<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)

Thesis (D. Phil.)--Københavns Universiteit, 2005. / With a summary in Danish. Includes bibliographical references.

Call number: LD2668 .T4 1959 D72

No description available.

Call number: LD2668 .T4 1950 W3 / Master of Science

Call number: LD2668 .T4 1952 C6 / Master of Science

Call number: LD2668 .T4 1957 M70 / Master of Science

Wong Kit Sum. / Includes bibliographical references / Thesis (M.Ph.)--Chinese University of Hong Kong, 1985

Made available in DSpace on 2014-06-11T19:31:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-11Bitstream added on 2014-06-13T20:41:03Z : No. of bitstreams: 1 khalil_oak_dr_araiq_parcial.pdf: 122903 bytes, checksum: 87266cce24ee42f91603bd596a620467 (MD5) Bitstreams deleted on 2015-07-02T12:36:14Z: khalil_oak_dr_araiq_parcial.pdf,. Added 1 bitstream(s) on 2015-07-02T12:37:34Z : No. of bitstreams: 1 000690213_20400528.pdf: 122681 bytes, checksum: c32b117b1b8d8496aaf7f3e5de89fbf4 (MD5) / Universidade Estadual Paulista (UNESP) / O excesso na geração de espécies reativas como os radicais livres pode resultar num desequilíbrio que, embora benéfico em casos específicos como no combate a microrganismos patógenos, está implicado na etiologia de diversas patologias crônicas e com o envelhecimento precoce. Muitos pesquisadores indicam o uso de antioxidantes como potenciais para a prevenção destas patologias e inclusive, algumas pesquisas com antioxidantes como a curcumina estão em etapas finais do desenvolvimento de novos medicamentos. Embora atividades biológicas como a antimicrobiana e antioxidante sejam bastante exploradas para várias substâncias, há um grande potencial para a investigação em relação às atividades de duas ou mais substâncias associadas. O ácido ascórbico, por exemplo, possui algumas atividades biológicas semelhantes às da curcumina, entretanto seu uso e custo são mais acessíveis. Deste modo, há perspectivas para investigações sobre os efeitos resultantes da associação entre a curcumina e o ácido ascórbico em relação a algumas atividades biológicas, com destaque para a curcumina. Assim, este trabalho objetivou determinar os efeitos resultantes desta associação em relação ao perfil de atividades antimicrobiana, antioxidante, hemolítica e na estabilidade da curcumina. Foram utilizadas metodologias de análise de atividade antioxidante como os ensaios de ação scavenger do DPPH·, ABTS·+, O2 ·-, HOCl e também por análise do sistema oxidativo catalisado por peroxidase. Em relação às análises celulares e antimicrobianas, foi determinada a toxicidade sobre eritrócitos e a atividade em relação à Sthaphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans e Candida krusei. A estabilidade da curcumina foi determinada por espectrofotometria... / The excessive generation of reactive species such as free radicals can result in an imbalance which is implicated in the etiology of various chronic diseases and premature aging, although it is beneficial in specific cases, such as in against microbial pathogens. Many researchers suggest the antioxidants usage to prevent these diseases. Some researches about curcumin and others antioxidants are even in final stages of developing new medicines. Although some biological activities are fully explored for various substances, there is great potential of research about the activities of two or more associated substances. Ascorbic acid, for example, has some biological activities similar to those of curcumin, but its use and cost are more accessible. Thus, there are prospects for research on the effects of the association between these molecules, especially curcumin, in relation to some biological activities. This study aimed to determine the effects of this association on antioxidant, antimicrobial and hemolytic activities of curcumin. Since this association can prevent the oxidative degradation of curcumin, it was also aimed to analyze the effects of ascorbic acid on the curcumin stability. Antioxidant activities were evaluated through DPPH , ABTS +, O2 - and HOCl scavenging assays and guaiacol oxidation catalyzed by peroxidase. Regarding the cellular and microbial analysis, the toxicity was determined on erythrocytes and the antimicrobial activity was studied to Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Candida krusei. The stability of curcumin was determined spectrophotometrically. The combination resulted in a increase in antioxidant activity of curcumin against DPPH , ABTS + and HOCl. We were unable to determine the effect of the association against... (Complete abstract click electronic access below)

The experiments in this thesis tested <i>in vitro</i> and <i>in vivo</i> the proposal that zinc-deficient superoxide dismutase, resulting from mutations or oxidative damage to the enzyme, gains ascorbate oxidase activity that contributes to the pathology of amyotrophic lateral sclerosis (ALS). They also tested whether flavonoids can help protect against this activity.<p>The <i>in vitro</i> experiments showed that zinc-extracted Cu/Zn-SOD (Cu-SOD) as well as SOD treated with H2O2 or H2O2 plus ascorbate accelerated ascorbate oxidation 100 to 300 %, while native SOD had no effect. With Cu-SOD, the activity was unaffected by EDTA, EGTA, or catalase, showing that the catalytic copper was firmly bound and that the H2O2 product of SOD activity was not responsible. Catechin and uric acid slowed ascorbate oxidation by Cu-SOD by 72% and 67%, respectively.<p>The <i>in vivo</i> study investigated tissue levels of ascorbate and biomarkers of oxidative stress in a transgenic mice bearing a mutation in Cu/Zn-SOD as a model of familial ALS (FALS mice), and the effects of dietary ascorbate and quercetin. In FALS mice on control modified AIN93G diet for 10 weeks compared to the wild-type, liver thiobarbituric acid reactive substances (TBARS) were 47% higher and liver oxidized vitamin C was 2800% higher. These results support, in liver, that mutant SOD acquired ascorbate oxidase activity and increased oxidative stress. The only difference in other tissues was a 136% increase in GSH/GSSG ratio in thigh muscle of FALS mice.<p>In dietary treatments of FALS mice, spinal cord TBARS was 93 % higher with ascorbate-supplemented diet compared to control diet, suggesting that dietary ascorbate increased oxidative stress. Also in spinal cord, oxidized-vitamin C was 250% higher in ascorbate + quercetin-fed FALS mice, which suggests there is no protection by quercetin against ascorbate oxidation. In brain, protein thiols were 56% and 58% lower in quercetin-fed and ascorbate + quercetin-fed FALS mice, suggesting that quercetin worsened oxidative damage. In liver, quercetin feeding produced a 40% decrease in vitamin C, total vitamin C and oxidized-vitamin C, perhaps by down-regulating ascorbate biosynthesis. Overall the results support a gain of ascorbate oxidase activity of mutant SOD in ALS, but do not support protection by dietary treatment with ascorbate or quercetin.