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<p> The effectiveness of vitamin C in treatment of cancer and heart disease is a matter of debate. While some studies show that vitamin C intake is correlated with improved clinical outcome in cancer patients and is associated with better cardiovascular health, others did not. In this thesis, we examine the biochemical and pharmacological properties of this vitamin in the hope that they will be conducive to resolving this controversy. </p> <p>In Chapter 1 of this thesis, we present a compilation of three publications reviewing the current knowledge about this nutrient, including its chemical and biological properties, with focus placed on its therapeutic potentials. From these literatures, we arrived at the hypothesis that vitamin C, at pharmacological concentrations in the serum, may have mitigative effect on cancer and cardiovascular disease. </p> <p> In Chapter 2 of this thesis, we examine the effectiveness of an alternative vitamin C delivery method using gene therapeutic vectors in a humanized transgenic mouse model. These mice have been rendered defective in endogenous vitamin C production by genetic knockout of gulonolactone oxidase ( GULO -/- encoding gene ( Gulo ), which is responsible for catalyzing ascorbic acid biosynthesis. In an earlier study, we constructed gene therapeutic helper-dependent adenoviral vectors (HDAd) carrying the coding sequence for Gulo under either human phosphoenolpyruvate carboxykinase (PEPCK) promoter (HDAd-PEPCK-Gulo) or munne cytomegalovirus(mCMV) immediate-early promoter (HDAd-mCMV-Gulo ). In this study, we sought to examine the ability of these vectors to mediate the expression of GULO and the production of ascorbic acid in human hepatocellular carcinoma (HEPG-2) and Gulo-knockout (Gulo -/-) mice. We found that HEPG-2 infected with HDAd-mCMV-Gulo expressed GULO, which can be readily detected in cells infected at a multiplicity of infection (MOl) of 10 viral particles per cell (vp/cell) using immuno-based blot. Immunoblot also showed that GULO expression occurred at 18 h post-infection in cells treated with HDAd-mCMV-Gulo at a MOl of 500 vp/cell. Vitamin C production was observed in HEPG-2 treated with HDAdmCMV- Gulo as measured by HPLC-electrochemical detection (HPLC-ECD). We showed that vitamin C production is dependent on the substrate, gulonolactone, concentrations. Gu/a-knockout mice treated with 2X1011 vp expressed GULO in the liver. Using HPLCECD, we showed that the serum vitamin C concentrations of these mice were elevated to levels comparable to those of the wild type mice (60 J.LM) after 4 days of infection and were maintained at 30 J.LM for the duration of the experiment (23 days and ongoing). Similar elevation was observed in urine and tissue vitamin C concentrations in vectortreated animals. In conclusion, we demonstrated here that gene therapeutic HDAdmCMV- Gulo vectors are able to mediate the expression of GULO and endogenous production of vitamin C in human cells and in Gulo -/- transgenic mice. Taken together, these findings support the feasibility of gene therapy as a novel vitamin C delivery method to achieve supra-physiological concentrations of vitamin C in the blood. </p> / Thesis / Master of Science (MSc)

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This study investigated effects of diet and probiotic supplement on stress in Thoroughbred foals at weaning. Twenty foals, whose dams were paired by age and breeding date, then randomly assigned to one of two diets prior to parturition, were used. Two groups were maintained on mixed grass pastures and fed supplements, one high in sugar and starch (SS) and one high in fat and fiber (FF) that met or exceeded NRC requirements. Half the foals on each diet were fed a commercial probiotic (Probios) containing lactic acid bacteria, while the rest were given a placebo. Plasma, fecal samples and behavioral ethograms were collected for four days pre- and post-weaning, and an ACTH response test was administered 48 h post-weaning. Cortisol, lactate, IgG, IgA and a-tocopherol were analyzed in plasma, volatile fatty acids and pH in feces. Foals fed FF had higher concentrations of IgA (P = 0.006), IgG (P = 0.012) and a-tocopherol (P = 0.005). Butyric and valeric acid concentrations were higher in feces of SS but not FF foals (P = 0.052), which may reflect better adaptation to forage in FF foals. Foals supplemented with probiotic had higher fecal lactate (P = 0.002) and lower fecal acetate (P = 0.0003) concentrations, suggesting that the lactic acid bacteria survived to the hindgut. Probiotic supplementation did not appear to benefit foals at weaning. Supplementation with FF may improve immune status and encourage a more diverse intestinal microbial population, enabling foals to better cope with the physiological stresses of weaning. / Master of Science

This thesis describes a series of pyridine-N-oxide derivatives of naphthoquinone that were prepared by the author. These compounds will be tested for medicinal activity by Parke-Davis and Company.

Thesis (M.A.)--Boston University, 2012. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Recent evidence has suggested that vitamin D may modulate innate immune function. We performed a prospective, observational investigation to assess the prevalence of vitamin D deficiency in adult critically ill patients with sepsis. Subjects were categorized by baseline 25-hydroxyvitamin D [25(0H)D]: Deficient: < 20 ng/ml, Insufficient: 21-29 ng/ml, or Normal: > 29 ng/ml. A total of 39 subjects were enrolled in the study. 25(0H)D deficiency is common with 23/39 (59%) of subjects either deficient or insufficient. In-hospital mortality was 15% (6/39) and 5/6 (83%) of the subjects who expired were 25(0H)D insufficient. There were modest differences in severity of illness across 25(0H)D categories (SAPS 3: p = 0.01) and statistically significant inverse associations between 25(0H)D and markers of inflammation (IL-6: p = 0.04; TN F-a: p = 0.03) and vascular endothelial dysfunction (E-selectin: p = 0.05). There is a high prevalence of vitamin D deficiency or insufficiency in critically ill patients with sepsis and an inverse association between vitamin D and inflammation and vascular endothelial dysfunction. Future studies should assess the causal relationship between vitamin D and inflammation and outcomes from sepsis. / 2999-01-02