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1.
Free Radic Res ; 55(4): 352-363, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33327809

RESUMO

Vitamin E acts as essential antioxidant against detrimental oxidation of biological molecules induced by multiple reactive species. To gain more insight into the physiological role of vitamin E, the levels of its oxidation products in humans under normal and pathological conditions were compared. α-Tocopherol quinone (α-TQ) and 5-nitro-γ-tocopherol (5-NgT) were focused. α-TQ is produced by multiple oxidants including oxygen radicals, peroxynitrite, hypochlorite, singlet oxygen, and ozone, while 5-NgT is produced by nitrogen dioxide radical derived from peroxynitrite and the reaction of nitrite and hypochlorite. The reported concentrations of α-TQ and 5-NgT in healthy human plasma are highly variable ranging from 15 to 360 and 4 to 170 nM, respectively. In general, the molar ratio 5-NgT/γ-tocopherol was higher than the ratio α-TQ/α-tocopherol. Both absolute concentrations of α-TQ and 5-NgT and the molar ratios to the parent tocopherols were elevated significantly in the plasma of patients with various diseases compared with healthy subjects except neurological diseases. The molar ratios of the products to the respective parent compounds decreased in the order of 5-NgT/γ-tocopherol > α-TQ/α-tocopherol > hydroxyoctadecadienoate/linoleate > 3-nitrotyrosine/tyrosine > isoprostane/arachidonate. The molar ratios of nitrated products to the respective parent compounds in human plasma are approximately 10-2 for 5-NgT and 10-5 for 3-nitrotyrosine, nitro-oleic acid, and 8-nitroguaine. These data indicate that vitamin E acts as an important physiological antioxidant and that α-TQ and 5-NgT represent biomarker for oxidative stress and nitrative stress respectively.


Assuntos
Antioxidantes/farmacologia , Oxidantes/biossíntese , Vitamina E/análogos & derivados , Vitamina E/farmacologia , gama-Tocoferol/análogos & derivados , Antioxidantes/química , Humanos , Estrutura Molecular , Oxidantes/química , Vitamina E/biossíntese , Vitamina E/química , gama-Tocoferol/química , gama-Tocoferol/metabolismo
2.
Chemosphere ; 221: 383-391, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30648644

RESUMO

Cu(II) enhanced the oxygen activation by Fe(II) to increase the yield of oxidants. However the factors controlling the catalytic performance and indeed the underlying influencing mechanisms remained unclear. Here, we presented the detailed study of Cu(II)-Fe(II) reactions for a range of pH and Cu(II)/Fe(II) ratios. From the results obtained, we provided insight into the factors controlling the redox reactions of Fe-Cu and the catalytic behaviours of active species. A reaction scheme for the Fe(II)/Cu(II) system was developed in which the in-situ formed Cu(I) mainly contributed to producing H2O2 and Fe(II) dominantly decomposed H2O2 to hydroxyl radical (HO) [see companion article] (Yufan Chen). Circumneutral conditions facilitated the catalytic processes; under acidic conditions, the reverse reaction between Fe(III) and Cu(I) was strongly favoured; alkaline conditions improved the reducing capacity, which subsequently enhanced the generation of Cu(0) instead of Cu(I). There was a saturated Cu(II)/Fe(II) ratio above which further addition of Cu(II) could not be reduced, and then excessive Cu(I) and Cu(II) consumed HO and O2-, respectively. Therefore, the highest removal efficiency of organic pollutants was achieved when the stoichiometric Cu(II)/Fe(II) ratio was 60% at circumneutral pH. The new findings have implications for the treatment of mixed wastewater where copper and organic pollutants coexist.


Assuntos
Cobre/química , Compostos Ferrosos/química , Oxidantes/biossíntese , Oxigênio/metabolismo , Catálise , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Oxirredução , Oxigênio/química , Águas Residuárias/química , Purificação da Água/métodos
3.
Redox Biol ; 20: 118-129, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30308475

RESUMO

Oxidative stress and mitochondrial dysfunction are critical events in neurodegenerative diseases; therefore, molecules that increase cellular antioxidant defenses represent a future pharmacologic strategy to counteract such conditions. The aim of this study was to investigate the potential protective effect of (PhSe)2 on mouse hippocampal cell line (HT22) exposed to tert-BuOOH (in vitro model of oxidative stress), as well as to elucidate potential mechanisms underlying this protection. Our results showed that tert-BuOOH caused time- and concentration-dependent cytotoxicity, which was preceded by increased oxidants production and mitochondrial dysfunction. (PhSe)2 pre-incubation significantly prevented these cytotoxic events and the observed protective effects were paralleled by the upregulation of the cellular glutathione-dependent antioxidant system: (PhSe)2 increased GSH levels (> 60%), GPx activity (6.9-fold) and the mRNA expression of antioxidant enzymes Gpx1 (3.9-fold) and Gclc (2.3-fold). Of note, the cytoprotective effect of (PhSe)2 was significantly decreased when cells were treated with mercaptosuccinic acid, an inhibitor of GPx, indicating the involvement of GPx modulation in the observed protective effect. In summary, the present findings bring out a new action mechanism concerning the antioxidant properties of (PhSe)2. The observed upregulation of the glutathione-dependent antioxidant system represents a future pharmacologic possibility that goes beyond the well-known thiol-peroxidase activity of this compound.


Assuntos
Derivados de Benzeno/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Modelos Biológicos , Oxidantes/biossíntese , Oxirredução/efeitos dos fármacos
4.
Br J Pharmacol ; 174(12): 1733-1749, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-26750203

RESUMO

Microglia are the resident immune cells of the CNS and constitute a self-sustaining population of CNS-adapted tissue macrophages. As mononuclear phagocytic cells, they express high levels of superoxide-producing NADPH oxidases (NOX). The sole function of the members of the NOX family is to generate reactive oxygen species (ROS) that are believed to be important in CNS host defence and in the redox signalling circuits that shape the different activation phenotypes of microglia. NOX are also important in pathological conditions, where over-generation of ROS contributes to neuronal loss via direct oxidative tissue damage or disruption of redox signalling circuits. In this review, we assess the evidence for involvement of NOX in CNS physiopathology, with particular emphasis on the most important surface receptors that lead to generation of NOX-derived ROS. We evaluate the potential significance of the subcellular distribution of NOX isoforms for redox signalling or release of ROS to the extracellular medium. Inhibitory mechanisms that have been reported to restrain NOX activity in microglia and macrophages in vivo are also discussed. We provide a critical appraisal of frequently used and recently developed NOX inhibitors. Finally, we review the recent literature on NOX and other sources of ROS that are involved in activation of the inflammasome and discuss the potential influence of microglia-derived oxidants on neurogenesis, neural differentiation and culling of surplus progenitor cells. The degree to which excessive, badly timed or misplaced NOX activation in microglia may affect neuronal homeostasis in physiological or pathological conditions certainly merits further investigation. LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.


Assuntos
Encefalopatias/metabolismo , Sistema Nervoso Central/metabolismo , Microglia/metabolismo , NADPH Oxidases/metabolismo , Oxidantes/biossíntese , Animais , Encefalopatias/tratamento farmacológico , Encefalopatias/patologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Inibidores Enzimáticos/farmacologia , Humanos , Microglia/efeitos dos fármacos , NADPH Oxidases/antagonistas & inibidores , Oxidantes/antagonistas & inibidores , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
5.
Redox Biol ; 9: 104-113, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27454768

RESUMO

Atherosclerosis, the underlying cause of ischemic heart disease and stroke, is an inflammatory disease of arteries in a hyperlipidemic milieu. Endothelial expression of cellular adhesion molecules, such as endothelial-leukocyte adhesion molecule-1 (E-selectin) and intercellular adhesion molecule-1 (ICAM-1), plays a critical role in the initiation and progression of atherosclerosis. The dietary flavonoid, quercetin, has been reported to inhibit expression of cellular adhesion molecules, but the underlying mechanisms are incompletely understood. In this study, we found that quercetin dose-dependently (5-20µM) inhibits lipopolysaccharide (LPS)-induced mRNA and protein expression of E-selectin and ICAM-1 in human aortic endothelial cells (HAEC). Incubation of HAEC with quercetin also significantly reduced LPS-induced oxidant production, but did not inhibit activation of the nuclear factor-kappaB (NF-κB). Furthermore, quercetin induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent mRNA and protein expression of the antioxidant enzymes, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase, quinone 1, and glutamate-cysteine ligase. The induction of Nrf2 and antioxidant enzymes was partly inhibited by the p38 mitogen-activated protein kinase (p38) inhibitor, SB203580. Our results suggest that quercetin suppresses LPS-induced oxidant production and adhesion molecule expression by inducing Nrf2 activation and antioxidant enzyme expression, which is partially mediated by p38; and the inhibitory effect of quercetin on adhesion molecule expression is not due to inhibition of NF-κB activation, but instead due to antioxidant-independent effects of HO-1.


Assuntos
Antioxidantes/farmacologia , Moléculas de Adesão Celular/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Oxidantes/biossíntese , Quercetina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1 , Humanos , Lipopolissacarídeos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo
6.
Redox Biol ; 8: 216-25, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26826574

RESUMO

Human metabolic diseases can be mimicked in rodents by using dietary interventions such as high fat diets (HFD). Nonalcoholic fatty liver disease (NAFLD) develops as a result of HFD and the disease may progress in a manner involving increased production of oxidants. The main intracellular source of these oxidants are mitochondria, which are also responsible for lipid metabolism and thus widely recognized as important players in the pathology and progression of steatosis. Here, we review publications that study redox and bioenergetic effects of HFD in the liver. We find that dietary composition and protocol implementations vary widely, as do the results of these dietary interventions. Overall, all HFD promote steatosis, changes in ß-oxidation, generation and consequences of oxidants, while effects on body weight, insulin signaling and other bioenergetic parameters are more variable with the experimental models adopted. Our review provides a broad analysis of the bioenergetic and redox changes promoted by HFD as well as suggestions for changes and specifications in methodologies that may help explain apparent disparities in the current literature.


Assuntos
Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/genética , Animais , Dieta Hiperlipídica , Metabolismo Energético , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Oxidantes/biossíntese , Oxidantes/metabolismo , Oxirredução , Ratos
7.
Free Radic Biol Med ; 73: 366-82, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24941891

RESUMO

The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state.


Assuntos
Envelhecimento , Peso Corporal/fisiologia , Restrição Calórica , Expectativa de Vida , Longevidade , Animais , Temperatura Corporal , Ingestão de Alimentos , Ingestão de Energia/fisiologia , Metabolismo Energético , Camundongos , Oxidantes/biossíntese , Ratos
8.
Chem Res Toxicol ; 27(6): 1070-7, 2014 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-24870066

RESUMO

Previous studies have shown that carboxylated single-walled carbon nanotubes (SWCNTs) can be catalytically biodegraded by hypochlorite (OCl-) and reactive radical intermediates of the human neutrophil enzyme myeloperoxidase (MPO). However, the importance of protein-SWCNT interactions in the biodegradation of SWCNTs was not stressed. Here, we used both experimental and theoretical approaches to investigate the interactions of SWCNTs with human serum albumin (HSA, one of the most abundant proteins in blood circulation) and found that the binding was involved in the electrostatic interactions of positively charged Arg residues of HSA with the carboxyls on the nanotubes, along with the π-π stacking interactions between SWCNTs and aromatic Tyr residues in HSA. Compared with SWCNTs, the binding of HSA could result in a reduced effect for OCl- (or the human MPO system)-induced SWCNTs degradation in vitro. However, the HSA-SWCNT interactions would enhance cellular uptake of nanotubes and stimulate MPO release and OCl- generation in neutrophils, thereby creating the conditions favorable for the degradation of the nanotubes. Upon zymosan stimulation, both SWCNTs and HSA-SWCNTs were significantly biodegraded in neutrophils, and the degree of biodegradation was more for HSA-SWCNTs under these relevant in vivo conditions. Our findings suggest that the binding of HSA may be an important determinant for MPO-mediated SWCNT biodegradation in human inflammatory cells and therefore shed light on the biomedical and biotechnological applications of safe carbon nanotubes by comprehensive preconsideration of their interactions with human serum proteins.


Assuntos
Ácido Hipocloroso/metabolismo , Nanotubos de Carbono/química , Neutrófilos/citologia , Neutrófilos/metabolismo , Oxidantes/biossíntese , Oxidantes/metabolismo , Albumina Sérica/metabolismo , Sítios de Ligação , Humanos , Modelos Moleculares , Oxirredução , Albumina Sérica/química
9.
Environ Microbiol ; 15(3): 956-66, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23206186

RESUMO

Oxidative cleavage of the recalcitrant plant polymer lignin is a crucial step in global carbon cycling, and is accomplished most efficiently by fungi that cause white rot of wood. These basidiomycetes secrete many enzymes and metabolites with proposed ligninolytic roles, and it is not clear whether all of these agents are physiologically important during attack on natural lignocellulosic substrates. One new approach to this problem is to infer properties of ligninolytic oxidants from their spatial distribution relative to the fungus on the lignocellulose. We grew Phanerochaete chrysosporium on wood sections in the presence of oxidant-sensing beads based on the ratiometric fluorescent dye BODIPY 581/591. The beads, having fixed locations relative to the fungal hyphae, enabled spatial mapping of cumulative extracellular oxidant distributions by confocal fluorescence microscopy. The results showed that oxidation gradients occurred around the hyphae, and data analysis using a mathematical reaction-diffusion model indicated that the dominant oxidant during incipient white rot had a half-life under 0.1 s. The best available hypothesis is that this oxidant is the cation radical of the secreted P. chrysosporium metabolite veratryl alcohol.


Assuntos
Lignina/metabolismo , Oxidantes/metabolismo , Phanerochaete/metabolismo , Madeira/microbiologia , Álcoois Benzílicos/química , Meia-Vida , Hifas/metabolismo , Oxidantes/biossíntese , Phanerochaete/química , Phanerochaete/genética
10.
Biol Pharm Bull ; 35(5): 781-5, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22687417

RESUMO

Superoxide dismutase (SOD) is a potent antioxidant agent that protects against UV-induced skin damage. However, its high molecular weight is a significant obstacle for efficient delivery into the skin through the stratum corneum and development of antioxidant activity. Recently, we developed a non-invasive transfollicular delivery system for macromolecules using a combination of liposomes and iontophoresis, that represents promising technology for enhancing transdermal administration of charged drugs (IJP, 403, 2011, Kajimoto et al.). In this study, in rats we attempted to apply this system to intradermal delivery of SOD for preventing UV-induced skin injury. SOD encapsulating in cationic liposomes was subjected to anodal iontophoresis. After iontophoretic treatment, the liposomes were diffused widely in the viable skin layer around hair follicles. In contrast, passive diffusion failed to transport liposomes efficiently into the skin. Iontophoretic delivery of liposomes encapsulating SOD caused a marked decrease in the production of oxidative products, such as malondialdehyde, hexanoyl lysine, and 8-hydroxi-2-deoxyguanosine, in UV-irradiated skin. These findings suggested that functional SOD can be delivered into the skin using a combination of iontophoresis and a liposomal system. In conclusion, we succeeded in developing an efficient intradermal SOD delivery system, that would be useful for delivery of other macromolecules.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Iontoforese/métodos , Absorção Cutânea/efeitos dos fármacos , Dermatopatias/tratamento farmacológico , Pele/efeitos dos fármacos , Superóxido Dismutase/administração & dosagem , Raios Ultravioleta/efeitos adversos , Administração Cutânea , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cátions , Folículo Piloso , Lipossomos , Masculino , Peso Molecular , Oxidantes/biossíntese , Ratos , Ratos Sprague-Dawley , Pele/efeitos da radiação , Dermatopatias/etiologia , Dermatopatias/metabolismo , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico
11.
Free Radic Res ; 46(8): 975-95, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22348603

RESUMO

Myeloperoxidase (MPO) is recognised to play important roles both in the immune system and during the development of numerous human pathologies. MPO is released by activated neutrophils, monocytes and some tissue macrophages, where it catalyses the conversion of hydrogen peroxide to hypohalous acids (HOX; X = Cl, Br, SCN) in the presence of halide and pseudo-halide ions. The major reactive species produced by MPO under physiological conditions are hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN), with the ratio of these oxidants critically dependent on the concentration of thiocyanate ions (SCN⁻). The reactivity and selectivity of HOCl and HOSCN for biological targets are markedly different, indicating that SCN⁻ ions have the potential to modulate both the extent and nature of oxidative damage in vivo. This article reviews recent developments in our understanding of the role of SCN⁻ in modulating the formation of MPO-derived oxidants, particularly in respect to the differences in reaction kinetics and targets of HOCl compared to HOSCN and the ability of these two oxidants to induce damage in biological systems.


Assuntos
Ácido Hipocloroso/metabolismo , Oxidantes/biossíntese , Peroxidase/metabolismo , Fagócitos/metabolismo , Tiocianatos/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Ácido Hipocloroso/farmacologia , Cinética , Oxidantes/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Fagócitos/citologia , Compostos de Sulfidrila/metabolismo , Tiocianatos/farmacologia
12.
Radiat Res ; 177(6): 792-803, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22175298

RESUMO

L-arginine is shown to protect hematopoietic progenitor (32D cl 3) cells from death due to exposure to γ radiation ((137)Cs). Some of the other intermediates in the urea cycle, namely ornithine and citrulline, plus urea itself, were not found to have any significant impact on cell survival after irradiation. Intriguingly, supplementation of irradiated cells with L-arginine results in decreased production of peroxynitrite, suggesting that suppression of superoxide generation by nitric oxide synthase in one or more microenvironments is an important factor in the observed radioprotection. The absence of any radioprotective effect of L-arginine in cells at 3% oxygen also confirms the involvement of one or more oxygen-derived species. Knockdown experiments with nitric oxide synthase (NOS) siRNAs in cells and NOS knockout animals confirm that the observed radioprotection is associated with nNOS (NOS-1). L-arginine also ameliorates the transient inhibition of the electron-transport chain complex I that occurs within 30 min of completing the dose (10 Gy) and that appears to be a functional marker for postirradiation mitochondrial oxidant production.


Assuntos
Arginina/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Protetores contra Radiação/farmacologia , Animais , Benzimidazóis/metabolismo , Carbocianinas/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/efeitos da radiação , Miocárdio/citologia , Óxido Nítrico/biossíntese , Oxidantes/biossíntese , Oxidantes/metabolismo , Ácido Peroxinitroso/biossíntese , Fatores de Tempo
13.
Biochim Biophys Acta ; 1807(12): 1562-72, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22015496

RESUMO

Flavonoids can protect cells from different insults that lead to mitochondria-mediated cell death, and epidemiological data show that some of these compounds attenuate the progression of diseases associated with oxidative stress and mitochondrial dysfunction. In this work, a screening of 5 flavonoids representing major subclasses showed that they display different effects on H2O2 production by mitochondria isolated from rat brain and heart. Quercetin, kaempferol and epicatechin are potent inhibitors of H2O2 production by mitochondria from both tissues (IC50 approximately 1-2 µM), even when H2O2 production rate was stimulated by the mitochondrial inhibitors rotenone and antimycin A. Although the rate of oxygen consumption was unaffected by concentrations up to 10 µM of these flavonoids, quercetin, kaempferol and apigenin inhibited complex I activity, while up to 100 µM epicatechin produced less than 20% inhibition. The extent of this inhibition was found to be dependent on the concentration of coenzyme Q in the medium, suggesting competition between the flavonoids and ubiquinone for close binding sites in the complex. In contrast, these flavonoids did not significantly inhibit the activity of complexes II and III, and did not affect the redox state of complex IV. However, we have found that epicatechin, quercetin and kaempferol are able to stoichiometrically reduce purified cytochrome c. Our results reveal that mitochondria are a plausible main target of flavonoids mediating, at least in part, their reported preventive actions against oxidative stress and mitochondrial dysfunction-associated pathologies.


Assuntos
Citocromos c/metabolismo , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Flavonoides/farmacologia , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxidantes/biossíntese , Animais , Antimicina A/farmacologia , Antioxidantes/farmacologia , Apigenina/farmacologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Catequina/farmacologia , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Quempferóis/farmacologia , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos , Quercetina/farmacologia , Ratos , Ratos Wistar , Rotenona/farmacologia , Ubiquinona/metabolismo , Desacopladores/farmacologia
14.
Appl Environ Microbiol ; 77(11): 3669-75, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21478304

RESUMO

Secondary metabolite (SM) production by fungi is hypothesized to provide some fitness attribute for the producing organisms. However, most SM clusters are "silent" when fungi are grown in traditional laboratory settings, and it is difficult to ascertain any function or activity of these SM cluster products. Recently, the creation of a chromatin remodeling mutant in Aspergillus nidulans induced activation of several cryptic SM gene clusters. Systematic testing of nine purified metabolites from this mutant identified an emodin derivate with efficacy against both human fungal pathogens (inhibiting both spore germination and hyphal growth) and several bacteria. The ability of catalase to diminish this antimicrobial activity implicates reactive oxygen species generation, specifically, the generation of hydrogen peroxide, as the mechanism of emodin hydroxyl activity.


Assuntos
Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Produtos Biológicos/biossíntese , Produtos Biológicos/farmacologia , Família Multigênica , Anti-Infecciosos/química , Produtos Biológicos/química , Vias Biossintéticas/genética , Emodina/química , Emodina/metabolismo , Emodina/farmacologia , Humanos , Oxidantes/biossíntese , Oxidantes/química , Oxidantes/farmacologia
15.
Eur J Pharmacol ; 660(2-3): 445-53, 2011 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-21497599

RESUMO

Apocynin, a methoxy-substituted catechol (4-hydroxy-3-methoxyacetophenone), originally extracted from the roots of Picrorhiza kurroa, has been extensively used as a non-toxic inhibitor of the multienzymatic complex NADPH oxidase. We discovered that the analogous methoxy-substituted catechol, 4-Fluoro-2-methoxyphenol (F-apocynin), in which the acetyl group present in apocynin was changed to a fluorine atom, was significantly more potent as an inhibitor of NADPH oxidase activity, myeloperoxidase (MPO) chlorinating activity and phagocytosis of microorganisms by neutrophils; it was also as potent as apocynin in inhibiting tumor necrosis factor-alpha (TNFα) release by peripheral blood mononuclear cells. We attribute the increased potency of F-apocynin to its increased lipophilicity, which could facilitate the passage of the drug through the cell membrane. The inhibition of MPO chlorination activity, phagocytosis and TNFα release shows that apocynin and F-apocynin actions are not restricted to reactive oxygen species inhibition, but further studies are needed to clarify if these mechanisms are related. Like apocynin, F-apocynin did not show cell toxicity, and is a strong candidate for use in the treatment of inflammatory diseases.


Assuntos
Acetofenonas/química , Guaiacol/análogos & derivados , Leucócitos/efeitos dos fármacos , Oxidantes/biossíntese , Fagocitose/efeitos dos fármacos , Acetofenonas/metabolismo , Acetofenonas/farmacologia , Acetofenonas/toxicidade , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Candida albicans/fisiologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Guaiacol/química , Guaiacol/metabolismo , Guaiacol/farmacologia , Guaiacol/toxicidade , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ácido Hipocloroso/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/microbiologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/fisiologia , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
J Bacteriol ; 193(7): 1643-52, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21257770

RESUMO

Selenium has been shown to be present as a labile cofactor in a small class of molybdenum hydroxylase enzymes in several species of clostridia that specialize in the fermentation of purines and pyrimidines. This labile cofactor is poorly understood, yet recent bioinformatic studies have suggested that Enterococcus faecalis could serve as a model system to better understand the way in which this enzyme cofactor is built and the role of these metalloenzymes in the physiology of the organism. An mRNA that encodes a predicted selenium-dependent molybdenum hydroxylase (SDMH) has also been shown to be specifically increased during the transition from planktonic growth to biofilm growth. Based on these studies, we examined whether this organism produces an SDMH and probed whether selenoproteins may play a role in biofilm physiology. We observed a substantial increase in biofilm density upon the addition of uric acid to cells grown in a defined culture medium, but only when molybdate (Mo) and selenite (Se) were also added. We also observed a significant increase in biofilm density in cells cultured in tryptic soy broth with 1% glucose (TSBG) when selenite was added. In-frame deletion of selD, which encodes selenophosphate synthetase, also blocked biofilm formation that occurred upon addition of selenium. Moreover, mutation in the gene encoding the molybdoenzyme (xdh) prevented the induction of biofilm proliferation upon supplementation with selenium. Tungstate or auranofin addition also blocked this enhanced biofilm density, likely through inhibition of molybdenum or selenium cofactor synthesis. A large protein complex labeled with (75)Se is present in higher concentrations in biofilms than in planktonic cells, and the same complex is formed in TSBG. Xanthine dehydrogenase activity correlates with the presence of this labile selenoprotein complex and is absent in a selD or an xdh mutant. Enhanced biofilm density correlates strongly with higher levels of extracellular peroxide, which is produced upon the addition of selenite to TSBG. Peroxide levels are not increased in either the selD or the xdh mutant upon addition of selenite. Extracellular superoxide production, a phenomenon well established to be linked to clinical isolates, is abolished in both mutant strains. Taken together, these data provide evidence that an SDMH is involved in biofilm formation in Enterococcus faecalis, contributing to oxidant production either directly or alternatively through its involvement in redox-dependent processes linked to oxidant production.


Assuntos
Biofilmes/crescimento & desenvolvimento , Enterococcus faecalis/enzimologia , Enterococcus faecalis/fisiologia , Oxidantes/biossíntese , Selênio/metabolismo , Xantina Desidrogenase/metabolismo , Auranofina/farmacologia , Meios de Cultura , Enterococcus faecalis/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Glucose , Molibdênio/metabolismo , Compostos de Tungstênio/farmacologia , Regulação para Cima , Ácido Úrico/farmacologia , Xantina Desidrogenase/genética
17.
Histol Histopathol ; 26(1): 1-11, 2011 01.
Artigo em Inglês | MEDLINE | ID: mdl-21117022

RESUMO

To clarify the clinical implications of neutrophils in vulnerable plaques we evaluated the function and activity of infiltrated neutrophils in an atherosclerotic plaque, focusing on oxidant production. A histopathological investigation was performed using carotid arterial samples obtained from seven patients. The atherosclerotic plaques were examined cytochemically for naphthol-ASD-chloroacetate esterase activity and oxidant-production, and immunohistochemically using N-formyl peptide receptor-like 1 (fPRL1)-, CD66b-, CD68- or p22phox-specific antibodies. The cytoplasmic fPRL1 intensity value of the neutrophils in the plaque was estimated using an activity index. Naphthol-ASD-chloroacetate esterase activity was found in cells located in the atherosclerotic plaque, indicating that the cells were neutrophils. The cytoplasmic fPRL1 intensity value of the neutrophils in the plaque decreased to approximately 60% of the intensity observed in the capillary vessels. Oxidant-production was also detected in the plaques, and both neutrophils and macrophages were observed at the corresponding oxidant-production sites. p22phox expression was also located in the same areas in which oxidant-production was observed in these plaques. We could not directly evaluate how much ROS generated from the infiltrated neutrophils contributed the plaque vulnerability followed by its rupture. However, the infiltrated neutrophils in the atherosclerotic plaques morphologically appeared activated and were actively generating oxidant, implying that neutrophils, together with macrophages, infiltrate into atherosclerotic plaques and contribute to plaque vulnerability.


Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Infiltração de Neutrófilos , Oxidantes/biossíntese , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Moléculas de Adesão Celular/metabolismo , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/metabolismo , Naftol AS D Esterase/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patologia , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo
18.
Plant Physiol Biochem ; 48(12): 999-1007, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20951054

RESUMO

Oxidative stress is commonly induced when plants are grown under high temperature (HT) stress conditions. Selenium often acts as an antioxidant in plants; however, its role under HT-induced oxidative stress is not definite. We hypothesize that selenium application can partly alleviate HT-induced oxidative stress and negative impacts of HT on physiology, growth and yield of grain sorghum [Sorghum bicolor (L.) Moench]. Objectives of this study were to investigate the effects of selenium on (a) leaf photosynthesis, membrane stability and antioxidant enzymes activity and (b) grain yield and yield components of grain sorghum plants grown under HT stress in controlled environments. Plants were grown under optimal temperature (OT; 32/22°C daytime maximum/nighttime minimum) from sowing to 63 days after sowing (DAS). All plants were foliar sprayed with sodium selenate (75mgL(-1)) at 63 DAS, and HT stress (40/30°C) was imposed from 65 DAS through maturity. Data on physiological, biochemical and yield traits were measured. High temperature stress decreased chlorophyll content, chlorophyll a fluorescence, photosynthetic rate and antioxidant enzyme activities and increased oxidant production and membrane damage. Decreased antioxidant defense under HT stress resulted in lower grain yield compared with OT. Application of selenium decreased membrane damage by enhancing antioxidant defense resulting in higher grain yield. The increase in antioxidant enzyme activities and decrease in reactive oxygen species (ROS) content by selenium was greater in HT than in OT. The present study suggests that selenium can play a protective role during HT stress by enhancing the antioxidant defense system.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Antioxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Selênio/farmacologia , Sorghum/efeitos dos fármacos , Membrana Celular/fisiologia , Clorofila/metabolismo , Grão Comestível/efeitos dos fármacos , Grão Comestível/crescimento & desenvolvimento , Grão Comestível/fisiologia , Temperatura Alta , Oxidantes/biossíntese , Fotossíntese/efeitos dos fármacos , Fotossíntese/fisiologia , Folhas de Planta/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Ácido Selênico , Compostos de Selênio/farmacologia , Sorghum/crescimento & desenvolvimento , Sorghum/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/fisiologia
19.
Chem Res Toxicol ; 21(12): 2227-8, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19053325

RESUMO

A new chemical synthesis has been disclosed for the oxidizing and nitrating species peroxynitrite. This nitric oxide and superoxide-derived cell signaling mediator can also serve as a toxicant at higher rates of generation. The new synthetic strategy reported by Sturzbecher-Höhne and colleagues overcomes long-standing issues with purity and quality of peroxynitrite preparations and should lay a foundation for nailing new insight into the redox reactions of peroxynitrite and its products.


Assuntos
Oxidantes/síntese química , Ácido Peroxinitroso/síntese química , Transdução de Sinais/fisiologia , Testes de Toxicidade/métodos , Peróxido de Hidrogênio/química , Mitocôndrias/metabolismo , Óxido Nítrico/química , Óxido Nítrico Sintase/metabolismo , Oxidantes/biossíntese , Oxirredução , Ácido Peroxinitroso/biossíntese
20.
Proc Natl Acad Sci U S A ; 105(44): 16912-7, 2008 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-18971328

RESUMO

Reactive oxygen species produced by phagocytosing neutrophils are essential for innate host defense against invading microbes. Previous observations revealed that antibody-catalyzed ozone formation by human neutrophils contributed to the killing of bacteria. In this study, we discovered that 4 amino acids themselves were able to catalyze the production of an oxidant with the chemical signature of ozone from singlet oxygen in the water-oxidation pathway, at comparable level to antibodies. The resultant oxidant with the chemical signature of ozone exhibited significant bactericidal activity in our distinct cell-free system and in human neutrophils. The results also suggest that an oxidant with the chemical signature of ozone produced by neutrophils might potentiate a host defense system, when the host is challenged by high doses of infectious agents. Our findings provide biological insights into the killing of bacteria by neutrophils.


Assuntos
Aminoácidos/metabolismo , Antibacterianos/metabolismo , Neutrófilos/metabolismo , Ozônio/metabolismo , Adulto , Aminoácidos/química , Catálise , Escherichia coli/metabolismo , Doença Granulomatosa Crônica/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Oxidantes/biossíntese , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Oxigênio Singlete/metabolismo
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