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Study of the expression and toxicity of catechol derivates in breast cancer cell lines
Vyoralová, Tereza ; Carazo Fernández, Alejandro (advisor) ; Jirkovský, Eduard (referee)
Studium exprese a toxicity derivátů katecholu v prsních nádorových buněčných liniích, Tereza Vyoralová ABSTRACT Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Tereza Vyoralová Supervisor: PharmDr. Alejandro Carazo Ph.D. Title of the diploma thesis: Study of the expression and toxicity of catechol derivates in breast cancer cell lines Estrogens have several important functions in the human organism and are also involved in the formation and development of breast cancer. These effects are mediated by binding to estrogen receptors (ER) and show complex spectrum of effects such as regulation of reproduction, menstrual cycle, brain function, bone density or mobilization of cholesterol. In addition the presence and quantification of ER in breast cancer is currently used as one of the most important predictive biomarkers in patients suffering from this disease. The occurence and activity of ER correlates with the response of breast cancer to hormonal treatment and with the patient's prognosis. Despite intensive research, breast cancer is still ranked among the cancers with the highest lethality. Catechols are organic compounds that are naturally present in food as pollutants, but also can be found in the human body, where they play an important role as...
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Placental transport of dopamine and norepinephrine
Turková, Helena ; Štaud, František (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Helena Turková Supervisor: prof. PharmDr. František Štaud, Ph.D. Title of diploma thesis: Placental transport of dopamine and norepinephrine During the whole course of pregnancy, it is important to maintain proper monoamine homeostasis, namely serotonin (5-HT), norepinephrine (NE), and dopamine (DA), which are crucial for proper placental function and fetal development. Monoamines are important neuromodulators, involved in cell proliferation, and differentiation. and neuronal migration. High fetal monoamine secretion during gestation demands a responsible clearance mechanism, as disruption of their balance may lead to long-lasting changes in brain structure and function, provoking a higher risk of attention deficit hyperactivity disorder (ADHD), autism or depression. However, uptake of NE a DA through the fetoplacental unit has not been fully and in detail described. Therefore, in this diploma thesis, we focus on the uptake of NE and DA through ex vivo isolated vesicles of microvillous (MVM) and basal (BM) membranes from healthy human term placentas. Our results show that NE and DA uptake is mediated via high-affinity and low-capacity serotonin (SERT) and norepinephrine (NET) transporters in...
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Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells
Králová, Adéla ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Králová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá Title of Diploma thesis: Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells Fms-like tyrosine kinase 3 (FLT3) inhibitors represent a new generation of drugs in the treatment of acute myeloid leukemia (AML). Standard therapeutic regimen of AML is initiated with induction therapy consisting of cytarabine and anthracyclines. The disadvantage of this combination is emerging resistance often caused by the ABCB1-mediated efflux. Therefore, simultaneous inhibition of FLT3 and ABCB1, which is inhibited by FLT3 inhibitors used in clinical practice, appears to be a beneficial approach to therapy. However, their effectiveness is declining hence the effort to develop new FLT3-inhibiting molecules. The aim of our work was to evaluate whether our two promising new FLT3-inhibiting compounds would inhibit ABCB1 as well. Promyelocyte cells overexpressing ABCB1 (HL60-ABCB1) and parent HL60-par were used in this study alongside AML-derived cell lines (MOLM-13, THP-1, Kasumi-1). Employing accumulation studies on HL60-ABCB1, strong inhibitory effect towards ABCB1 was demonstrated...
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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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Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells
Králová, Adéla ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Králová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá Title of Diploma thesis: Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells Fms-like tyrosine kinase 3 (FLT3) inhibitors represent a new generation of drugs in the treatment of acute myeloid leukemia (AML). Standard therapeutic regimen of AML is initiated with induction therapy consisting of cytarabine and anthracyclines. The disadvantage of this combination is emerging resistance often caused by the ABCB1-mediated efflux. Therefore, simultaneous inhibition of FLT3 and ABCB1, which is inhibited by FLT3 inhibitors used in clinical practice, appears to be a beneficial approach to therapy. However, their effectiveness is declining hence the effort to develop new FLT3-inhibiting molecules. The aim of our work was to evaluate whether our two promising new FLT3-inhibiting compounds would inhibit ABCB1 as well. Promyelocyte cells overexpressing ABCB1 (HL60-ABCB1) and parent HL60-par were used in this study alongside AML-derived cell lines (MOLM-13, THP-1, Kasumi-1). Employing accumulation studies on HL60-ABCB1, strong inhibitory effect towards ABCB1 was demonstrated...
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Study of the expression and toxicity of catechol derivates in breast cancer cell lines
Vyoralová, Tereza ; Carazo Fernández, Alejandro (advisor) ; Jirkovský, Eduard (referee)
Studium exprese a toxicity derivátů katecholu v prsních nádorových buněčných liniích, Tereza Vyoralová ABSTRACT Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Tereza Vyoralová Supervisor: PharmDr. Alejandro Carazo Ph.D. Title of the diploma thesis: Study of the expression and toxicity of catechol derivates in breast cancer cell lines Estrogens have several important functions in the human organism and are also involved in the formation and development of breast cancer. These effects are mediated by binding to estrogen receptors (ER) and show complex spectrum of effects such as regulation of reproduction, menstrual cycle, brain function, bone density or mobilization of cholesterol. In addition the presence and quantification of ER in breast cancer is currently used as one of the most important predictive biomarkers in patients suffering from this disease. The occurence and activity of ER correlates with the response of breast cancer to hormonal treatment and with the patient's prognosis. Despite intensive research, breast cancer is still ranked among the cancers with the highest lethality. Catechols are organic compounds that are naturally present in food as pollutants, but also can be found in the human body, where they play an important role as...
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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 influence of antidepressants on serotonin homeostasis in placenta
Váchalová, Veronika ; Štaud, František (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Veronika Váchalová Supervisor: Prof. PharmDr. František Štaud, Ph.D. Consultant: Mgr. Rona Karahoda Title of diploma thesis: The influence of antidepressants on serotonin homeostasis in placenta Depression is a serious mental disorder affecting 10-20% of women during pregnancy. Up to 10% of these pregnant women are prescribed antidepressants (ADs), most frequently from the class of selective serotonin (5-HT) reuptake inhibitors (SSRIs). While the safety of this treatment is questionable due to reported impaired pregnancy/fetal outcomes, understanding of potential mechanistic causes is still lacking. During pregnancy, 5-HT is important for normal placental function and proper fetal development and programming. 5-HT homeostasis in the placenta is maintained via the 5-HT transporter (SERT/SLC6A4) on the apical side and the recently characterized organic cation transporter 3 (OCT3/SLC22A3) on the basal side of trophoblast. These transporters take up 5-HT from the maternal and fetal circulations, respectively into the syncytiotrophoblast (STB) where it is degraded by monoamine oxidase-A (MAO-A). As all ADs interfere with the 5-HT system it is important to study their potential interactions in the...
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In vitro study of novel derivatives of iron chelator salicylaldehyde isonicotinoyl hydrazone.
Maťašová, Nikola ; Šimůnek, Tomáš (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Nikola Maťašová Supervisor: prof. PharmDr. Tomáš Šimůnek, Ph.D. Consultants: PharmDr. Hana Jansová, Ph.D. Mgr. Jan Kubeš Title of diploma thesis: In vitro study of novel derivatives of iron chelator salicylaldehyde isonicotinoyl hydrazone Heart disease is one of the most common causes of death and disability worldwide. Oxidative stress, which can also be generated or propagated by iron ions, plays an important role in the development of cardiovascular diseases. Excessive amounts of this metal lead to the apoptosis, necrosis, as well as recently described regulated cell death - ferroptosis. This type of cell death is associated with cardiomyocytes, but studies have also been described linking ferroptosis to other pathological conditions, such as cancer, nervous system disease, ischemia-reperfusion injury, kidney damage and blood disease. Therefore, research on iron chelators capable of forming a non-toxic complex with iron and thus preventing cell death is promising not only from the point of view of cardiovascular diseases. This work is focused on the in vitro study of new potential iron chelators derived from the structure of salicylaldehyde isonicotinoyl hydrazone (SIH). SIH selectively and...
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