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Effect of stress on expression of glucocorticoid receptors and enzymes of glucocorticoid metabolism in specific structures of rat brain
Kvapilová, Pavlína ; Pácha, Jiří (advisor) ; Telenský, Petr (referee)
Stress response is trigerred by a number of factors, which, depending on the type of response they generate, involve different brain structures. These structures then relay the information to the paraventricular nucleus of hypothalamus (PVN), which is the main integration center for information about the imbalance of homeostasis induced by stressors. If it meets a sufficient number of excitatory signals, the PVN activates the hypothalamic pituitary adrenal axis, which ultimately triggers the secretion of stress hormones glucocorticoids, which then act back on the brain. This action is influenced by several factors, mainly the presence of local metabolism of glucocorticoids. Local metabolism is provided by the enzymes 11-hydroxysteroid dehydrogenases, which can locally activate or deactivate the hormone molecules and thus amplify or attenuate their effects.
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Oxidative degradation of ticagrelor
Kvapilová, Pavlína ; Kubíčková, Anna (advisor) ; Kozlík, Petr (referee)
This thesis deals with the oxidative degradation of the active pharmaceutical substance ticagrelor, which is used together with acetylsalicylic acid as a prevention against atherothrombotic events in adult patients. In this thesis, oxidation was studied both in the traditional way using hydrogen peroxide and the new electrochemical approach. The oxidation was performed with a 3% solution of hydrogen peroxide at 50 řC in various solvents. An electrochemical method for the oxidation of ticagrelor was developed as part of the thesis. This method was then optimized to achieve the highest possible oxidation efficiency. The thesis also investigated the effect of excipients on the oxidation rate. Degradation products were evaluated using the ultra-high performance liquid chromatography. The structures of all the degradation products formed were identified using a QDA mass detector. Key words: UPLC, electrolysis, degradation studies, pharmaceuticals
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Effect of inflammation on local expression of 11β-HSD1
Kvapilová, Pavlína ; Telenský, Petr (referee)
Inflammation is first-line host defense mechanism of organism that aims to remove unwanted pathogens, repair damaged tissue and restore homeostasis. Glucocorticoids belong to effective immune response regulators. Their availibility in the tissue is due to several factors, including local metabolism in the cell that provide 11β-hydroxysteroid dehydrogenase enzymes. We know two isoforms 11HSD1 and 11HSD2. 11HSD1 locally in the cell catalyzes the conversion of the inactive glucocorticoid molecule to active, and thus appears to be a significant player in regulating the inflammatory response. The aim of this work was to analyze gene expression of 11HSD1 together with expression of cytokines in specific microanatomical compartments of the immune system involved in immune response to experimental DSS colitis. Keywords Metabolism of glucocorticoids; Cytokine microenvironment; Lymphoid organs; Colon; Dextran-sodium-sulfate colitis
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Synthesis of five-membered ring analogues of Amaryllidaceae alkaloids
Kvapilová, Pavlína ; Matoušová, Eliška (advisor) ; Jindřich, Jindřich (referee)
This bachelor Thesis deals with the synthesis of polycyclic compounds containing all-carbon quaternary centres. Quaternary centres with a similar substitution as our target compounds can be found in some natural products. In particular, nitrogen-containing compounds, structurally related to Amaryllidaceae alkaloids, have been prepared in this work. For the construction of the all-carbon quaternary centre we used tandem cyclization/Suzuki cross-coupling and halocarbocyclisation reaction sequence. The first part of the Thesis is dedicated to compounds that have a nitrogen atom protected by a p-methoxybenzenesulfonyl group. In the second part we deal with the preparation of N-methyl derivatives of these compounds. The third part is dedicated to the synthesis of a protected amine from 2-oxazolidinone, which we have unsuccessfully used for the preparation of polycyclic compounds with a hydroxyethyl group on the nitrogen atom. Key words: Synthesis, Amaryllidaceae alkaloids, polycyclic compounds, biological activity
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Inhibition of 11β-hydroxysteroid dehydrogenase 1 in hippocampus
Kvapilová, Pavlína ; Pácha, Jiří (advisor) ; Horníková, Daniela (referee)
This diploma thesis deals with the inhibition of 11-hydroxysteroid dehydrogenase 1 in the hippocampus. The aim was to determine whether the selected inhibitors with intraperitoneal administration pass through the blood-brain barrier, to determine the time course of inhibition of hippocampal 11-HSD1, to compare the efficacy of different inhibitors and to find out plasma concentrations of the most effective inhibitors and compare them with plasma concentrations of glucocorticoids. Selected inhibitors were emodin, quercetin, glycyrrhetinic acid and substituted adamantyl C544. The most significant effect on the inhibition of 11-HSD1 demonstrated nonselective inhibitor glycyrrhetinic acid and selective inhibitor substituted adamantyl C544. By comparing the plasma levels of these inhibitors, and the plasma levels of glucocorticoids was found that the selective inhibition by the C544 does not affect the overall level of corticosterone, and thus the activity of the HPA axis, which makes it important potent inhibitor of 11-HSD1 suitable for further studies. Key words 11-hydroxysteroiddehydrogenase 1, HPA axis, glucocorticoids, hippocampus, inhibition, emodin, quercetin, glycyrrhetinic acid, substituted adamantyl C544
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Effect of stress on expression of glucocorticoid receptors and enzymes of glucocorticoid metabolism in specific structures of rat brain
Kvapilová, Pavlína ; Pácha, Jiří (advisor) ; Telenský, Petr (referee)
Stress response is trigerred by a number of factors, which, depending on the type of response they generate, involve different brain structures. These structures then relay the information to the paraventricular nucleus of hypothalamus (PVN), which is the main integration center for information about the imbalance of homeostasis induced by stressors. If it meets a sufficient number of excitatory signals, the PVN activates the hypothalamic pituitary adrenal axis, which ultimately triggers the secretion of stress hormones glucocorticoids, which then act back on the brain. This action is influenced by several factors, mainly the presence of local metabolism of glucocorticoids. Local metabolism is provided by the enzymes 11-hydroxysteroid dehydrogenases, which can locally activate or deactivate the hormone molecules and thus amplify or attenuate their effects.
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