Transplantation is an acceptable treatment for end-stage lung and liver disease patients. In lung transplantation, long-term survival is limited due to Bronchiolitis Obliterans Syndrome (BOS) and in liver transplantation, Hepatitis C Virus (HCV) disease recurrence significantly impacts long-term survival. Treatment options are limited and often not successful. It is therefore important to conduct research on the factors contributing to the pathogenesis and disease severity of BOS and HCV to improve our understanding of the mechanisms and potentially reduce morbidity and mortality. Several factors may play a role. The focus of this thesis is to assess the role of Oxidative Stress (OxS) and nutrition on these patient populations. BOS is a frequent complication of lung transplantation. OxS may contribute to its pathogenesis and induce further tissue injury and inflammation. OxS can be influenced by several factors including nutrition. The cross-sectional study showed that BOS lung recipients have elevated markers of OxS in their Bronchoalveolar Lavage Fluid (BALF) compared to those without BOS. However, there was no difference in nutritional factors potentially affecting OxS. HCV reinfection post transplant is universal, significantly increasing morbidity and mortality. OxS is involved in the pathogenesis of chronic HCV but its role in HCV disease recurrence is unknown. A first study determined whether HCV liver recipients (HCV-LT) were more oxidatively stressed when compared to controls or HCV non-transplant patients. A second study assessed OxS at six-and 12 months post transplant and compared results between those with and without recurrence. The results showed that HCV-LT were more oxidatively stressed, vitamin A intakes were significantly lower and plasma gamma- tocopherol was significantly higher in HCV-LT. Additionally, those with recurrence were more oxidatively stressed at six-months (before recurrence) and 12 months compared to those without recurrence. No differences were seen regarding nutrition parameters. These results suggest that OxS is present in transplant recipients but that nutritional factors do not play a significant role. Other causes of OxS likely play a more significant role such as the presence of inflammation due to immunological reactions associated with BOS and the generation of reactive oxygen species (ROS/RNS) seen in patients with HCV disease.

Oxidative protein folding within the ER depends on the enzymatic action of numerous chaperones and oxidoreductases. In addition, this process requires the influx of metabolites and energy, including FAD (flavin adenine dinucleotide) and molecular oxygen. Secretory proteins and proteins destined to the secretory pathway need to undergo this process in order to obtain stability and full functionality. Since secretory proteins that fail to fully fold are eliminated by degradation, the process of ER oxidative protein folding is part of a group of ER-associated mechanisms commonly referred to as ER quality control. Interestingly, the proteins that mediate ER quality control can be found in a variety of diverse subdomains of the ER. We have found that the ER-oxidoreductase Ero1 is located on the mitochondria-associated-membrane, the MAM. This specialized subdomain of the ER has been shown to be crucial for a number of processes such as the synthesis of phospholipids as well as calcium-channelling between the ER and mitochondria. The goal of this thesis was to identify possible retention mechanisms and motifs of Ero1 to the MAM.

Malaria remains a major cause of morbidity and death, especially in developing countries. The effectiveness of conventional antimalarial drugs is waning and there is an urgent need for novel therapeutic approaches. An understanding of malaria parasite biology should facilitate the development of effective therapies that prevent and/or treat malaria. The present studies explore the potential of vitamin A (retinol) as an antimalarial agent. Retinol may act by changing the oxidant milieu within the malaria parasite. Therefore, the nature and consequences of oxidant injury during malaria infection, and its treatment with retinol, have also been explored. The antimalarial potential of retinol was characterised using an established in vitro culture system allowing assessment of efficacy through [3H]-hypoxanthine uptake at different erythrocytic stages of development of Plasmodium falciparum. Retinol losses during culture were significant (>50%). After adjusting for these losses, all parasite stages (early rings to mature trophozoites) showed similar retinol sensitivity, with values of the mean assayed concentration resulting in 50% growth inhibition (IC50) ranging from 10.1 to 21.4 μM. This range was above that in normal human serum (<3 μM) but below that associated with haemolysis in culture (>43 μM). Retinol pre-treatment of uninfected erythrocytes did not inhibit merozoite invasion. Retinol-treated parasites exhibited vacuolisation of the food vacuole and membrane rupture. A P. berghei murine model was used to determine the in vivo preventive and therapeutic efficacy of retinol. Multiple-dose retinol given to healthy Swiss mice before parasite inoculation reduced parasitaemia by 30%, a result comparable to the previously reported reduction in morbidity after vitamin A supplementation in children. A lesser reduction in parasitaemia of 10% was observed when retinol was given after the parasitaemia reached 10-15%. Retinol was ineffective in reducing parasitaemia when given either as single-dose supplementation post-inoculation or at regular intervals before and after infection. Retinol supplementation did not change plasma retinol concentrations during malaria infection whether or not retinol was given, but malaria attenuated the increase in liver retinol content. These data suggest that retinol has most value as prophylaxis. In contrast to published data from humans, previously healthy mice did not develop low plasma retinol concentrations during acute infection

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available online.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Tartu, 2004. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Louisville, 2003. / Department of Pharmacology and Toxicology. Vita. "December 2003." Includes bibliographical references (leaves 161-185).

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

Theses (M.S.)--Marshall University, 2007. / Title from document title page. Includes abstract. Includes vitae. Document formatted into pages: contains ix, 81 pages including illustrations. Bibliography: p. 69-77.