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Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukemia
Nálevková, Karolína ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Karolína Nálevková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: PharmDr. Aleš Šorf, Ph.D. Title of diploma thesis: Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukaemia. Acute myeloid leukaemia (AML) is a malignant disease of hematopoietic system. Available treatment does not produce suitable results, as the 5-year survival is only about 30%. The primary induction therapy has remained the same for many years - combination of cytarabine and anthracycline, known as "7+3". By karyotyping and immunophenotyping of patients in the last few years, heterogeneity of the disease was confirmed, which also led to the development of targeted drugs. Other factors such as transporters that play a role in drug transport across plasma membranes may affect the treatment outcome. In my diploma thesis, I therefore focused on the effect of selected membrane transporters OCTN1, OCTN2 and ABCC4 on the prognosis and therapy of AML patients. First, we specified the number of transcripts of studied genes using the RT-PCR and ddPCR methods in samples isolated from mononuclear cells of the blood of de...
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Study of adenosine effects on proliferation of BeWo cell line
Papírník, Josef ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Josef Papírník Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Studium of adenosine on proiferation activity in BeWo cell line The placenta is a rapidly developing organ that provides nutrition, protection and environment for the growing fetus. Fetal development is dependent on the supply of nutrients from the mother's blood either by passive diffusion or mediated by transporters. One of the essential nutrients are nucleosides, which are known to promote DNA synthesis and thus the growth of certain tissues. In order to pass across the plasma membrane they need nukleoside transporters (NTs) because of its hydrophilic feature. Additionally Ado takes part in cell signaling. Its wide- ranging effects, including influencing proliferation, are mediated by its binding to adenosine receptors (ARs). The placenta expresses NTs and ARs, which means that it is equipped to uptake nucleosides from maternal blood and has ability to receive signals from the external environment via the adenosine molecule. However, the importance of nucleosides for placental growth has not been investigated yet. The aim of this thesis is to test the effect of nucleosides on the proliferation of...
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Study of adenosine effects on proliferation of JEG-3 cell line
Nguyen, Ngoc Duong ; Červený, Lukáš (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Nguyen Ngoc Duong Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of adenosine on the proliferation of JEG-3 cell line Adenosine is a purinergic signaling molecule that is used in nucleic acid synthesis. Transport of hydrophilic nucleosides through the plasma and/or organelle membranes is provided by equilibrative nucleoside transporters (ENTs), members of the SLC29A transporter family, and concentrative nucleoside transporters (CNTs), members of the SLC28A transporter family. The placenta is a complex and rapidly growing organ. It shows some patterns similar to tumors except for the fact that the placenta's growth is fully controlled. It was found that extracellular nucleosides support the proliferation of cancerous and some non-cancerous cells. The placenta expresses high levels of NTs which indicates the placenta's ability to take up the nucleosides from circulation, however, the contribution of this process to placental growth is known. The diploma thesis aims to test the effect of adenosine and other nucleosides on trophoblast proliferation. We evaluated whether adenosine and other nucleosides increase the proliferation of the choriocarcinoma-derived JEG-3 cell...
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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...
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Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukemia
Nálevková, Karolína ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Karolína Nálevková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: PharmDr. Aleš Šorf, Ph.D. Title of diploma thesis: Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukaemia. Acute myeloid leukaemia (AML) is a malignant disease of hematopoietic system. Available treatment does not produce suitable results, as the 5-year survival is only about 30%. The primary induction therapy has remained the same for many years - combination of cytarabine and anthracycline, known as "7+3". By karyotyping and immunophenotyping of patients in the last few years, heterogeneity of the disease was confirmed, which also led to the development of targeted drugs. Other factors such as transporters that play a role in drug transport across plasma membranes may affect the treatment outcome. In my diploma thesis, I therefore focused on the effect of selected membrane transporters OCTN1, OCTN2 and ABCC4 on the prognosis and therapy of AML patients. First, we specified the number of transcripts of studied genes using the RT-PCR and ddPCR methods in samples isolated from mononuclear cells of the blood of de...
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Migraine and its treatment
Petríková, Andrea ; Jirkovský, Eduard (advisor) ; Červený, Lukáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmacology and Toxicology Supervisor: PharmDr. Eduard Jirkovský, Ph.D. Author: Andrea Petríková Title of Diploma Thesis: Migraine and its treatment Migraine is one of the primary headaches, manifested in repeated attacks of severe one-sided and throbbing headaches, usually lasting 4-72 hours. They are accompanied by one of the following symptoms: photophobia, phonophobia, odorophobia, nausea, vomiting. From one seizure to the next, the patient feels like a healthy patient. In my work I describe current pharmacotherapeutic procedures in the treatment of migraine. In the first part of the diploma thesis, I presented a literature review of migraines, which begins with the classification of headaches. I continue with the definition of migraine, history, classification of migraine, pathophysiology, prevalence and diagnostic criteria of migraine. In the second part I describe the different types of treatment with their procedures and the drugs that are used. Based on our knowledge of the pathophysiology of migraine, new drugs have been developed for the treatment of acute migraine attacks that target calcitonin gene-related peptide (CGRP) and serotonin 5-HT1F receptors. I describe their mechanism, which drugs have been...
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The impact of SIRT1 inhibition on zebrafish morphology and behavior
Faustová, Zuzana ; Červený, Lukáš (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Zuzana Faustová Supervisor: Prof. Doutor Jorge Miguel de Ascenção Oliveira PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: The impact of SIRT1 inhibition on zebrafish morphology and behavior After discovery of connection between yeast Silent Information Regulator 2 (Sir2) and its ability to alter lifespan, Sir2 and its seven mammalian orthologs became very attractive therapeutic target. These so called sirtuins are members of a histone deacetylase family. They possess unique catalytic activity having nicotinamide adenine dinucleotide as a cofactor and their function can be influenced by environmental factors. The aim of this diploma thesis was to extend knowledge of Sirtuin 1 (SIRT1), which is from all mammalian sirtuins considered to have the closest relation to yeast Sir2. At first we tested the impact of SIRT1 inhibition on early developmental stages of zebrafish (Danio rerio) embryos and larvae, finding out that SIRT1 is important for normal development and SIRT1 inhibition or malfunction result in cardiovascular defects, delayed development, and death. Additionally, we tried to learn more about SIRT1 and its connection with Parkinson's disease by combining nontoxic doses...
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Study of the role of nucleoside transporters in intestinal absorption with the use of in vitro transport method based on the Caco-2 cell line.
Ďurišová, Markéta ; Červený, Lukáš (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Mgr. Markéta Ďurišová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of rigorosum thesis: Study of the role of nucleoside transporters in intestinal absorption with the use of in vitro transport method based on the Caco-2 cell line. Perorally used drugs are primarly absorbed in the small intestine. Enterocytes, forming the intestinal barrier, express a large number of transporters, representing both ATP-binding (ABC) and "solute carrier" (SLC) transporters, which can significantly affect the pharmacokinetics of the drugs transmitted by them. For this reason, FDA and EMA are currently focusing on studying these interactions and their effects on drug permeability. The aim of this thesis was to investigate whether the equilibrative nucleoside transporters (ENTs), belonging to the SLC transporters, are involved in the absorption of nucleosides (adenosine and thymidine) and subsequently abacavir, the nucleoside antiretroviral. The in vitro transport method was performed on polarized, Caco-2 cell monolayer. By the statistical analysis of acquired data was found, that although the expression of ENTs was confirmed on the apical side of the Caco-2 cell membrane, the transport of nucleosides [3H]ADE and...
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Analysis of association of MHC and KIR variants with the course of lentivirus induced disease by next-generation sequencing.
Zelníková, Jana ; Jílek, Petr (advisor) ; Červený, Lukáš (referee)
Jana Zelníková Analysis of association of MHC and KIR variants with the course of lentivirus induced disease by next-generation sequencing Thesis Univerzita Karlova v Praze, Farmaceutická fakulta v Hradci Králové Farmacie Background: The aim of this work was to use the SIV infection in macaques (the only available model of human HIV infection) to show potential differences in MHC I haplotypes in macaques experimentally infected with SIVmac239 (or SHIV clade C) and their correlation with low or high viral loads, using pyrosequencing. Methods: The RNA samples from leukocytes from experimental macaques were reversely transcribed into cDNA and subjected to PCR of the 190 bp fragment of MHC I using fusion primers containing MIDs and FastStart High Fidelity Taq DNA polymerase. Subsequently the PCR generated samples were subjected to pyrosequencing using GS Junior System (Roche) according to the manufacturer`s protocol. The generated data were analyzed by a series of data filtration steps using scripts in Python and subsequently by DNAStar Lasergene 11. Final alleles were identified by ncbi-blast+ 2.25. Results: A total of 98 known aleles and 11 new aleles of MHC class I were found. The analysis identified those aleles, which correlate with fast or slow disease course. The aleles associated with slow...
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Neurogenetický potenciál kmenových buněk u myší
Slabá, Barbora ; Štaud, František (advisor) ; Červený, Lukáš (referee)
Neural stem cells (NSCs) are present in the mammalian adult nervous system and are found in two specific regions: the subventricular zone of the forebrain and the subgranular zone in the dentate gyrus of the hippocampus. NSCs undergo fate specification, maturation and functional integration before they can take part in neuronal circuits. Less is known about the mechanisms controlling these processes or the function of the newly born neurons in the adult brain. A large number of molecular and environmental factors can regulate various aspects of proliferation, maturation and differentiation of adult stem cells in adult nervous system. NSCs can give rise to three main types of neural cells: neurons, astrocytes and oligodendrocytes. It is suggested that astrocytes may play critical role in regulating neurogenesis in both the intact adult brain and after injury. Therefore, determining how astrocytes regulate adult neurogenesis at the molecular level is an essential step toward understanding the regulation of adult neurogenesis. To find out how genetic alteration of astrocytic intermediate filament will affect neural stem cells of postnatal mice, the neurosphere assay was performed in order to compare the proliferative and differentiation characteristics of neural stem/progenitor cells in GFAP-/- Vim-/-...
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