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ABSTRACT: BACKGROUND: This study evaluated the effect of statins in Primary biliary cirrhosis (PBC) on endothelial function, anti-oxidant status and vascular compliance. METHODS: Primary biliary cirrhosis patients with hypercholesterolaemia were randomized to receive 20 mg simvastatin or placebo in a single blind, randomized controlled trial. Body mass index, blood pressure, glucose, liver function, lipid profile, immunoglobulin levels, serological markers of endothelial function and anti-oxidant status were measured as well as vascular compliance, calculated from pulse wave analysis and velocity, at recruitment and again at 3, 6, 9 and 12 months. RESULTS: Twenty-one PBC patients (F = 20, mean age = 55) were randomized to simvastatin 20 mg (n = 11) or matched placebo (n = 10). At completion of the trial, serum cholesterol levels in the simvastatin group were significantly lower compared with the placebo group (4.91 mmol/L vs. 6.15 mmol/L, P = 0.01). Low-density lipoprotein (LDL) levels after 12 months were also significantly lower in the simvastatin group (2.33 mmol/L vs. 3.53 mmol/L, P = 0.01). After 12 months of treatment, lipid hydroperoxides were lower (0.49 μmol/L vs. 0.59 μmol/L, P = 0.10) while vitamin C levels were higher (80.54 μmol/L vs. 77.40 μmol/L, P = 0.95) in the simvastatin group. Pulse wave velocity remained similar between treatment groups at 12 months (8.45 m/s vs. 8.80 m/s, P = 0.66). Only one patient discontinued medication owing to side effects. No deterioration in liver transaminases was noted in the simvastatin group. CONCLUSIONS: Statin therapy in patients with PBC appears safe and effective towards overall reductions in total cholesterol and LDL levels. Our initial study suggests that simvastatin may also confer advantageous effects on endothelial function and antioxidant status.
Liver international: official journal of the International Association for the Study of the Liver 05/2013; · 3.82 Impact Factor
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ABSTRACT: Introduction: Although pharmacological antioxidants have previously been investigated for a prophylactic effect against exercise oxidative stress, is not known if α-lipoic acid supplementation can protect against DNA damage following high intensity isolated quadriceps exercise. This randomised controlled investigation was designed to test the hypothesis that fourteen days of α-lipoic acid supplementation can attenuate exercise-induced oxidative stress. Methods: Twelve (n=12) apparently healthy male participants (age 28 ± 10 years, stature 177 ± 12 cm and body mass 81 ± 15 kg) were randomly assigned to receive either a daily supplement of 1000mg of α-lipoic acid (2 × 500mg tablets) for fourteen days (n = 6) or receive no supplement (n = 6) in a double blinded experimental approach. Blood and muscle biopsy tissue samples were taken at rest and following the completion of 100 isolated and continuous maximal knee extension (minimum force = 200 N, speed of contraction = 60°/sec). Results: Exercise increased mitochondrial 8-OHdG concentration in both groups (P < 0.05 vs. rest) with a concomitant decrease in total antioxidant capacity (P < 0.05 vs. rest). There was a marked increase in blood total antioxidant capacity following oral α-lipoic acid supplementation (P < 0.05 vs. non-supplemented), while DNA damage (Comet assay and 8-OHdG) lipid peroxidation and hydrogen peroxide increased following exercise in the non-supplemented group only (P < 0.05 vs. supplemented). Exercise increased protein oxidation in both groups (P < 0.05 vs. rest). Conclusion: These findings suggest that short-term α-lipoic acid supplementation can selectively protect DNA (but not in muscle mitochondria) and lipids against exercise-induced oxidative stress.
Medicine and science in sports and exercise 03/2013; · 3.71 Impact Factor
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Karl J New,
Michael E Reilly,
Kath Templeton,
Gethin Ellis,
Philip E James, Jane McEneny,
Michael Penney,
James Hooper,
Dave Hullin,
Bruce Davies,
Damian M Bailey
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ABSTRACT: BACKGROUND The metabolic vasodilator mediating postexercise hypotension (PEH) is poorly understood. Recent evidence suggests an exercise-induced reliance on pro-oxidant-stimulated vasodilation in normotensive young human subjects, but the role in the prehypertensive state is not known. METHODS Nine prehypertensives (mean arterial pressure (MAP), 106±5mm Hg; 50 ± 10 years old) performed 30 minutes of cycle exercise and a nonexercise trial. Arterial distensibility was characterized by simultaneously recording upper- and lower-limb pulse wave velocity (PWV) via oscillometry. Systemic vascular resistance and conductance were determined by MAP/Q and Q/MAP, respectively. Venous blood was assayed for indirect markers of oxidative stress (lipid hydroperoxides (LOOH); spectrophotometry), plasma nitric oxide (NO) and S-nitrosothiols (fluorometry), atrial natriuretic peptide (ANP), and angiotensin II (ANG-II) (radioimmunoassay). RESULTS Exercise reduced MAP (6mm Hg) and vascular resistance (15%) at 60 minutes after exercise, whereas conductance was elevated (20%) (P < 0.05). The hypotension resulted in a lower MAP at 60 and 120 minutes after exercise compared with nonexercise (P < 0.05). Upper-limb PWV was also 18% lower after exercise compared with baseline (P < 0.05). Exercise increased LOOH coincident with the nadir in hypotension and vascular resistance but failed to affect plasma NO or S-nitrosothiols. Exercise-induced increases in LOOH were related to ANG-II (r = 0.97; P < 0.01) and complemented by elevated ANP concentrations. CONCLUSIONS These data indicate attenuated vascular resistance after exercise with increased oxidative stress and unchanged NO. Whether free radicals are obligatory for PEH requires further investigation, although it seems that oxidative stress occurs during the hyperemia underlying PEH.
American Journal of Hypertension 01/2013; 26(1):126-34. · 3.18 Impact Factor
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ABSTRACT: INTRODUCTION: High density lipoproteins (HDL) have considerable potential for improving cardiovascular health. Additionally, epidemiological studies have identified an inverse relationship between α-tocopherol intake and cardiovascular disease, which has not been translated in randomised controlled trials. OBJECTIVES: This study assessed if increased α-tocopherol within HDL(2) and HDL(3) (HDL(2&3)) influenced their antiatherogenic potential. In the first of two in vitro investigations, the oxidation potential of HDL(2&3) was assessed when α-tocopherol was added following their isolation. In the second, their oxidation potential was assessed when HDL(2&3) were isolated from serum pre-incubated with α-tocopherol. Additionally, a 6-week placebo-controlled intervention with α-tocopherol assessed if α-tocopherol influenced the oxidation potential and activities of HDL(2&3)-associated enzymes, paraoxonase-1 (PON-1) and lecithin cholesteryl acyltransferase (LCAT). RESULTS: Conflicting results arose from the in vitro investigations, whereby increasing concentrations of α-tocopherol protected HDL(2&3) against oxidation in the post-incubated HDL(2&3), and promoted HDL(2&3)-oxidation when they were isolated from serum pre-incubated with α-tocopherol. Following the 6-week placebo-controlled investigation, α-tocopherol increased in HDL(2&3), while HDL(2&3) became more susceptible to oxidation, additionally the activities of HDL(2&3)-PON-1 and HDL(2)-LCAT decreased. CONCLUSION: These results have shown for the first time that α-tocopherol induces changes to HDL(2&3), which could contribute to the pathophysiology of cardiovascular disease.
Atherosclerosis 12/2012; · 3.79 Impact Factor
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ABSTRACT: BACKGROUND: The worldwide epidemic of obesity is a major public health concern and is persuasively linked to the rising prevalence of diabetes and cardiovascular disease. Obesity is often associated with an abnormal lipoprotein profile, which may be partly negated by pioglitazone intervention, as this can influence the composition and oxidation characteristics of low-density lipoprotein (LDL). However, as pioglitazone's impact on these parameters within high-density lipoprotein (HDL), specifically HDL(2&3), is absent from the literature, this study was performed to address this shortcoming. METHODS: Twenty men were randomized to placebo or pioglitazone (30 mg/day) for 12 weeks. HDL(2&3) were isolated by rapid-ultracentrifugation. HDL(2&3)-cholesterol and phospholipid content were assessed by enzymatic assays and apolipoprotein AI (apoAI) content by single-radial immunodiffusion. HDL(2&3) oxidation characteristics were assessed by monitoring conjugated diene production and paraoxonase-1 activity by spectrophotometric assays. RESULTS: Compared with the placebo group, pioglitazone influenced the composition and oxidation potential of HDL(2&3). Specifically, total cholesterol (P < 0.05), phospholipid (P < 0.001) and apoAI (P < 0.001) were enriched within HDL(2). Furthermore, the resistance of HDL(2&3) to oxidation (P < 0.05) and the activity of paroxonase-1 were also increased (P < 0.001). CONCLUSIONS: Overall, these findings indicate that pioglitazone treatment induced antiatherogenic changes within HDL(2&3), which may help reduce the incidence of premature cardiovascular disease linked with obesity.
Annals of Clinical Biochemistry 11/2012; · 2.17 Impact Factor
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ABSTRACT: Lipid peroxidation is a common feature of many chemical and biological processes, and is governed by a complex kinetic scheme. A fundamental stage in kinetic investigations of lipid peroxidation is the accurate determination of the rate of peroxidation, which in many instances is heavily reliant on the method of finite differences. Such numerical approximations of the first derivative are commonly employed in commercially available software, despite suffering from considerable inaccuracy due to rounding and truncation errors. As a simple solution to this, we applied three empirical sigmoid functions (viz. the Prout-Tompkins, Richards & Gompertz functions) to data obtained from the AAPH-mediated peroxidation of aqueous linoleate liposomes in the presence of increasing concentrations of Trolox, evaluating the curve fitting parameters using the widely available Microsoft Excel Solver add-in. We have demonstrated that the five-parameter Richards' function provides an excellent model for this peroxidation, and when applied to the determination of fundamental rate constants, produces results in keeping with those available in the literature. Overall, we present a series of equations, derived from the Richards' function, which enables direct evaluation of the kinetic measures of peroxidation. This procedure has applicability not only to investigations of lipid peroxidation, but to any system exhibiting sigmoid kinetics.
Chemistry and physics of lipids 07/2012; 165(6):682-8. · 2.15 Impact Factor
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ABSTRACT: Individuals with impaired glucose tolerance (IGT) are at greater risk of developing diabetes than in normoglycaemia. The aim of this study was to examine the effects of 12-weeks exercise training in obese humans with IGT. Eleven participants (6 males and 5 females; 49±9 years; mean Body Mass Index (BMI) 32.4 kg · m(-2)), completed a 12-week brisk walking intervention (30 min per day, five days a week (d · wk(-1)), at 65% of age-predicted maximal heart rate (HR(max)). Anthropometric measurements, dietary intake, pulse wave velocity (PWV, to determine arterial stiffness) and blood pressure (BP) were examined at baseline and post intervention. Fasting blood glucose, glycosylated haemoglobin, insulin, blood lipids, indices of oxidative stress and inflammation (lipid hydroperoxides; superoxide dismutase; multimeric adiponectin concentration and high-sensitivity C-reactive protein) were also determined. Post intervention, PWV (9.08±1.27 m · s(-1) vs. 8.39±1.21 m · s(-1)), systolic BP (145.4±14.5 vs. 135.8±14.9 mmHg), triglycerides (1.52±0.53 mmol · L(-1) vs. 1.31±0.54 mmol · L(-1)), lipid hydroperoxides (1.20±0.47 μM · L(-1) vs. 0.79±0.32 μM · L(-1)) and anthropometric measures decreased significantly (P < 0.05). Moderate intensity exercise training improves upper limb vascular function in obese humans with IGT, possibly by improving triglyceride metabolism, which may subsequently reduce oxidative stress. These changes were independent of multimeric adiponectin modification and alterations in other blood biomarkers.
Journal of Sports Sciences 03/2012; 30(8):725-32. · 1.93 Impact Factor
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ABSTRACT: Even though intense exercise has traditionally been associated with a statistically significant accumulation of blood-borne biomarkers of free radical-mediated lipid peroxidation, it remains to be determined if the oxidative stress response is biologically significant. To examine biological significance, we calculated the critical difference of selected biomarkers of oxidants-antioxidants in the peripheral circulation of ten male subjects aged 24±3 years. Venous blood was drawn in the resting supine position every hour over an 8-h period (Study 1). As proof-of-concept, supine venous blood was also obtained at rest and following maximal cycling exercise in a separate group of 13 males, mean age 22±3 years (Study 2). The critical difference of electron paramagnetic resonance spin-trapped alkoxyl free radicals, lipid hydroperoxides, malondialdehyde, ascorbic acid, retinol, lycopene, α-tocopherol, β-carotene and α-carotene was calculated as 121%, 28%, 50%, 9%, 29%, 106%, 13%, 28% and 107%, respectively (Study 1). Maximal exercise was associated with a statistically significant (P<0.05 vs. rest) reduction in α-tocopherol and retinol, and a corresponding rise in alkoxyl free radicals and lipid hydroperoxides (Study 2). However, these changes were all within the critical difference percentage value. In conclusion, these findings highlight the importance of distinguishing biological from statistical significance when assessing the physiological and clinical impact of exercise-induced oxidative stress.
Journal of physiology and biochemistry 02/2012; 68(3):377-84. · 1.71 Impact Factor
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ABSTRACT: Obese subjects with impaired glucose tolerance (IGT) are more susceptible than healthy individuals to oxidative stress and cardiovascular disease. This randomised controlled investigation was designed to test the hypothesis that α-lipoic acid supplementation and exercise training may elicit favourable clinical changes in obese subjects with IGT. All data were collected from 24 obese (BMI ≥ 30 kg/m2) IGT patients. Following participant randomisation into two groups, fasting venous blood samples were obtained at baseline, and before and following intervention. The first group consisted of 12 participants who completed a 12 week control phase followed by 12 weeks of chronic exercise at 65% HRmax for 30 minutes a day, 5 days per week, while ingesting 1 gram per day of α-lipoic acid for 12 weeks. The second group consisted of 12 participants who completed the same 12 week control phase, but this was followed by 12 weeks of 1 gram per day of α-lipoic acid supplementation only (no exercise). The main findings show a comparatively greater rate of low density lipoprotein (LDL) oxidation in the group consisting of α-lipoic acid only (p < 0.05 vs. pre intervention), although total oxidant status was lower post intervention (p < 0.05 vs. baseline) in this group. However, exercise and α-lipoic acid in combination attenuates LDL oxidation. Furthermore, in the α-lipoic acid supplement plus exercise training group, total antioxidant capacity was significantly increased (p < 0.05 vs. baseline and pre intervention). Body fat percentage and waist and hip circumference decreased following exercise training (p < 0.05 vs. post intervention). There were no selective treatment differences for a range of other clinical outcomes including glycaemic regulation (p > 0.05). These findings report that α-lipoic acid ingestion may increase the atherogenicity of LDL when ingested in isolation of exercise, suggesting that in IGT the use of this antioxidant treatment does not ameliorate metabolic disturbances, but instead may detrimentally contribute to the pathogenesis of atherosclerosis and development of CVD. However, when α-lipoic acid is combined with exercise, this atherogenic effect is abolished.
Lipids in Health and Disease 11/2011; 10:217. · 2.17 Impact Factor
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Damian M Bailey,
Kevin A Evans, Jane McEneny,
Ian S Young,
David A Hullin,
Philip E James,
Shigehiko Ogoh,
Philip N Ainslie,
Céline Lucchesi,
Antal Rockenbauer,
Marcel Culcasi,
Sylvia Pietri
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ABSTRACT: The present study examined whether dynamic cerebral autoregulation and blood-brain barrier function would become compromised as a result of exercise-induced oxidative-nitrosative stress. Eight healthy men were examined at rest and after an incremental bout of semi-recumbent cycling exercise to exhaustion. Changes in a dynamic cerebral autoregulation index were determined during recovery from continuous recordings of blood flow velocity in the middle cerebral artery (MCAv) and mean arterial pressure during transiently induced hypotension. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites in venous blood. Neuron-specific enolase, S100β and 3-nitrotyrosine were determined by ELISA. While exercise did not alter MCAv, it caused a mild reduction in the autoregulation index (from 6.9 ± 0.6 to 5.5 ± 0.9 a.u., P < 0.05) that correlated directly against the exercise-induced increase in the ascorbate radical, 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide and N-tert-butyl-α-phenylnitrone adducts, 3-nitrotyrosine and S100β (r = -0.66 to -0.76, P < 0.05). In contrast, no changes in neuron-specific enolase were observed. In conclusion, our findings suggest that intense exercise has the potential to increase blood-brain barrier permeability without causing structural brain damage subsequent to a free radical-mediated impairment in dynamic cerebral autoregulation.
Experimental physiology 08/2011; 96(11):1196-207. · 3.17 Impact Factor
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ABSTRACT: Vitamin E and its derivatives, namely, the tocopherols, are known antioxidants, and numerous clinical trials have investigated their role in preventing cardiovascular disease; however, evidence to date remains inconclusive. Much of the in vitro research has focused on tocopherol's effects during low-density lipoprotein (LDL) oxidation, with little attention being paid to very LDL (VLDL) and high-density lipoprotein (HDL). Also, it is now becoming apparent that γ-tocopherol may potentially be more beneficial in relation to cardiovascular health.
Do α- and γ-tocopherols become incorporated into VLDL, LDL and HDL and influence their oxidation potential in an in vitro and ex vivo situation?
Following (i) an in vitro investigation, where plasma was preincubated with increasing concentrations of either α- or γ-tocopherol and (ii) an in vivo 4-week placebo-controlled intervention with α- or γ-tocopherol. Tocopherol incorporation into VLDL, LDL and HDL was measured via high-pressure liquid chromatography, followed by an assessment of their oxidation potential by monitoring conjugated diene formation.
In vitro: Both tocopherols became incorporated into VLDL, LDL and HDL, which protected VLDL and LDL against oxidation. However and surprisingly, the incorporation into HDL demonstrated pro-oxidant properties. Ex vivo: Both tocopherols were incorporated into all three lipoproteins, protecting VLDL and LDL against oxidation; however, they enhanced the oxidation of HDL.
These results suggest that α- and γ-tocopherols display conflicting oxidant activities dependent on the lipoprotein being oxidized. Their pro-oxidant activity toward HDL may go some way to explain why supplementation studies with vitamin E have not been able to display cardioprotective effects.
The Journal of nutritional biochemistry 06/2011; 23(7):845-51. · 4.29 Impact Factor
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ABSTRACT: Both obesity and acute high-intensity exercise increase oxidant stress levels. This study investigates whether selenium (Se) supplementation could be a potential effective therapy to reduce obesity-associated oxidant stress and exercise-induced oxidant stress. Ten normal-weight (NW) (22.80 ± 0.41 kg/m(2)) and ten overweight (OW) healthy subjects (28.00 ± 0.81 kg/m(2)) were assessed during a randomized double-blind Se supplementation study (200 µg sodium selenite/day for 3 weeks) with a 3-week placebo control and inversion of treatment periods. Blood levels of lipid hydroperoxide (LH), superoxide dismutase (SOD), erythrocyte glutathione (GSH), and total antioxidant status (TAS), were measured at rest, pre-, and postexercise (30 min 70% VO(2) max before and after treatment (pretreatment (week 0 and 12) and post-treatment (week 3 or 15)). At rest, compared to placebo, Se supplementation had no significant effect on LH, SOD, GSH, and TAS levels. However, Se supplementation decreased LH levels in the OW group, immediately postexercise (-0.25 ± 0.12 µmol/l, P = 0.05) compared to placebo treatment. Postexercise, with or without Se supplementation, no changes in TAS, SOD, and GSH levels were observed in both the NW and OW group. This study has highlighted a potential benefit of Se in reducing LH levels postexercise in OW individuals. Given that oxidant stress is a predictor of coronary events, it is imperative to better understand oxidant stress-related responses to lifestyle factors (in particular "high-risk" population groups) and potential antioxidant therapy.
Obesity 05/2011; 20(4):794-801. · 4.28 Impact Factor
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ABSTRACT: Aim: Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which is associated with hypercholesterolaemia. Further, cholestatic diseases are associated with deficiencies of anti-oxidant vitamins. Despite these associations PBC is not associated with an increase in cardiovascular mortality. The aim of this study is to assess if primary biliary cirrhosis is associated with oxidative stress, endothelial dysfunction and alteration of vascular compliance which is a surrogate marker for cardiovascular risk. Methods: Fifty-one PBC patients and 34 control subjects were studied. Lipid soluble vitamins A, and E in addition to ascorbate and carotenoids were measured to assess anti-oxidant status. C-reactive protein, hydroperoxides and adhesion molecules sICAM-l/sVCAM-l were assessed as serological measures of endothelial function. Finally, measures of vascular compliance were assessed by applanation tonometer. Results: CRP, sICAM and sVCAM were all significantly higher in PBC patients (469.14 vs 207.13, P < 0.001; 768.12 vs 308.03,P < 0.001; 708.40 vs 461.31, P < 0.001) whilst anti-oxidant vitamin levels were lower in PBC patients, with ascorbate, vitamin E and vitamin A all significantly lower in PBC patients (39.91 vs 72.68, P < 0.001; 2.63 vs 3.14, P = 0.02; 1.08 vs 1.81, P < 0.001). Despite these findings PBC patients have a lower pulse wave velocity than control subjects (8.22 m/s vs 8.78 m/s, P = 0.022). Conclusion: PBC patients appear to have reduced vascular risk as assessed by pulse wave velocity but concurrently have evidence of endothelial dysfunction, inflammation and anti-oxidant deficiency.
Hepatology Research 11/2010; 40(11):1098-106. · 2.20 Impact Factor
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ABSTRACT: The traditional approach for identifying subjects at risk from cardiovascular diseases (CVD) is to determine the extent of clustering of biological risk factors adjusted for lifestyle. Recently, markers of endothelial dysfunction and low grade inflammation, including high sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecules (sICAM), and soluble vascular adhesion molecules (sVCAM), have been included in the detection for high risk individuals. However, the relationship of these novel biomarkers with CVD risk in adolescents remains unclear. The purpose of this study, therefore, was to establish the association of hsCRP, sICAM, and sVCAM with CVD risk in an adolescent population.
Data from the Young Hearts 2000 cross-sectional cohort study, carried out in 1999-2001, were used. From a total of 2,017 male and female participants, 95 obese subjects were identified and matched according to age, sex, and cigarette smoking, with 95 overweight and 95 normal-weight adolescents. Clustered CVD risk was computed using a sum of Z-scores of biological risk factors. The relationship was described using multiple linear regression analyses.
hsCRP, sICAM, and sVCAM showed significant associations with CVD risk. hsCRP and sICAM had a positive relation with CVD risk, whereas sVCAM showed an inverse relationship. In this study, lifestyle factors showed no relation with CVD risk.
The results fit the hypothesized role of low grade inflammation and endothelial dysfunction in CVD risk in asymptomatic adolescents. The inverse relationship of VCAM, however, is hard to explain and indicates the complex mechanisms underlying CVD. Further research is needed to draw firm conclusions on the biomarkers used.
Journal of Adolescent Health 10/2010; 47(4):346-51. · 3.33 Impact Factor
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Damian M Bailey,
Christoph Dehnert,
Andrew M Luks,
Elmar Menold,
Christian Castell,
Guido Schendler,
Vitalie Faoro,
Mariusz Gutowski,
Kevin A Evans,
Sarah Taudorf,
Philip E James, J McEneny,
Ian S Young,
Erik R Swenson,
Heimo Mairbäurl,
Peter Bärtsch,
Marc M Berger
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ABSTRACT: High altitude (HA)-induced pulmonary hypertension may be due to a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A(·-)), NO metabolites and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with AMS and three of four HAPE-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv(D)) resulting in a net transpulmonary loss of ascorbate, α-tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a-cv(D) and net output of A(·-) and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r = 0.56-0.62, P < 0.05) and arterial 3-NT (r = 0.48-0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical-mediated reduction in pulmonary NO bioavailability.
The Journal of Physiology 09/2010; 588(Pt 23):4837-47. · 4.72 Impact Factor
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ABSTRACT: Mitochondrial free radical formation has been implicated as a potential mechanism underlying degenerative senescence, although human data are lacking. Therefore, the present study was designed to examine if resting and exercise-induced intramuscular free radical-mediated lipid peroxidation is indeed increased across the spectrum of sedentary aging. Biopsies were obtained from the vastus lateralis in six young (26 + or - 6 yr) and six aged (71 + or - 6 yr) sedentary males at rest and after maximal knee extensor exercise. Aged tissue exhibited greater (P < 0.05 vs. the young group) electron paramagnetic resonance signal intensity of the mitochondrial ubisemiquinone radical both at rest (+138 + or - 62%) and during exercise (+143 + or - 40%), and this was further complemented by a greater increase in alpha-phenyl-tert-butylnitrone adducts identified as a combination of lipid-derived alkoxyl-alkyl radicals (+295 + or - 96% and +298 + or - 120%). Lipid hydroperoxides were also elevated at rest (0.190 + or - 0.169 vs. 0.148 + or - 0.071 nmol/mg total protein) and during exercise (0.567 + or - 0.259 vs. 0.320 + or - 0.263 nmol/mg total protein) despite a more marked depletion of ascorbate and uptake of alpha/beta-carotene, retinol, and lycopene (P < 0.05 vs. the young group). The impact of senescence was especially apparent when oxidative stress biomarkers were expressed relative to the age-related decline in mitochondrial volume density and absolute power output at maximal exercise. In conclusion, these findings confirm that intramuscular free radical-mediated lipid peroxidation is elevated at rest and during acute exercise in aged humans.
Journal of Applied Physiology 08/2010; 109(2):449-56. · 3.75 Impact Factor
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Damian M Bailey,
Sarah Taudorf,
Ronan M G Berg,
Carsten Lundby, Jane McEneny,
Ian S Young,
Kevin A Evans,
Philip E James,
Angharad Shore,
David A Hullin,
Joe M McCord,
Bente K Pedersen,
Kirsten Möller
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ABSTRACT: This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O(2)). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P < 0.05 vs. normoxia) that correlated with the increase in AMS/headache scores (r = -0.50 to -0.90, P < 0.05). This was associated with a reduction in a-v(D) and hence net cerebral uptake of plasma nitrite and increased cerebral output of 3-NT (P < 0.05 vs. normoxia) that also correlated against AMS/headache scores (r = 0.74-0.87, P < 0.05). In contrast, hypoxia did not alter the cerebral exchange of S100beta and both global cerebral oxidative metabolism (cerebral metabolic rate of oxygen) and neuronal integrity (NSE) were preserved (P > 0.05 vs. normoxia). These findings indicate that hypoxia stimulates cerebral oxidative-nitrative stress, which has broader implications for other clinical models of human disease characterized by hypoxemia. This may prove a risk factor for AMS by a mechanism that appears independent of impaired BBB function and cerebral oxidative metabolism.
AJP Regulatory Integrative and Comparative Physiology 09/2009; 297(5):R1283-92. · 3.34 Impact Factor
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ABSTRACT: Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.
We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean +/- SD] BMI 33.6 +/- 3.7 kg/m(2), aged 39 +/- 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.
Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance-related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.
This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.
Diabetes 08/2009; 58(12):2741-8. · 8.29 Impact Factor
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ABSTRACT: Individuals with impaired glucose tolerance (IGT) have a greater risk of developing diabetes and cardiovascular disease compared with those with normal glycemic control. The aim of this study was to examine the effects of acute aerobic exercise on glycemia, regional arterial stiffness, and oxidative stress in obese subjects with IGT.
Twelve obese subjects (7 men and 5 women; 48.0±9.4 years; body mass index 32.4±7.0kg/m(2)) with IGT participated in a 30-minute bout of walking at 65% of maximum predicted heart rate. Pulse wave velocity (PWV, for determination of arterial stiffness) and blood pressure were examined before and after exercise, whereas venous blood samples were drawn for the determination of glucose, blood lipids, and indices of oxidative stress and inflammation (lipid hydroperoxides; superoxide dismutase; high-sensitivity C-reactive protein).
After exercise PWV (9.1±1.2m/s vs. 8.6±1.0m/s), glucose (5.7±0.6 mmol·L(-1) vs. 5.4±0.6 mmol·L(-1)), and diastolic blood pressure (94±14mm Hg vs. 86±13mm Hg) decreased, respectively (P < .05). A correlation was observed between PWV and glucose (r=0.544, P < .05). There were no changes in lipid hydroperoxides, superoxide dismutase, high-sensitivity C-reactive protein, or blood lipids (P > .05).
These findings suggest that acute aerobic exercise can reduce regional arterial stiffness in obese subjects with IGT by possibly improving glucose metabolism, independent of changes in oxidative stress.
Journal of Clinical Lipidology 08/2009; 3(4):262-8. · 1.58 Impact Factor
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ABSTRACT: This study was undertaken to investigate the association among BMI and lipid hydroperoxide (LH), total antioxidant status (TAS), superoxide dismutase (SOD), and reduced glutathione (GSH). Ninety (n = 90) healthy males and females (n = 23/67) (29 normal weight (BMI: 22.74 +/- 0.25 kg/m(2)), 36 overweight (BMI: 27.18 +/- 0.23 kg/m(2)), and 25 obese (33.78 +/- 0.48 kg/m(2))) participated in the study. Data collected included anthropometric measures, fasting blood glucose, lipid profile, LH, TAS, and enzymatic antioxidants (SOD, and reduced GSH). The results of the study showed that obese individuals had significantly increased LH levels compared to normal-weight individuals (obese vs. normal weight (0.88 +/- 0.05 vs. 0.67 +/- 0.03 micromol/l, P < 0.01)) but the increased levels were not significantly different when compared to the overweight group (obese vs. overweight (0.88 +/- 0.05 vs. 0.79 +/- 0.05 micromol/l)). No other consistent significant differences in TAS, SOD, and GSH were identified between groups. This study concluded that only obesity and not moderate overweight elevates LH levels. Furthermore, the levels of TAS, SOD, and GSH in obesity do not explain the increased LH levels observed in obesity.
Obesity 02/2009; 17(3):460-6. · 4.28 Impact Factor
