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Superoxide
Kinds of Superoxide Terms modified by Superoxide Selected AbstractsSumatriptan Scavenges Superoxide, Hydroxyl, and Nitric Oxide Radicals: In Vitro Electron Spin Resonance StudyHEADACHE, Issue 9 2002DMSc, Yukio Ikeda MD Background.,The molecular mechanisms of migraine have not yet been clarified. Oxygen free radicals have been implicated in the genesis of many pathological processes, including migraine. Sumatriptan succinate is known to be a very effective drug for acute relief of migraine attack. Objective.,To investigate the direct scavenging activities of sumatriptan for superoxide, hydroxyl, and nitric oxide (NO) radicals using electron spin resonance (ESR) spectroscopy. Methods.,Measurement of superoxide and hydroxyl radical scavenging activities was performed by ESR using 5,5-dimethyl-1-pyrroline- N -oxide as a spin trap. NO was generated from 1-hydroxy-2-oxo-3-(N -3-methyl-3-aminopropyl)-3-methyl-1-triazene and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl produced from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and NO. Results.,The ESR study demonstrated that sumatriptan scavenged superoxide, hydroxyl, and NO in a dose-dependent manner. Conclusion.,Sumatriptan has direct scavenging activity on free radicals and NO. Acute migraine drugs with antioxidant properties may provide heretofore unheralded benefits via this mechanism. [source] Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell deathLIVER INTERNATIONAL, Issue 6 2009Sandra Dunning Abstract Background: In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been implicated as a driving force of HSC activation and proliferation, although contradictory results have been described. Aim: To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways. Methods: Serum-starved culture-activated rat HSCs were exposed to the superoxide anion donor menadione (5,25 ,mol/L) or hydrogen peroxide (0.2,5 mmol/L). Haem oxygenase-1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen-activated protein (MAP) kinases and proliferation were investigated. Results: Menadione induced apoptosis in a dose- and time-dependent, but caspase-independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N-terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal-regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione-induced apoptosis. Non-toxic concentrations of menadione or hydrogen peroxide inhibited platelet-derived growth factor- or/and serum-induced proliferation. Conclusion: Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion-induced HSC apoptosis is dependent on JNK activation and glutathione status. [source] Anti-inflammatory responses and oxidative stress in Nippostrongylus brasiliensis -induced pulmonary inflammationPARASITE IMMUNOLOGY, Issue 1 2002Kathryn S. McNeil summary Migration of L3 larvae of Nippostrongylus brasiliensis through the lungs of the rat, during primary infection, was studied at 24 h, 72 h and 8 days. At 24 h p.i., there was evidence of damage to lung epithelial cells and microvasculature, with increased protein and ,-glutamyl transpeptidase in the bronchoalveolar lavage (BAL) fluid. However, there was little evidence of inflammatory cell recruitment. At 24 h p.i., there was a significant reduction in the inflammatory cytokine tumour necrosis factor ,. Superoxide (O2,·) production was also reduced, accompanied by an increase in superoxide dismutase activity. Lipid peroxidation was reduced at 24 h p.i. and L3 larvae were shown to possess high levels of glutathione compared to host lung tissue. Nitric oxide, detected as nitrite, was produced in BAL fluid, and inducible nitric oxide synthase protein was increased by 72 h p.i. There was evidence of peroxynitrite production throughout the infection period with specific protein bands nitrosylated at 75, 30 and 25 kDa. It appears that despite early evidence of lung damage, the inflammation was reduced in response to L3 larvae of N. brasiliensis. [source] arNOX activity of saliva as a non-invasive measure of coenzyme Q10 response in human trialsBIOFACTORS, Issue 1-4 2008D. James Morré arNOX is a coenzyme Q10 -inhibited, aging-related ECTO-NOX protein of the cell surface also present in sera. It is capable of Superoxide generation measured as Superoxide dismutase-inhibited reduction of ferricytochrome c and is a potential contributor to atherogenic risk. Here, we report an arNOX activity of saliva of older individuals also inhibited by coenzyme Q10. The activity first appears after age 30 to a near maximum at about age 55. Those surviving beyond age 55 usually have reduced arNOX activities. Our studies demonstrate significant (25 to 30%) reduction of arNOX levels with coenzyme Q10 supplementation of 60 mg (2 × 30 mg) per day for 28 days. Activity correlated with age. Response to coenzyme Q10 increased with age being greatest between ages 60 and 65. Saliva arNOX levels varied in a regular pattern throughout the day so it was important that samples be collected at approximately the same time each day for comparative purposes. The coenzyme Q10 response was reversible and within 12 h after the last intake of coenzyme Q10, the salivary arNOX levels returned to base line. The findings suggest that salivary arNOX provides a convenient and non-invasive method to monitor arNOX levels in clinical coenzyme Q10 intervention trials with the response levels paralleling those seen with serum and cellular arNOX. [source] Studies on the Reactivity Pattern of in situ Generated Tetraethylammonium Superoxide with 2-Oxazolin-5-ones.CHEMINFORM, Issue 24 2005Krishna Nand Singh Abstract For Abstract see ChemInform Abstract in Full Text. [source] Potassium Superoxide as an Alternative Reagent for Winterfeldt Oxidation of ,-Carbolines.CHEMINFORM, Issue 21 2003Weiqin Jiang Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Tetraethylammonium Bromide Catalyzed Phase Transfer Reaction of Potassium Superoxide with Hydrazones and Tosylhydrazones.CHEMINFORM, Issue 41 2001Rajesh Kumar Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Henry and Knoevenagel Type Condensation Reactions Initiated by Tetraethylammonium Superoxide in Aprotic Medium.CHEMINFORM, Issue 33 2001Ajay Kumar Shukla Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Chemoselective and Efficient Oxidation of Sulfides to Sulfoxides Mediated by Trimethylsilyl Chloride and Superoxide via a Trimethylsilylperoxy Radical.CHEMINFORM, Issue 6 2001Yao-Jung Chen Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] The role of caveolin-1 in cardiovascular regulationACTA PHYSIOLOGICA, Issue 2 2009A. Rahman Abstract Caveolae are omega-shaped membrane invaginations present in essentially all cell types in the cardiovascular system, and numerous functions have been ascribed to these structures. Caveolae formation depends on caveolins, cholesterol and polymerase I and transcript release factor-Cavin (PTRF-Cavin). The current review summarizes and critically discusses the cardiovascular phenotypes reported in caveolin-1-deficient mice. Major changes in the structure and function of heart, lung and blood vessels have been documented, suggesting that caveolae play a critical role at the interface between blood and surrounding tissue. According to an emerging paradigm, many of these changes are secondary to uncoupling of endothelial nitric oxide synthase. Thus, nitric oxide synthase not only synthesizes more nitric oxide in the absence of caveolin-1, but also more superoxide with potential pathogenic consequences. It is further argued that the vasodilating drive from increased nitric oxide production in caveolin-1-deficient mice is balanced by changes in the vascular media that favour increased dynamic resistance regulation. Harnessing the therapeutic opportunities buried in caveolae, while challenging, could expand the arsenal of treatment options in cancer, lung disease and atherosclerosis. [source] Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L -arginine and antioxidantsACTA PHYSIOLOGICA, Issue 4 2007M. P. Koeners Abstract Aim:, Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. Methods:, Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. N, -nitro- l -arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). Results:, Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 ± 4 vs. 33 ± 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 ± 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. Conclusion:, Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation. [source] Acetaminophen prevents aging-associated hyperglycemia in aged rats: effect of aging-associated hyperactivation of p38-MAPK and ERK1/2DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2009Miaozong Wu Abstract Background Aging-related hyperglycemia is associated with increased oxidative stress and diminished muscle glucose transporter-4 (Glut4) that may be regulated, at least in part, by the mitogen-activated protein kinases (MAPK). Methods To test the possibility that aging-related hyperglycemia can be prevented by pharmacological manipulation of MAPK hyperactivation, aged (27-month old) Fischer 344/NNiaHSD × Brown Norway/BiNia F1 (F344BN) rats were administered acetaminophen (30 mg/kg body weight/day) for 6 months in drinking water. Results Hepatic histopathology, serum aspartate aminotransferase and alanine aminotransferase analyses suggested that chronic acetaminophen did not cause hepatotoxicity. Compared with adult (6-month) and aged (27-month) rats, very aged rats (33-month) had higher levels of blood glucose, phosphorylation of soleus p38-MAPK and extracellular-regulated kinase 1/2 (ERK1/2), superoxide and oxidatively modified proteins (p < 0.05), and these changes were associated with decreased soleus Glut4 protein abundance (p < 0.05). Chronic acetaminophen treatment attenuated age-associated increase in blood glucose by 61.3% (p < 0.05) and increased soleus Glut4 protein by 157.2% (p < 0.05). These changes were accompanied by diminished superoxide levels, decrease in oxidatively modified proteins (,60.8%; p < 0.05) and reduced p38-MAPK and ERK1/2 hyperactivation (,50.4% and , 35.4%, respectively; p < 0.05). Conclusions These results suggest that acetaminophen may be useful for the treatment of age-associated hyperglycemia. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effects of diabetes on plasma nitrotyrosine levelsDIABETIC MEDICINE, Issue 6 2004X. L. Wang Abstract Background Oxidative stress plays a major role in disease processes such as atherosclerosis and diabetes. Peroxynitrite is a reaction product of nitric oxide (NO) and superoxide and a potent oxidant. The peroxynitrite-mediated tyrosine nitration, which forms nitrotyrosine (NT), is associated with several pathological conditions. Methods We measured plasma NT levels using the HPLC method in 40 Mexican Americans with diabetes, but not taking medications, and 40 age- and sex-matched euglycaemic controls. Results Plasma-free NT levels were not different between subjects with diabetes (11.0 ± 1.7 nmol/l, n = 40) and with non-diabetes (10.4 ± 1.5 nmol/l, n = 40). There was also no association with levels of fasting glucose (r = ,0.049, P = 0.663) or 2-h glucose (r = ,0.099, P = 0.390). However, females had significantly lower free NT level (7.6 ± 1.4 nmol/l, n = 40) than males (13.8 ± 1.7 nmol/l, n = 40, P = 0.005), which were not affected by age, smoking status, BMI and glucose levels. Conclusions In contrast to some earlier reports, our study shows that diabetes has no effect on plasma NT levels in Mexican Americans. We have also demonstrated lower free NT levels in females than males, which may partly explain the lower risk profile to vascular disease in women. [source] Development of spray- and freeze-dried high-concentration sesamol emulsions and antioxidant evaluation in fibroblasts and UV-exposed rat skin slicesDRUG DEVELOPMENT RESEARCH, Issue 5 2008Juliana Alencar Abstract Dry sesamol emulsions were synthesized from several combinations of saccharose with hydroxypropylmethylcellulose (HPMC) or sodium caseinate (SC) using spray-drying techniques at 120° to 180°C, or freeze-drying. On the basis of physical characteristics such as droplet size distribution, residual moisture, and microscopic structure, the best material was obtained when spray-drying was applied at either 150° or 180°C with SC or HPMC as excipients, respectively. The extent to which the antioxidant properties of free sesamol towards a set of free radicals (galvinoxyl, diphenylpicrylhydrazyl, superoxide, and hydroxyl) were altered in the starting and reconstituted liquid emulsions submitted to normal storage or pre-exposed to a flux hydroxyl radicals was investigated. Emulsions were further evaluated for their antioxidant properties in cultured 3T3 murine fibroblasts and in an ex vivo model of ultraviolet irradiated rat skin. It was found that, in the material having the best physical properties, encapsulation was decisive in: (1) improving the overall antioxidant behavior of reconstituted versus starting liquid emulsions: (2) sparing sesamol consumption due to free radical attack; and (3) significantly protecting cells and skin against free radical- or irradiation-induced enzymatic release and/or lipid peroxidation. Demonstrating a high activity at high dilutions where interactions of excipient become negligible, the new emulsions could be of great interest in sesamol-based pharmacology or topical applications. Drug Dev Res 69:251,266, 2008. © 2008 Wiley-Liss, Inc. [source] Effect of mangiferin on radiation-induced micronucleus formation in cultured human peripheral blood lymphocytesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2005Ganesh Chandra Jagetia Abstract Irradiation causes a variety of lesions in important biomolecules of the cell through generation of free radicals leading to genomic instability. DNA strand breaks, acentric fragments, or defective kinetochores are manifested as micronuclei after the first cell division. Chemicals that can trap free radicals may reduce the deleterious effects of ionizing radiation. Mangiferin (MGN), a glucosylxanthone derived from Mangifera indica (mango), was investigated for its ability to reduce the frequency of radiation-induced micronucleated binucleate cells (MNBNCs) in cultured human peripheral blood lymphocytes (HPBLs). HPBL cultures were pretreated with 0, 5, 10, 20, 50, and 100 ,g/ml of MGN for 30 min before exposure to 3 Gy of 60Co ,-radiation. The maximum decline in radiation-induced micronuclei was observed at a concentration of 50 ,g/ml MGN; thereafter, a nonsignificant elevation in MNBNC frequency was observed at 100 ,g/ml MGN. Since the lowest MNBNC frequency was observed for 50 ,g/ml MGN, dose-response studies were undertaken using this concentration. Irradiation of HPBLs with 0, 1, 2, 3, or 4 Gy of ,-radiation caused a dose-dependent elevation in the MNBNC frequency, while treatment of HPBLs with 50 ,g/ml MGN 30 min before radiation resulted in significant declines in these frequencies. MGN alone did not alter the proliferation index. Irradiation caused a dose-dependent decline in the proliferation index, while treatment of HPBLs with 50 ,/ml MGN significantly elevated the proliferation index in irradiated cells. MGN treatment reduced hydrogen peroxide-induced lipid peroxidation in HPBLs in a concentration-dependent fashion. In cell-free studies, MGN inhibited the induction of ·OH (hydroxyl), O2·, (superoxide), DPPH (1,1-diphenyl-2-picrylhydrazyl), and ABTS·+ (2,2-azino-bis-3-ethyl benzothiazoline-6-sulphonic acid) radicals in a dose-dependent manner. The results of this study indicate that MGN possesses radioprotective properties by suppressing the effects of free radicals. Environ. Mol. Mutagen. 45:000,000, 2005. © 2005 Wiley-Liss, Inc. [source] Alteration of normal cellular profiles in the scleractinian coral (Pocillopora damicornis) following laboratory exposure to fuel oilENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2006Luc Rougée Abstract Petroleum contamination from oil spills is a continuing threat to our ocean's fragile ecosystems. Herein, we explored the effects of the water-soluble fraction of crude oil on a stony coral, Pocillopora damicornis (Linneaeus 1758). We developed methods for exposing corals to various concentrations of crude oil and for assessing the potential molecular responses of the corals. Corals were exposed to water-accommodated fraction solutions, and appropriate cellular biomarkers were quantified. When compared to the "healthy" control specimens, exposed corals exhibited shifts in biomarker concentrations that were indicative of a shift from homeostasis. Significant changes were seen in cytochrome P450 1-class, cytochrome P450 2-class, glutathione- S -transferase-pi, and cnidarian multixenobiotic resistance protein-1 biomarkers, which are involved the cellular response to, and manipulation and excretion of, toxic compounds, including polycyclic aromatic hydrocarbons. A shift in biomarkers necessary for porphyrin production (e.g., protoporphyrinogen oxidase IX and ferrochelatase) and porphyrin destruction (e.g., heme oxygenase-1 and invertebrate neuroglobin homologue) illustrates only one of the cellular protective mechanisms. The response to oxidative stress was evaluated through measurements of copper/zinc superoxide dismutase-1 and DNA glycosylase MutY homologue-1 concentrations. Likewise, changes in heat shock protein 70 and small heat shock proteins indicated an adjustment in the cellular production of proteins. Finally, the results of this laboratory study were nearly identical to what we observed previously among corals of a different species, Porites lobata, exposed to an oil spill in the field after the grounding of the Merchant Vessel Kyowa Violet. [source] Effect of byproducts from the ozonation of pyrene: Biphenyl-2,2,,6,6,-tetracarbaldehyde and biphenyl-2,2,,6,6,-tetracarboxylic acid on gap junction intercellular communication and neutrophil functionENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2005Stephanie L. Luster-Teasley Abstract In this study, biphenyl-2,2,,6,6,-tetracarbaldehyde, an initial by product formed from the ozonation of pyrene, and biphenyl-2,2,,6,6,-tetracarboxylic acid, a subsequent pyrene ozonation byproduct, were evaluated using two toxicology assays to compare the toxicity of ozonation byproducts with that of the parent compound. The first assay measured the potential for the compounds to block gap junctional intercellular communication (GJIC) using the scrape loading/dye transfer technique in normal WB-344 rat liver epithelial cells. The second assay evaluated the ability of the compounds to affect neutrophil function by measuring the production of superoxide in a human cell line (HL-60). Pyrene significantly blocked intercellular communication (f= 0.2,0.5) at 40 ,M and complete inhibition of communication (f < 0.2) occurred at 50 ,M. Gap junctional intercellular communication in cells exposed to biphenyl-2,2,,6,6,-tetracarbaldehyde reached f < 0.5 at a concentration of 15 ,M. At concentrations greater than 20 ,M, biphenyl-2,2,,6,6,-tetracarbaldehyde was cytotoxic and the inhibition of GJIC was caused by cell death. Biphenyl-2,2,,6,6,-tetracarboxylic acid was neither cytotoxic nor inhibitory to GJIC at the concentrations tested (10,500 ,M). Exposure to biphenyl-2,2,,6,6,-tetracarbaldehyde resulted in a concentration-dependent decrease in phorbol 12-myristate 13-acetate,stimulated O12 production. Neither exposure to pyrene nor biphenyl-2,2,,6,6,-tetracarboxylic acid caused a significant toxic effect on neutrophil function. [source] Haemodialysis induces mitochondrial dysfunction and apoptosisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2007D. S. C. Raj Abstract Background Mitochondria play a crucial role in the regulation of the endogenous pathways of apoptosis activated by oxidant stress. Nuclear factor-,B (NF-,B) is a central integration site for pro-inflammatory signals and oxidative stress. Materials and methods Peripheral blood mononuclear cells (PBMC) were isolated from eight end-stage renal disease (ESRD) patients before haemodialysis (Pre-HD) and during the last 10 min of HD (End-HD). A new polysulfone membrane (F70, Fresenius) was used for dialysis. Intracellular generation of reactive oxygen species (ROS), mitochondrial redox potential (,,m) and PBMC apoptosis were determined by flow-cytometry. Results Plasma levels of interleukin-6 (IL-6) (24·9 ± 7·0 vs. 17·4 ± 5·5 pg dL,1, P < 0·05), IL-6 soluble receptor (52·2 ± 4·9 vs. 37·6 ± 3·2 ng dL,1, P < 0·02) and IL-6 gp130 (405·7 ± 41·0 vs. 235·1 ± 38·4 ng dL,1, P < 0·02) were higher end-HD compared to pre-HD. IL-6 secretion by the isolated PBMC (24·0 ± 2·3 vs. 19·3 ± 3·5 pg dL,1, P < 0·02) increased end-HD. Percentage of lymphocytes exhibiting collapse of mitochondrial membrane potential (43·4 ± 4·6% vs. 32·6 ± 2·9%, P < 0·01), apoptosis (33·4 ± 7·1% vs. 23·7 ± 7·7%, P < 0·01), and generation of superoxide (20·7 ± 5·2% vs. 12·5 ± 2·9%, P < 0·02) and hydrogen peroxide (51·1 ± 7·8% vs.38·2 ± 5·9%, P < 0·04) were higher at end-HD than pre-HD. NF-,B activation (3144·1 ± 208·1 vs. 2033·4 ± 454·6 pg well,1, P < 0·02), expression of B-cell lymphoma protein-2 (6494·6 ± 1461 vs. 3501·5 ± 796·5 ng mL,1, P < 0·03) and heat shock protein-70 (9·81 ± 1·47 vs. 6·38 ± 1·0 ng mL,1, P < 0·05) increased during HD. Conclusions Intra-dialytic activation of cytokines, together with impaired mitochondrial function, promotes generation of ROS culminating in augmented PBMC apoptosis. There is concomitant activation of pathways aimed at attenuation of cell stress and apoptosis during HD. [source] Studies of Pyridinyl-Containing 14-Membered Macrocyclic Copper(II) ComplexesEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 7 2003Sabrina Autzen Abstract Six copper(II) complexes of tetracoordinating, pyridinyl-containing 14-membered macrocycles with varying ratios of nitrogen and oxygen donor atoms were prepared and characterized by IR, UV/Vis, and EPR spectroscopy and cyclic voltammetry. A distorted tetragonal coordination of the copper center in the solid-state was established by X-ray crystallography for the tetraazamacrocyclic complex Cu-3 carrying a methoxybenzyl pendent arm and the trioxaaza complex Cu-6. The superoxide dismutase-like activity of the CuII complexes was investigated by inhibition of NADH oxidation. Although the UV/Vis and EPR spectra of the complexes were strongly affected when the coordinating nitrogen atoms were successively replaced by oxygen atoms, no significant change in their reactivity towards superoxide was observed. In all cases a 1:1 or 1:2 stoichiometry for the reaction with superoxide was found, with the exception of the methoxybenzyl-substituted tetraaza complex, which showed a low catalytic activity with a turnover number of about 10. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Glial-derived arginine, the nitric oxide precursor, protects neurons from NMDA-induced excitotoxicityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Gilbert Grima Abstract Excitotoxic neuronal cell death is characterized by an overactivation of glutamate receptors, in particular of the NMDA subtype, and the stimulation of the neuronal nitric oxide synthase (nNOS), which catalyses the formation of nitric oxide (NO) from l -arginine (L-Arg). At low L-Arg concentrations, nNOS generates NO and superoxide (O2,,), favouring the production of the toxin peroxynitrite (ONOO,). Here we report that NMDA application for five minutes in the absence of added L-Arg induces neuronal cell death, and that the presence of L-Arg during NMDA application prevents cell loss by blocking O2,, and ONOO, formation and by inhibiting mitochondrial depolarization. Because L-Arg is transferred from glial cells to neurons upon activation of glial glutamate receptors, we hypothesized that glial cells play an important modulator role in excitotoxicity by releasing L-Arg. Indeed, as we further show, glial-derived L-Arg inhibits NMDA-induced toxic radical formation, mitochondrial dysfunction and cell death. Glial cells thus may protect neurons from excitotoxicity by supplying L-Arg. This potential neuroprotective mechanism may lead to an alternative approach for the treatment of neurodegenerative diseases involving excitotoxic processes, such as ischemia. [source] Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamineEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2001Åsa Petersén Abstract Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N -methyl- d -aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age. [source] Aerobic exercise acutely improves insulin- and insulin-like growth factor-1-mediated vasorelaxation in hypertensive ratsEXPERIMENTAL PHYSIOLOGY, Issue 5 2010Ai-Lun Yang Limited information is available concerning the effects of aerobic exercise on vasorelaxation in hypertension. The aim of this study was to investigate the effects of a single bout of aerobic exercise on insulin- and insulin-like growth factor-1 (IGF-1)-induced vasorelaxation in hypertensive rats. Four-month-old spontaneously hypertensive rats were randomly divided into a sedentary group (SHR) and an exercise group (SHR+Ex) subjected to a single bout of aerobic exercise conducted by treadmill running at 21 m min,1 for 1 h. Age-matched Wistar,Kyoto rats were used as a normotensive control group (WKY). Insulin- and IGF-1-induced vasorelaxant responses in the three groups were evaluated by using isolated aortic rings, with or without endothelial denudation, in organ baths. Possible roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS) involved in the NO-dependent vasorelaxation were examined by adding selective inhibitors. The role of superoxide was also clarified by adding superoxide dismutase (SOD). In addition, the endothelium-independent vascular responses to sodium nitroprusside (SNP), a NO donor, were examined. The insulin- and IGF-1-induced vasorelaxation was significantly (P < 0.05) decreased in the SHR group compared with the WKY group. This decreased response in SHR was improved by exercise. These vasorelaxant responses among the three groups became similar after endothelial denudation and pretreatment with the PI3K inhibitor, NOS inhibitor or SOD. Also, no difference among groups was found in the SNP-induced vasorelaxation. We concluded that a single bout of aerobic exercise acutely improves insulin- and IGF-1-mediated vasorelaxation in an endothelium-dependent manner in hypertensive rats. [source] Brain superoxide as a key regulator of the cardiovascular response to emotional stress in rabbitsEXPERIMENTAL PHYSIOLOGY, Issue 3 2007Dmitry N. Mayorov Cardiovascular reactivity, an abrupt increase in blood pressure and heart rate in response to emotional stress, is a risk factor for hypertension and heart disease. Brain angiotensin II (Ang II) type 1 (AT1) receptor is increasingly recognized as an important regulator of cardiovascular reactivity. Given that a wide variety of AT1 receptor signalling pathways exists in neurones, the precise molecular mechanisms that underlie central cardiovascular actions of Ang II during emotional stress are yet to be determined. Growing evidence, however, indicates that reactive oxygen species, and in particular superoxide (·O2,), are important intracellular messengers of many actions of brain Ang II. In particular, studies employing microinjection of ·O2, scavengers directly into the rostral ventrolateral medulla (RVLM) and dorsomedial hypothalamus of rabbits have shown that the activation of AT1 receptor,·O2, signalling is required for full manifestation of the cardiovascular response to emotional stress. This role of ·O2, appears to be highly specific, because ·O2, scavengers in the RVLM do not alter the sympathoexcitatory response to baroreceptor unloading or sciatic nerve stimulation. The subcellular mechanisms for the stress-induced ·O2, production are likely to include the activation of NADPH oxidase and are essentially independent of nitric oxide. This review summarizes current knowledge of redox-sensitive signalling mechanisms in the brain that regulate cardiovascular effects of stress. Additionally, it presents initial evidence that ·O2, may be less important in the activation of central pressor pathways mediating cardiovascular arousal associated with appetitive events, such as food anticipation and feeding. [source] Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen speciesFEBS JOURNAL, Issue 13 2008Hideki Sumimoto NADPH oxidases of the Nox family exist in various supergroups of eukaryotes but not in prokaryotes, and play crucial roles in a variety of biological processes, such as host defense, signal transduction, and hormone synthesis. In conjunction with NADPH oxidation, Nox enzymes reduce molecular oxygen to superoxide as a primary product, and this is further converted to various reactive oxygen species. The electron-transferring system in Nox is composed of the C-terminal cytoplasmic region homologous to the prokaryotic (and organelle) enzyme ferredoxin reductase and the N-terminal six transmembrane segments containing two hemes, a structure similar to that of cytochrome b of the mitochondrial bc1 complex. During the course of eukaryote evolution, Nox enzymes have developed regulatory mechanisms, depending on their functions, by inserting a regulatory domain (or motif) into their own sequences or by obtaining a tightly associated protein as a regulatory subunit. For example, one to four Ca2+ -binding EF-hand motifs are present at the N-termini in several subfamilies, such as the respiratory burst oxidase homolog (Rboh) subfamily in land plants (the supergroup Plantae), the NoxC subfamily in social amoebae (the Amoebozoa), and the Nox5 and dual oxidase (Duox) subfamilies in animals (the Opisthokonta), whereas an SH3 domain is inserted into the ferredoxin,NADP+ reductase region of two Nox enzymes in Naegleria gruberi, a unicellular organism that belongs to the supergroup Excavata. Members of the Nox1,4 subfamily in animals form a stable heterodimer with the membrane protein p22phox, which functions as a docking site for the SH3 domain-containing regulatory proteins p47phox, p67phox, and p40phox; the small GTPase Rac binds to p67phox (or its homologous protein), which serves as a switch for Nox activation. Similarly, Rac activates the fungal NoxA via binding to the p67phox -like protein Nox regulator (NoxR). In plants, on the other hand, this GTPase directly interacts with the N-terminus of Rboh, leading to superoxide production. Here I describe the regulation of Nox-family oxidases on the basis of three-dimensional structures and evolutionary conservation. [source] Cloning, expression and characterization of a gene encoding nitroalkane-oxidizing enzyme from Streptomyces ansochromogenesFEBS JOURNAL, Issue 24 2002Jihui Zhang A nitroalkane-oxidizing enzyme gene (naoA) was cloned from a genomic DNA library of Streptomyces ansochromogenes 7100. The deduced protein (NaoA) of this gene contains 363 amino acids and has high similarity to several nitroalkane-oxidizing enzymes from various micro-organisms. The naoA gene was subcloned into an expression vector pET23b and overexpressed in Escherichia coli BL21(DE3). The protein was then purified, and its characteristics were studied. Experimental results showed that NaoA can convert 1-nitropropane, 2-nitropropane and nitroethane into the corresponding carbonyl compounds. The optimal pH and temperature for NaoA was found to be pH 7,8 and 48,56 °C, respectively. The Km of NaoA for nitroethane is ,,26.8 mm. NADH and nitro blue tetrazolium are strong inhibitors of NaoA, and thiol compounds and superoxide dismutase partially inhibit the enzyme activity. Therefore, superoxide may be an essential intermediate in the oxidation of nitroalkane by NaoA. [source] Tyrosine 9 is the key amino acid in microcin J25 superoxide overproductionFEMS MICROBIOLOGY LETTERS, Issue 1 2009Miriam C. Chalon Abstract Escherichia coli microcin J25 (MccJ25) is a lasso-peptide antibiotic comprising 21 l -amino acid residues (G1 -G-A-G-H5 -V-P-E-Y-F10 -V-G-I-G-T15 -P-I-S-F-Y20 -G). MccJ25 has two independent substrates: RNA-polymerase (RNAP) and the membrane respiratory chain. The latter is mediated by oxygen consumption inhibition together with an increase of superoxide production. In the present paper, the antibiotic MccJ25 was engineered by substituting Tyr9 or Tyr20 with phenylalanine. Both mutants were well transported into the cells and remained active on RNAP. Only the Y9F mutant lost the ability to overproduce superoxide and inhibit oxygen consumption. The last results confirm that the Tyr9, and not Tyr20, is involved in the MccJ25 action on the respiratory chain target. [source] Bacterial cell death induced by human pro-apoptotic Bax is blocked by an RNase E mutant that functions in an anti-oxidant pathwayGENES TO CELLS, Issue 3 2000Rika Nanbu-Wakao Background Bax is a member of the Bcl-2 family and induces apoptosis of mammalian cells. We have shown that a trace amount of human Bax induces the cell death of Escherichia coli, accompanied by damage to DNA, and that the region of Bax which is lethal to E. coli is also responsible for apoptosis-inducing activity in the mammalian cells. Results We isolated a Bax-resistant mutant from E. coli cells that survive in the presence of paraquat, a generator of superoxide, by screening a library constructed from the random insertion of a transposon. Psb1 (paraquat-resistant, suppressor of Bax-1) mutant had a Tn 10 transposon inserted in the rne gene of E. coli, splitting the RNase E gene (rne) into N- and C-terminal halves. The introduction of the truncated 5, end of rne specifically enhanced resistance to paraquat, prevented cell death induced by Bax and decreased the intracellular H2O2 concentration. The region responsible for the paraquat- and Bax-resistance was not the catalytic site for the endoribonuclease activity of RNase E. Conclusions The N-terminal region of the RNase E protein inhibits bacterial death induced by human Bax as well as paraquat through a unique mechanism that is distinct from RNA digestion. This study implies that the protection of bacterial death induced by Bax is associated with an anti-oxidant pathway and that a mutant RNase E has a novel function as an anti-oxidant. [source] Sumatriptan Scavenges Superoxide, Hydroxyl, and Nitric Oxide Radicals: In Vitro Electron Spin Resonance StudyHEADACHE, Issue 9 2002DMSc, Yukio Ikeda MD Background.,The molecular mechanisms of migraine have not yet been clarified. Oxygen free radicals have been implicated in the genesis of many pathological processes, including migraine. Sumatriptan succinate is known to be a very effective drug for acute relief of migraine attack. Objective.,To investigate the direct scavenging activities of sumatriptan for superoxide, hydroxyl, and nitric oxide (NO) radicals using electron spin resonance (ESR) spectroscopy. Methods.,Measurement of superoxide and hydroxyl radical scavenging activities was performed by ESR using 5,5-dimethyl-1-pyrroline- N -oxide as a spin trap. NO was generated from 1-hydroxy-2-oxo-3-(N -3-methyl-3-aminopropyl)-3-methyl-1-triazene and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl produced from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and NO. Results.,The ESR study demonstrated that sumatriptan scavenged superoxide, hydroxyl, and NO in a dose-dependent manner. Conclusion.,Sumatriptan has direct scavenging activity on free radicals and NO. Acute migraine drugs with antioxidant properties may provide heretofore unheralded benefits via this mechanism. [source] Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection,HEPATOLOGY, Issue 1 2010Nabora Soledad Reyes de Mochel Oxidative stress has been identified as a key mechanism of hepatitis C virus (HCV),induced pathogenesis. Studies have suggested that HCV increases the generation of hydroxyl radical and peroxynitrite close to the cell nucleus, inflicting DNA damage, but the source of reactive oxygen species (ROS) remains incompletely characterized. We hypothesized that HCV increases the generation of superoxide and hydrogen peroxide close to the hepatocyte nucleus and that this source of ROS is reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase 4 (Nox4). Huh7 human hepatoma cells and telomerase-reconstituted primary human hepatocytes, transfected or infected with virus-producing HCV strains of genotypes 2a and 1b, were examined for messenger RNA (mRNA), protein, and subcellular localization of Nox proteins along with the human liver. We found that genotype 2a HCV induced persistent elevations of Nox1 and Nox4 mRNA and proteins in Huh7 cells. HCV genotype 1b likewise elevated the levels of Nox1 and Nox4 in telomerase-reconstituted primary human hepatocytes. Furthermore, Nox1 and Nox4 proteins were increased in HCV-infected human liver versus uninfected liver samples. Unlike Nox1, Nox4 was prominent in the nuclear compartment of these cells as well as the human liver, particularly in the presence of HCV. HCV-induced ROS and nuclear nitrotyrosine could be decreased with small interfering RNAs to Nox1 and Nox4. Finally, HCV increased the level of transforming growth factor beta 1 (TGF,1). TGF,1 could elevate Nox4 expression in the presence of infectious HCV, and HCV increased Nox4 at least in part through TGF,1. Conclusion: HCV induced a persistent elevation of Nox1 and Nox4 and increased nuclear localization of Nox4 in hepatocytes in vitro and in the human liver. Hepatocyte Nox proteins are likely to act as a persistent, endogenous source of ROS during HCV-induced pathogenesis. Hepatology 2010 [source] Effect of immune serum and role of individual Fc, receptors on the intracellular distribution and survival of Salmonella enterica serovar Typhimurium in murine macrophagesIMMUNOLOGY, Issue 2 2006Hazel Uppington Summary Immune serum has a protective role against Salmonella infections in mice, domestic animals and humans. In this study, the effect of antibody on the interaction between murine macrophages and S. enterica serovar Typhimurium was examined. Detailed analysis at the single-cell level demonstrated that opsonization of the bacteria with immune serum enhanced bacterial uptake and altered bacterial distribution within individual phagocytic cells. Using gene-targeted mice deficient in individual Fc gamma receptors it was shown that immune serum enhanced bacterial internalization by macrophages via the high-affinity immunoglobulin G (IgG) receptor, Fc gamma receptor I. Exposure of murine macrophages to S. enterica serovar Typhimurium opsonized with immune serum resulted in increased production of superoxide, leading to enhanced antibacterial functions of the infected cells. However, opsonization of bacteria with immune serum did not increase either nitric oxide production in response to S. enterica serovar Typhimurium or fusion of phagosomes with lysosomes. [source] | |||||||||||||||||||||||||||||||||||||