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dc.contributor.advisorWu, Lingyunen_US
dc.creatorWang, Huien_US
dc.date.accessioned2009-06-24T15:15:07Zen_US
dc.date.accessioned2013-01-04T04:40:31Z
dc.date.available2010-06-29T08:00:00Zen_US
dc.date.available2013-01-04T04:40:31Z
dc.date.created2009en_US
dc.date.issued2009en_US
dc.date.submitted2009en_US
dc.identifier.urihttp://hdl.handle.net/10388/etd-06242009-151507en_US
dc.description.abstractMethylglyoxal (MG) is a reactive á-oxoaldehyde and a glucose metabolite. Previous studies in our laboratory have shown that MG induces the production of reactive oxygen species (ROS), such as superoxide (O2.-), nitric oxide (NO) and peroxynitrite (ONOO-), in vascular smooth muscle cells (VSMCs, A-10 cells). However, the effect of endogenous MG and mechanisms of MG-induced oxidative stress have not been thoroughly explored. The present study investigated fructose (a precursor of MG)- induced ONOO- formation in A-10 cells and whether this process was mediated via endogenous MG formation; roles of MG in regulating mitochondrial ROS (mtROS) production and mitochondrial functions in A-10 cells; and effect of MG on neutrophils in patients with type 2 diabetes mellitus (T2DM). Fructose induced intracellular production of MG in a concentration- and time- dependent manner. A significant increase in the production of NO, O2.−, and ONOO− was observed in the cells exposed to fructose or MG. Fructose- or MG-induced ONOO− generation was significantly inhibited by MG scavengers and by O2.− or NO inhibitors. The data showed that fructose treatment increased the formation of ONOO− via increased NO and O2.− production in A-10 cells, and this effect was directly mediated by an elevated intracellular concentration of MG. By inhibiting complex III and manganese superoxide dismutase activities, MG induced mitochondrial overproduction of O2.-, and mitochondrial ONOO- further. MG also reduced mitochondrial ATP synthesis, indicating the dysfunction of mitochondria. In addition, MG increased plasma NO levels in patients with T2DM, which reflected the oxidative status in those patients. MG-induced oxidative stress in patients with T2DM significantly enhanced levels of cytokines released from neutrophils. Moreover, the neutrophils from T2DM patients showed a greater proclivity for apoptosis, which was further increased by in vitro MG treatment. Our data demonstrate that MG-induced oxidative damage, particularly ONOO- production, contributes to the pathogenesis of T2DM and its vascular complications.en_US
dc.language.isoen_USen_US
dc.subjectPeroxynitriteen_US
dc.subjectMethylglyoxalen_US
dc.subjectMitochondriaen_US
dc.subjectType 2 diabetesen_US
dc.subjectSmooth muscle cellen_US
dc.titleMethylglyoxal-induced increase in peroxynitrite and inflammation related to diabetesen_US
thesis.degree.departmentPharmacologyen_US
thesis.degree.disciplinePharmacologyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophy (Ph.D.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US


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