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Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action
Štefancová, Monika ; Pourová, Jana (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Monika Štefancová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action It is known from clinical studies that the intake of polyphenols from food acts as a prevention of cardiovascular diseases. However, the parent compounds themselves often have low bioavailability. The emphasis is therefore on their bioactive metabolites. 3-hydroxy phenylacetic acid (3-HPAA) is among such metabolites. The aim of this study was to verify the mechanism of the vasodilatory effect of 3-HPAA using standardized ex vivo method on an isolated pig coronary artery. The administration of 3-HPAA resulted in relaxation of maximally contracted segments of porcine artery by mechanism partially dependent on the integrity of endothelium. By inhibiting endothelial nitric oxide synthase, the relaxation was significantly impaired. The blockage of SKCa and IKCa channels, muscarinic receptors, cyclooxygenase or L-type calcium channels did not affect relaxation. Thus, 3-HPPA causes dose-dependent vasodilatation of coronary arteries ex vivo at least partially mediated by endothelium with the participation of nitric oxide. Key words:...
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Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Podhorná, Pavla ; Vokřál, Ivan (advisor) ; Ambrož, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Pavla Podhorná Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices Dexamethasone is a corticosteroid that has anti-inflammatory, immunosuppressive, and anti-allergic effects. The mechanism of dexamethasone action involves its ability to bind to intracellular glucocorticoid receptors, which are present in many types of cells, including intestinal mucosal cells. Upon binding to these receptors, it translocates to the nucleus of the cells and affects gene expression. This mechanism also affects the expression of genes important for the metabolism and transport of xenobiotics in the intestinal mucosa. The most important such genes include ABCB1, an important intestinal transporter, and CYP3A4, a significant biotransformationenzyme.Their localizationinthe wall of the small intestine can significantlyaffect the absorptionof orallyadministereddrugs.Studyingdrug interactions with this transporter and biotransformation enzyme is important for safe and effective pharmacotherapy. To determine whether dexamethasone affects the expression of these genes in the intestinal barrier,we used the method of...
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Changes of internal organs after percutaneous exposure to sulfur mustard
Šulová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Šulová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. External supervisor: pplk. doc. MUDr. Jaroslav Pejchal, Ph.D. et Ph.D. Title of diploma thesis: Changes of internal organs after percutaneous exposure to sulfur mustard Sulfur mustard is a chemical warfare agent belonging to the group of blistering agents. The theoretical section of the thesis is mainly focused on the description of acute toxic effects, the mechanism of action, and deals with the current possibilities of poisoning therapy. The experimental section is focused on monitoring the effect of sulfur mustard poisoning in the liver, lung, and kidney of female C57BL/6J mice after the percutaneous administration. This work aimed to evaluate markers of oxidative stress and histopathological changes of the selected organs at 3, 5, and 7 days after the poisoning. Ferric reducing antioxidant power (FRAP) and thiobarbituric acid reactive substances (TBARS) methods were used to determine markers of oxidative stress. Histopathological changes were evaluated microscopically using the hematoxylin-eosin staining method. The airness of the lung parenchyma was also assessed by computer image analysis. First, the LD50 of sulfur mustard was...
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Use of cannabis in pregnancy; effect on placental functions
Sáňková, Eliška ; Štaud, František (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Eliška Sáňková Supervisor: Prof. PharmDr. František Štaud, Ph.D. Consultant: Dr. Ramon Portillo, Ph.D. Title of diploma thesis: Use of cannabis in pregnancy; effect on placental functions The increasing use of cannabinoids among pregnant women, including tetrahydrocannabinol, hexahydrocannabinol, cannabidiol, cannabigerol, and cannabinol, has become a major cause for concern due to the potential adverse effects on fetal health. Prenatal cannabis exposure has been linked to cognitive, attention, and memory deficits in the developing fetus, although the mechanisms underlying these effects are not fully understood. The placenta, a vital organ for fetal development, immune protection, and regulating inflammatory cytokines, may play a role in the relationship between cannabis use during pregnancy and fetal neurodevelopmental disorders. Inflammation during pregnancy, whether from infections or other sources, can impair placental function and further increase the risk of the above-mentioned disorders in the child. Despite the growing evidence of placental dysfunction and abnormal fetal neurodevelopment due to prenatal cannabis exposure, little is known about the relationship between them. This study...
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Study of the expression and toxicity of catechol derivates in MCF-7 cell line
Kleplová, Dominika ; Carazo Fernández, Alejandro (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Dominika Kleplová Supervisor: PharmDr. Alejandro Carazo, PhD. Title of the Diploma thesis: Study of the expression and toxicity of catechol derivatives in MCF-7 cell line Estrogens perform many important functions in the human body. They act by binding to estrogen receptors (ER) and thus regulate reproduction, the menstrual cycle, bone density, cholesterol metabolism or brain function. They also play an important role in the development and onset of breast cancer, where the amount of ER expressed is used as a very important biomarker in patients suffering from this disease. Despite ongoing research, breast cancer is considered to have the highest mortality rate. Catechols are organic compounds. In the human body, they can occur as metabolites in the degradation of benzene and estrogens or other endogenous compounds such as neurotransmitters and their precursors. Catechols are known to be involved in redox processes in the body, to exert antioxidant and toxic effects, to interfere with protein function and to cause DNA strand breaks. Their positive effect on breast cancer therapy is the subject of research, but it has not yet been fully explored. The subject of this thesis is to study the...
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Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Podhorná, Pavla ; Vokřál, Ivan (advisor) ; Ambrož, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Pavla Podhorná Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices Dexamethasone is a corticosteroid that has anti-inflammatory, immunosuppressive, and anti-allergic effects. The mechanism of dexamethasone action involves its ability to bind to intracellular glucocorticoid receptors, which are present in many types of cells, including intestinal mucosal cells. Upon binding to these receptors, it translocates to the nucleus of the cells and affects gene expression. This mechanism also affects the expression of genes important for the metabolism and transport of xenobiotics in the intestinal mucosa. The most important such genes include ABCB1, an important intestinal transporter, and CYP3A4, a significant biotransformationenzyme.Their localizationinthe wall of the small intestine can significantlyaffect the absorptionof orallyadministereddrugs.Studyingdrug interactions with this transporter and biotransformation enzyme is important for safe and effective pharmacotherapy. To determine whether dexamethasone affects the expression of these genes in the intestinal barrier,we used the method of...
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Cell senescence in aging, cell stress and chemoresistance
Andrašková, Tereza ; Vokřál, Ivan (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Tereza Andrašková Supervisor: Prof. Dr. Alexandra K. Kiemer and PharmDr. Ivan Vokřál, PhD. Title of diploma thesis: Cell senescence in aging, cell stress, and chemoresistance The process of biological aging is connected with a loss of tissue function leading to the various pathologies, including cardiovascular diseases and cancer. Cellular senescence, the phenomenon characterized by permanent cell cycle arrest triggered by endogenous or exogenous stress plays a significant role in age-related metabolic diseases development. Senescent endothelial cells have been found in atherosclerotic plaque and due to the inflammation-inducing factors participate to its progression. Nevertheless, by triggering antiproliferative reaction, senescence may also have a potential as a cancer suppressor. The aim of this work was to establish assay determining senescence with different origins and subsequently, to analyse compounds with a potential to reduce H2O2-induced senescence as well as factors, which may be altered in the senescent phenotype. Senescence-associated β- galactosidase (SA-β-gal) assay in primary human endothelial cells revealed the senescence-inhibiting ability of statins and curcumin in contrast...
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Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action
Štefancová, Monika ; Pourová, Jana (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Monika Štefancová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action It is known from clinical studies that the intake of polyphenols from food acts as a prevention of cardiovascular diseases. However, the parent compounds themselves often have low bioavailability. The emphasis is therefore on their bioactive metabolites. 3-hydroxy phenylacetic acid (3-HPAA) is among such metabolites. The aim of this study was to verify the mechanism of the vasodilatory effect of 3-HPAA using standardized ex vivo method on an isolated pig coronary artery. The administration of 3-HPAA resulted in relaxation of maximally contracted segments of porcine artery by mechanism partially dependent on the integrity of endothelium. By inhibiting endothelial nitric oxide synthase, the relaxation was significantly impaired. The blockage of SKCa and IKCa channels, muscarinic receptors, cyclooxygenase or L-type calcium channels did not affect relaxation. Thus, 3-HPPA causes dose-dependent vasodilatation of coronary arteries ex vivo at least partially mediated by endothelium with the participation of nitric oxide. Key words:...
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