National Repository of Grey Literature 37 records found  1 - 10nextend  jump to record: Search took 0.01 seconds. 
Modulation of cholesterol and bile acid metabolism via soluble endoglin and pharmacotherapy
Igreja e Sá, Ivone Cristina ; Nachtigal, Petr (advisor) ; Vítek, Libor (referee) ; Červený, Lukáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Biological and Medical Sciences Doctoral Degree Program Pharmacology and Toxicology Candidate M.Sc. Ivone Cristina Igreja e Sá Supervisor prof. PharmD. Petr Nachtigal, Ph.D. Advisor Title of Doctoral Thesis Modulation of cholesterol and bile acid metabolism via soluble endoglin and pharmacotherapy Endoglin (Eng, CD105) is a transmembrane glycoprotein and co-receptor of the Transforming growth factor-β (TGFβ) receptor complex. Upregulated expression of Eng has been implicated in endothelial dysfunction, liver impairment, and hepatic fibrosis development. When Eng is cleaved by the matrix metalloproteinase-14 (MMP14), its soluble form termed soluble endoglin (sEng, sCD105) is released into the circulation. Increased plasma levels of sEng have not only been observed in patients with cardiovascular and metabolic diseases associated with hypercholesterolemia (e.g., atherosclerosis) but have also been reported to promote conditions of the metabolic syndrome (e.g., hypertension). However, the direct role of sEng in the modulation of hepatic metabolism and liver functions under physiologic or pathological conditions has not been previously explored. Therefore, this doctoral thesis aimed to test the hypothesis that...
Modulation of cholesterol and bile acid metabolism via soluble endoglin and pharmacotherapy
Igreja e Sá, Ivone Cristina ; Nachtigal, Petr (advisor) ; Vítek, Libor (referee) ; Červený, Lukáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Biological and Medical Sciences Doctoral Degree Program Pharmacology and Toxicology Candidate M.Sc. Ivone Cristina Igreja e Sá Supervisor prof. PharmD. Petr Nachtigal, Ph.D. Advisor Title of Doctoral Thesis Modulation of cholesterol and bile acid metabolism via soluble endoglin and pharmacotherapy Endoglin (Eng, CD105) is a transmembrane glycoprotein and co-receptor of the Transforming growth factor-β (TGFβ) receptor complex. Upregulated expression of Eng has been implicated in endothelial dysfunction, liver impairment, and hepatic fibrosis development. When Eng is cleaved by the matrix metalloproteinase-14 (MMP14), its soluble form termed soluble endoglin (sEng, sCD105) is released into the circulation. Increased plasma levels of sEng have not only been observed in patients with cardiovascular and metabolic diseases associated with hypercholesterolemia (e.g., atherosclerosis) but have also been reported to promote conditions of the metabolic syndrome (e.g., hypertension). However, the direct role of sEng in the modulation of hepatic metabolism and liver functions under physiologic or pathological conditions has not been previously explored. Therefore, this doctoral thesis aimed to test the hypothesis that...
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...
Targeting mitochondria to overcome resistance of breast cancer to therapy
Rohlenová, Kateřina ; Neužil, Jiří (advisor) ; Špíšek, Radek (referee) ; Vítek, Libor (referee)
(EN) Tumours are heterogeneous and consist of multiple populations of cells. The population of cells with tumour-initiating capability is known as cancer stem cells (CSC). Cells with increased stemness properties and elevated resistance to anti-cancer treatment have been shown to be highly affected upon decline of mitochondrial respiration, linking the concept of CSCs to deregulated bioenergetics. Consistently, functional electron transport chain (ETC) is crucial in tumorigenesis. Expression of HER2 oncogene, associated with resistance to treatment in breast cancer, has been connected with regulation of mitochondrial function. We therefore investigated the possibility that manipulation of mitochondrial bioenergetics via disruption of ETC eliminates the conventional therapy-resistant populations of tumour, such as CSCs and HER2high cells. We demonstrate that HER2high cells and tumours have increased complex I-driven respiration and increased assembly of respiratory supercomplexes (SC). These cells are highly sensitive to MitoTam, a novel mitochondria-targeted derivative of tamoxifen, acting as a CI inhibitor and SC disruptor. MitoTam was able to overcome resistance to tamoxifen, and to reduce the metastatic potential of HER2high cells. Higher sensitivity of HER2high cells to MitoTam is dependent on...
Role of microbiota and gut inflammation in the pathogenesis of experimental colorectal cancer
Klimešová, Klára ; Tlaskalová - Hogenová, Helena (advisor) ; Vítek, Libor (referee) ; Reiniš, Milan (referee)
Mucosal surface of the gut is in continuous contact with foreign compounds derived from diet as well as from commensal or pathogenic microorganisms. Thousands of years of symbiosis resulted in tight cooperation between the host and its microbiota. Microbiota composition and metabolism actively influence host's physiological as well as pathological processes. Chronic inflammation is characterized by prolonged active inflammatory response associated with tissue damage. This status results from accumulation of defects in various factors including gut barrier functions as well as mechanisms of innate and adaptive immunity. It's commonly accepted that chronic inflammatory diseases of the gastrointestinal tract like IBD, are associated with an increased risk of CAC development. Two publications related to this thesis deal with modulatory effects of peroral administration of components of commensal bacteria or probiotics on intestinal inflammation. Using acute or chronic model of DSS-induced colitis, we demonstrated that oral treatment of BALB/c mice with membranous fraction of the commensal, Parabacteroides distasonis, as well as with lysate of probiotic bacterium Lactobacillus casei DN-114 001 significantly reduces the severity of intestinal inflammation. Moreover, the treatment was associated with reduction of...
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...
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...
Genetic profile of genes involved in cell cycle control and the risk of sporadic colorectal cancer in the Czech Republic
Poláková, Veronika ; Vodička, Pavel (advisor) ; Kozubík, Alois (referee) ; Vítek, Libor (referee) ; Försti, Asta (referee)
The Czech Republic has one of the highest incidence rates of colorectal cancer (CRC) worldwide. The vast majority of the CRC cases arises sporadically, with susceptibility determined by genetic factors in interaction with an environment. Cell cycle and DNA repair genes play a fundamental role in CRC development and presents many common variants. In the present study, we genotyped common variants in cell cycle and DNA repair genes to assess the influence of genetic variation on the CRC risk, in 614 hospital-based CRC cases and 614 matched controls.
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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