Institut für Mangostan & natürliche Antioxidantien

Freie Radikale & Oxidativer Stress

Aktuelle wissenschaftliche Studien | 41-60

41: Behav Brain Res. 2007 May 16;179(2):321-5. Epub 2007 Feb 21.
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Possible involvement of free radicals in the differential neurobehavioral responses to stress in male and female rats.

Chakraborti A, Gulati K, Banerjee BD, Ray A.

Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India.

The effect of restraint stress (RS) on neurobehavioral and brain oxidative stress parameters, and their modulation by antioxidants were evaluated in male and cycling female rats. Exposure to RS suppressed both open arm entries and open arm time in the elevated plus maze and these changes were more marked in males than in females. Assay of brain homogenates revealed that the behavioral suppression was associated with similar differential increases in malondialdehye (MDA) and decreases in glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels in males and females. Pretreatment with alpha-tocopherol (25 and 50 mg/kg) and N-acetylcysteine (100 and 200 mg/kg), attenuated the stress induced alteration of behavioral and oxidative stress markers in a consistent manner in both male and female rats. These findings suggest that males may be more susceptible than females to stress induced neurobehavioral changes and free radicals may exert a regulatory influence in such gender dependent responses to stress.

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PMID: 17368574 [PubMed - indexed for MEDLINE]

42: Free Radic Res. 2007 Mar;41(3):303-15.
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Modulation of oxidative damage by nitroxide free radicals.

Dragutan I, Mehlhorn RJ.

Institute of Organic Chemistry, Romanian Academy. P.O.B. 35-108, Bucharest, 060023. Romania.

Piperidine nitroxides like 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) are persistent free radicals in non-acidic aqueous solutions and organic solvents that may have value as therapeutic agents in medicine. In biological environments, they undergo mostly reduction to stable hydroxylamines but can also undergo oxidation to reactive oxoammonium compounds. Reactions of the oxoammonium derivatives could have adverse consequences including chemical modification of vital macromolecules and deleterious effects on cell signaling. An examination of their reactivity in aqueous solution has shown that oxoammonium compounds can oxidize almost any organic as well as many inorganic molecules found in biological systems. Many of these reactions appear to be one-electron transfers that reduce the oxoammonium to the corresponding nitroxide species, in contrast to a prevalence of two-electron reductions of oxoammonium in organic solvents. Amino acids, alcohols, aldehydes, phospholipids, hydrogen peroxide, other nitroxides, hydroxylamines, phenols and certain transition metal ions and their complexes are among reductants of oxoammonium, causing conversion of this species to the paramagnetic nitroxide. On the other hand, thiols and oxoammonium yield products that cannot be detected by ESR even under conditions that would oxidize hydroxylamines to nitroxides. These products may include hindered secondary amines, sulfoxamides and sulfonamides. Thiol oxidation products other than disulfides cannot be restored to thiols by common enzymatic reduction pathways. Such products may also play a role in cell signaling events related to oxidative stress. Adverse consequences of the reactions of oxoammonium compounds may partially offset the putative beneficial effects of nitroxides in some therapeutic settings.

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PMID: 17364959 [PubMed - indexed for MEDLINE]

43: J Neurosci. 2007 Jan 31;27(5):1129-38.
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Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation.

Abramov AY, Scorziello A, Duchen MR.

Department of Physiology, University College London, London WC1E 6BT, United Kingdom.

Ischemia is a major cause of brain damage, and patient management is complicated by the paradoxical injury that results from reoxygenation. We have now explored the generation of reactive oxygen species (ROS) in hippocampal and cortical neurons in culture in response to oxygen and glucose deprivation or metabolic inhibition and reoxygenation. Fluorescence microscopy was used to measure the rate of ROS generation using hydroethidine, dicarboxyfluorescein diacetate, or MitoSOX. ROS generation was correlated with changing mitochondrial potential (rhodamine 123), [Ca2+]c (fluo-4, fura-2, or Indo-1), or ATP consumption, indicated by increased [Mg2+]c. We found that three distinct mechanisms contribute to neuronal injury by generating ROS and oxidative stress, each operating at a different stage of ischemia and reperfusion. In response to hypoxia, mitochondria generate an initial burst of ROS, which is curtailed once mitochondria depolarize or prevented by previous depolarization with uncoupler. A second phase of ROS generation that followed after a delay was blocked by the xanthine oxidase (XO) inhibitor oxypurinol. This phase correlated with a rise in [Mg2+]c, suggesting XO activation by accumulating products of ATP consumption. A third phase of ROS generation appeared at reoxygenation. This was blocked by NADPH oxidase inhibitors and was absent in cells from gp91(phox-/-) knock-out mice. It was Ca2+ dependent, suggesting activation by increased [Ca2+]c during anoxia, itself partly attributable to glutamate release. Inhibition of either the NADPH oxidase or XO was significantly neuroprotective. Thus, oxidative stress contributes to cell death over and above the injury attributable to energy deprivation.

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PMID: 17267568 [PubMed - indexed for MEDLINE]

44: Graefes Arch Clin Exp Ophthalmol. 2007 Sep;245(9):1327-33. Epub 2007 Jan 25.
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Influence of oxygen free radicals on the tone of ciliary arteries: a model of vasospasms of ocular vasculature.

Zeitz O, Wagenfeld L, Wirtz N, Galambos P, Matthiesen N, Wiermann A, Richard G, Klemm M.

Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

BACKGROUND: Altered regulation of vascular tone and particularly vasospasms are thought to be a risk factor for the progression of primary open angle glaucoma (POAG). Apoptosis of retinal ganglion cells and possibly vascular tone regulation in glaucoma might be caused by oxidative stress. The aim of the present study was to investigate the influence of oxygen free radicals on the tone of ciliary arteries. METHODS: The experiments were carried out with fresh ring preparations from porcine ciliary arteries obtained from a slaughterhouse. The preparations were placed in a self-designed myograph system and were kept under physiologic conditions (pH 7.4, 37 degrees C, Krebs-Henseleit-Buffer, 1.75 mM Ca(2+)). The muscles were sub-maximally activated by depolarization to -41 mV Nernst potential for K(+). The pre-activated preparations were exposed to hydroxyl radicals generated by the Fenton reaction (4 mM H(2)O(2); 30 microM Fe(3+)). Exposure time varied between 10 s and 60 s in order to obtain different radical-time-doses. The developed force was evaluated relatively to the developed force at maximal depolarization to -4 mV. RESULTS: Ten seconds of radical exposure result in an additional increase of the relative developed force from 0.35 +/- .08 to 0.62 +/- 0.12 (P = 0.003; n = 8). Comparable results were obtained for 20 s and 60 s radical exposures. The developed force of a maximal activation to -4 mV was not reduced after a 10 s radical exposure (0.84 +/- 0.13; P = 0.25; n = 5), but was significantly reduced after 20 s exposure (0.25 +/- 0.21; P = 0.005; n = 6) and was virtually 0 after 60 s exposure. DISCUSSION: The data shows that oxygen free radicals induce transient contractions of isolated ciliary artery rings. The shape of these contractions shows parallels to vasospasms. Thus the established system may serve as an in vitro model of vasospasms.

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PMID: 17252259 [PubMed - indexed for MEDLINE]

45: Neurosci Res. 2007 Mar;57(3):477-80. Epub 2007 Jan 23.
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An acute dysfunction of the glutamate transport activity has been shown to generate free radicals and suppress the anti-oxidant ability in the hippocampus of rats.

Nagatomo K, Ueda Y, Doi T, Nakajima A.

Section of Psychiatry, Department of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Japan.

In this study, we attempted to elucidate whether or not an acute inhibition of glutamate transports activity with l-trans-pyrrolidine-2,4-dicarboxylic acid (l-trans PDC) would cause neuroexcitoxicity in the hippocampus. We used in vivo microdialysis and X-band electron spin resonance (ESR) spectroscopy to measure the changes in the redox state during the perfusion of l-trans PDC. ESR signals from rats using l-trans PDC were characteristically a six-line spectra, for which the hfc was a(N)=1.57mT and a(H)=0.25mT; these hfc's were obtained from the lipoxygenase/linoleic acid system that was used for the generation of lipid radicals. The antioxidant effect was measured using an ESR analysis to monitor sequential changes in the signal amplitude of nitroxide radical in the dialysate of both l-trans PDC and control animals. The pattern showed exponential decay with median half-life of the nitroxide radical took significantly longer in the l-trans PDC group. Acute changes in the glutamate transport resulted in the generation of a lipid radical and a depletion in the anti-oxidant effect in the hippocampus. Our data indicate that a dysfunction of a glutamate transport resulted in the collapse of the redox state, which thus eventually led to neuronal necrosis in the hippocampus. This study provides clear evidence for the mechanisms associated with neuronal disorder in relation to glutamate.

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PMID: 17250916 [PubMed - indexed for MEDLINE]

46: Am J Physiol Heart Circ Physiol. 2007 Mar;292(3):H1516-22. Epub 2006 Nov 17.
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Exercise-induced brachial artery vasodilation: role of free radicals.

Richardson RS, Donato AJ, Uberoi A, Wray DW, Lawrenson L, Nishiyama S, Bailey DM.

Dept of Medicine, Physiology Division, Univ of California San Diego, La Jolla, CA 92093-0623, USA.

Originally thought of as simply damaging or toxic "accidents" of in vivo chemistry, free radicals are becoming increasingly recognized as redox signaling molecules implicit in cellular homeostasis. Indeed, at the vascular level, it is plausible that oxidative stress plays a regulatory role in normal vascular function. Using electron paramagnetic resonance (EPR) spectroscopy, we sought to document the ability of an oral antioxidant cocktail (vitamins C, E, and alpha-lipoic acid) to reduce circulating free radicals, and we employed Doppler ultrasound to examine the consequence of an antioxidant-mediated reduction in oxidative stress on exercise-induced vasodilation. A total of 25 young (18-31 yr) healthy male subjects partook in these studies. EPR spectroscopy revealed a reduction in circulating free radicals following antioxidant administration at rest ( approximately 98%) and as a consequence of exercise ( approximately 85%). Plasma total antioxidant capacity and vitamin C both increased following the ingestion of the antioxidant cocktail, whereas vitamin E levels were not influenced by the ingestion of the antioxidants. Brachial artery vasodilation during submaximal forearm handgrip exercise was greater with the placebo (7.4 +/- 1.8%) than with the antioxidant cocktail (2.3 +/- 0.7%). These data document the efficacy of an oral antioxidant cocktail in reducing free radicals and suggest that, in a healthy state, the aggressive disruption of the delicate balance between pro- and antioxidant forces can negatively impact vascular function. These findings implicate an exercise-induced reliance upon pro-oxidant-stimulated vasodilation, thereby revealing an important and positive vascular role for free radicals.

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PMID: 17114239 [PubMed - indexed for MEDLINE]

47: J Appl Physiol. 2007 Apr;102(4):1677-86. Epub 2006 Nov 9.
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The role of free radicals in the pathophysiology of muscular dystrophy.

Tidball JG, Wehling-Henricks M.

Department of Physiological Science, University of California, Los Angeles, California 90095, USA.

Null mutation of any one of several members of the dystrophin protein complex can cause progressive, and possibly fatal, muscle wasting. Although these muscular dystrophies arise from mutation of a single gene that is expressed primarily in muscle, the resulting pathology is complex and multisystemic, which shows a broader disruption of homeostasis than would be predicted by deletion of a single-gene product. Before the identification of the deficient proteins that underlie muscular dystrophies, such as Duchenne muscular dystrophy (DMD), oxidative stress was proposed as a major cause of the disease. Now, current knowledge supports the likelihood that interactions between the primary genetic defect and disruptions in the normal production of free radicals contribute to the pathophysiology of muscular dystrophies. In this review, we focus on the pathophysiology that results from dystrophin deficiency in humans with DMD and the mdx mouse model of DMD. Current evidence indicates three general routes through which free radical production can be disrupted in dystrophin deficiency to contribute to the ensuing pathology. First, constitutive differences in free radical production can disrupt signaling processes in muscle and other tissues and thereby exacerbate pathology. Second, tissue responses to the presence of pathology can cause a shift in free radical production that can promote cellular injury and dysfunction. Finally, behavioral differences in the affected individual can cause further changes in the production and stoichiometry of free radicals and thereby contribute to disease. Unfortunately, the complexity of the free radical-mediated processes that are perturbed in complex pathologies such as DMD will make it difficult to develop therapeutic approaches founded on systemic administration of antioxidants. More mechanistic knowledge of the specific disruptions of free radicals that underlie major features of muscular dystrophy is needed to develop more targeted and successful therapeutic approaches.

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PMID: 17095633 [PubMed - indexed for MEDLINE]

48: Mol Cell Biochem. 2007 Mar;297(1-2):199-207. Epub 2006 Nov 2.
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Release of secondary free radicals during post-ischaemic reperfusion is not influenced by extracellular calcium levels in isolated rat hearts.

Perrin-Sarrado C, Bouchot O, Vergely C, Rochette L.

Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales (LPPCE), Facultés de Médecine et de Pharmacie, 7 Bd Jeanne d'Arc, BP 87900, 21079, Dijon Cedex, France.

In this study, we evaluated the impact of the calcium concentration present in the perfusion medium (1.2-3 mM) on contractile performance, lactate dehydrogenase (LDH) release and secondary free radical production during post-ischaemic reperfusion of isolated rat hearts. The impact of calcium concentration on post-ischaemic free radical release was investigated using the Electron Paramagnetic Resonance (EPR) technique and spin trapping with the lipophilic spin trap alpha-phenyl N-tert-butylnitrone (PBN). The evolution of left ventricular end diastolic pressure (LVEDP) in both groups followed the same pattern, but we observed that ischaemic and post-ischaemic contracture was more severe in the group of hearts perfused with 3 mM of calcium as compared with those perfused with 1.2 mM of calcium. A large release of alkyl/alkoxyl species occurred in all hearts from the onset of reperfusion and remained at a high level during the 30 min of reperfusion with no return to basal values. The kinetics and intensity of these releases were the same in both groups. In conclusion, in a range of extracellular calcium levels (1.2-3 mM), the release of alkyl/alkoxyls radicals does not seem to be calcium-dependent. Due to the protective actions of PBN itself, the results of simultaneous investigations of the effects of radical scavengers on isolated heart function may be limited. However, since many pharmacological properties (antioxidant, cellular protector, NO precursor ...) are attributed to PBN, studies investigating oxidative stress with such a multi-faceted tool make interpretation difficult.

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PMID: 17080311 [PubMed - indexed for MEDLINE]

49: Circ Res. 2006 Oct 27;99(9):924-32.
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Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells.

Gutierrez J, Ballinger SW, Darley-Usmar VM, Landar A.

Department of Physiology and Biophysics, Center for Free Radical Biology, University of Alabama at Birmingham, USA.

Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. It was also recognized early in mitochondrial research that the reduction of oxygen to generate the free radical superoxide occurs at various sites in the respiratory chain and was postulated that this could lead to mitochondrial dysfunction in a variety of disease states. Over recent years, this view has broadened substantially with the discovery that reactive oxygen, nitrogen, and lipid species can also modulate physiological cell function through a process known as redox cell signaling. These redox active second messengers are formed through regulated enzymatic pathways, including those in the mitochondrion, and result in the posttranslational modification of mitochondrial proteins and DNA. In some cases, the signaling pathways lead to cytotoxicity. Under physiological conditions, the same mediators at low concentrations activate the cytoprotective signaling pathways that increase cellular antioxidants. Thus, it is critical to understand the mechanisms by which these pathways are distinguished to develop strategies that will lead to the prevention of cardiovascular disease. In this review, we describe recent evidence that supports the hypothesis that mitochondria have an important role in cell signaling, and so contribute to both the adaptation to oxidative stress and the development of vascular diseases.

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PMID: 17068300 [PubMed - indexed for MEDLINE]

50: J Agric Food Chem. 2006 Oct 18;54(21):8212-21.
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Inhibitory effect of known antioxidants and of press juice from herring (Clupea harengus) light muscle on the generation of free radicals in human monocytes.

Gunnarsson G, Undeland I, Sannaveerappa T, Sandberg AS, Lindgård A, Mattsson-Hultén L, Soussi B.

Department of Chemical and Biological Engineering, Food Science, Chalmers University of Technology, Göteborg, Sweden.

Reactive oxygen species (ROS) can cause oxidative stress, which has been linked to various diseases. It has been suggested that antioxidant-rich foods can reduce such oxidative stress. However, the lack of suitable model systems to screen for in vivo effects of food-derived antioxidants has prevented a clear consensus in this area. In this study, the aim was to use a single-cell model system (human monocyte) to evaluate whether certain pure antioxidants and complex muscle extracts (herring light muscle press juice, PJ) could prevent ROS formation under in vivo like conditions. ROS were excreted from the monocytes upon stimulation with phorbol myristate acetate and were then detected as isoluminol-enhanced chemiluminescence (CL). Adding 2000 units of catalase and 50 units of superoxide dismutase to the monocytes model lowered the CL response by 35 and 86%, respectively. Ascorbate (14.1 mM) lowered the response by 99%, alpha-tocoperhol (188 microM) by 37%, and Trolox (50 microM) by almost 100%. Crude herring PJ gave a dose-dependent reduction in the CL response. At 10, 100, and 1000 times dilution, the PJ reduced the CL signal by 93, 60.5, and 10.6%. PJ fractionated into low molecular weight (LMW) (<1000 Da) and high molecular weight (>3500 Da) fractions decreased the CL response by 52.9 and 71.4%, respectively, at a 100-fold dilution. Evaluation of the PJ samples in the oxygen radical absorbance capacity test indicated that proteins may be the primary radical scavenging compounds of PJ, whereas the ROS-preventing effect obtained from the LMW fraction may also be attributed to other mechanisms. Thus, this study proved that the monocyte assay can be a useful tool for studying whether food-derived antioxidants can limit ROS production under physiologically relevant conditions. It also showed that herring contains numerous aqueous compounds demonstrating antioxidative effects in the monocyte model system.

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PMID: 17032031 [PubMed - indexed for MEDLINE]

51: Free Radic Res. 2006 Sep;40(9):901-9.
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Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects.

Rosias PP, Den Hartog GJ, Robroeks CM, Bast A, Donckerwolcke RA, Heynens JW, Suykerbuyk J, Hendriks HJ, Jöbsis Q, Dompeling E.

Department of Pediatric Pulmonology, University Hospital of Maastricht, Maastricht, The Netherlands.

Many markers of airway inflammation and oxidative stress can be measured non-invasively in exhaled breath condensate (EBC). However, no attempt has been made to directly detect free radicals using electron paramagnetic resonance (EPR) spectroscopy. Condensate was collected in 14 children with cystic fibrosis (CF) and seven healthy subjects. Free radicals were trapped by 5,5-dimethyl-1-pyrroline-N-oxide. EPR spectra were recorded using a Bruker EMX spectrometer. Secondly, to study the source of oxygen centered radical formation, catalase or hydrogen peroxide was added to the condensate. Radicals were detected in 18 out of 21 condensate samples. Analysis of spectra indicated that both oxygen and carbon centered radicals were trapped. Within-subject reproducibility was good in all but one subject. Quantitatively, there was a trend towards higher maximal peak heights of both oxygen and carbon centered radicals in the children with CF. Catalase completely suppressed the signals in condensate. Addition of hydrogen peroxide resulted in increased radical signal intensity. Detection of free radicals in EBC of children with CF and healthy subjects is feasible using EPR spectroscopy.

PMID: 17015269 [PubMed - indexed for MEDLINE]

52: Free Radic Res. 2006 Aug;40(8):789-97.
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Free radicals act as effectors in the growth inhibition and apoptosis of iron-treated Burkitt's lymphoma cells.

Habel ME, Jung D.

Héma-Québec, Recherche et Développement, 1009, Département de Biochimie et Microbiologie, Université Laval, route du Vallon, Sainte-Foy, Qué., Canada G1V 5C3.

The addition of ferric citrate to Burkitt's lymphoma (BL) cell lines inhibits growth, leads to the accumulation of cells in the phase G(2)/M of the cell cycle and to the modulation of translocated c-myc expression. The increase in the labile iron pool (LIP) of iron-treated BL cells leads to cytotoxicity. Indeed, intracellular free iron catalyzes the formation of highly reactive compounds such as hydroxyl radicals and nitric oxide (NO) that damages macromolecular components of cells, eventually resulting in apoptosis. In this report, we have investigated the possible involvement of free radicals in the response of Ramos cells to iron. When added to Ramos cells, iron increased the intracellular levels of peroxide/peroxynitrite and NO. Moreover, the addition of free radicals scavengers (TROLOX and Carboxy-PTIO) neutralized the effects of iron on Ramos cells while addition of an NO donor or hydrogen peroxide (H2O2) to cells generated effects which partially mimicked those induced by iron addition. Collectively, our results suggest the involvement of free radicals as effectors in the iron specific growth inhibition of BL cells observed in vitro.

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PMID: 17015257 [PubMed - indexed for MEDLINE]

53: Int J Biochem Cell Biol. 2007;39(1):44-84. Epub 2006 Aug 4.
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Free radicals and antioxidants in normal physiological functions and human disease.

Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J.

Faculty of Chemical and Food Technology, Slovak Technical University, SK-812 37 Bratislava, Slovakia.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.

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PMID: 16978905 [PubMed - indexed for MEDLINE]

54: Int J Environ Res Public Health. 2006 Sep;3(3):286-91.
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Free radicals: emerging challenge in environmental health research in childhood and neonatal disorders.

Sharda B.

Dept of Pediatrics, RNT Medical College, Krishna, 5 Charak Marg, Nr. Charak Hostel, Udaipur, India.

Infants and children may undergo severe oxidative stress due to disease state, pre-existing nutritional status, frequent use of oxygen, and lower levels of antioxidant defenses. Antioxidant defenses, made up of intracellular and extra-cellular components, work synergistically to prevent oxidative damage. Total antioxidant activity (TAA) was analyzed by method of ferric reducing antioxidant power assay (FRAP). Patients admitted in Pediatric Dept, RNT Medical College, Udaipur, India were selected for these studies. TAA level in neonates with hypoxic-ischemic-encephalopathy (HIE) stage III and in poor outcome cases was significantly low. Erythrocyte SOD activity level was low in pre-term neonates. TAA level in severely malnourished children at the time of hospital admission was low. This low antioxidant level in severely malnourished children could be multi-factorial viz. low zinc, selenium, vitamin A & C deficiency, recurrent infections, elevated free iron and chronic starvation stage. Delayed recovery of oxidant injury may lead to delayed incomplete recovery at cellular level. In a study of 29 tuberculosis patients TAA level was found to be low in tubercular patients compared with control. TAA level decreased more in CNS tuberculosis compared with other system tuberculosis. In a study of nutritional tremor syndrome TAA, ascorbic acid and alpha-tocopherol levels were low during pre-tremor phase compared with tremor phase (ATS). Pre-term neonates have incompletely developed antioxidant defenses and are deficient in vitamin E, which is normally derived from maternal circulation at the end of 3rd trimester. Therefore, decreased TAA level in HIE with poor outcome indicates addition of antioxidants in therapeutic strategy. Since rise in TAA in antioxidant supplemented group of severely malnutrition children was higher with good outcome compared with nonsupplemented group it would be prudent to supplement antioxidant during nutritional management. These studies have shown that health benefits can be obtained by children with a reduced risk of disease from supplements of antioxidant nutrients. The amounts of optimal supplements in these disorders, whether pharmacologic or large, are to be determined. Further work is needed to show whether modest increases in nutrient intakes in children with these disorders will delay or prevent the complications and improve the outcome. Therefore, available evidence regarding health benefits to be achieved by supplementing antioxidant nutrients is encouraging. Free radical injury and antioxidant deficiency is more common than what we think. Severely malnourished children and children suffering from chronic infections and diseases are at several fold increased risk of antioxidant deficiency and likely to suffer from free radical injury. Appropriate interventions are required in reducing the risk associated with these observations.

PMID: 16968976 [PubMed - indexed for MEDLINE]

55: Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1103-11.
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A computational model for free radicals transport in the microcirculation.

Kavdia M.

Biomedical Engineering Program, University of Arkansas, Fayetteville, 72701, USA.

Nitric oxide (NO), superoxide (O(2)(-)), and peroxynitrite (ONOO(-)) interactions in pathophysiologic conditions such as cardiovascular disease, hypertension, and diabetes have been studied extensively in vivo and in vitro. A reduction in bioavailability of NO is a common event that is known as the endothelial dysfunction in these conditions. Despite intense investigation of NO biotransport and O(2)(-) and ONOO(-) biochemical interactions in vasculature, we have very little quantitative knowledge of distributions and concentrations of NO, O(2)(-), and ONOO(-) under normal physiologic and pathophysiologic conditions. Based on fundamental principles of mass balance, vessel geometry, and reaction kinetics, we developed a mathematical model of these free radicals transport in and around an arteriole during oxidative stress. We investigated the role of O(2)(-) and ONOO(-) in inactivating vasoactive NO. The model predictions include (a) NO interactions with oxygen, O(2)(-), and ONOO(-) have relatively little effect on the NO level in the vascular smooth muscle under physiologic conditions; (b) superoxide diffuses only a few microns from its source, whereas peroxynitrite diffuses over a larger distance; and (c) reduced superoxide dismutase levels significantly increase O(2)(-) and peroxynitrite concentrations and decrease NO concentration. Model results indicate that the reduced NO bioavailability and enhanced peroxynitrite formation may vary depending on the location of oxidative stress in the microcirculation, which occurs at diverse vascular cell locations in diabetes, aging, and cardiovascular diseases. The results will have significant implications for our understanding of these free radical interactions in physiologic and pathophysiologic conditions resulting from endothelial dysfunction.

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PMID: 16910758 [PubMed - indexed for MEDLINE]

56: J Soc Gynecol Investig. 2006 Sep;13(6):390-8. Epub 2006 Jul 26.
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Female infertility and free radicals: potential role in adhesions and endometriosis.

Alpay Z, Saed GM, Diamond MP.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, Wayne State University, Detroit, Michigan 48201, USA.

Free radicals are highly reactive molecules produced in the cell either as part of, or as end-products of, biochemical reactions that have crucial roles in the homeostasis of the organism. Thus, excess production or impaired elimination of free radicals leads to increased oxidative stress, which has been implicated in the development of several different disease states, including hypoxia-reperfusion injury, cancer, and aging. Peritoneal adhesions and endometriosis are relatively commonly identified in women, and are known to be associated with infertility without clearly understood pathophysiology. The prevention and treatment strategies of these conditions, both of which have tremendous propensity to recur, have not been completely established. The development of both disorders has been shown to be closely related to the presence of increased oxidative stress in the tissues. In this article, we review this relationship with reference to the mechanistic steps involved and their regulation. As our knowledge of both conditions expands, we believe there will be opportunities for specific steps to intervention in free radical metabolism to reduce and/or prevent further development of endometriosis and adhesions.

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PMID: 16872846 [PubMed - indexed for MEDLINE]

57: FEMS Immunol Med Microbiol. 2006 Jul;47(2):167-77.
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Oxidative stress and septic shock: metabolic aspects of oxygen-derived free radicals generated in the liver during endotoxemia.

Sakaguchi S, Furusawa S.

First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, Sendai, Japan.

This review describes the role of oxidative stress caused by endotoxin challenge in sepsis or septic shock symptoms. We observed that endotoxin injection resulted in lipid peroxide formation and membrane damage (near 60-150 kDa) in the livers of experimental animals, causing decreased levels of scavengers or quenchers of free radicals. The administration of alpha-tocopherol completely prevented injury to the liver plasma membrane caused by endotoxin, and suggested that lipid peroxidation by free radicals might occur in a tissue ischemic state, probably by disseminated intravascular coagulation (DIC), in endotoxemia. In mice, depression of Ca(2+)-ATPase activity in the liver plasma membrane may contribute to the membrane damage caused by endotoxin, and the increase of [Ca(2+)](i) in the liver cytoplasm may partially explain the oxidative stress that occurs in endotoxemia. It seems that endotoxin-induced free radical formation is regulated by Ca(2+) mobilization. Moreover, we have suggested that the oxidative stress caused by endotoxin may be due, at least in part, to the changes in endogenous zinc or selenium regulation during endotoxemia. Interestingly, the extent of TNF-alpha-induced oxidative stress may be the result of a synergism between TNF-alpha and gut-derived endotoxin. It is likely that bacterial or endotoxin translocation plays a significant role in TNF-alpha-induced septic shock. On the other hand, although nitric oxide (NO) has been implicated in the pathogenesis of vascular hyporesponsiveness and hypotension in septic shock in our experimental model, it is unlikely that NO plays a significant role in liver injury caused by free radical generation in endotoxemia.

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PMID: 16831203 [PubMed - indexed for MEDLINE]

58: Biomed Khim. 2006 Mar-Apr;52(2):130-7.
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[Possible mechanism and physiopathological significance of superoxide dismutase regulation by oxygen free radicals]

[Article in Russian]

Miliakova MN, Shabanov VV.

Possible mechanism of regulation of Cu,Zn-superoxide dismutase activity by oxygen free radicals is considered. It consists in the increase of dissociation of aggregated forms of this enzyme. The increase of specific activity may have pathophysiological importance under conditions of oxidative stress.

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PMID: 16805383 [PubMed - indexed for MEDLINE]

59: Neurotox Res. 2000;2(2-3):293-310.
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Neuroprotective strategies in Parkinson's disease: protection against progressive nigral damage induced by free radicals.

Chiueh CC, Andoh T, Lai AR, Lai E, Krishna G.

Unit on Neurodegeneration and Neuroprotection, Laboratory of Clinical Science, National Institute of Mental Health, NIH, Building 10, Room 3D-41, Bethesda, MD 20892-1264, USA.

Brain undergoes neurodegeneration when excess free radicals overwhelm antioxidative defense systems during senescence, head trauma and/or neurotoxic insults. A site-specific accumulation of ferrous citrate-iron complexes in the substantia nigra dopaminergic neurons could lead to exaggerated dopamine turnover, dopamine auto-oxidation, free radical generation, and oxidant stress. Eventually, this iron-catalyzed dopamine auto-oxidation results in the accumulation of neuromelanin, a progressive loss of nigral neurons, and the development of Parkinson's disease when brain dopamine depletion is greater than 80%. Emerging evidence indicates that free radicals such as hydroxyl radicals ((.-)OH) and nitric oxide ((.-)NO) may play opposite role in cell and animal models of parkinsonism. (.-)OH is a cytotoxic oxidant whereas oNO is an atypical neuroprotective antioxidant. (.-)NO and S-nitrosoglutathione (GSNO) protect nigral neurons against oxidative stress caused by 1-methyl-4-phenylpyridinium (MPP(+)), dopamine, ferrous citrate, hemoglobin, sodium nitroprusside and peroxynitrite. MPP(+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), increases the nigral uptake of iron complexes and dopamine overflow leading to the generation of (.-)OH, protein oxidation, lipid peroxidation, and associated retrograde degeneration. In addition to GSNO, MPP(+)-induced oxidative neurotoxicity can be prevented by antioxidants including selegiline, 7-nitroindazole, 17beta-estradiol, melatonin, alpha-phenyl-tert-butylnitrone and U78517F. Similar to selegiline, 7-nitroindazole is a MAO-B inhibitor, which blocks the bio-activation of MPTP and oxidative stress. Freshly prepared but not light exposed, (.-)NO-exhausted GSNO is about 100 times more potent than the classic antioxidant glutathione. Via S-nitrosylation, GSNO also inhibits proteolysis and cytotoxicity caused by caspases and HIV-1 protease. Furthermore, in addition to protection against serum deprivation stress, the induction of neuronal NOS1 in human cells increases tolerance to MPP(+)-induced neuro-toxicity since newly synthesized (.-)NO prevents apoptosis possibly through up-regulation of bcl-2 and down regulation of p66(shc). In conclusion, reactive oxygen species are unavoidable by-products of iron-catalyzed dopamine auto-oxidation, which can initiate lipid peroxidation, protein oxidation, DNA damage, and nigral loss, all of which can be prevented by endogenous and exogenous (.-)NO. Natural and man-made antioxidants can be employed as part of preventative or neuroprotective treatments in Parkinson's disease and perhaps dementia complexes as well. For achieving neuroprotection and neuro-rescue in early clinical parkinsonian stages, a cocktail therapy of multiple neuroprotective agents may be more effective than the current treatment with extremely high doses of a single antioxidative agent.

PMID: 16787846 [PubMed]

60: Toxicol Ind Health. 2006 May;22(4):157-63.
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Prominent free radicals scavenging activity of tannic acid in lead-induced oxidative stress in experimental mice.

El-Sayed IH, Lotfy M, El-Khawaga OA, Nasif WA, El-Shahat M.

Department of Molecular and Cellular Biology, Genetic Engineering and Biotechnology Research Institute, Minufiya University, Sadat City, Minufiya, Egypt.

Lead (Pb) is known to disrupt the pro-oxidant/antioxidant balance of tissues leading to biochemical and physiological dysfunction. The present study was designed to investigate the effect of tannic acid on some biochemical parameters in Swiss albino mice exposed to lead acetate. The levels of thiobarbaturic acid-reactive substances (TBARS) as an index of lipid peroxidation, nitric oxide (NO), and serum lead (Pb) were significantly increased following intragastric administration of 50 micromole lead acetate/kg body weight three times a week, every other day for three weeks, compared to the corresponding control values. On the other hand, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione content (GSH) and serum copper (Cu) and zinc (Zn) were significantly diminished relative to the control values. The administration of 20 mg tannic acid/kg body weight three times a week every other day for three weeks, enhanced the endogenous antioxidant capacity of the cells by increasing the activities of antioxidant enzymes (SOD, CAT, GSH-R, GST), GSH content and serum Cu and Zn levels. Compared to the lead acetate-exposed group, the levels of TBARS, NO and Pb were decreased in the lead acetate exposed group treated with tannic acid. These results afford evidence supporting the hypothesis that lead induces oxidative stress in hepatic cells. Moreover, tannic acid has a potential in sustaining global antioxidant effect in hepatic cells leading to decreased oxidative stress and cellular damage initiated through free radical production by lead acetate.

PMID: 16786837 [PubMed - indexed for MEDLINE]


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