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The influence of metabolites and their parent phenolic compounds on blood platelets
Hrubša, Marcel ; Mladěnka, Přemysl (advisor) ; Moťovská, Zuzana (referee) ; Kollár, Peter (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmacology and Toxicology Candidate: Mgr. Marcel Hrubša Supervisor: Prof. PharmDr. Přemysl Mladěnka, Ph.D. Title of dissertation thesis: The influence of metabolites and their parent phenolic compounds on blood platelets Acute cardiovascular events (ACEs), such as stroke and acute coronary syndromes encompassing acute myocardial infarction, are one of the main causes of cardiovascular mortality in the world. Current pharmacotherapy focuses primarily on secondary prevention of their recurrence, where antiplatelet drugs play a key role. These drugs reduce platelet hyperreactivity, which is present in the majority of cardiovascular and metabolic diseases, and significantly decrease the risk of ACEs. However, the palette of currently available drugs faces many issues, such as resistance, high variability in both pharmacokinetics and pharmacodynamics, serious side effects and the route of administration. This thesis firstly briefly summarizes the current knowledge of platelet physiology along with available antiplatelet drugs and their mechanism of action. Second part of the theoretical introduction is dedicated to polyphenolic compounds, as polyphenol-rich diet is associated with many beneficial effects, particularly...
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Interaction of chalcones with transition metals II.
Šulcová, Martina ; Macáková, Kateřina (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague Faculty of Phramacy in Hradec Králové Department of Pharmaceutical Botany Candidate: Martina Šulcová Supervisor: Assoc. Prof. Ing. Kateřina Macáková, Ph.D. Title of the diploma thesis: Interaction of chalcones with transition metals II. Copper is one of the essencial elements in human body which is involved in the functioning of many enzymes and metabolic pathways. Although it appears in trace amounts in the body, its functions are irreplaceable. However, the ion level must be kept in balance by the various mechanisms of the body. If there is an excess or deficiency of copper in the body, this condition can lead to the development of health issues. Chalcones are substances belonging to the group of flavonoids. Their polyphenolic structure does not have a closed ring C. Studies describe their anticancer, anti-inflammatory, antiviral, antidiabetic, antibacterial, antioxidant, immunosuppressive and other properties. Chosen substances in the group of dihydrochalcones (naringin dihydrochalcone, neohesperidin dihydrochalcone, phloretin, phlorizin) and chalcones (isoliquiritigenin, licochalcone A) were tested for their chelation and reduction activity of the copper ions in this diploma thesis. The activity was measured at different pH environments (7.5; 6.8; 5.5 and 4.5) and...
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Evaluation of gene expression of selected ABC and SLC transporters in the HTR-8/SVneo cell line during stimulation with pro-inflammatory cytokines
Pokorná, Petra ; Čečková, Martina (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Petra Pokorná Supervisor: Assoc. Prof. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Dudičová Title of diploma thesis: Evaluation of gene expression of selected ABC and OATP transporters in the HTR-8/SVneo cell line during stimulation with pro-inflammatory cytokines Placenta is the first and the largest fetal organ that gradually develops during pregnancy and plays an essential role in the development of the fetus. It fulfills the entire spectrum of functions, ensures the transport of nutrients to the fetus and the removal of waste substances back into the maternal circulation, protects the fetus from toxins, and at the same time fulfills a certain mechanical and especially immunological barrier between mother and fetus. One of the main functions of the placenta is the transport function which is made possible by membrane transporters present mainly in the syncytiotrophoblast layer of the placenta. Transporters in the human placenta can be divided into two families, SLC and ABC which are further divided into several subfamilies. The expression of transporters changes physiologically during pregnancy, but pathological conditions such as inflammation can also influence the expression....
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Comparison of platelet aggregation in healthy population.
Minarovičová, Júlia ; Mladěnka, Přemysl (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Júlia Minarovičová Supervisor: prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of diploma thesis: Comparison of platelet aggregation in healthy population Platelets have an irreplaceable role in the process of aggregation. Nevertheless, their increased activity is associated with the development of many cardiovascular diseases. This process can be influenced by clinical used substances from the group of antiplatelet drugs, which differ in their effectiveness within the population. Within this study, platelet aggregation was tested using impedance aggregometry, whose principle is the change in electrical impedance between electrodes caused by the adhesion of activated platelets. Firstly, whole blood was incubated with clinically used antiplatelet drugs (ticagrelor, vorapaxar, and acetylsalicylic acid) and a flavonoid metabolite, 4-methylcatechol. Subsequently, a platelet aggregation inducer (ADP, thrombin receptor activating peptide 6 /TRAP/, collagen, arachidonic acid, ristocetin, U-46619, and platelet-activating factor /PAF/) was added, and the process was monitored for 6 minutes. The most potent inhibitor of the aggregation induced by arachidonic acid was acetylsalicylic acid in a concentration of 70 μM...
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Are currently used chelators of heavy metals also chelators of calcium and magnesium?
Skoupilová, Karolína ; Mladěnka, Přemysl (advisor) ; Šuťák, Róbert (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Karolína Skoupilová Supervisor: prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of diploma thesis: Are currently used chelators of heavy metals also chelators of calcium and magnesium? Calcium and magnesium are important elements for the human body. Calcium plays an important role in blood clotting and intracellular signalling, thus participating in muscle contraction and platelet aggregation, among other processes. Magnesium is a cofactor for many enzymes. A significant deficiency of both ions can manifest as disorders of heart rhythm and increased neuromuscular excitability. The aim of this study was to determine the chelating activity of currently used heavy metal chelators and to determine the stability of the indicator. First, the ideal pH for the experiment was determined. In the next step, the chelation rate of 21 known metal chelators was measured using an in vitro spectrophotometric method. Finally, the chelation of the most active calcium chelators was verified on platelet aggregation in a human blood sample. At the same time, the long-term stability of the indicator o- cresolphthalein complexone (CC) was determined. In the first step, pH 7.5 was chosen, which was the only one...
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The impact of benzoic acids, metabolites of flavonoids, on the iron-catalysed Fenton reaction
Klenovičová, Alexandra ; Mladěnka, Přemysl (advisor) ; Karlíčková, Jana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Alexandra Klenovičová Supervisor: Prof. Přemysl Mladěnka, PharmDr., Ph.D. Consultant: Zuzana Lomozová, Ph.D. Title of diploma thesis: The impact of benzoic acids, metabolites of flavonoids, on the iron-catalysed Fenton reaction Oxidative stress is a condition in which there is an increased production of free radicals that exceeds endogenous antioxidant activity and leads to damage of biomolecules. A number of human diseases are associated with oxidative stress. However the use of antioxidants has failed in clinical trials, but it is possible that the fact that antioxidants may preferentially exhibit prooxidant activity under elevated antioxidant concentrations in various pathophysiological conditions. Various in vitro and epidemiological studies have confirmed the presence of antioxidant and prooxidant properties in flavonoids. However, on the basis of their pharmacokinetics, it is evident that after their oral intake, significant metabolism in the colon takes place, where small phenolic substances are formed in interaction with the intestinal microflora. There is a possibility that the antioxidant and harmful prooxidant properties that have been attributed to flavonoids are in fact a...
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The influence of LDL-apheresis on aggregation of blood platelets, blood coagulation, and the effect of standard drugs.
Černotová, Veronika ; Mladěnka, Přemysl (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Černotová Supervisor: prof. Přemysl Mladěnka, PharmD., Ph.D. Consultant: Lukáš Konečný, MSc. Title of diploma thesis: The influence of LDL-apheresis on aggregation of blood platelets, blood coagulation and the effect of standard drugs LDL-apheresis is a method that removes LDL-cholesterol (LDL-C) from the blood. It is used to treat familial hypercholesterolemia (FH), a genetic disorder causing high LDL-C levels and an early development of cardiovascular diseases. Blood platelets and coagulation system play an important role in these diseases and their activity is also affected by lipids. The aim of this thesis was to analyze possible differences in platelet aggregation and blood coagulation in patients suffering from FH. Two methods of treatment in this group were compared - lipid apheresis and PCSK9Ab (proprotein convertase subtilisin/kexin type 9 monoclonal antibodies). The observed parameters were also compared with age-matched healthy volunteers. Our cohort consisted of 15 patients and 15 healthy donors. Six patients were treated with lipid apheresis and also PCSK9Ab, six subjects only with PCSK9Ab. Platelet aggregation was measured with an impedance aggregometer using 7 different...
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Copper metabolism in Acanthamoeba castellanii
Doležalová, Taťána ; Šuťák, Róbert (advisor) ; Mladěnka, Přemysl (referee)
Copper is an essential element that, due to its redox properties, is involved as a cofactor in many enzymes, the most well-known example is the cytochrome c oxidase. At the same time, in higher concentrations, this element shows toxic effects on several levels, it can disrupt iron-sulfur clusters, damage proteins and lead to cell death. This is the reason why this thesis studies copper metabolism in the parasitic amoeba Acanthamoeba castellanii, which causes serious diseases such as acanthamoeba keratitis or granulomatous amoebic encephalitis. Understanding how copper homeostasis is maintained in this organism could lead to targeted disruption of this balance and the exploitation of the toxic effects of copper. In this work, the function of the P-type ATPase homologous to CCC2 from Saccharomyces cerevisiae, responsible for the transfer of copper ions from the cytoplasm to the Golgi apparatus, was characterized by functional complementation. Furthermore, a carrier from the Ctr family has been described that transfers copper ions presumably across the cytoplasmic membrane. The expression of these carriers was monitored in copper excess and deficiency. To get a better picture of how A. castellanii maintains copper homeostasis, the cellular accumulation of copper and the ability of this amoeba to deal...
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Interactions of natural phenolic compounds with biogenic metals
Lomozová, Zuzana ; Mladěnka, Přemysl (advisor) ; Bittner Fialová, Silvia (referee) ; Patočka, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Zuzana Lomozová, MSc. Supervisor: Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: Interactions of natural phenolic compounds with biogenic metals Phenolic compounds are one of the most widely distributed groups of secondary plant metabolites. They are an integral part of the human diet and their consumption is associated with a number of positive effects. They include a wide range of substances, from simple molecules such as phenolic acids to large polymeric compounds such as tannins. Because of their structure, which includes, among others, free hydroxyl groups, they are able to interact with biogenic metals and form metal complexes with them. Under normal conditions, the homeostasis of these transition metals in the body is tightly regulated, but it can be disturbed in pathological conditions such as acute myocardial infarction, when the levels of free iron and copper increase as a result of a significant decrease in pH. Similar metal imbalance is observed as well as in inflammatory and neurodegenerative diseases, tumours, or diabetes mellitus. The aim of this dissertation was to find out how these substances react with biogenic metals using in vitro and ex...
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The influence of metabolites and their parent phenolic compounds on blood platelets
Hrubša, Marcel ; Mladěnka, Přemysl (advisor) ; Moťovská, Zuzana (referee) ; Kollár, Peter (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmacology and Toxicology Candidate: Mgr. Marcel Hrubša Supervisor: Prof. PharmDr. Přemysl Mladěnka, Ph.D. Title of dissertation thesis: The influence of metabolites and their parent phenolic compounds on blood platelets Acute cardiovascular events (ACEs), such as stroke and acute coronary syndromes encompassing acute myocardial infarction, are one of the main causes of cardiovascular mortality in the world. Current pharmacotherapy focuses primarily on secondary prevention of their recurrence, where antiplatelet drugs play a key role. These drugs reduce platelet hyperreactivity, which is present in the majority of cardiovascular and metabolic diseases, and significantly decrease the risk of ACEs. However, the palette of currently available drugs faces many issues, such as resistance, high variability in both pharmacokinetics and pharmacodynamics, serious side effects and the route of administration. This thesis firstly briefly summarizes the current knowledge of platelet physiology along with available antiplatelet drugs and their mechanism of action. Second part of the theoretical introduction is dedicated to polyphenolic compounds, as polyphenol-rich diet is associated with many beneficial effects, particularly...
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