Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [48]-59).

Thesis (Ph. D.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 155-169).

Thesis (M.S.)--Brandeis University, 2009. / Title from PDF title page (viewed on June 29, 2009). Includes bibliographical references.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 71-79). Also available via the World Wide Web.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 107-130).

Thesis (Ph. D.)--Lund University.

Thesis (Ph. D.)--Lund University.

Thesis (Ph. D.)--University of North Texas, May, 2007. / Title from title page display. Includes bibliographical references.

Aging, a major risk factor in Alzheimer's disease (AD), is associated with an increased free radical (ROS) generation, probably linked to mitochondrial dysfunction. While NADH is the ultimate electron donor for many redox reactions, glutathione (GSH) is the major ROS detoxifying redox buffer within the cell and cysteines are the major reducing buffer in the extracellular matrix. Since the relationship of the prominent ROS damage to aging and AD is unclear, we wanted to know whether A) an oxidative redox shift precedes these markers and leads to macromolecular damage, B) age and AD-related changes can be reversed using redox interventions in neurons and C) modification of the extracellular Cys/CySS redox can change intracellular redox and increase neuron survival. Hippocampal/cortical neurons were isolated across the age-span from non-transgenic (non-Tg) and a triple transgenic Alzheimer's mouse model (3xTg-AD) and cultured in common nutrients to control for age-related hormonal and vascular differences. We found an increase of NAD(P)H levels and redox state in non-Tg neurons until middle age, followed by a decline in old age. The 3xTg-AD neurons maintained much lower resting NAD(P)H and redox state after 4 months, but the NADH regenerating capacity continuously declined with age beginning at 2 months. Compared to non-Tg neurons, 3xTg-AD neurons had lower glutathione (GSH) levels, which preceded age-related increases in ROS levels. The redox deficits in NAD(P)H and GSH were partially reversed using the NADH precursor, nicotinamide. To determine the relative importance of GSH to ROS and cell death, we simultaneously determined GSH depletion and ROS elevation in live neurons across the age-span by titrating with buthionine sulfoximine (BSO), an inhibitor of the rate-limiting enzyme for GSH synthesis, γ-glutamylcysteine synthetase, subunit c (GCLC). We observed that in old age, neuron loss was more dependent on GSH depletion than ROS elevation. Remarkably, the rate of neuron loss with ROS was the same for both genotypes, indicating that cognitive deficits in the AD-model were not caused by ROS. Therefore, we targeted activation of the redox sensitive transcription factor, Nrf2 (Nuclear erythroid-related factor 2) for neuroprotection by 18α-glycyrrhetinic acid to stimulate glutathione synthesis through GCL. . By combining the Nrf2 activator together with nicotinamide, we increased neuron survival against glutathione depletion and beta-amyloid stress in an additive manner. Further, we explored the relative importance of NAD(P)H and GSH to neuron loss in aging and AD. Neurons stressed by either depleting NAD(P)H or GSH indicated that NAD(P)H redox control is upstream of GSH levels and compared to GSH depletion, higher neuron loss was observed with declining NAD(P)H, especially in old age and in the 3xTg-AD neurons. We also observed an age-dependent loss of gene expression of key redox dependent biosynthetic enzymes, NAMPT (nicotinamide phosphoribosyl transferase) and NNT (nicotinamide nucleotide transhydrogenase). Moreover, age-related correlations between brain NNT or NAMPT gene expression and NADPH levels suggest that these genes contribute to the age-related declines in NAD(P)H. Lastly, since extracellular redox deficits are seen in aging and AD, and Cys/CySS is the major redox buffer in the extracellular microenvironment, we determined the effects of extracellular redox modification on intracellular redox state, neuron survival and signaling through pAkt/Akt. We found that a reductive shift in extracellular Cys/CySS improved neuron survival, maintained intracellular GSH and NAD(P)H as well as increased pAkt/Akt in aging. Overall, our results strongly support the EORS theory of aging that an oxidative redox shift precedes ROS-mediated damage. A therapeutic reductive redox shift might be used to minimize aging and treat AD

Made available in DSpace on 2016-04-01T17:55:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-11-26. Added 1 bitstream(s) on 2016-04-01T18:00:49Z : No. of bitstreams: 1 000860346.pdf: 661518 bytes, checksum: 42e9ea64ab3804296fcd201dac5bcbe9 (MD5) / A síndrome cólica um dos distúrbios de maior importância em equinos, a se destacar entre suas causas os quadros obstrutivos, decorrentes de corpos estranhos e ou enterólitos localizados no cólon menor. No desenvolvimento da cólica há diminuição do fluxo sanguíneo local ao qual se segue, quando de sua correção, a reperfusão sanguínea. A isquemia seguida de reperfusão é a causa do aumento da lesão degenerativa principal pós-cirúrgica. As lesões de reperfusão podem ser causadas pela produção e liberação de espécies reativas de oxigênio(EROs). Diante disto, objetivou-se no presente trabalho analisar moléculas decorrentes da oxidação celular e substâncias antioxidantes no soro e no tecido do cólon menor em equinos submetidos experimentalmente a obstrução intraluminal do cólon menor. Também foram avaliados parâmetros físicos frequência cardíaca (FC), frequência respiratória (FR), temperatura retal (Tr), motilidade, tempo de preenchimento capilar (TPC), coloração de mucosas, pulso digital e turgor cutâneo. Análises hematimétricas e leucométricas foram efetuadas em diferentes momentos. Análises no soro para determinação de malondialdeido (MDA), produto protéico de oxidação avançada (AOPP) (metabólitos da oxidação), glutationa (GSH) e vitamina E (Vit. E) (substâncias antioxidantes), foram realizadas em diferentes momentos: M0 (momento antes do procedimento anestésico e precurção da obstrução), M4 (4 horas, retirada da obstrução), M12, M24, M36, M48, M60 e M72 (correspondendo a 12, 24, 36, 48, 60 e 72 horas após a obstrução). No cólon menor foram obtidas amostras em M0 (antes da obstrução), após 4 horas de obstrução intestinal (M4) foram obtidas na região oral, obstruída e aboral. Após 72 horas de pós cirúrgico (M72) realizou-se nova coleta das regiões do cólon menor. Nestas amostras de tecido foram realizadas as analises de MDA, AOPP, GSH e catalase. Nos parâmetros... / The syndrome colic one of the most important disorders in horses, stand out among its causes obstructive frames, resulting from foreign bodies and or enteroliths located in the lower colon. The development of colic there is reduced local blood flow which follows, when their correction, blood reperfusion. The ischemia followed by reperfusion is the cause of increased postoperative primary degenerative injury. Reperfusion injury can be caused by the production and release of reactive oxygen species (ROS). In view of this, the aim of the present study to analyze molecules resulting from cellular oxidation and antioxidants in serum and lower colonic tissue in horses submitted to experimental intraluminal obstruction of the lower colon. They also evaluated physical parameters heart rate (HR), respiratory rate (RR), rectal temperature (Tr), motility, capillary refill time (TPC), color of mucous membranes, digital pulse and skin turgor. Hematological analysis and leukocytes were made at different times. Analysis of serum for determination of malondialdehyde (MDA) and vitamin E (Vit E), protein product of advanced oxidation (AOPP) (oxidation metabolites), glutathione (GSH) (antioxidant flux), were held at different times: M0 (time before the anesthetic and procedure obstruction), M4 (4 hours, removal of the obstruction), M12, M24, M36, M48, M60 and M72 (corresponding to 12, 24, 36, 48, 60 and 72 hours after occlusion). In the lower colon samples were obtained from M0 (before blocking) after 4 hours of intestinal obstruction (M4) were obtained in the oral region and aboral obstructed. After 72 hours of post surgical (M72) held new collection regions of the lower colon. In these tissue samples were carried out analysis of MDA, AOPP, catalase and GSH. In physiological parameters we observed a significant increase in HR and Tr in M12, and an increase in RR in M24. Hematological evaluation showed a decrease compared to red blood cell count ...