, and may be a major mechanism for obesity-related diseases. Nonsmokers (n=396) were randomized to 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Treatment effect was examined in multiple regression analyses using an intention-to-treat approach. Vitamin C (P=0.001) and vitamin E (P=0.043) reduced plasma F2-isoprostanes. In the overall sample, changes from baseline were +6.8, -10.6, and -3.9% for placebo, vitamin C, and vitamin E groups, respectively. However, a significant interaction with baseline F2-isoprostane was found. When baseline F2-isoprostane was >50 microg/mL, vitamin C reduced F2-isoprostane by 22% (P=0.01). Vitamin E reduced it by 9.8% (P=0.46). Below that cut point, neither treatment produced further reductions. F2-isoprostane>50 microg/mL was strongly associated with obesity, and was present in 42% of the sample. Change in malondialdehyde concentration was minimal. These findings suggest a role for vitamin C in reducing lipid peroxidation. Future research on effects of vitamins C or E on plasma F2-isoprostane should limit participants to those with baseline levels >50 mug/mL. Further studies are needed to establish whether treatment with vitamins C or E in persons with concentrations above that cut point could slow the development of cardiovascular disease.     

Alteration of plasma total F2-isoprostanes before and after hemodialysis in end-stage renal disease patients

F(2)-isoprostanes are derived in vivo principally from the following: (1) the formation of positional peroxyl radicals of arachidonic acid, (2) endocyclization to prostaglandin G(2)-like structures, and (3) reduction to PGF(2)-like compounds. F(2)-isoprostanes have been proposed as biomarkers of lipid peroxidation, oxidative stress status, and the oxidation of low-density lipoprotein (LDL). Using gas chromatography-ion trap-mass spectrometry, we studied how hemodialysis (HD) affects plasma total F(2)-isoprostanes. We examined the plasma total F(2)-isoprostanes in end-stage renal disease (ESRD) patients, before HD, after HD, between HD, and in control subjects. Plasma concentrations of total F(2)-isoprostanes were significantly higher in the after HD ESRD patients than the before hemodialysis ESRD patients (P < 0.05). There is no difference between before HD ESRD patients and normal controls. Moreover, a positive or negative correlation was seen between LDL and plasma total F(2)-isoprostanes (P < 0.001), and between age and plasma total F(2)-isoprostanes (P < 0.001). This study indicates HD treatment may be the major contributor of oxidative stress in ESRD patients.     

Fever and acute-phase response induced in rabbits by intravenous and intracerebroventricular injection of interleukin-6

We investigated the effect of human recombinant interleukin-6 (IL-6) on body temperature and acute-phase response, including changes in plasma levels of iron, zinc, copper, and fibrinogen and in circulating leukocyte count. The intravenous (IV) injection of IL-6 (2 micrograms/kg) produced a monophasic fever. The intracerebroventricular (ICV) injection of IL-6 produced a dose-dependent fever that developed gradually and remained elevated throughout the 5-h recording period. The IV injection of IL-6 decreased the plasma concentration of iron and zinc and increased the circulating leukocyte count. The ICV injection of IL-6 resulted in similar trace metal and leukocyte changes, and increased plasma levels of fibrinogen. These results show that IL-6 can cause fever when injected IV or ICV and induces some acute-phase responses through its action on peripheral target organs and in the central nervous system.     

Plasma F2-isoprostanes are elevated in newborns and inversely correlated to gestational age

F(2)-isoprostanes, prostaglandin F(2)-like compounds formed by free radical-catalyzed lipid peroxidation, are considered the most reliable markers of oxidative stress. It has been repeatedly suggested that newborns are exposed to conditions of oxidative stress resulting from the change from a low oxygen pressure in utero to a high oxygen pressure at birth. We measured the levels of F(2)-isoprostanes in plasma of newborns by gas chromatography/mass spectrometry and we found that F(2)-isoprostanes are significantly higher in term newborns compared to healthy adults. The greatest values were found in preterm newborns in whom F(2)-isoprostanes are even higher than in term babies. Moreover a significant inverse correlation was found between the plasma levels of isoprostanes and the gestational age. A quite normal level of isoprostanes was found in the mothers both at delivery and during pregnancy. Placental total F(2)-isoprostanes (sum of free plus esterified) were significantly higher in preterm compared to term deliveries and such a difference might account for the difference in plasma isoprostanes. Plasma non-protein-bound iron is higher in preterm than in term newborns, even if no correlation was found with plasma F(2)-isoprostanes. Erythrocyte desferrioxamine-chelatable iron content (0 time) and release (24 h of aerobic incubation) are higher in newborns than in adults and in preterm than in term newborns, but again no correlation was found with plasma F(2)-isoprostanes. The marked increase in plasma isoprostanes suggests that oxidative stress is a feature of the physiopathological changes seen in the perinatal period.     

Analysis of monohydroxyeicosatetraenoic acids and F2-isoprostanes as markers of lipid peroxidation in rat brain mitochondria

We have introduced two specific techniques for the quantitative measurement of monohydroxyeicosatetraenoic acids (HETEs) and F2-isoprostanes by gas chromatography-mass spectrometry/negative ion chemical ionization (GC-MS/NICI) to study lipid peroxidation in isolated rat brain mitochondria by iron/ascorbate. The analysis of HETEs involved hydrogenation, solid phase extraction on a C18-cartridge, formation of pentafluorobenzyl bromide and trimethylsilyl ether derivatives. In the case of F2-isoprostanes, the analytical procedure was similar to that of HETEs except that the hydrogenation step was omitted. We found that HETE content (sum of 5-, 8-12-, and 15-isomers) in freshly prepared rat brain mitochondria was 220 +/- 40pmol/mg protein. The corresponding content for the F2-isoprostane, 8-iso-PGF2alpha, was 0.21 +/-+/- 0.10 pmol/mg protein. HETEs and 8-iso-PGF2alpha were predominantly present in the esterified form. The content of both HETEs and 8-iso-PGF2alpha were increased in presence of iron/ascorbate as oxidation system. After 30 min incubation with Fe2+ ascorbate, the content of HETE isomers was increased about 6-fold compared with baseline levels whereas that for 8-iso-PGF2alpha was elevated 100-fold. Formation of HETEs and F2-isoprostanes corresponded to the consumption of arachidonic acid (AA) and alpha-tocopherol, respectively. There were almost no changes in the content of free (non-esterified) HETEs and 8-iso-PGF2alpha during the course of iron/ascorbate induced oxidation of the brain mitochondria. Our data provide the first direct evidence for the presence of HETEs and F2-isoprostanes in freshly isolated rat brain mitochondria and that esterified HETEs and 8-iso-PGF2alpha are predominantly generated during iron/ascorbate induced lipid peroxidation. Sensitive quantification of these products of non-enzymatic lipid peroxidation as indicators of oxidant injury opens new areas of investigation regarding the role of free radicals in the pathogenesis of human diseases. In addition, HETEs and F2-isoprostanes may be important mediators for mitochondrial functions.     

Biomarkers of oxidative damage in cigarette smokers: Which biomarkers might reflect acute versus chronic oxidative stress?

Cigarette smoking predisposes to the development of multiple diseases involving oxidative damage. We measured a range of oxidative damage biomarkers to understand which differ between smokers and nonsmokers and if the levels of these biomarkers change further during the act of smoking itself. Despite overnight abstinence from smoking, smokers had higher levels of plasma total and esterified F(2)-isoprostanes, hydroxyeicosatetraenoic acid products (HETEs), F(4)-neuroprostanes, 7-ketocholesterol, and 24- and 27-hydroxycholesterol. Levels of urinary F(2)-isoprostanes, HETEs, and 8-hydroxy-2'-deoxyguanosine were also increased compared with age-matched nonsmokers. Several biomarkers (plasma free F(2)-isoprostanes, allantoin, and 7β-hydroxycholesterol and urinary F(2)-isoprostane metabolites) were not elevated. The smokers were then asked to smoke a cigarette; this acute smoking elevated plasma and urinary F(2)-isoprostanes, plasma allantoin, and certain cholesterol oxidation products compared to presmoking levels, but not plasma HETEs or urinary 8-hydroxy-2'-deoxyguanosine. Smokers showed differences in plasma fatty acid composition. Our findings confirm that certain oxidative damage biomarkers are elevated in smokers even after a period of abstinence from smoking, whereas these plus some others are elevated after acute smoking. Thus, different biomarkers do not measure identical aspects of oxidative stress.     

Streamlined F2-isoprostane analysis in plasma and urine with high-performance liquid chromatography and gas chromatography/mass spectroscopy

F2-Isoprostanes in plasma and urine are generally determined by labor-intensive methods requiring sample purification by solid-phase extraction and thin-layer chromatography (TLC). A streamlined and more sensitive method for the measurement of esterified plasma F2-isoprostanes was developed by replacing these steps with high-performance liquid chromatography (HPLC) using an amino column with a hexane/2-propanol gradient. Pentafluorobenzyl esters of F2-isoprostanes were prepared and purified by HPLC, silylated, and then analyzed by gas chromatography (GC) with negative chemical ionization mass spectroscopy (NCI-MS). This method permits analysis with lower plasma volumes (100 microL) and greater sensitivity (to 10 pg; allowing detection to 50 pg/mL) than provided by other methods. Urinary F2-isoprostanes can also be efficiently quantified by this method, with 8-iso-PGF2alpha being identified as a major isomer. With this procedure, esterified plasma F2-isoprostanes were found to be 8.3-fold higher in an end-stage renal failure patient on hemodialysis and urinary 8-iso-PGF2alpha was 7.1-fold higher in a cigarette smoker than respective control subjects. This method, particularly the substitution of the TLC step common to other methods with HPLC, results in a more sensitive and reproducible assay.     

Oxidative stress in human hypertension: association with antihypertensive treatment, gender, nutrition, and lifestyle

There is growing evidence that oxidative stress contributes to the pathogenesis of hypertension. Our aim was to measure markers of oxidative stress in hypertensive subjects, and assess the potential confounding influences of antihypertensive therapy, other cardiovascular risk factors, gender, lifestyle, and nutrition. Markers of oxidative stress, including plasma and 24 h urinary F2-isoprostanes, were measured in 70 untreated (men = 43, women = 27) and 85 treated (men = 43, women = 42) hypertensive subjects and 40 normotensive controls (men = 20, women = 20). Overall, F2-isoprostanes were not elevated in hypertensive subjects compared with controls. However, urinary and plasma F2-isoprostanes were significantly lower in treated compared with untreated hypertensive men, but not women. In hypertensive men, the number of antihypertensive drugs taken was inversely associated with both urinary and plasma F2-isoprostanes (p <.05). Self-reported alcohol intake and biomarkers of alcohol consumption (gamma-glutamyl transpeptidase and high-density lipoprotein cholesterol) were positively associated with plasma but not urinary, F2-isoprostanes in men. Several nutrients were independently associated with plasma and urinary F2-isoprostanes in women. The results do not support the hypothesis that treated or untreated hypertensive subjects are under increased oxidative stress compared with normotensive controls.     

Oxidative stress contributes to muscle atrophy in chronic kidney disease patients

Abstract

Objectives

Patients with chronic kidney disease have impaired muscle metabolism, resulting in muscle atrophy. Oxidative stress has previously been identified as a significant contributor to muscle atrophy in other populations, but the contribution in chronic kidney disease is unknown. The aim of this study was to investigate the association between oxidative stress, grip strength, and lean mass in patients with chronic kidney disease.

Methods

This is a cross-sectional study of 152 participants with stage 3 or 4 chronic kidney disease. Outcome measures include grip strength, lean mass, plasma total F2-isoprostanes, inflammation, peak oxygen uptake, and standard clinical measures.

Results

Thirty four (22.4%) chronic kidney disease patients had elevated oxidative stress levels (plasma F2-isoprostanes >250 pg/ml), with 82% of patients below age-predicted grip strength normative values. There was a significant negative association between plasma F2-isoprostanes and grip strength (r = ?0.251) and lean mass (r = ?0.243). There were no associations with inflammation markers. Multiple linear regression identified plasma F2-isoprostanes as a significant predictor of grip strength independent of other predictors: sex, diabetes status, body mass index, body fat percent, and phosphate (adjusted r² = 69.5, P < 0.001).

Discussion

Plasma F2-isoprostanes were independently associated with reduced strength in chronic kidney disease patients.     

Oxidative effect of several intravenous iron complexes in the rat

The objective of this study was to compare the oxidative stress induced in rat internal organs by the administration of the following clinically used intravenous (IV) iron (Fe) containing compounds: iron sucrose (IS), iron dextran (ID), ferric carboxymaltose and ferumoxytol. Groups of six adult rats received 1 mg/kg of each compound weekly for 5 doses. Seven days following the last dose, animals were euthanized and tissue samples of heart, lung, liver, and kidney were obtained, washed in warmed saline and frozen under liquid nitrogen and stored at ?80 °C for analysis for nitrotyrosine (NT) and dinitro phenyl (DNP) as markers of oxidative stress. All tissues showed a similar pattern of oxidative stress. All Fe products stimulated an increase in the tissue concentration of both NT and DNP. In general, DNP was stimulated significantly less than NT except for IS. DNP was stimulated to an equal degree except for ID where NT was significantly higher than the NT concentrations in all other Fe compounds. ID produced over 10-fold the concentration of NT than any other Fe. IV Fe compounds present a risk of oxidative stress to a variety of internal organs. However, we found that IS was the least damaging and ID was the worst.     

Usefulness of F2-isoprostanes in early prognostication after cardiac arrest: a topical review of the literature and meta-analysis of preclinical data

Abstract

Prognostication after cardiac arrest (CA) represents a challenging issue, and several biomarkers have been proposed in the attempt to predict outcome. Among these, F2-isoprostanes stand out as potential biomarkers for early prognostication, providing information on the magnitude of global oxidative injury after return of spontaneous circulation (ROSC). We performed a topical review searching PubMed and Scopus databases to identify studies evaluating the modifications of F2-isoprostanes in the early period after CA, and a meta-analysis of studies providing curves of F2-isoprostanes plasma levels seeking to describe the biomarker’s kinetics after CA. Evidence suggests that plasma levels of F2-isoprostanes increase in the early post-resuscitation period and seem well correlated with the burden of ischaemia-reperfusion injury. Our meta-analysis shows a possible increase as early as 5?minutes after ROSC, which persists at 2?hours and is attenuated at 4?hours. Clinical studies are warranted to evaluate the utility of this biomarker for prognostication purposes in CA survivors.     

Oxidative stress is associated with decreased heart rate variability in patients with chronic kidney disease

Objectives: Elevated oxidative stress and reduced heart rate variability (HRV) is prevalent in patients with chronic kidney disease (CKD) and is associated with increased morbidity and mortality. Previous studies have identified a positive association between elevated oxidative stress and autonomic dysfunction, however this relationship has not yet been investigated in the CKD population.

Methods: Plasma was collected from 78 patients with stage 3–4 CKD (estimated glomerular filtration rate 25–60?ml/min/1.73?m²) for the assessment of oxidative stress, including plasma total F2-isoprostanes, glutathione peroxidase activity and total antioxidant capacity. Time and frequency HRV parameters were measured from a three lead electrocardiogram.

Results: Participants with elevated F2-isoprostanes had reduced HRV compared to patients with normal levels of F2-isoprostanes. A number of HRV parameters were found to be inversely correlated with F2-isoprostanes in all CKD patients, including SDNN (r?=??0.337; P?r?=??0.281, P?=?0.01), LF (r?=??0.315, P?r?=??0.288, P?=?0.01). Multiple linear regression found F2-isoprostanes to be an independent predictor of SDNN (r²?=?0.287, β?=??0.272, P?=?0.01).

Discussion: Oxidative stress is significantly and independently associated with HRV in patients with CKD. Identifying oxidative stress in the pathogenesis of autonomic dysfunction may help target therapeutic strategies.     

Isoprostanes and hepatic fibrosis

After a brief introduction to oxidative stress, the discovery of F(2)-isoprostanes as specific and reliable markers of oxidative stress is described. Isoprostanes are also agonists of important biological effects. Since a relation between oxidative stress and collagen hyperproduction has been previously suggested and since lipid peroxidation products have been proposed as possible mediators of liver fibrosis, we investigated whether collagen synthesis is induced by F(2)-isoprostanes the most proximal products of lipid peroxidation. In a rat model of carbon tetrachloride-induced hepatic fibrosis, plasma isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content was also increased. When hepatic stellate cells from normal liver were cultured up to activation (expression of alpha-smooth muscle-alpha actin) and then treated with F(2)-isoprostanes in the concentration range found in the in vivo studies (10(-9)-10(-8)M), a striking increase in DNA synthesis, in cell proliferation and in collagen synthesis was observed. Moreover, F(2)-isoprostanes increased the production of transforming growth factor-beta1 by U937 cells, assumed as a model of Kupffer cells or liver macrophages. The data suggest the possibility that F(2)-isoprostanes generated by lipid peroxidation in hepatocytes mediate hepatic stellate cell proliferation and collagen hyperproduction seen in hepatic fibrosis.     

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

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

Effects of oral deoxynivalenol exposure on immune-related parameters in lymphoid organs and serum of mice vaccinated with porcine parvovirus vaccine

Mice were exposed to deoxynivalenol (DON) via drinking water at a concentration of 2 mg/L for 36 days. On day 8 of treatment, inactivated porcine parvovirus vaccine (PPV) was injected intraperitoneally. The relative and absolute weight of the spleen was significantly decreased in the DON-treated group (DON). Antibody titers to parvovirus in serum were 47.9?±?2.4 in the vaccination group (Vac), but 15.2?±?6.5 in the group treated with DON and vaccine (DON?+?Vac). The IgA and IgG was not different in the DON, Vac an,d DON?+?Vac groups. IgM was significantly lower only in the DON?+?Vac group. However IgE was significantly increased in the Vac and DON?+?Vac group, but no change was observed between the Vac and DON?+?Vac groups. The concentrations of IL-2, IL-4, GM-CSF, MCP-1 and Rantes in serum, and IL-1α in mesenteric lymph node and MIP-1β in spleen were significantly increased by DON treatment compared to control. The concentrations of IL-2, IL-5, IL-6, IL-9, IL-12, IL-13 and Rantes in thymus, of IL-2 in spleen, and of IL-1α, IL-1β, IL-3, IL-5, IL-10, IL-17, G-CSF, GM-CSF and MCP-1 in mesenteric lymph nodes were significantly decreased in mice compared to those in the Vac group, while concentrations of IL-1α, IL-2, IL-9, IL-13,G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1α and TNF-α were significantly increased in serum compared to the Vac group. In conclusion, the results presented here indicate that exposure to DON at 2.0 mg/L via drinking water can disrupt the immune response in vaccinated mice by modulating cytokines and chemokines involved in their immune response to infectious disease.     

F2-isoprostanes as biomarkers of lipid peroxidation in patients with chronic renal failure

Chronic renal failure patients on long-term hemolysis are found to be under increased oxidative stress, caused by antioxidant deficiency, neutrophil activation during hemodialysis (HD), platelet activation and/or chronic inflammation. Increased levels of oxidants (e.g. malondialdehyde, 4-hydroxynonenal, hydrocarbons, lipohydroperoxides, oxycholesterols, carbonyls) in HD patients are thought to play an important role in the development of endothelial dysfunction, atherogenesis and cardiovascular disease, which is a frequent condition in end-stage renal disease. F2-isoprostanes have been established as chemically stable, highly specific and reliable biomarkers of in vivo oxidative stress which can very sensitively measured by gas chromatography-mass spectrometry (Morrow et al. [17]). An up to 6-fold increase of plasma F2-isoprostanes in HD patients is accompanied by an enhanced formation of indicators of inflammation (e.g. C-reactive protein) and decreases of endogenous antioxidants (e.g. ascorbate, alpha-tocopherol). In their esterified form F2-isoprostanes may be a useful criteria to evaluate the effectiveness of clinical interventions to diminish oxidant stress and associated inflammation. Furthermore, F2-isoprostanes possess potent biological activities (e.g. 8-iso-PGF2alpha is known as a renal vasoconstrictor) suggesting that they may also act as mediators of the cellular effects of oxidative stress and inflammation.     

The Effect of Iron–Vitamin C Co-supplementation on Biomarkers of Oxidative Stress in Iron-Deficient Female Youth

There is no study that assessed the effect of co-supplementation of iron and vitamin C on biomarkers of oxidative stress in non-anemic iron-deficient females. We investigated the effects of iron vs. iron?+?vitamin C co-supplementation on biomarkers of oxidative stress in iron-deficient girls. In a double-blind randomized controlled clinical trial, performed among 60 non-anemic iron-deficient girls, participants were randomly assigned to receive either 50 mg/day elemental iron supplements or 50 mg/day elemental iron?+?500 mg/day ascorbic acid for 12 weeks. Fasting blood samples were taken at baseline, weeks 6 and 12 for assessment of biomarkers of oxidative stress. Compared with the baseline levels, both iron and iron?+?vitamin C supplementation resulted in a significant reduction in serum malondialdehyde (MDA) levels (P _time?<?0.001) and remarkable elevation in serum total antioxidant capacity (TAC; P _time?<?0.001) and vitamin C levels (P _time?=?0.001); however, comparing the two groups we failed to find an additional effect of iron?+?vitamin C supplementation to that of iron alone on serum TAC and MDA levels (P _group was not statistically significant). Iron?+?vitamin C supplementation influenced serum vitamin C levels much more than that by iron alone (P _group?<?0.01). We also found a significant interaction term between time and group about serum vitamin C levels while this interaction was not significant about serum TAC and MDA levels. In conclusion, we found that iron supplementation with/without vitamin C improve biomarkers of oxidative stress among non-anemic iron-deficient females and may strengthen the antioxidant defense system by decreasing reactive oxygen species. Co-supplementation of iron?+?vitamin C has no further effect on oxidative stress compared with iron alone.     

Oxidative Stress,Inflammation, and Diabetic Vasculopathies: The Role of Alpha Tocopherol Therapy

The diabetic state confers an increased propensity to accelerated atherogenesis. In addition to the established risk factors, there is evidence for increased oxidative stress and inflammation in diabetes. Increased oxidative stress is manifested by increased lipid peroxidation (e.g. increased F 2 -isoprostanes) and increased DNA damage. Evidence for increased inflammation includes increased monocyte superoxide and pro-inflammatory cytokine release (IL-1, IL-6, and TNF- &#102 ), increased monocyte adhesion to endothelium and increased levels of plasma C-reactive protein, the prototypic marker of inflammation. Most importantly, alpha tocopherol therapy, especially at high doses, clearly shows a benefit with regards to LDL oxidation, isoprostanes and a decrease in inflammatory markers such as C-reactive protein, pro-inflammatory cytokines and PAI-1 levels. Thus, it appears that, in diabetes, alpha tocopherol therapy could emerge as an additional therapeutic modality.     

Antioxidant supplementation prevents exercise-induced lipid peroxidation, but not inflammation, in ultramarathon runners

To determine if 6 weeks of supplementation with vitamins E and C could alleviate exercise-induced lipid peroxidation and inflammation, we studied 22 runners during a 50 km ultramarathon. Subjects were randomly assigned to one of two groups: (1) placebos (PL) or (2) antioxidants (AO: 1000 mg vitamin C and 300 mg RRR-alpha-tocopheryl acetate). Blood samples were obtained prior to supplementation (baseline), after 3 weeks of supplementation, 1 h pre-, mid-, and postrace, 2 h postrace and for 6 days postrace. Plasma levels of alpha-tocopherol (alpha-TOH), ascorbic acid (AA), uric acid (UA), F2-isoprostanes (F2-IsoPs), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP) were measured. With supplementation, plasma alpha-TOH and AA increased in the AO but not the PL group. Although F2-IsoP levels were similar between groups at baseline, 28 +/- 2 (PL) and 27 +/- 3 pg/ml (AO), F2-IsoPs increased during the run only in the PL group (41 +/- 3 pg/ml). In PL women, F2-IsoPs were elevated postrace (p <.01), but returned to prerace concentrations by 2 h postrace. In PL men, F2-IsoP concentrations were higher postrace, 2 h postrace, and 1, 2, 3, 4, and 6 days postrace (PL vs. AO group, each p <.03). Markers of inflammation were increased dramatically in response to the run regardless of treatment group. Thus, AO supplementation prevented endurance exercise-induced lipid peroxidation but had no effect on inflammatory markers.