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.

Iron is an essential element for living organisms. However, as it is a transition metal, it can participate in Fenton reaction resulting in generation of free radicals and oxidative damage to tissues. Antioxidants may prevent possible iron toxicity by chelating free iron or scavenging free radicals. Falvonoids are naturally occurring substances that are capable of formation of complexes with metals, including iron. T h e y have been show to possess antioxidant activity, which depends on molecular complexity of numerous types of flavonoids, e.g. quercetin and silibinin. Bisphosphonates are synthetic drugs used to treat various metabolic diseases of bones. Their principál effect is an inhibition of osteclast activity leading to a decreased bone resorption. Bisphosphonates have been however shown to exert some antioxidant activity in in vitro experiments, too. The aim of this PhD thesis was to investigate the role of iron in toxicity of other metals (cadmium) and the effect of flavonoids (quercetin and silibinin) and bisphosphonates (clodronate, etidronate and risedronate) on iron-induced oxidative damage in vivo. Experiments were performed in male mice (CD-1, Charles River, 25-35 body weight). Iron was administered intraperitoneally or in the diet. Cadmium was administered subcutaneously. Flavonoids and...

The purposes of this study were 1) to investigate the release of cardiac biomarkers resulting from acute bouts of maximal intermittent exercise in a laboratory-based setting and set up an exercise-induced cardiac biomarker release (EICBR) model; 2) to compare the changes in cardiac biomarkers in normoxic and hypoxic environments and determine the effects of hypoxia; 3) to investigate the changes in oxidative stress biomarkers resulting from acute bouts of maximal intermittent exercise in normoxic and hypoxic environments at multiple time points; and 4) to observe the relationship between oxidative stress and EICBR and explore the hypothesis that lipid peroxidation triggers the release of cardiac biomarkers from the cytosolic pool. The maximal oxygen consumption (VO2max) and the corresponding velocity of VO2max (vVO2max) of ten well-trained male marathon runners (age 22.1±2.6 y, body mass 64.0±4.9 kg and height 177.3±3.9 cm) was determined under normoxic (FIO2=21.0%, VO2max_N=64.72±5.63 ml∙kg-1∙min-1 and vVO2max_N=18.2±1.0 km∙h-1) and hypoxic (FIO2=14.4%, VO2max_H=62.16±6.74 ml∙kg-1∙min-1 and vVO2max_H=16.7±0.7 km∙h-1) conditions in two experimental trials. One set of conditions was tested in each trial. The order in which each participant faced each trial was selected at random and the trials were separated by 72 h. The ten participants also completed three maximal intermittent exercise protocols, under normoxic (trial N, FIO2=21.0%), absolutely hypoxic (trial AH, FIO2=14.4%) and relatively hypoxic (trial RH, FIO2=14.4%) conditions. The order in which the participants faced the three conditions was once again selected at random and the protocols were separated by at least 7 d. Each bout of maximal intermittent exercise in trials N and AH consisted of a hard run of 16.4±0.9 km∙h-1 (90% vVO2max_N) for 2 min, followed by an easy run of 9.1±0.5 km∙h-1 (50% vVO2max_N) for 2 min with a 2% slope. In trial RH, each bout of exercise consisted of a hard run of 15.0±0.6 km∙h-1 (90% vVO2max_H) for 2 min, followed by an easy run of 8.4±0.3 km∙h-1 (50% vVO2max_H) for 2 min with a 2% slope. Each of the three trials consisted of 23 bouts of maximal intermittent exercise, performed over 92 min. Measurements of the serum of the antecubital venous blood were performed pre- and post- (0 h, 2 h, 4 h and 24 h) exercise. The measurements were taken at five time points for each of the three conditions. The cardiac damage biomarkers of high sensitivity cardiac troponin T (hs-cTnT) and cardiac troponin I (cTnI) and the oxidative stress biomarkers of malondialdehyde (MDA), lipid hydroperoxide (LH), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and total antioxidant capacity (TAOC) were analysed. Heart rate (HR) and arterial oxygen saturation (SaO2) were recorded before and during exercise. Due to the skewed distribution of the data (P<0.05), a non-parametric Friedman’s test was used to compare the differences in the levels of hs-cTnT and cTnI between pre- and post-exercise and at each time point for the three conditions. MDA, LH, SOD, CAT, GSH, TAOC and HR were normally distributed (P>0.05) and were analysed using one-way repeated ANOVA tests. Pearson’s product moment correlation coefficients were used to determine the degree of association between the peak levels of hs-cTnT and cTnI, and MDA, LH, SOD, CAT, GSH and TAOC. In trial N, the level of hs-cTnT was elevated 0 h post-exercise (9.628±3.797 pg∙ml-1 was significantly different from the pre-exercise level of 5.118±1.857 pg∙ml-1, P=0.005), reached its peak level 2 h post-exercise (24.290±18.628 pg∙ml-1 was significantly different from the pre-exercise level, P=0.005) and returned to the baseline level at 24 h post-exercise (5.978±1.849 pg∙ml-1). The peak levels of hs-cTnT (N, AH 37.001±31.995 pg∙ml-1, RH 28.614±23.628 pg∙ml-1) and cTnI (N 0.0375±0.0437 ng∙ml-1, AH 0.0475±0.0533 ng∙ml-1, RH 0.0345±0.0375 ng∙ml-1) did not significantly differ under the three conditions. In trial AH, the peak levels of hs-cTnT (2 h, 4 h) and cTnI (2 h, 4 h) were highly related to the MDA_0h and the TAOC_24h. In trial RH, the peak levels of hs-cTnT (2 h, 4 h) and cTnI (2 h, 4 h) were highly related to the TAOC_4h. It was concluded that maximal intermittent exercise can be used to trigger EICBR. The stimulus of hypoxia did not induce more cardiac damage in this exercise model. Maximal intermittent exercise potentially triggers EICBR through oxidative stress, especially lipid peroxidation. Keywords: cardiac biomarkers, hs-cTnT, cTnI, oxidative stress, hypoxia