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Novel bile acid derivatives as a promising therapeutic approach for liver and metabolic disorders
Štefela, Alžbeta ; Pávek, Petr (advisor) ; Vítek, Libor (referee) ; Juřica, Jan (referee)
IN ENGLISH LANGUAGE Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology Candidate: Mgr. Alžbeta Štefela Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of the doctoral thesis: Novel bile acid derivatives as promising therapeutic approach Bile acids (BAs) are amphipathic steroidal molecules that are traditionally known to facilitate intestinal digestion and absorption of lipids and fat-soluble substances. On top, the recent findings have revealed that they represent important signaling agents involved in the orchestration of lipid, glucose and energy metabolism and immune response. BAs exhibit these roles by activating intracellular nuclear receptors such as farnesoid X (FXR), pregnane X (PXR) vitamin D receptors. Furthermore, BAs act as endocrine signaling molecules and activate numerous biological cascades via a membrane G-protein-coupled receptor, termed TGR5. Therefore, the extensive modulation of BA scaffold underwent to identify compounds with specific targeting of above-mentioned receptors as a promising therapeutic approach for the treatment of various liver and metabolic disorders including cholestasis, biliary cirrhosis, nonalcoholic steatohepatitis or diabetes. The principal aim of this doctoral thesis was to investigate the structure...
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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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The biological role of the metabolic products of haem and bilirubin.
Jašprová, Jana ; Vítek, Libor (advisor) ; Farghali, Hassan (referee) ; Mičuda, Stanislav (referee)
Present work has been focused on the importance of the products of the heme catabolic pathway, in particular under conditions of unconjugated hyperbilirubinemias (neonatal jaundice and Crigler-Najjar syndrome (CNS)). The second part of the project was focused on the improvement of some pharmacological approaches used in the treatment of these diseases, as well as on studies of bilirubin products that are formed during the treatment by phototherapy (PT). Neonatal jaundice is one of the most common complications in neonates. Currently, there is no efficient pharmacotherapy and the treatment with blue light is used as a gold standard for severe neonatal jaundice. However, the absolute safety of PT has still not been confirmed. In this context, it is important to note that some neonatologists start the PT before serum bilirubin levels reach the recommended values and that patients with CNS type I (CNSI) are forced to be on life-long PT (unless undergoing liver transplantation). The focus of the present project was to study biological effects of bilirubin photoisomers (PI) in an in vitro model of the human neuroblastoma SH-SY5Y cells that are used for studies of the neuronal metabolism. In further studies performed on animal model of hyperbilirubinemic rats and mice, we investigated a suitable gene...
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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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Study on intracellular signal molecules of carbon monoxide and nitric oxide related to hepatotoxic and hepatoprotective effects of selected substances
Černý, Dalibor ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Vítek, Libor (referee)
Background and aims: Treatment of acute fulminant liver damage arising as a result of various origins (ischemia-reperfusion injury, toxic shock, an infectious cause or cholestasis) still remains a major clinical problem. We currently do not have available clinically proven, pharmacologically effective and universal compound for the treatment of acute liver injury. The main aim of my research work was, therefore, to test the potential hepatoprotective effect of selected cytoprotective drugs and try to find out or suggest their mechanism of action, which we have examined in the systems for the intracellular gaseous signaling molecules NO and CO, where the key enzymes for their formation are NOS / HO respectively. My PhD study had two main directions: 1) Experimental study of the relationship between HO / CO and NOS / NO systems in the environment of hepatotoxic substances on isolated primary rat hepatocytes and in rat model, 2) Evaluation of ameliorative effect of selected substances in the hepatotoxicity models and to test the relationship of this effect on changes in some parameters of cytotoxicity / cytoprotection, antioxidant parameters, gene expression of mRNA for selected genes and histological changes in the state of cells / tissues / organs. Methods: We measured urea, bilirubin and liver...
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The role of oxidative stress in hepatocarcinogenesis.
Kubíčková, Kristýna ; Vítek, Libor (advisor) ; Zelenka, Jaroslav (referee) ; Fraňková, Soňa (referee)
This thesis focuses on the importance of heme catabolic pathway in hepatic carcinogenesis. Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumour. It is primarily caused by hepatic cirrhosis or chronic viral hepatitis. Hepatic carcinogenesis is associated with increased oxidative stress. Thus, our study aimed to assess the expression of the genes involved in the homeostasis of oxidative stress in patients with HCC. The study was performed on patients with primary HCC (n = 29) and control subjects (n = 11), gene expressions of heme oxygenase 1 (HMOX1), biliverdin reductase A/B (BLVRA/B), endothelial growth factor (VEGFA), NADPH oxidase 2 (NOX2) and p22phox were analyzed in the liver tissue; the identical gene expressions were analyzed in peripheral blood leukocytes (PBL) in HCC patients (n = 32) and in healthy controls (n = 27). Expression of BLVRA in liver tissue and PBL was significantly increased in cancer patients, as was NOX2 expression in PBL. Expression of VEGFA in liver tissue and PBL was significantly decreased in cancer patients. The expression of the other genes studied did not differ between HCC patients and controls. These data are consistent with the results of our previous study on patients with chronic hepatitis C, in which BLVRA expression was also...
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Practical aspects of high-carbohydrate dieting in top sport
Jurková, Kateřina ; Vítek, Libor (advisor) ; Kovářová, Lenka (referee)
Topic: Practical aspects of high-carbohydrate dieting in top sport The topic of this thesis is sports nutrition. After a comprehensive summary of current scientific and generally accepted guidelines, the practical part is based on an example of the current state of sports nutrition in one concrete men's basketball team. Subsequently, the practical part combines the knowledge of theory and results of diet analysis of the current nutritional status in the team. The aim of the analytical part of the thesis was to find out the individual and subsequently average data of the monitored file through the registration of weekly eating diaries, both in terms of macro and micronutrients. These data were statistically processed using the program Sportvital-Nutrition (http://www.bonfit.cz/), whose database contains the most comperhensive information about the composition of individual foods and meals, allowing analysis of up to 30 nutritional parameters. The main aim of the application part of the thesis was to design and calculate a sample menu for seven whole days for top athletes based on predetermined and defined criteria based on theoretical background and analysis of collected eating diaries. These criteria were to follow the principles of healthy nutrition, i.e. primarily the variety, regularity and...
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Enzyme activity analysis of function domains belonging to model heme-containing sensor proteins
Prošková, Veronika ; Martínková, Markéta (advisor) ; Macek, Tomáš (referee) ; Vítek, Libor (referee)
EN This Ph.D. thesis focuses on the heme containing gas sensor proteins. These proteins are predominantly present in bacteria, in which play an important role in processes like, sporulation, antibiotic resistance and so on. Heme containing sensor proteins composed of two domains. First one is a globin domain, which contains the heme molecule. Interaction of heme with gas molecule acts as a signal for the activation/inactivation of the second functional domain. Part of this thesis is formed by a review, which summarized the current knowledge about heme containing sensor proteins. In the next part of this thesis we focused on three representatives from the group of oxygen sensor proteins - histidine kinase AfGcHK, diguanylate cyclase YddV and phosphodiesterase EcDOS. The main aim of this thesis was to solve the mechanism of interdomain/intraprotein signal transduction in two oxygen sensor proteins with globin fold of their sensor domain (AfGcHK, YddV). For this purpose, we used the kinetic analysis of their functional domain activity and the methods of structural biology. We also studied the mechanism of interprotein signal transduction in AfGcHK and its cognate partner RR protein. It was also tested, how the presence of sodium disulfide affects the functional properties of oxygen sensor proteins...
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Biological effects of edible algae.
Vaňková, Kateřina ; Vítek, Libor (advisor) ; Brůha, Radan (referee) ; Mičuda, Stanislav (referee)
Nutritional factors with antioxidant properties, such as those contained in edible algae or green plants, might be implicated in protection against cancer development. Chlorophyll and other tetrapyrrolic compounds, structurally related to heme and antioxidant bile pigment bilirubin, belong to important candidate molecules, which might be responsible for these effects. Based on our studies demonstrating antiproliferative effects of S. platensis edible alga extract on experimental model of human pancreatic adenocarcinoma we investigated in detail the effect of chlorophyll occurring abundantly in this alga. Since only scarce data exist on the antiproliferative effects of chlorophylls, the aim of our study was to assess these effects. The study was performed on experimental models of human pancreatic and prostate cancer. The inhibitory effects of chlorophylls (chlorophyll a, chlorophyll b, chlorophyllin and pheophytin a) on cell proliferation and cell viability were investigated in in vitro studies. Chlorophylls reduced the mRNA expression as well as activity of hemeoxygenase in tested pancreatic cancer cells. Simultaneously, chlorophylls played an important role in redox environment of studied cancer cell lines including modulation of mitochondrial membrane potential, reactive oxygen species (ROS)...
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