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The Role of Neuropeptides in Stress and in Pathophysiology of EAE
Kramáriková, Ivana ; Slanař, Ondřej (advisor) ; Kmoníčková, Eva (referee) ; Slíva, Jiří (referee)
Introduction and Aim: Neuropeptides are widely distributed group of biologically active substances and their effects depend on their activity and localization of specific receptors. The mechanism of the regulatory / modulatory effects of neuropeptides has not been fully elucidated yet, and these gaps in our knowledge make it difficult for them to influence them therapeutically. Our hypothesis was that similar to the effects of the galaninergic system on the cardiovascular system, the galaninergic system may be one of the important modulators of the hypothalamic-pituitary-adrenal axis and may therefore modulate the stress response or pathophysiology of selected neurological diseases. The aim of our study was to investigate presence and expression of CRH and Galanin receptors in the basal conditions and in stress in adenohypohysis and in hypophysis and in pathological conditions - in the spinal cords in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) and determine GalR1 cellular localization (oligodendrocytes, microglia, astrocytes, ependymal cells, and endothelial cells in the capillaries). Results: The expression of all tested galaninergic peptides was determined in the adenohypophysis. It was found that the expression of the GalR2 mRNA in adenohypophysis...
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Applied pharmacokinetics in preclinical research
Královičová, Jana ; Šíma, Martin (advisor) ; Večeřa, Rostislav (referee) ; Kmoníčková, Eva (referee) ; Paluch, Zoltán (referee)
Title: Applied pharmacokinetics in preclinical research Author: Mgr. Jana Královičová Abstract: This thesis addresses the topic of development and practical utilization of rat models in preclinical pharmacokinetic studies. An analysis dealing with the impact of intra- and inter- individual variability on the results of animal comparative studies showed that cross-over design brings more accurate conclusions in these experiments than the often-used parallel setting. Results obtained on the basis of a parallel design significantly differed in our investigation (AUClast ranged from 9.62 to 44.62 mg/ml.min.g). Furthermore, in 4 cases out of 15 pair comparisons of individual parallel groups, the confidence interval did not include the 100% value. That means that in more than a quarter of studies it would be misjudged that the compared drug formulations have different pharmacokinetic properties, though they are in fact the same product. The practical use of cross-over design is demonstrated in pharmacokinetic studies comparing the absorption of various formulations with abiraterone and cinacalcet. In a fasted state, a new, innovated formulation with abiraterone was better absorbed than the reference (AUClast of a reference 30.3 mg/ml.min.g, innovated formulation 81.0 mg/ml.min.g). Thiscorresponds to anticipations...
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The Role of Neuropeptides in Stress and in Pathophysiology of EAE
Kramáriková, Ivana ; Slanař, Ondřej (advisor) ; Slíva, Jiří (referee) ; Kmoníčková, Eva (referee)
Introduction and Aim: Neuropeptides are widely distributed group of biologically active substances and their effects depend on their activity and localization of specific receptors. The mechanism of the regulatory / modulatory effects of neuropeptides has not been fully elucidated yet, and these gaps in our knowledge make it difficult for them to influence them therapeutically. Our hypothesis was that similar to the effects of the galaninergic system on the cardiovascular system, the galaninergic system may be one of the important modulators of the hypothalamic-pituitary-adrenal axis and may therefore modulate the stress response or pathophysiology of selected neurological diseases. The aim of our study was to investigate presence and expression of CRH and Galanin receptors in the basal conditions and in stress in adenohypohysis and in hypophysis and in pathological conditions - in the spinal cords in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) and determine GalR1 cellular localization (oligodendrocytes, microglia, astrocytes, ependymal cells, and endothelial cells in the capillaries). Results: The expression of all tested galaninergic peptides was determined in the adenohypophysis. It was found that the expression of the GalR2 mRNA in adenohypophysis...
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Chromosomal damage and shortening of telomeres in cancer patients and healthy subjects
Kroupa, Michal ; Vodička, Pavel (advisor) ; Kmoníčková, Eva (referee) ; Rössner, Pavel (referee)
Impaired chromosome segregation during mitosis, inaccurate DNA damage response and excessive telomere shortening may all modulate the frequency of chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBL). There is evidence that increased frequency of structural CAs in PBL may be considered as a marker of enhanced cancer risk. In the present Thesis, an effect of variants in genes involved in mitotic checkpoint and DNA damage response on the inter-individual differences in CAs frequency in PBL was investigated. Considering the importance of disrupted telomere structure and its function in cancer biology, a link between telomere length and clinicopathological and molecular features of cancer patients was analysed. Furthermore, the relevance of telomere length and CAs frequency as markers of patients' survival was examined. The major outcomes of the Thesis, fully reported in detail in seven attached Manuscripts, are: I) Increased frequency of structural CAs and/or disrupted telomere length in PBL may be considered as risk factors for the different types of solid cancer; II) Telomere shortening in PBL of healthy subjects increased the frequency of structural CAs; III) Binary interactions of gene variants in mitotic checkpoint and DNA repair pathways may modulate the frequency of structural...
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The Study of Mechanisms of Hepatotoxic and Hepatoprotective Effects in a Model of Damaged Hepatocytes
Moravcová, Alena ; Lotková, Halka (advisor) ; Kmoníčková, Eva (referee) ; Kanďár, Roman (referee)
Liver damage has a variety of causes. Due to the role of liver in the metabolism of xenobiotics, liver damage is often caused by toxic substances. Despite the variety of causes, the mechanisms of damage may be common. Most often, oxidative stress is induced in the cell or important organelles are directly damaged. This leads to cell death, the initiation of an inflammatory response and the development of fibrosis. A major problem in Western civilization is Non Alcoholic Fatty Liver Disease (NAFLD), in which fat is stored in liver tissue. Steatotic hepatocytes may be more sensitive to damage compared to non-fatty ones. The study of hepatotoxicity and possible hepatoprotection requires suitable models for in vitro experiments. The first part of this work is therefore dedicated to the introduction of a model background using hepatocytes isolated from rat liver. First, we introduced a method of culturing hepatocytes in a sandwich and evaluated its benefit over cultivation in a monolayer, even for experiments lasting 48 hours, which are frequently used in our laboratory. Significant differences were recorded from day 4 of culture, when the sandwich model provides better preservation of morphological and functional parameters of hepatocytes. However, for our purposes of studying the mechanisms of...
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Chromosomal damage and shortening of telomeres in cancer patients and healthy subjects
Kroupa, Michal ; Vodička, Pavel (advisor) ; Kmoníčková, Eva (referee) ; Rössner, Pavel (referee)
Impaired chromosome segregation during mitosis, inaccurate DNA damage response and excessive telomere shortening may all modulate the frequency of chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBL). There is evidence that increased frequency of structural CAs in PBL may be considered as a marker of enhanced cancer risk. In the present Thesis, an effect of variants in genes involved in mitotic checkpoint and DNA damage response on the inter-individual differences in CAs frequency in PBL was investigated. Considering the importance of disrupted telomere structure and its function in cancer biology, a link between telomere length and clinicopathological and molecular features of cancer patients was analysed. Furthermore, the relevance of telomere length and CAs frequency as markers of patients' survival was examined. The major outcomes of the Thesis, fully reported in detail in seven attached Manuscripts, are: I) Increased frequency of structural CAs and/or disrupted telomere length in PBL may be considered as risk factors for the different types of solid cancer; II) Telomere shortening in PBL of healthy subjects increased the frequency of structural CAs; III) Binary interactions of gene variants in mitotic checkpoint and DNA repair pathways may modulate the frequency of structural...
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