Thesis (Ph. D.)--University of Adelaide, Dept. of Plant Science, 1998. / Includes bibliographical references (leaves 218-233).

Thesis (D.Sc.) --University of Adelaide, 1958.

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Atherosclerosis is a chronic inflammatory disease thought to be initiated by endothelial cell dysfunction. Research described in this dissertation is focused on the role of zinc deficiency in endothelial cell activation with an emphasis on the function of the transcription factors nuclear factor-κB (NF-κB), peroxisome proliferator activated receptor (PPAR), and the aryl hydrocarbon receptor (AhR), which all play critical roles in the early pathology of atherosclerosis. Cultured porcine aortic vascular endothelial cells were deprived of zinc by the zinc chelator TPEN and/or treated with the NF-κB inhibitor CAPE or the PPARγ agonist rosiglitazone, followed by measurements of PPARα expression, cellular oxidative stress, NF-κB and PPAR DNA binding, COX-2 and E-selectin expression, and monocyte adhesion. Cellular labile zinc deficiency increased oxidative stress and NF-κB DNA binding activity, and induced COX-2 and Eselectin gene expression, as well as monocyte adhesion in endothelial cells. CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-κB signaling. PPAR can inhibit NF-κB signaling. Zinc deficiency down-regulated PPARα expression and PPAR DNA binding activity in endothelial cells. Zinc deficiency compromised PPARγ transactivation activity in PPARγ and PPRE co-transfected rat aortic vascular smooth muscle cells. Furthermore, rosiglitazone was unable to inhibit the adhesion of monocytes to endothelial cells during zinc deficiency. Most of these effects of zinc deficiency could be reversed by zinc supplementation. An in vivo study utilizing the atherogenic LDL-R-/- mouse model generally supported the importance of PPAR dysregulation during zinc deficiency. LDLR-/- mice were maintained for four weeks on either zinc deficient or zinc adequate diets. Half of the mice within each zinc group were gavaged daily with rosiglitazone during the last stage of the study. Selected inflammation and lipid parameters were measured. The anti-inflammatory properties of rosiglitazone were compromised during zinc deficiency. Specifically, rosiglitazone induced inflammatory genes (MCP-1) in abdominal aorta only during zinc deficiency, and adequate zinc was required for rosiglitazone to down-regulate pro-inflammatory markers such as iNOS in abdominal aorta of the mice. Rosiglitazone significantly up-regulated liver IκBα protein expression only in zinc adequate mice. Plasma data also suggest an overall pro-inflammatory environment during zinc deficiency and support the concept that zinc is required for proper anti-inflammatory or protective functions of PPAR. Zinc deficiency also altered PPAR-regulated lipid metabolism in LDL-R-/- mice. Specifically, zinc deficiency increased plasma total cholesterol, and non- HDL (VLDL, IDL and LDL)-cholesterol. Plasma total fatty acids tended to be increased during zinc deficiency, and rosiglitazone treatment resulted in similar changes in fatty acid profile in zinc deficient mice. FAT/CD36 expression in abdominal aorta was upregulated by rosiglitazone only in zinc-deficient mice. In contrast, rosiglitazone treatment markedly increased LPL expression only in zinc-adequate mice. These data suggest that in this atherogenic mouse model treated with rosiglitazone, lipid metabolism can be compromised during zinc deficiency. AhR is another transcription factor involved in the development and homeostasis of the cardiovascular system. Cultured porcine aortic endothelial cells were exposed to the AhR ligands PCB77 or beta-naphthoflavone (β-NF) alone or in combination with the zinc chelator TPEN, followed by measurements of the AhR responsive cytochrome P450 enzymes CYP1A1 and 1B1. Zinc deficiency significantly reduced PCB77- induced CYP1A1 activity and mRNA expression, as well as PCB77 or β-NF-induced CYP1A1 protein expression, which could be restored by zinc supplementation. These data suggest that adequate zinc is required for the activation of the AhR-CYP1A1 pathway. Impairment of the AhR pathway presents an additional mechanism by which zinc deficiency negatively affects transcription factor function and homeostasis of the vascular system. Taken together, zinc nutrition can markedly modulate the pathogenesis of inflammatory diseases such as atherosclerosis.

Zinc status of Egyptian children 18-30 months and 6-10 years of age was characterized in relation to morbidity, growth, and socioeconomic variables. In a pilot study of children whose general nutrition ranged from adequately nourished to moderately malnourished, mean hair zinc was 135 ug/g (63-230 ug/g), with suboptimal zinc status suggested for 44%. Predictors of hair and serum zinc levels were explored for 23 school-aged and 40 preschool children. Included in models were weaning age for preschool children, body size (length- or height- and weight-for-age Z scores), current growth over 6 months or longer, illness experience over 10 to 12 months, demographic variables affecting food availability and distribution, sex, and season. Data were collected by Egyptian workers as part of a larger field project. Hair and serum samples were analyzed for zinc content by atomic absorption spectrophotometry. Results showed no difference in hair zinc levels by color, presence or absence of louse egg fragments and mucilage, or presence or absence of henna dye. In multiple regression models, the best predictor of hair zinc in preschool children was season of year, with zinc lower in summer. Season, negative effect of percent of weeks ill with diarrhea, and positive effects of socioeconomic status (SES) based on father's education/literacy and economic subsistence base excluding agriculture (ESB-A) predicted 23% of total hair zinc variation in preschool children. In preschool children serum zinc was lower in summer. Season, positive effect of rate of weight increase, and negative effects of rate of height increase, SES based on father's occupation(s) (SES2), and ESB-A predicted 53% of total serum zinc variation in preschool children. Serum zinc was higher in summer in school-aged children. Season, negative effect of SES2 and ESB-A, and positive effects of percent weeks ill with diarrhea and height for age Z scores predicted 60% of total serum zinc variation in school-age children. Negative effects of percent weeks ill with diarrhea and parents' age and child:adult ratio predicted 29% of hair zinc in school-aged children.

Resumo: Não disponível / Abstract: Upper aero digestive tract (UADT) cancer is an important cause of morbidity and mortality worldwide. Chronic alcohol intake and dietary deficiency zinc, tobacco smoking, and gastroesophageal reflux disease are the major risk factors to the UADT cancer. In the present study, we utilized a diet that mimic inadequate zinc intake (Zn-) diet and supplemented it with unconjugated bile deoxycholic acid (DCA), a component associated with gastroesophageal reflux disease and high fat diets. The aim of this study was to assess the additional influence of exposure to cigarette smoke and ethanol intake on the epithelial alterations of the esophagus and tongue induced by Zn-+DCA diet. Male C57BL/6 mice animals were allocated into six groups: Groups 1 to 3 were fed modified diet (Zn-+ 0.2% DCA) and groups 4 to 6 were fed control diet. After 5-weeks, groups 2 and 5 intake ethanol 10% ad libitum and groups 3 and 6 were exposed to cigarette smoke for 15 weeks. All animals were euthanized at the end of week 20 and tongue and esophagus were collected for histological analysis and immunohistochemical analysis of cell proliferation using Ki- 67 marker and cyclooxygenase 2 expression (COX-2). The Zn-+DCA diet treatment trend to increased cell proliferation indexes and the incidence of hyperkeratosis in the tongue and esophagus but not in COX-2 expression. No additional effect of 15-week treatment with ethanol or cigarette smoke was observed. These findings indicate that dietary zinc deficiency supplemented with deoxycolic acid appears to be an important factor of epithelial aggression and that deleterious effect of ethanol and cigarette smoke could be detected in a long-term exposure. / Orientador: Luis Fernando Barbisan / Coorientador: Maria Aparecida Marchesan Rodrigues / Banca: Noeme Souza Rocha / Banca: Luis Antonio Justulin Junior / Mestre

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Thesis (Ph. D.)--University of Missouri-Columbia, 2001. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2001. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2001. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.