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The importance of biosynthetic and catabolic pathway of cholesterol in inflammatory and tumor diseases
Leníček, Martin ; Vítek, Libor (advisor) ; Haluzík, Martin (referee) ; Mareček, Zdeněk (referee)
This thesis focuses on the importance of intermediate products of biosynthetic and catabolic pathway of cholesterol. The aim of the first part of the thesis is mainly to investigate, whether statins (HMG- CoA reductase inhibitors) possess antitumor properties and to compare the differences in antitumor potential of individual statins. The other part of the thesis aims at the utilization of 7α-hydroxycholest-4-en-3-one (C4), a promising marker of cholesterol 7α-monooxygenase (CYP7A1) activity and bile acid malabsorption. We demonstrated antitumor effect of statins on an experimental model of pancreatic cancer. Individual statins, however, differed significantly in their efficacy, depending on their physico-chemical properties. Our data suggests, that the most likely (but not the only) mechanism of antitumor effect of statins is decreased prenylation of signaling proteins, especially Ras protooncogene. We set up a reliable method for measurement of C4, which facilitated our research in CYP7A1 regulation. We demonstrated, that promoter polymorphism -203A>C might affect CYP7A1 activity, that diurnal variability of CYP7A1 activity might be triggered by insulin, and that insulin resistance in patients with non-alcoholic fatty liver disease impedes the feedback regulation of CYP7A1, which may lead to disease...
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Enterohepatic circulation of bilirubin
Zelenka, Jaroslav ; Vítek, Libor (advisor) ; Entlicher, Gustav (referee) ; Červinková, Zuzana (referee)
Bilirubin is a main physiological product of heme degradation possessing important antioxidant and antiinflammatory properties. On the other hand, it could be neurotoxic during severe unconjugated hyperbilirubinemia combined with insufficiency of blood-brain barrier (neonatal jaundice). It is secreted from the body via bile and is further metabolized in the intestine. Part of the substance is reduced to urobilinoids, part is adsorbed to the intestinal content and some part could be reabsorbed back to the systemic circulation. This enterohepatically and enterosystemically circulating fraction varies in size depending on the rate of bilirubin secretion, solubility in the intestine and intensity of its intestinal metabolism. Under specific circumstances, EHC and ESC may significantly increase serum and bile bilirubin levels and influence physiological as well as pathological processes occuring in the body. Among the most important is the protective elevation of UCB levels in Gilbert syndrome subjects and dangerous increase in severity of neonatal jaundice. In the presented thesis, the mechanisms affecting EHC and ESC of bilirubin and tools for further research in BP metabolism were investigated. The solubility of intestinal UCB is strongly decreased by addition of divalent cations. However, such approach to...
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The influence of pharmacology and reduction diet on metabolism of adipose tissue in obese patients with diabetes type 2
Anderlová, Kateřina ; Haluzík, Martin (advisor) ; Vítek, Libor (referee) ; Stárka, Luboslav (referee)
Insulin resistance, obesity, type 2 diabetes mellitus and their complications are linked together under definition called Metabolic or Reaven Syndrome. The presence of Metabolic Syndrome increases the risk of atherosclerosis and consequently cardiovascular morbidity and mortality. Metabolic Syndrome belongs among civilization diseases and due to changes in our life styles becomes major health and social-economic issue. The insulin resistance is considered primary pathology that may induce other components of Metabolic Syndrome. Research conducted within last decade brought significant results and showed how important is the adipose tissue in the development of insulin resistance especially in the context of discovery of endocrine function of adipose tissue. The existence of nuclear receptors PPAR (peroxisome proliferator activated receptor) could explain the interaction between particular tissues and hormonal factors which may induce insulin resistance. When the PPAR receptors are bound by lipophilic ligands they directly affect transcriptional processes in cell nucleus and induce expression of genes involved in metabolism of lipids and carbohydrates, in the regulation of inflammation, in tumor growth regulation, in immune response, in cell differentiation and etc. In current medical practice...
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Th Role of Experimental Treatment with Statins on the Expression of Genes Involved in the Pathogenesiis of Pancreatic Cancer
Marková, Lucie ; Vítek, Libor (advisor) ; Krechler, Tomáš (referee)
Úvod: Karcinom pankreatu patří mezi nádorová onemocnění s nejhorší prognózou. Vzhledem к lokalizaci pankreatu v retroperitoneu i dalším anatomickým a patofyziologickým souvislostem se příznaky karcinomu slinivky objevují velmi pozdě a u většiny nemocných již není možné zahájit radikální léčbu. Z těchto důvodů jen 5% nemocných přežívá 5 let od stanovení diagnózy. Většinou postihuje nemocné mezi 30-70 lety, přičemž průměrný věk v době stanovení diagnózy je přibližně 56 let. V posledním desetiletí se dostává do popředí zájmu tzv. DNA microarray technologie umožňující monitorování exprese genů. Exprese genů představuje komplexní proces, kterým je genetická informace uložená ve formě deoxyribonukleové kyseliny (DNA) přeměněna v konkrétní buněčné struktury a metabolické nástroje. Produkty exprese genů jsou molekuly bílkovin, jsou jimi však i ribonukleové kyseliny (RNA). Statiny (inhibitory HMG-CoA reduktázy) patří mezi klíčové léky v léčbě hypercholesterolémie. Z výzkumných studií vyplývá, že tato skupina léků má velmi významné protinádorové vlastnosti. Inhibicí HMGCoA reduktázy, klíčového enzymu v syntéze cholesterolu, totiž dochází také к depleci jednotlivých meziproduktů v syntéze cholesterolu, z nichž nejvýznamnější je farnesyl pyrofosfát hrající důležitou roli v buněčné signalizaci ovlivňující apoptózu....
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Immune Reactivity of Hepatic T Lymphocytes and Their Role in Pathogenesis of Liver Diseases
Carey, Ivana ; Vítek, Libor (advisor) ; Urbánek, Petr (referee) ; Červinková, Zuzana (referee)
The interaction of different pathogens with systemic and liver immune system is suggested an important factor in pathogenesis of various liver diseases. The variable aspects of this interaction and different immune system patways were subject of the present thesis. The ultimate goal of the present thesis was to investigate the reactivity of the local and systemic immune system against different disease related antigens and to demonstrate their participation in liver diseases and liver damage pathogenesis. Chronic hepatitis B infection, chronic hepatitis C infection and drug-induced liver damage were investigeted by 7 different studies using ex-vivo and in-vitro methods. In general, chronic liver diseases are associated with increased oxidative stress. Due to this fact, the role bilirubin, a potent endogenous antioxidant, was also analysed. The results of presented studies demonstrate clearly active participation of immune system to the pathogenesis of liver diseases, its direct involvement in liver damage and its effect on outcome of disease. The protective role of bilirubin in oxidative stress was confirmed. In conclusion, the results of all presented studies in this thesis illustrate the role of systemic as well as liver based immune system as a crucial player in the pathogenesis of liver...
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Complement landscape problems in document Politika územního rozvoje on the basis compare landscape problems in Czech republic and Great Britain
VÍTEK, Libor
This thesis is to evaluate and compare some approach of the solution spatial aspects of landscape problems among choose Czech and Britain documents. This study is oriented on Czech policy dokument Politika územního rozvoje (2008 {--} 2012) and other similar document of the single regions Great Britain. Partial goals of thesis have to been searched out the documents for planning in Czech republic and Great Britain, explored and described hierarchy of planning of both countries. Subsequently compare similar documents accordance with degree attention, which devote the define spatial aspects of landscape problems. Primary objective have to been determined poorly places in solution landscape problems in document Politika územního rozvoje and propose their inclusion for up-dating document in 2012.
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