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1.
Diabetes Metab Res Rev ; 22(3): 198-203, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16453381

RESUMO

BACKGROUND: It has been previously shown that hyperglycemia enhances free radical production, inducing oxidative damage, which in its turn activates the death pathways implicated in cell apoptosis and necrosis. But the possible involvement of this pathway in the hyperglycemia-induced apoptosis of endothelial cells has not yet been reported. METHODS: To verify a possible connection between mitochondrial ROS production and apoptosis induced by both stable and oscillating high glucose, SOD, MnTBAP and TTFA was added to HUVEC cell culture medium. We measured nitrotyrosine and 8OHdG as oxidative stress parameters and Bcl-2 expression and Caspase-3 expression and activity as apoptosis indicators. RESULTS: Our results show that hyperglycemia, both stable or oscillating, increases oxidative stress and endothelial cell apoptosis through ROS overproduction at the mitochondrial transport chain level. CONCLUSION: The prevention of mitochondrial oxidative damage seems to be a future important therapeutic strategy in diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Endotélio Vascular/fisiologia , Glucose/farmacologia , Superóxidos/metabolismo , Caspase 3 , Caspases/metabolismo , Técnicas de Cultura de Células , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Veias Umbilicais
2.
Atherosclerosis ; 183(2): 259-67, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16285992

RESUMO

In this study the effects of stable and intermittent high glucose concentrations on ICAM-1, VCAM-1 and E-selectin production, PKC activity and PKCbetaI, betaII and delta isoforms expression in cultured HUVEC have been examined. In stable high glucose ICAM-1, VCAM-1 and E-selectin concentration and mRNA expression increased, and this effect was even more evident in intermittent high glucose. PKC activity increased in fluctuating glucose compared to stable high glucose, due to an over-expression of betaI, betaII and delta isoforms. ICAM-1, VCAM-1 and E-selectin, after the adding of total PKC inhibitor bisindolylmaleimide-I (BIMI-I) and LY379196, a specific inhibitor of PKCbeta, were equally reduced. 8-Hydroxydeoxyguanosine (8-OHdG), a sensitive indicator of oxidative damage to DNA, increased in stable and even more in intermittent high glucose and was reduced by both BIMI-I and LY379196. However, when thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial complex II and the SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP) were added, all adhesion molecules, any PKC isoforms expression and 8-hydroxydeoxyguanosine were normalized in both constant and oscillating glucose. In conclusion intermittent high glucose induces a greater expression of the adhesion molecules than stable high glucose; this effect seems to be related to an activation of PKCbeta, but completely dependent from mitochondrial free radicals over-production.


Assuntos
Selectina E/biossíntese , Endotélio Vascular/metabolismo , Glucose/administração & dosagem , Molécula 1 de Adesão Intercelular/biossíntese , Mitocôndrias/enzimologia , Proteína Quinase C/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossíntese , 8-Hidroxi-2'-Desoxiguanosina , Northern Blotting , Western Blotting , Células Cultivadas , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Relação Dose-Resposta a Droga , Selectina E/efeitos dos fármacos , Selectina E/genética , Endotélio Vascular/citologia , Ensaio de Imunoadsorção Enzimática , Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Recém-Nascido , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/genética , Estresse Oxidativo/efeitos dos fármacos , Proteína Quinase C/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Superóxidos/metabolismo , Edulcorantes/administração & dosagem , Veias Umbilicais/citologia , Veias Umbilicais/metabolismo , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/genética
3.
Circulation ; 111(19): 2518-24, 2005 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-15867169

RESUMO

BACKGROUND: Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction and inflammation through oxidative stress. Statins and angiotensin type 1 receptor blockers have been shown to reduce oxidative stress and inflammation, improving endothelial function. METHODS AND RESULTS: Twenty type 2 diabetic patients ate 3 different test meals: a high-fat meal, 75 g glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, endothelial function, nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 were assayed during the tests. Subsequently, diabetics took atorvastatin 40 mg/d, irbesartan 300 mg/d, both, or placebo for 1 week. The 3 tests were performed again between 5 and 7 days after the start of each treatment. High-fat load and glucose alone produced a decrease in endothelial function and increases in nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6. These effects were more pronounced when high-fat load and glucose were combined. Short-term atorvastatin and irbesartan treatments significantly counterbalanced these phenomena, and their combination was more effective than either therapy alone. CONCLUSIONS: This study confirms an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function and inflammation, suggesting oxidative stress as a common mediator of such an effect. Short-term treatment with atorvastatin and irbesartan may counterbalance this phenomenon; the combination of the 2 compounds is most effective.


Assuntos
Compostos de Bifenilo/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Ácidos Heptanoicos/administração & dosagem , Pirróis/administração & dosagem , Tetrazóis/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Quimioterapia Combinada , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/patologia , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Irbesartana , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Período Pós-Prandial , Resultado do Tratamento
4.
Diabetes ; 53(3): 701-10, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14988255

RESUMO

Adhesion molecules, particularly intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, have been associated with cardiovascular disease. Elevated levels of these molecules have been reported in diabetic patients. Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease, and evidence suggests that postprandial hypertriglyceridemia and hyperglycemia may induce an increase in circulating adhesion molecules. However, the distinct role of these two factors is a matter of debate. Thirty type 2 diabetic patients and 20 normal subjects ate three different meals: a high-fat meal, 75 g of glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, plasma nitrotyrosine, ICAM-1, VCAM-1, and E-selectin were assayed during the tests. Subsequently, diabetic subjects took simvastatin 40 mg/day or placebo for 12 weeks. The three tests were performed again at baseline, between 3 and 6 days after starting the study, and at the end of each study. High-fat load and glucose alone produced an increase of nitrotyrosine, ICAM-1, VCAM-1, and E-selectin plasma levels in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters, but reduced the effect on adhesion molecules and nitrotyrosine, which was observed during every different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations in ICAM-1, VCAM-1, E-selectin, and nitrotyrosine during the tests. This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on ICAM-1, VCAM-1, and E-selectin plasma levels, suggesting oxidative stress as a common mediator of such effects. Simvastatin shows a beneficial effect on oxidative stress and the plasma levels of adhesion molecules, which may be ascribed to a direct effect in addition to the lipid-lowering action of the drug.


Assuntos
Complicações do Diabetes , Hiperglicemia/sangue , Hipertrigliceridemia/sangue , Hipolipemiantes/uso terapêutico , Molécula 1 de Adesão Intercelular/sangue , Estresse Oxidativo/fisiologia , Sinvastatina/uso terapêutico , Tirosina/análogos & derivados , Índice de Massa Corporal , Estudos Cross-Over , Diabetes Mellitus/sangue , Método Duplo-Cego , Selectina E/sangue , Eletrocardiografia , Feminino , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/imunologia , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/imunologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Período Pós-Prandial , Triglicerídeos/sangue , Tirosina/sangue , Molécula 1 de Adesão de Célula Vascular/sangue
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