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STAT3 signalling pathway modulation and its impacts on cell phenotype, senescence and secretome.
Novotný, Ondřej ; Reiniš, Milan (advisor) ; Šmahel, Michal (referee)
Cellular senescence represents an effective barrier to tumour growth on the one hand, on the other hand, senescent cells secrete substances that create a protumourigenic environment. Understanding and influencing these processes will bring new approaches in the fight against tumours and other serious diseases. The IL-6/JAK2/STAT3 signalling pathway is crucial both in oncogenesis and in the induction of cellular senescence and it also has a major influence on the composition of the secretome of senescent cells. Targeted blockade of this pathway could therefore change the tumour microenvironment, either by directly affecting the induction of senescence itself, or by adjusting secretion and thereby by attenuation of the immunosuppressive environment induced by produced cytokines. The aim of this thesis is to find out whether and how inhibitors of the STAT3 signalling pathway can change the secretome of senescent and proliferating tumour cells. Based on the comparison of the toxicity and effectiveness of the STAT3 signalling pathway inhibition by Stattic analogues on proliferating TC-1 tumour cells, I selected two suitable inhibitor molecules for further experiments. I found out that these selected inhibitors significantly reduce the secretion of important pro-tumour signalling molecules by TC-1 tumour...
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Malonate and succinate as potential corrosion inhibitors of AZ31 magnesium alloy in 0.9% NaCl
Tkáčová, Karolína ; Buchtík, Martin (referee) ; Doskočil, Leoš (advisor)
The aim of this work was to evaluate the inhibitory effects of malonic acid, succinic acid and their mixture in a 0,15M NaCl solution at pH 7 on AZ31 magnesium alloy. The theoretical part focuses on magnesium, its alloys and alloying elements. It also discusses magnesium corrosion in aqueous environments and the influence of microstructure on corrosion. The final section is dedicated to corrosion inhibitors and small aliphatic acids. The practical part of this work involves potentiodynamic measurements, immersion tests, and subsequent analysis of alloy surfaces. The following concentrations of acids were chosen for studying inhibitory properties: 0.025M, 0.05M, 0.075M, and 0.1M, as well as various mixtures of both acids. Suppression of corrosion was observed in immersion tests for both acids individually and in their mixture. The best inhibitory results in both potentiodynamic polarization (PDP) analysis and immersion tests were achieved with a mixture of 0.025M malonic acid solution and 0.075M succinic acid solution.
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Examination of the activity and possibility verification ability of various types of corrosion inhibitors
Kroča, Michal ; Švehla, Vladimír (referee) ; Drochytka, Rostislav (advisor)
The aim of the work is to describe the degradation of concrete structures from the perspective of corrosion of steel reinforcement. The basis of a detailed survey and analysis of additives containing corrosion inhibitors, designed to improve the concrete matrix and increased protection of steel reinforcement. The essential part is a summary of the detection methods designed to verify the presence of inhibitors in reinforced concrete (direct method) or anti - corrosion effect on steel reinforcement (indirect method). Subsequently, to compare the available products in the market based on their characteristics and parameters, including prices and environmental point of view. From the data obtained is drawn optimization calculation, the output of which is to determine nevhodnějšího product for protection of steel reinforcement embedded in concrete structures, especially at a dosage rate specified by the manufacturer.
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Cardioprotective effects of sodium-glucose cotransporter SGLT2 inhibitors.
Thořová, Markéta ; Horníková, Daniela (advisor) ; Vávra, Jiří (referee)
Cardiovascular diseases are one of the most common causes of death in both non-diabetic and diabetic patients. Nowadays, a large number of drugs target cardiovascular problems. One of the very promising therapies is the use of sodium-glucose cotransporter type 2 (SGLT2) inhibitors. SGLT2 inhibitors have gained a wide interest in the treatment of type 2 diabetes (DM2) due to their ability to lower blood glucose levels independently of insulin action. However, in addition to their main effect on glycemic control, there is increasing evidence of their beneficial effects on the cardiovascular system beyond their hypoglycaemic effects. These drugs reduce hyperglycemia, hypertension, and improve diabetic retinopathy through multiple mechanisms, many of which have not been fully explained. The main focus has been on identifying the mechanisms through which these drugs affect the heart and blood vessels, whether by reducing blood pressure, affecting cardiac cells, or improving metabolic processes in blood vessels. Key words: SGLT2, inhibitors of SGLT2, cardioprotective effect, diabetes mellitus, heart
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Synthesis of novel viral methyltransferase inhibitors
Kocek, Hugo ; Nencka, Radim (advisor) ; Česnek, Michal (referee)
Methyltransferases (MTases) are a class of enzymes that catalyze methylation of their substrates. These enzymes are found in all living organisms (including some viruses) as methylations are involved in numerous biological processes. Therefore, MTases are attractive targets for medicinal chemistry. Currently, only inhibitors of human MTases are used in medicine, for example, 5-azacytidine targeting DNA-MTase. However, viral MTases are potential drug targets as well. They enable viruses to escape the immune system and to use the host's translation machinery. As a consequence of the SARS-CoV-2 pandemic, coronaviral MTases became the center of attention, followed by the Mpox virus, which spread in the population in 2022. This thesis is focused on the synthesis of potential MTase inhibitors derived from adenosine-5'-carboxylic acid. The primary target is SARS-CoV-2 nsp14, however, the compound library will be used for screening against other MTases as well. Key words: methyltransferase; inhibitor; SARS-CoV-2; medicinal chemistry
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Functional characterization of selected Kunitz proteins of Eudiplozoon nipponicum
Tymich, Alexandr ; Mikeš, Libor (advisor) ; Kašný, Martin (referee)
Proteins containing the Kunitz domain are mostly 6-10 kDa inhibitors of serine proteases, but in exceptional cases they can also inhibit cysteine and aspartic proteases. The main characteristic is the presence of six cysteine residues forming three disulfide bridges creating a typical active loop, which is complementary to the active site of various proteases. The specificity of this binding is largely determined by the amino acid in the P1 position. Their functions include the regulation of a number of physiological events based on proteolysis, e.g. the blood coagulation cascade or immune reactions. However, due to their nature, they have also become a powerful tool for parasitic organisms to interact with their host, where they again target proteases involved in the host's physiological events and thus allow the parasite to survive the interaction with the host. Until recently, representatives of the class Monogenea were a neglected group from the point of view of molecular parasite-host interactions, and only a few works were devoted to their biochemistry and the description of biologically active molecules. In this work, I focused on two selected Kunitz proteins in Eudiplozoon nipponicum, a blood-sucking ectoparasite from the Monogenea class, which has become a fairly common parasite of common...
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Synthesis of novel inhibitors of human topoisomerase based on highly substituted phenyl scaffold
Domanský, Miroslav ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Supervisor: Assoc. Prof. PharmD. Jan Zitko, PhD. Consultant: Mgr. Marek Kerda Author: Miroslav Domanský Title of diploma thesis: Synthesis of novel inhibitors of human Topoisomerase based on highly substituted phenyl scaffold. Despite progress in anticancer therapy, cancer is still one of the leading causes of death in the world. Patients treated with current anticancer therapy suffer from many side effects. This is caused by the low selectivity of the current drugs. The development of chemotherapeutics aims to prepare more selective and therefore better tolerated anticancer drugs. Topoisomerases are nuclear enzymes occurring in every cell. They have an essential role - to preserve DNA and repair it. Topoisomerase isoform IIα is an isoform that controls and edits the conformation of DNA during cell replication. Its expression is highly elevated in proliferating cells. That makes it a good target for anticancer drugs. The design of synthesized molecules is based on previously reported ATP-competitive inhibitors of human topoisomerase IIα. Alterations of 3,4-dichloro-5-methyl-N-phenyl-1H- pyrrole-2-carboxamide have been synthesized based on Computational-Aided Drug Design. The in silico study is based on the previous discovery of the...
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Methionine synthase as a potential therapeutic target
Kellovská, Kristýna ; Baszczyňski, Ondřej (advisor) ; Snášel, Jan (referee)
This thesis focuses on the enzyme methionine synthase (MS), which catalyzes methylation of homocysteine to produce methionine. Two main families of these enzymes are recognized in nature - cobalamin-dependent and cobalamin-independent. These two enzymes share no sequence homology, and they also use different catalytic mechanisms, substrates and cofactors. Cobalamin-dependent MS is found in humans, whereas cobalamin-independent MS is typical for plants and fungi. In humans, the enzyme provides a connection between folate and methionine cycle - two metabolic pathways which are crucial for example for DNA synthesis and S-adenosylmethionine-dependent biological methylations. Recently, the enzyme has been recognized as a potentially promising target for the development of chemotherapeutics and antifungal drugs, mainly based on its essentiality for the proliferation of cancer cells and both viability and virulence of pathogenic fungal species.
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