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Ronald P. Mason - One of the best experts on this subject based on the ideXlab platform.
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Role of Superoxide and Trace Transition Metals in the Production of α-Hydroxyethyl Radical from Ethanol by Microsomes from Alcohol Dehydrogenase-Deficient Deermice
Archives of biochemistry and biophysics, 1993Co-Authors: K.t. Knecht, R.g. Thurman, Ronald P. MasonAbstract:The formation of alpha-hydroxyethyl radical from ethanol by deermouse microsomes supplemented with NADPH has been demonstrated with the EPR technique of spin trapping with alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN) as the spin trap, in the presence of Deferoxamine Mesylate. Superoxide dismutase prevented the formation of the radical adduct of the alpha-hydroxyethyl radical in a dose-dependent fashion, causing complete inhibition of radical formation at a concentration of 20 micrograms/ml, while catalase, azide, or azide and hydrogen peroxide had no effect. Boiling the microsomes or omission of NADPH abolished free radical formation. Metyrapone, cimetidine, isoniazid, octylamine, and p-nitrophenol, inhibitors of cytochrome P450IIE1 activity, decreased free radical formation by 24 to 74% at concentrations ranging from 0.05 to 10 mM. The POBN/.CH(OH)CH3 radical adduct signal was also diminished by formate or mannitol, indicating competition by so-called "hydroxyl radical scavengers. "The involvement of trace transition metals in alpha-hydroxyethyl radical formation by deermouse microsomes was demonstrated by a decrease in free radical adduct signal when metal ions were removed from reagents by treatment with Chelex 100 resin. Chelex treatment was effective even though the metal chelator Deferoxamine Mesylate, which is generally presumed to render iron catalytically inactive, was present in all incubations. Thus, it is concluded that free radical formation from ethanol in deermouse microsomes is mediated by a transition metal- and cytochrome P450-derived superoxide-dependent oxidizing species even in the presence of Deferoxamine Mesylate.
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Trace transition metal-catalyzed reactions in the microsomal metabolism of alkyl hydrazines to carbon-centered free radicals.
The Journal of biological chemistry, 1991Co-Authors: G.v. Rumyantseva, C H Kennedy, Ronald P. MasonAbstract:Radical production from alkyl hydrazines (i.e. phenelzine and benzylhydrazine) in rat liver microsomes has been proposed to occur via cytochrome P-450-catalyzed one-electron oxidation followed by beta-scission of an alkyl radical. In microsomes treated with phenelzine (2-phenylethylhydrazine), NADPH, and the spin trap alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN), the 4-POBN/2-phenylethyl radical adduct was detected by electron paramagnetic resonance spectroscopy. The addition of catalase and superoxide dismutase resulted in a 28.5 and 24% decrease in radical production, respectively. The concentration of the 4-POBN/2-phenylethyl radical adduct decreased significantly in the presence of metal chelators, i.e. EDTA, diethylenetriaminepentaacetic acid (DTPA), or Deferoxamine Mesylate. When phenelzine was incubated with Deferoxamine Mesylate-washed microsomes and NADPH in Chelex-treated incubation buffer, no significant radical adduct formation was detected. Addition of iron-chelator complexes (either Fe(3+)-DTPA or Fe(3+)-EDTA) greatly stimulated production of the 4-POBN/2-phenylethyl radical adduct in this system. These results show that the 2-phenylethyl radical produced from phenelzine in a microsomal system arises via a trace transition metal-catalyzed reaction. This reaction may occur through oxidation of phenelzine by the hydroxyl radical, which has also been spin-trapped with 4-POBN in this system.
T. Hamada - One of the best experts on this subject based on the ideXlab platform.
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Vanadium induced hemolysis of vitamin E deficient erythrocytes in Hepes buffer.
Cellular and Molecular Life Sciences, 1994Co-Authors: T. HamadaAbstract:Several vanadium compounds were tested for their ability to induce in vitro hemolysis of vitamin E-deficient hamster erythrocytes. Free vanadyl caused hemolysis in Hepes buffer but not in Tris or phosphate buffer, while hemolysis was inhibited by catalase, chelators such as Deferoxamine Mesylate and EDTA, and hydroxyl radical scavengers such as ethanol andd-mannitol. Although metavanadate itself could not induce hemolysis, metavanadate with NAD(P)H caused hemolysis in Hepes buffer only, and superoxide dismutase prevented it. Hydrogen peroxide, hydroxyl radical and Hepes radical were involved in vanadyl-induced hemolysis; superoxide anion was further involved in metavanadate plus NAD(P)H-induced hemolysis. Vitamin E prevented hemolysis under both conditions.
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Vanadium induced hemolysis of vitamin E deficient erythrocytes in Hepes buffer.
Cellular and Molecular Life Sciences, 1994Co-Authors: T. HamadaAbstract:Several vanadium compounds were tested for their ability to induce in vitro hemolysis of vitamin E-deficient hamster erythrocytes. Free vanadyl caused hemolysis in Hepes buffer but not in Tris or phosphate buffer, while hemolysis was inhibited by catalase, chelators such as Deferoxamine Mesylate and EDTA, and hydroxyl radical scavengers such as ethanol andd-mannitol. Although metavanadate itself could not induce hemolysis, metavanadate with NAD(P)H caused hemolysis in Hepes buffer only, and superoxide dismutase prevented it. Hydrogen peroxide, hydroxyl radical and Hepes radical were involved in vanadyl-induced hemolysis; superoxide anion was further involved in metavanadate plus NAD(P)H-induced hemolysis. Vitamin E prevented hemolysis under both conditions.
Magdy Selim - One of the best experts on this subject based on the ideXlab platform.
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Deferoxamine Mesylate in patients with intracerebral haemorrhage i def a multicentre randomised placebo controlled double blind phase 2 trial
Lancet Neurology, 2019Co-Authors: Magdy Selim, Lydia D Foster, Claudia S Moy, Michael D Hill, Lewis B Morgenstern, Steven M Greenberg, Michael L James, Vineeta Singh, Wayne M ClarkAbstract:Summary Background Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator Deferoxamine Mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial. Methods We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18–80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive Deferoxamine Mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0–2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of Deferoxamine Mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed. Findings We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the Deferoxamine Mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the Deferoxamine Mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0–2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the Deferoxamine Mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the Deferoxamine Mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related. Interpretation Deferoxamine Mesylate was safe. However, the primary result showed that further study of the efficacy of Deferoxamine Mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0–2) at day 90 would be futile. Funding US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.
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Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage
Stroke, 2011Co-Authors: Magdy Selim, Lewis B Morgenstern, Steven M Greenberg, G. Schlaug, S Yeatts, J Gomes, Joshua N. Goldstein, Michel T. Torbey, Bonnie D. WaldmanAbstract:Background and Purpose—Treatment with the iron chelator, Deferoxamine Mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies. Methods—This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and computed tomography neuroimaging pre- and post-drug-administration. Results—Twenty subjects were enrolled onto 5 dose tiers, starting with 7 mg/kg per day and ending with 62 mg/kg per day as the maximum tolerated dose. Median age was 68 years (range, 50–90); 60% were men; and median Glasgow Coma Scale and National Institutes of Health Stroke Scale scores on ...
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Treatment with the Iron Chelator, Deferoxamine Mesylate, Alters Serum Markers of Oxidative Stress in Stroke Patients
Translational Stroke Research, 2010Co-Authors: Magdy SelimAbstract:The iron chelator, Deferoxamine Mesylate (DFO), has shown neuroprotective effects, mediated via suppression of iron-induced hydroxyl radical formation, in various animal models of ischemic and hemorrhagic stroke. Therefore, the objective of this study was to investigate whether DFO can exert similar actions in stroke patients, by examining the effects of treatment with DFO on biological markers of oxidative stress, namely serum total hydroperoxides and lipoperoxides and total radical trapping antioxidant capacity (TRAP), in stroke patients. We found that serum levels of peroxides were reduced, and TRAP levels increased after a 3-day treatment with DFO (500 mg). These findings provide a preliminary proof of concept that DFO can exert potential antioxidant neuroprotective effects in stroke patients. Future, larger-scale, randomized, and controlled studies to further evaluate the safety and efficacy of DFO in patients with stroke are warranted.
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Deferoxamine Mesylate A New Hope for Intracerebral Hemorrhage: From Bench to Clinical Trials
Stroke, 2008Co-Authors: Magdy SelimAbstract:Iron resulting from hemoglobin degradation is linked to delayed neuronal injury after intracerebral hemorrhage. Extensive preclinical investigations indicate that the iron chelator, Deferoxamine Mesylate, is effective in limiting hemoglobin- and iron-mediated neurotoxicity. However, clinical studies evaluating the use of Deferoxamine in intracerebral hemorrhage are shortcoming. This article reviews the potential role of Deferoxamine as a promising neuroprotective agent to target the secondary effects of intracerebral hemorrhage to limit brain injury and improve outcome, and ongoing efforts to translate the preclinical findings into clinical investigations.
K.t. Knecht - One of the best experts on this subject based on the ideXlab platform.
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Role of Superoxide and Trace Transition Metals in the Production of α-Hydroxyethyl Radical from Ethanol by Microsomes from Alcohol Dehydrogenase-Deficient Deermice
Archives of biochemistry and biophysics, 1993Co-Authors: K.t. Knecht, R.g. Thurman, Ronald P. MasonAbstract:The formation of alpha-hydroxyethyl radical from ethanol by deermouse microsomes supplemented with NADPH has been demonstrated with the EPR technique of spin trapping with alpha-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN) as the spin trap, in the presence of Deferoxamine Mesylate. Superoxide dismutase prevented the formation of the radical adduct of the alpha-hydroxyethyl radical in a dose-dependent fashion, causing complete inhibition of radical formation at a concentration of 20 micrograms/ml, while catalase, azide, or azide and hydrogen peroxide had no effect. Boiling the microsomes or omission of NADPH abolished free radical formation. Metyrapone, cimetidine, isoniazid, octylamine, and p-nitrophenol, inhibitors of cytochrome P450IIE1 activity, decreased free radical formation by 24 to 74% at concentrations ranging from 0.05 to 10 mM. The POBN/.CH(OH)CH3 radical adduct signal was also diminished by formate or mannitol, indicating competition by so-called "hydroxyl radical scavengers. "The involvement of trace transition metals in alpha-hydroxyethyl radical formation by deermouse microsomes was demonstrated by a decrease in free radical adduct signal when metal ions were removed from reagents by treatment with Chelex 100 resin. Chelex treatment was effective even though the metal chelator Deferoxamine Mesylate, which is generally presumed to render iron catalytically inactive, was present in all incubations. Thus, it is concluded that free radical formation from ethanol in deermouse microsomes is mediated by a transition metal- and cytochrome P450-derived superoxide-dependent oxidizing species even in the presence of Deferoxamine Mesylate.
David E. Heinrichs - One of the best experts on this subject based on the ideXlab platform.
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Deferoxamine Mesylate enhances virulence of community-associated methicillin resistant Staphylococcus aureus.
Microbes and infection, 2014Co-Authors: Andrew J. Arifin, Mélissa Hannauer, Ian Welch, David E. HeinrichsAbstract:Staphylococcus aureus is a leading cause of bacterial infections. Strains of community-associated methicillin-resistant S. aureus (CA-MRSA), such as USA300, display enhanced virulence and fitness. Patients suffering from iron overload diseases often undergo iron chelation therapy with Deferoxamine Mesylate (DFO). Here, we show that USA300 uses this drug to acquire iron. We further demonstrate that mice administered DFO I.P., versus those not administered DFO, had significantly higher bacterial burden in livers and kidneys after I.V. challenge with USA300, associated with increased abscess formation and tissue destruction. The virulence of USA300 mutants defective for DFO uptake was not affected by DFO treatment.
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Short communication Deferoxamine Mesylate enhances virulence of community-associated methicillin resistant Staphylococcus aureus
2014Co-Authors: Andrew J. Arifin, Ian Welch, David E. HeinrichsAbstract:AbstractStaphylococcus aureus is a leading cause of bacterial infections. Strains of community-associated methicillin-resistant S. aureus (CA-MRSA), such as USA300, display enhanced virulence and fitness. Patients suffering from iron overload diseases often undergo iron chelationtherapy with Deferoxamine Mesylate (DFO). Here, we show that USA300 uses this drug to acquire iron. We further demonstrate that miceadministered DFO I.P., versus those not administered DFO, had significantly higher bacterial burden in livers and kidneys after I.V. challengewith USA300, associated with increased abscess formation and tissue destruction. The virulence of USA300 mutants defective for DFO uptakewas not affected by DFO treatment.© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. Keywords: Staphylococcus aureus; MRSA; Virulence; Iron; DFO 1. IntroductionStaphylococcus aureus is a Gram-positive coccoid-shapedbacterium that commonly exists as a commensal on skin andmucosal surfaces. Pathogenesis occurs when S. aureusbreaches these barriers, developing into infections such asendocarditis, pneumonia, osteomyelitis, and bacteremia.Methicillin-resistant S. aureus (MRSA) isolates are of partic-ular clinical importance, and can be categorized into twobroad groups: (i) hospital-associated MRSA (HA-MRSA) thatprimarily infect immunocompromised individuals; and (ii)community-associated MRSA (CA-MRSA) which, by com-parison to HA-MRSA, are hyper-virulent and can infecthealthy individuals. CA-MRSA strain USA300, the strain usedin this study, by far accounts for the most CA-MRSA in-fections in the United States [1].A key determinant of microbial pathogenicity is the amountof bioavailable iron in the host. Iron is required for the growthof all organisms, acting as a cofactor in essential processessuch as cellular respiration. However, free iron is found inverylow concentrations in vertebrates, as proteins such as trans-ferrin sequester most extracellular iron, and intracellular ironis found in ferritin or hemoglobin. S. aureus has two primaryiron acquisition strategies: (i) the production and uptake ofsiderophores, small molecules that scavenge ferric iron; and(ii) heme acquisition from hemoglobin. S. aureus can producetwo endogenous siderophores called staphyloferrin A andstaphyloferrin B, but can also uptake siderophores producedby other microorganisms, conferring a growth advantage overother microbes in the same niche [2]. One such xenosider-ophore is desferrioxamine B (DFO), a hydroxamate-typesiderophore produced by Streptomyces pilosus that is takenup by S. aureus through the ferric hydroxamate uptake (fhu)system (Fig. 1A). Under the trade name Desferal
