Increased endothelial microparticles and oxidative stress at extreme altitude.

PURPOSE Hypoxia and oxidative stress affect endothelial function. Endothelial microparticles (MP) are established measures of endothelial dysfunction and influence vascular reactivity. To evaluate the effects of hypoxia and antioxidant supplementation on endothelial MP profiles, a double-blind, placebo-controlled trial, during a high altitude expedition was performed. METHODS 29 participants were randomly assigned to a treatment group (n = 14), receiving vitamin E, C, A, and N-acetylcysteine daily, and a control group (n = 15), receiving placebo. Blood samples were obtained at 490 m (baseline), 3530, 4590, and 6210 m. A sensitive tandem mass spectrometry method was used to measure 8-iso-prostaglandin F2α and hydroxyoctadecadienoic acids as markers of oxidative stress. Assessment of MP profiles including endothelial activation markers (CD62+MP and CD144+MP) and cell apoptosis markers (phosphatidylserine+MP and CD31+MP) was performed using a standardized flow cytometry-based protocol. RESULTS 15 subjects reached all altitudes and were included in the final analysis. Oxidative stress increased significantly at altitude. No statistically significant changes were observed comparing baseline to altitude measurements of phosphatidylserine expressing MP (p = 0.1718) and CD31+MP (p = 0.1305). Compared to baseline measurements, a significant increase in CD62+MP (p = 0.0079) and of CD144+MP was detected (p = 0.0315) at high altitudes. No significant difference in any MP level or oxidative stress markers were found between the treatment and the control group. CONCLUSION Hypobaric hypoxia is associated with increased oxidative stress and induces a significant increase in CD62+ and CD144+MP, whereas phosphatidylserine+MP and CD31+MP remain unchanged. This indicates that endothelial activation rather than an apoptosis is the primary factor of hypoxia induced endothelial dysfunction.

Involvement of NADPH oxidases in cardiac remodelling and heart failure

Cardiac remodelling occurs in response to stress, such as chronic hypertension or myocardial infarction, and forms the substrate for subsequent development of heart failure. Key pathophysiological features include ventricular hypertrophy, interstitial fibrosis, contractile dysfunction, and chamber dilatation. Although the molecular mechanisms are complex and not fully defined, substantial evidence now implicates increased oxidative stress as being important. The NADPH oxidase ('Nox') enzymes are a particularly important source of reactive oxygen species that are implicated in redox signalling. This article reviews the evidence for an involvement of NADPH oxidases in different aspects of adverse cardiac remodelling. A better understanding of the roles of this complex enzyme family may define novel therapeutic targets for the prevention of heart failure. Copyright © 2007 S. Karger AG.

The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

info:eu-repo/semantics/publishedVersion

NADPH oxidases as regulators of tumor angiogenesis : current and emerging concepts

Significance Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and peroxynitrite are generated ubiquitously by all mammalian cells and have been understood for many decades as inflicting cell damage and as causing cancer by oxidation and nitration of macromolecules, including DNA, RNA, proteins, and lipids. Recent Advances A current concept suggests that ROS can also promote cell signaling pathways triggered by growth factors and transcription factors that ultimately regulate cell proliferation, differentiation, and apoptosis, all of which are important hallmarks of tumor cell proliferation and angiogenesis. Moreover, an emerging concept indicates that ROS regulate the functions of immune cells that infiltrate the tumor environment and stimulate angiogenesis, such as macrophages and specific regulatory T cells. Critical Issues In this article, we highlight that the NADPH oxidase family of ROS-generating enzymes are the key sources of ROS and, thus, play an important role in redox signaling within tumor, endothelial, and immune cells thereby promoting tumor angiogenesis. Future Directions Knowledge of these intricate ROS signaling pathways and identification of the culprit NADPH oxidases is likely to reveal novel therapeutic opportunities to prevent angiogenesis that occurs during cancer and which is responsible for the revascularization after current antiangiogenic treatment.

Atmospheric pressure gas plasma-induced colorectal cancer cell death is mediated by Nox2-ASK1 apoptosis pathways and oxidative stress is mitigated by Srx-Nrf2 anti-oxidant system

Atmospheric pressure gas plasma (AGP) generates reactive oxygen species (ROS) that induce apoptosis in cultured cancer cells. The majority of cancer cells develop a ROS-scavenging anti-oxidant system regulated by Nrf2, which confers resistance to ROS-mediated cancer cell death. Generation of ROS is involved in the AGP-induced cancer cell death of several colorectal cancer cells (Caco2, HCT116 and SW480) by activation of ASK1-mediated apoptosis signaling pathway without affecting control cells (human colonic sub-epithelial myofibroblasts; CO18, human fetal lung fibroblast; MRC5 and fetal human colon; FHC). However, the identity of an oxidase participating in AGP-induced cancer cell death is unknown. Here, we report that AGP up-regulates the expression of Nox2 (NADPH oxidase) to produce ROS. RNA interference designed to target Nox2 effectively inhibits the AGP-induced ROS production and cancer cell death. In some cases both colorectal cancer HT29 and control cells showed resistance to AGP treatment. Compared to AGP-sensitive Caco2 cells, HT29 cells show a higher basal level of the anti-oxidant system transcriptional regulator Nrf2 and its target protein sulfiredoxin (Srx) which are involved in cellular redox homeostasis. Silencing of both Nrf2 and Srx sensitized HT29 cells, leads to ROS overproduction and decreased cell viability. This indicates that in HT29 cells, Nrf2/Srx axis is a protective factor against AGP-induced oxidative stress. The inhibition of Nrf2/Srx signaling should be considered as a central target in drug-resistant colorectal cancer treatments.

Robust Glyoxalase activity of Hsp31, a ThiJ/DJ-1/PfpI Family Member Protein, Is Critical for Oxidative Stress Resistance in Saccharomyces cerevisiae

Methylglyoxal (MG) is a reactive metabolic intermediate generated during various cellular biochemical reactions, including glycolysis. The accumulation of MG indiscriminately modifies proteins, including important cellular antioxidant machinery, leading to severe oxidative stress, which is implicated in multiple neurodegenerative disorders, aging, and cardiac disorders. Although cells possess efficient glyoxalase systems for detoxification, their functions are largely dependent on the glutathione cofactor, the availability of which is self-limiting under oxidative stress. Thus, higher organisms require alternate modes of reducing the MG-mediated toxicity and maintaining redox balance. In this report, we demonstrate that Hsp31 protein, a member of the ThiJ/DJ-1/PfpI family in Saccharomyces cerevisiae, plays an indispensable role in regulating redox homeostasis. Our results show that Hsp31 possesses robust glutathione-independent methylglyoxalase activity and suppresses MG-mediated toxicity and ROS levels as compared with another paralog, Hsp34. On the other hand, glyoxalase-defective mutants of Hsp31 were found highly compromised in regulating the ROS levels. Additionally, Hsp31 maintains cellular glutathione and NADPH levels, thus conferring protection against oxidative stress, and Hsp31 relocalizes to mitochondria to provide cytoprotection to the organelle under oxidative stress conditions. Importantly, human DJ-1, which is implicated in the familial form of Parkinson disease, complements the function of Hsp31 by suppressing methylglyoxal and oxidative stress, thus signifying the importance of these proteins in the maintenance of ROS homeostasis across phylogeny.

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Oxidized and/or glycated low-density lipoprotein (LDL) may mediate capillary injury in diabetic retinopathy. The mechanisms may involve pro-inflammatory and pro-oxidant effects on retinal capillary pericytes. In this study, these effects, and the protective effects of pigment epithelium-derived factor (PEDF), were defined in a primary human pericyte model. Human retinal pericytes were exposed to 100 microg/ml native LDL (N-LDL) or heavily oxidized glycated LDL (HOG-LDL) with or without PEDF at 10-160 nM for 24 h. To assess pro-inflammatory effects, monocyte chemoattractant protein-1 (MCP-1) secretion was measured by ELISA, and nuclear factor-kappaB (NF-kappaB) activation was detected by immunocytochemistry. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS), peroxynitrite (ONOO(-)) formation, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) production. The results showed that MCP-1 was significantly increased by HOG-LDL, and the effect was attenuated by PEDF in a dose-dependent manner. PEDF also attenuated the HOG-LDL-induced NF-kappaB activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kappaB activation. Further studies demonstrated that HOG-LDL, but not N-LDL, significantly increased ONOO(-) formation, NO production, and iNOS expression. These changes were also alleviated by PEDF. Moreover, PEDF significantly ameliorated HOG-LDL-induced ROS generation through up-regulation of superoxide dismutase 1 expression. Taken together, these results demonstrate pro-inflammatory and pro-oxidant effects of HOG-LDL on retinal pericytes, which were effectively ameliorated by PEDF. Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future.

Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

<p>Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (∼2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima–media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">2</sub><sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; line-height: 0.7em; white-space: nowrap; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">–</sup>) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3–4 (acute high altitude) and 12–14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders’ FMD (7.9 ± 0.4 <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 6.8 ± 0.4%; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> = 0.004) and GTN-induced dilatation (16.6 ± 0.9 <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 14.5 ± 0.8%; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> = 0.006), and raised central PWV (6.0 ± 0.2<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 6.6 ± 0.3 m s<sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; line-height: 0.7em; white-space: nowrap; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">−1</sup>; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> = 0.001). These changes persisted at days 12–14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (∼19%, <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">2</sub><sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; line-height: 0.7em; white-space: nowrap; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">–</sup> increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">n</em> = 11, <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">r</em> = −0.53) and chronic (<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">n</em> = 7, <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">r</em> = −0.69; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> ≤ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">n</em> = 11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspired O<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">2</sub> fraction () = 0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure when compared to normoxic baseline (5.7 ± 1.6 <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 8.0 ±1.3%; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> &lt; 0.01); this decline in FMD was largely reversed following α<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">1</sub>-adrenoreceptor blockade. In conclusion, high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation. Although a lifetime of high-altitude exposure neither intensifies nor attenuates the impairments seen with short-term exposure, chronic high-altitude exposure appears to be associated with arterial remodelling.</p>

Mitochondrial uncoupling prevents cold-induced oxidative stress: a case study using UCP1 knockout mice.

The relationship between metabolism and reactive oxygen species (ROS) production by the mitochondria has often been (wrongly) viewed as straightforward, with increased metabolism leading to higher generation of pro-oxidants. Insights into mitochondrial functioning show that oxygen consumption is principally coupled with either energy conversion as ATP or as heat, depending on whether the ATP-synthase or the mitochondrial uncoupling protein 1 (UCP1) is driving respiration. However, these two processes might greatly differ in terms of oxidative costs. We used a cold challenge to investigate the oxidative stress consequences of an increased metabolism achieved either by the activation of an uncoupled mechanism (i.e. UCP1 activity) in the brown adipose tissue (BAT) of wild-type mice or by ATP-dependent muscular shivering thermogenesis in mice deficient for UCP1. Although both mouse strains increased their metabolism by more than twofold when acclimatised for 4 weeks to moderate cold (12°C), only mice deficient for UCP1 suffered from elevated levels of oxidative stress. When exposed to cold, mice deficient for UCP1 showed an increase of 20.2% in plasmatic reactive oxygen metabolites, 81.8% in muscular oxidized glutathione and 47.1% in muscular protein carbonyls. In contrast, there was no evidence of elevated levels of oxidative stress in the plasma, muscles or BAT of wild-type mice exposed to cold despite a drastic increase in BAT activity. Our study demonstrates differing oxidative costs linked to the functioning of two highly metabolically active organs during thermogenesis, and advises careful consideration of mitochondrial functioning when investigating the links between metabolism and oxidative stress.

Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)(2)] triggers apoptosis in SH-SY5Y cells through the induction of the AMP-activated protein kinase/p38(MAPK)/p53 signalling axis: evidence for a combined use with 3-bromopyruvate in neuroblastoma treatment

We have demonstrated previously that the complex bis[(2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N`]copper(II), named [Cu(isaepy)(2)], induces AMPK (AMP-activated protein kinase)-dependent/p53-mediated apoptosis in tumour cells by targeting mitochondria. In the present study, we found that p38(MAPK) (p38 mitogen-activated protein kinase) is the molecular link in the phosphorylation cascade connecting AMPK to p53. Transfection of SH-SY5Y cells with a dominant-negative mutant of AMPK resulted in a decrease in apoptosis and a significant reduction in phospho-active p38(MAPK) and p53. Similarly, reverse genetics of p38(MAPK) yielded a reduction in p53 and a decrease in the extent of apoptosis, confirming an exclusive hierarchy of activation that proceeds via AMPK/p38(MAPK)/p53. Fuel supplies counteracted [Cu(isaepy)(2)]-induced apoptosis and AMPK/p38(MAPK)/p53 activation, with glucose being the most effective, suggesting a role for energetic imbalance in [Cu(isaepy)(2)] toxicity. Co-administration of 3BrPA (3-bromopyruvate), a well-known inhibitor of glycolysis, and succinate dehydrogenase, enhanced apoptosis and AMPK/p38(MAPK)/p53 signalling pathway activation. Under these conditions, no toxic effect was observed in SOD (superoxide dismutase)-overexpressing SH-SY5Y cells or in PCNs (primary cortical neurons), which are, conversely, sensitized to the combined treatment with [Cu(isaepy)(2)] and 3BrPA only if grown in low-glucose medium or incubated with the glucose-6-phosphate dehydrogenase inhibitor dehydroepiandrosterone. Overall, the results suggest that NADPH deriving from the pentose phosphate pathway contributes to PCN resistance to [Cu(isaepy)(2)] toxicity and propose its employment in combination with 3BrPA as possible tool for cancer treatment.

Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats

This study examined whether sucrose-rich diet (SRD)-induced hyperglycaemia, dyslipidemia and oxidative stress may be inhibited by N-acetylcysteine (C5H9-NO3S), an organosulfur from Allium plants. Male Wistar 40 rats were divided into four groups (n = 10): (C) given standard chow and water; (N) receiving standard chow and 2 mg/l N-acetylcysteine in its drinking water; (SRD) given standard chow and 30% sucrose in its drinking water; and (SRD-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water. After 30 days of treatment, SRD rats had obesity with increased abdominal circumference, hyperglycaemia, by dyslipidemia and hepatic triacylglycerol accumulation. These adverse effects were associated with oxidative stress and depressed lipid degradation in hepatic tissue. The SRD adverse effects were not observed in SDR-N rats. N-Acetylcysteine reduced the oxidative stress, enhancing glutathione-peroxidase activity, and normalizing lipid hydroperoxyde, reduced glutathione and superoxide dismutase in hepatic tissue of SRD-N rats. The beta-hydroxyacyl coenzyme-A dehydrogenase and citrate-synthase activities were increased in SRD-N rats, indicating enhanced lipid degradation in hepatic tissue as compared to SRD. SRD-N rats had reduced serum oxidative stress and diminished glucose, triacylglycerol, very-low-density lipoprotein (VLDL), oxidized low-density lipoprotein (alpha-LDL) and cholesterol/highdensity lipoprotein (HDL) ratio in relation to SRD. In conclusion, NAC offers promising therapeutic values in prevention of dyslipidemic profile and alleviation of hyperglycaemia in high-sucrose intake condition by improving antioxidant defences. N-Acetylcysteine had also effects preventing metabolic shifting in hepatic tissue, thus enhancing fat degradation and reducing body weight gain in conditions of excess sucrose intake. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection. (c) 2006 Elsevier B.V All rights reserved.

Alcoholism and alcohol abstinence: N-acetylcysteine to improve energy expenditure, myocardial oxidative stress, and energy metabolism in alcoholic heart disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Weekend ethanol consumption and high-sucrose diet: resveratrol effects on energy expenditure, substrate oxidation, lipid profile, oxidative stress and hepatic energy metabolism

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Dietary restriction and fibre supplementation: Oxidative stress and metabolic shifting for cardiac health

Dietary modification ought to be the first line of strategy in prevention of the development of cardiac disease. The purpose of this study was to investigate whether dietary restriction, dietary-fibre-enriched diet, and their interactions might affect antioxidant capacity and oxidative stress in cardiac tissue. Male Wistar rats (180-200 g; n = 10) were divided into four groups: control ad libitum diet (C), 50% restricted diet (DR), fed with fibre-enriched diet (F), and 50% restricted fibre-enriched diet (DR-F). After 35 days of the treatments, F, DR, and DR-F rats showed low cholesterol, LDL-cholesterol, and triacylglycerol, and high HDL-cholesterol in serum. The DR, DR-F, and F groups had decreased myocardial lipoperoxide and lipid hydroperoxide. The DR-F and F treatments increased superoxide dismutase and glutatione peroxidase (GSH-Px). The DR treatment increased GSH-Px and catalase activities. Dietary fibre beneficial effects were related to metabolic alterations. The F and DR-F groups showed high cardiac glycogen and low lactate dehydrogenase/citrate synthase ratios, indicating diminished anaerobic and elevated aerobic myocardial metabolism in these animals. There was no synergistic effect between dietary restriction and dietary fibre addition, since no differences were observed in markers of oxidative stress in the F and DR-F groups. Dietary fibre supplementation, rather than energy intake and dietary restriction, appears to be the main process retarding oxidative stress in cardiac tissue.

Cardiac Energy Metabolism and Oxidative Stress Biomarkers in Diabetic Rat Treated with Resveratrol

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)