Thesis (Ph. D.)--University of Missouri--Rolla, 2007. / Vita. The entire thesis text is included in file. Title from title screen of thesis/dissertation PDF file (viewed January 28, 2008) Includes bibliographical references (p. 117-131).

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Thesis (M. Sc.)--University of Canterbury, 2008. / Typescript (photocopy). Includes bibliographical references (leaves 74-83). Also available via the World Wide Web.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). "April 2006." Includes bibliographical references (leaves 101-122). Also available via the World Wide Web.

Free radicals which have critical roles in living systems through their beneficial and detrimental effects play an important role in medical revolution in health. Radicals are produced in the cells and tissues of our bodies by various processes and reactions. Diabetes mellitus is an extremely common disease in the world which seems to be accompanied by a shortage of antioxidants and an increase in free radicals, the end result of oxidative stress. Glutathione S-Transferases (GST / EC 2.5.1.18) are found in enzymatic defense system which has a role in defending cells against potentially toxic and/or carcinogenic compounds. In this study, the changes in the activities and expressions of various GST isozymes in the liver of diabetic rats related to oxidative stress were studied. The effects of antioxidants, Vitamin C and &amp / #945 / -Lipoic acid on GST isozyme activities and mRNA expressions were also investigated. According to our results, diabetic rats exhibited decreased mRNA expressions of both GSTA2 and GSTM1 genes, but the activities of only GST Mu isozyme decreased in diabetic rats, compared to controls and GST Alpha isozyme activity remained unchanged in diabetic animals. Our results also showed that &amp / #945 / -Lipoic acid individually has no significant effect on both GSTA2 and GSTM1 gene expressions and activities. Furthermore, although the administration of Vitamin C alone showed no significant effect on all GST isozyme activities, it decreased GSTA2 mRNA expression significantly. The administration of Vitamin C and &amp / #945 / -Lipoic acid together affected both GSTA2 and GSTM1 mRNA expressions in control rats, but only GST Mu activity showed a significant change. The results of this study showed that, the administration of two antioxidants, &amp / #945 / -Lipoic acid and Vitamin C alone and together did not reverse the results of diabetes at the level of both gene expression and activities of GST isozymes.

Free radicals are the compounds having one or more unpaired electrons in their outer orbital and this unpaired electron make these compounds very reactive. Especially as their concentration increases, they initiate a chain oxidation reaction of lipids, proteins and nucleic acids. The condition, in which the production of free radicals exceeds their elimination or tissue defense mechanism decrease against them or both occur together, is called oxidative stress. In diabetes mellitus which is a glucose metabolism disorder, there occurs excessive non-enzymatic protein oxidation, glucose autoxidation and enhanced activity of polyol pathway enzymes, which are the possible sources of the oxidative stress in this disease. In this study, the conditions of the activity measurements of major antioxidant enzymes, namely superoxide dismutase (SOD, EC 1.15.1.1), catalase (CAT, EC 1.11.1.6), glutathione peroxidase (GPx, 1.11.1.9) and glutathione S-transferase (GST, EC 2.5.1.18) were studied and the optimum conditions (pH, temperature and substrate concentrations) for each assay were determined. Further objectives of the study were to characterize the enzymatic antioxidant systems (catalase, superoxide dismutase, glutathione peroxidase and glutathione S-transferase), tissue oxidation status (concentrations of TBARS, protein carbonylation, and lipid/protein ratios) and nonenzymatic antioxidant (reduced glutathione) levels of the diabetic rat liver tissues. According to our results, the hepatic SOD and GPx activities significantly increased whereas CAT activity markedly decreased in diabetic rats compared to control group. Also, GST activities did not change in diabetes. As a result of oxidative stress, TBARS concentration, lipid/protein ratios and protein carbonylation increased and GSH levels decreased in diabetic rats compared to control rats. This increase in tissue damage, in spite of the increase in antioxidant enzyme activities, could have been due to the overproduction of reactive oxygen species that exceeded the capacity of the antioxidant enzymes during the eight week of diabetes.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 155-182).

Thesis (PhD) -- Macquarie University, Division of Environmental and Life Sciences, Dept. of Chemistry and Biomolecular Sciences, 2007. / Bibliography: leaves 295-322.

Introdução: A Doença arterial periférica (DAP) é uma manifestação clínica da aterosclerose, quando esta afeta principalmente as artérias que irrigam os membros inferiores. O exercício aeróbico provoca nos membros afetados pela doença um ciclo de reperfusão-isquemia que desencadeia uma resposta sistêmica aguda caracterizada por aumento do estresse oxidativo, inflamação e disfunção endotelial. Assim, uma terapia antioxidante pode ser uma terapia alternativa para esses pacientes. Os microRNAs (miRNAs) foram recentemente reconhecidos como reguladores pós-transcricionais, e a identificação desses pode elucidar mecanismos gênicos adicionais pelos quais o exercício é atuante, levando a identificação de genes que são modulados, abrindo perspectivas de abordagens de terapia gênica que podem levar à reversão do quadro da doença arterial periférica. Objetivo: Verificar o efeito de uma sessão aguda de exercício aeróbico máxima com e sem uso do antioxidante Nacetilcisteína (NAC) sobre a expressão de microRNAs e marcadores inflamatórios e de estresse oxidativo circulantes em pacientes com DAP. Métodos: Foram recrutados pacientes com DAP estágio II do Ambulatório da Disciplina de Cirurgia Vascular do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram submetidos a duas sessões experimentais após a suplementação de NAC ou Placebo. Foi analisado o perfil de expressão de microRNAs circulantes dos indivíduos em repouso e após o exercício máximo, e confirmado a expressão gênica dos miRNAs alterados após o exercício e de seus alvos; e dos níveis plasmáticos de endotelina-1 (ET-1), proteína quimiotática de monócitos-1 (MCP-1), molécula de adesão intercelular-1 (ICAM-1), molécula de adesão celular vascular-1 (VCAM-1), substâncias reativas ao ácido tiobarbitúrico, 8- isoprostano e glutationa. Resultados: O tratamento com NAC não alterou o xvii tempo de caminhada, as respostas hemodinâmicas e cardiopulmonar dos pacientes com DAP. O fluxo sanguíneo em repouso da perna desses pacientes foi maior após a realização do exercício e o tratamento com NAC não alterou essa resposta. Após o exercício houve aumento plasmático de MCP-1, ET-1, VCAM-1 e TBARS, mas o tratamento com NAC não alterou essa resposta. Porém, o tratamento com NAC aumentou os níveis plasmáticos de glutationa durante toda a sessão experimental. Houve alteração da expressão dos cmiRNAs -126, -100 e -92a após a realização do exercício e o tratamento com NAC aboliu essas respostas. Encontramos ainda alteração da expressão gênica circulante de alguns alvos desses miRNAS: PI3KR2, mTOR, ITGA5; e de alguns genes relacionados com angiogênese: VEGF, eNOS, HIF-1?. Conclusão: O exercício aeróbico máximo foi um estímulo capaz de alterar a expressão gênica de marcadores angiogênicos circulantes em pacientes com DAP e os c-miRNAs parecem estar envolvidos nesse processo. Por outro lado, a NAC alterou o balanço redox dos pacientes com DAP. Entretanto, o tratamento com NAC aboliu essa resposta angiogênica sistêmica mediada por c-miRNAs ao exercício aeróbico máximo / Introduction: Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis, when it mainly affects the arteries supplying the lower limbs. Aerobic exercise causes the member affected by the disease cycle of reperfusion-ischemia triggers an acute systemic response characterized by increased oxidative stress, inflammation and endothelial dysfunction. Thus, an antioxidant therapy is an alternative therapy for these patients. MicroRNAs (miRNAs) have been recognized as posttranscriptional regulators, and identifying these may elucidate additional gene mechanisms by which the exercise is active, leading to identification of genes that are modulated, opening prospects of gene therapy approaches that can lead to picture reversal of peripheral arterial disease. Aim: To determine the effect of an acute bout of maximal aerobic exercise with and without the antioxidant N-acetylcysteine (NAC) on the expression of microRNAs and inflammatory markers and circulating oxidative stress in patients with PAD. Methods: We recruited patients with PAD stage II Clinic of Vascular Surgery of Hospital das Clinicas, Faculty of Medicine, University of São Paulo. The patients underwent two experimental sessions after supplementation of NAC or placebo. the expression profile of circulating microRNAs of individuals at rest and after maximal exercise was analyzed and confirmed the gene expression of miRNAs changed after exercise and its targets; and plasma levels of endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) cell vascular cell adhesion molecule-1 (VCAM-1) , reactive substances to thiobarbituric acid, 8-isoprostane and glutathione. Results: Treatment with NAC did not change the walking time, and cardiopulmonary hemodynamic responses of patients with PAD. The rest blood flow in the leg of these patients was higher after the completion of the exercise and treatment with NAC did not change this response. After the exercise was increased plasma MCP-1, ET-1, VCAM-1 and TBARS, but the treatment with NAC did not change this response. However, treatment with NAC increased plasma glutathione levels xix throughout the experimental session. There were change in the expression of c-miRNAs - 126, -100 and -92a after the exercise and treatment with NAC abolished those answers. We find still change in current gene expression of some targets of these miRNAs: PI3KR2, mTOR, ITGA5; and some angiogenesis-related genes: VEGF, eNOS, HIF-1?. Conclusion: The maximum aerobic exercise was a able to change gene expression of circulating angiogenic markers in patients with PAD and c-miRNAs stimulus seem to be involved in this process. Moreover, NAC change the redox balance of patients with PAD. However, treatment with NAC abolished the systemic angiogenic response mediated by c-miRNAs the maximum aerobic exercise

Introdução: A Doença arterial periférica (DAP) é uma manifestação clínica da aterosclerose, quando esta afeta principalmente as artérias que irrigam os membros inferiores. O exercício aeróbico provoca nos membros afetados pela doença um ciclo de reperfusão-isquemia que desencadeia uma resposta sistêmica aguda caracterizada por aumento do estresse oxidativo, inflamação e disfunção endotelial. Assim, uma terapia antioxidante pode ser uma terapia alternativa para esses pacientes. Os microRNAs (miRNAs) foram recentemente reconhecidos como reguladores pós-transcricionais, e a identificação desses pode elucidar mecanismos gênicos adicionais pelos quais o exercício é atuante, levando a identificação de genes que são modulados, abrindo perspectivas de abordagens de terapia gênica que podem levar à reversão do quadro da doença arterial periférica. Objetivo: Verificar o efeito de uma sessão aguda de exercício aeróbico máxima com e sem uso do antioxidante Nacetilcisteína (NAC) sobre a expressão de microRNAs e marcadores inflamatórios e de estresse oxidativo circulantes em pacientes com DAP. Métodos: Foram recrutados pacientes com DAP estágio II do Ambulatório da Disciplina de Cirurgia Vascular do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram submetidos a duas sessões experimentais após a suplementação de NAC ou Placebo. Foi analisado o perfil de expressão de microRNAs circulantes dos indivíduos em repouso e após o exercício máximo, e confirmado a expressão gênica dos miRNAs alterados após o exercício e de seus alvos; e dos níveis plasmáticos de endotelina-1 (ET-1), proteína quimiotática de monócitos-1 (MCP-1), molécula de adesão intercelular-1 (ICAM-1), molécula de adesão celular vascular-1 (VCAM-1), substâncias reativas ao ácido tiobarbitúrico, 8- isoprostano e glutationa. Resultados: O tratamento com NAC não alterou o xvii tempo de caminhada, as respostas hemodinâmicas e cardiopulmonar dos pacientes com DAP. O fluxo sanguíneo em repouso da perna desses pacientes foi maior após a realização do exercício e o tratamento com NAC não alterou essa resposta. Após o exercício houve aumento plasmático de MCP-1, ET-1, VCAM-1 e TBARS, mas o tratamento com NAC não alterou essa resposta. Porém, o tratamento com NAC aumentou os níveis plasmáticos de glutationa durante toda a sessão experimental. Houve alteração da expressão dos cmiRNAs -126, -100 e -92a após a realização do exercício e o tratamento com NAC aboliu essas respostas. Encontramos ainda alteração da expressão gênica circulante de alguns alvos desses miRNAS: PI3KR2, mTOR, ITGA5; e de alguns genes relacionados com angiogênese: VEGF, eNOS, HIF-1?. Conclusão: O exercício aeróbico máximo foi um estímulo capaz de alterar a expressão gênica de marcadores angiogênicos circulantes em pacientes com DAP e os c-miRNAs parecem estar envolvidos nesse processo. Por outro lado, a NAC alterou o balanço redox dos pacientes com DAP. Entretanto, o tratamento com NAC aboliu essa resposta angiogênica sistêmica mediada por c-miRNAs ao exercício aeróbico máximo / Introduction: Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis, when it mainly affects the arteries supplying the lower limbs. Aerobic exercise causes the member affected by the disease cycle of reperfusion-ischemia triggers an acute systemic response characterized by increased oxidative stress, inflammation and endothelial dysfunction. Thus, an antioxidant therapy is an alternative therapy for these patients. MicroRNAs (miRNAs) have been recognized as posttranscriptional regulators, and identifying these may elucidate additional gene mechanisms by which the exercise is active, leading to identification of genes that are modulated, opening prospects of gene therapy approaches that can lead to picture reversal of peripheral arterial disease. Aim: To determine the effect of an acute bout of maximal aerobic exercise with and without the antioxidant N-acetylcysteine (NAC) on the expression of microRNAs and inflammatory markers and circulating oxidative stress in patients with PAD. Methods: We recruited patients with PAD stage II Clinic of Vascular Surgery of Hospital das Clinicas, Faculty of Medicine, University of São Paulo. The patients underwent two experimental sessions after supplementation of NAC or placebo. the expression profile of circulating microRNAs of individuals at rest and after maximal exercise was analyzed and confirmed the gene expression of miRNAs changed after exercise and its targets; and plasma levels of endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) cell vascular cell adhesion molecule-1 (VCAM-1) , reactive substances to thiobarbituric acid, 8-isoprostane and glutathione. Results: Treatment with NAC did not change the walking time, and cardiopulmonary hemodynamic responses of patients with PAD. The rest blood flow in the leg of these patients was higher after the completion of the exercise and treatment with NAC did not change this response. After the exercise was increased plasma MCP-1, ET-1, VCAM-1 and TBARS, but the treatment with NAC did not change this response. However, treatment with NAC increased plasma glutathione levels xix throughout the experimental session. There were change in the expression of c-miRNAs - 126, -100 and -92a after the exercise and treatment with NAC abolished those answers. We find still change in current gene expression of some targets of these miRNAs: PI3KR2, mTOR, ITGA5; and some angiogenesis-related genes: VEGF, eNOS, HIF-1?. Conclusion: The maximum aerobic exercise was a able to change gene expression of circulating angiogenic markers in patients with PAD and c-miRNAs stimulus seem to be involved in this process. Moreover, NAC change the redox balance of patients with PAD. However, treatment with NAC abolished the systemic angiogenic response mediated by c-miRNAs the maximum aerobic exercise