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Effects of heme metabolism on HIV-1 latency reversal
Kompas, Maroš ; Mělková, Zora (advisor) ; Trejbalová, Kateřina (referee)
Progression of HIV infection in HIV-positive patients can now be successfully controlled by the combined antiretroviral therapy. However, due to persistence of the latent reservoir, HIV infection cannot be cured. The immune system nor current therapeutic approaches can target the pool of latently infected cells, thus strategies aiming at reactivation and subsequent elimination of the reservoir cells are recognized as possibly curative. This thesis has examined previously demonstrated latency-reversing capacity of heme arginate (HA), another redox modulator, and their synergism with Protein Kinase C inducer phorbol myristate acetate (PMA) to reactivate HIV-1 in the context of heme metabolism. HIV-1 reactivation was assessed by the intensity of green fluorescence in the model Jurkat cell line clone (A2), containing HIV-1 "mini-virus" (LTR-Tat-IRES-EFGP-LTR), as well as in the A2 cells stably transfected with plasmid vectors encoding cDNA for specific factors of heme metabolism and for control luciferase. While the administration of redox modulator alone did not stimulate expression from the HIV-1 LTR and HA reactivated the "mini-virus" only slightly, both compounds revealed a synergy with PMA in all cell lines studied. Basal and induced expression of EGFP was found variable in cells transfected with...
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Antiproliferative effects of heme catabolic pathway's products
Koníčková, Renata ; Vítek, Libor (advisor) ; Haluzík, Martin (referee) ; Farghali, Hassan (referee)
Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....
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Antiproliferative effects of heme catabolic pathway's products
Koníčková, Renata ; Vítek, Libor (advisor) ; Haluzík, Martin (referee) ; Farghali, Hassan (referee)
Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....
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