Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves 171-191).

Thesis (M.S.P.H.)--University of Michigan, 1941.

Zugl.: Berlin, Freie University, Diss., 2009.

Thesis (doctoral)--Göteborg University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Göteborg University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (M.S.P.H.)--University of Michigan, 1941.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1959. / Typescript. Abstracted in Dissertation abstracts, v. 19 (1959) no. 11, p. 2745-2746. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Incretins are gastric hormones released by intestinal K-cells in response to food consumption and stimulate insulin secretion from pancreatic beta cells. One of these hormones, glucose-dependent insulinotropic peptide (GIP) is also anabolic in bone. Individuals with diabetes experience diminished bone quality caused by a low bone formation osteopenia. The present study seeks to identify a mechanism for diabetic osteopenia in which diabetes interferes with GIP-stimulated increases in the collagen cross-linking enzyme lysyl oxidase (LOX) in osteoblasts, leading to decreased collagen integrity and the trabecular abnormalities seen in diabetic bone. Micro-CT analysis and picrosirius red histology of long bones from LOX +/- and wild type mice made diabetic by low dose streptozotocin induction revealed a profound exacerbation of the decreased bone volume, impaired trabecular structure, and disorganized collagen matrix seen in diabetic mice when the mice were also haploinsufficient for LOX. Furthermore, qPCR of RNA isolated from diabetic long bones revealed a more than 20 fold decrease in LOX expression in diabetic bone from wild type mice. Treatment of wild type osteoblasts in culture with GIP results in a significant increase in LOX transcript and protein levels. Interestingly in our diabetic mice there is a decrease in osteoblast derived LOX and an abnormal increase in serum levels of the anti-incretin gut-derived dopamine, which is known to inhibit the effects of GIP in the pancreas. Therefore the ability of dopamine to inhibit GIP-stimulated signaling in osteoblasts was examined. Data indicate a strong dose-dependent inhibition of GIP-stimulated LOX expression when primary osteoblast cultures are pretreated with dopamine. Finally, pretreatment of primary osteoblasts with the dopamine receptor inhibitor amisulpride restored the impaired GIP stimulated increases in LOX expression in osteoblasts isolated from diabetic mice. This study defines a potential mechanism for diabetic bone disease and suggests that interference with dopamine signaling would likely restore bone health in diabetes.

A deficiência de sulfito oxidase é uma doença autossômica recessiva que afeta o metabolismo da metionina e cisteína. Os indivíduos afetados comumente apresentam, no período neonatal, convulsões refratárias, retardo mental e desordens do movimento cuja fisiopatologia é desconhecida. Os distúrbios no desenvolvimento e o dano cerebral podem ocorrer como resultado do acúmulo tecidual de sulfito no cérebro. Os objetivos deste estudo foram verificar os efeitos in vitro e in vivo do sulfito sobre alguns parâmetros de estresse oxidativo (avaliação de lipoperoxidação e capacidade antioxidante tecidual) e sobre a atividade da Na+, K+-ATPase em córtex cerebral, estriado e hipocampo de ratos. Primeiramente, verificamos o efeito in vitro do sulfito sobre o estresse oxidativo e a Na+, K+-ATPase em cérebro de ratos de 10 e 60 dias. Posteriormente, nos estudos in vivo, investigamos o efeito da administração intracerebroventricular de sulfito sobre os parâmetros estudados in vitro. Os estudos in vitro demonstraram uma ação direta do sulfito (500μM) na indução de estresse oxidativo verificada pela redução na atividade da catalase e aumento da peroxidação lipídica, enquanto que nos estudos in vivo o sulfito não alterou a atividade das enzimas antioxidantes, TRAP ou TBARS. Tanto nos estudos in vitro como in vivo, o sulfito mostrou-se incapaz de alterar a atividade da Na+,K+-ATPase. Nossos resultados, em conjunto, não excluem o potencial efeito neurotóxico do sulfito na fisiopatologia da doença. O conhecimento dos níveis deste composto no cérebro pode evidenciar além da condição de estresse oxidativo, o comprometimento de outras vias metabólicas importantes no funcionamento cerebral e podem apontar estratégias terapêuticas na prevenção dos efeitos neurológicos da deficiência de sulfito oxidase. / The sulfite oxidase deficiency is a rare autosomal recessive disorder affecting the metabolism of methionine and cysteine. Affected individuals commonly present in the neonatal period intractable seizures, mental retardation and movement disorder which the physiopathology is unknown. The disturbed development and damage to the brain might occur as a result of tissue accumulation of sulfite in the cerebro. The objectives of this study was to investigate the in vitro and in vivo effects of sulfite on some parameters of oxidative stress (lipoperoxidation and antioxidant capacity) and on Na+, K+-ATPase activity in cerebral cortex, striatum and hippocampus from rats. Firstly, we verified the in vitro effects of sulfite on oxidative stress and Na+, K+- ATPase in brains from 10 and 60 days old rats. In the subsequent events, in the in vitro studies, we investigated the effect of intracerebroventricular injection of sulfite on the same parameters studied in vitro. The in vitro studies showed a direct action of sulfite (500 μM) in the induction of oxidative stress through the decrease of catalase activity and increase of peroxidation lipid, while the in vivo studies didn’t alter the antioxidants enzyme activity, TRAP or TBARS. Both in vitro and in vivo studies, showed that sulfite was incapable to disturb the Na+,K+-ATPase activity. Our results, together, don’t exclude the potencial neurotoxic effect of sulfite in the physiopathology of disease. The kwonledge of levels from this compound in the brain can show over there the oxidative stress, the compromise of others metabolic patways important to the brain function and can to lead to strategies therapeutics in the prevention of neurologic effects on sulfite oxidase deficiency.