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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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The impact of synthetic chelators from the group of 4-acylpyrazole-5-ones on alcohol dehydrogenase
Sobolová, Zuzana ; Mladěnka, Přemysl (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Zuzana Sobolová Supervisor: Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Consultant: Marcel Hrubša, MS.c. Title of diploma thesis: The impact of synthetic chelators from the group of 4-acylpyrazole-5-ones on alcohol dehydrogenase Inhibitors of alcohol dehydrogenase play a key role in the treatment of poisoning caused by methanol, ethanol, ethylene glycol, and their toxic metabolites. Such treatment can therefore be considered as life-saving. In clinical practice, a single substance, fomepizole, is used. This thesis is aimed at investigation of the effect of eleven experimental chelators from the 4- acylpyrazol-5-ones group on equine and yeast alcohol dehydrogenases, and the possible definition of structural features that would be the most suitable for interaction with this enzyme. Due to the ability of these substances to chelate zinc ions, it is believed that they could inhibit an enzyme that has a zinc molecule in the structure. The measurement itself is based on principle of increase in absorbance during the enzymatic reaction, which is caused by the formation of NADH. This measurement is relatively simple, efficient and, due to used kinetic method, also less susceptible to be affected by...
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Expression of selected membrane transporters in placentas of pregnant women diagnosed for preterm rupture of membranes
Michalská, Martina ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martina Michalská Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Expression of selected membrane transporters in placentas of pregnant women diagnosed for preterm rupture of membranes Placenta is a key organ for pregnancy maintenance. One of its main functions is transport of compounds between mother and her fetus. The transplacental penetration is ensured due to membrane transporters that are present in the apical or basal side of trophoblast. Their expression level is affected by many physiological and pathological factors, among others it can be influenced by infection and inflamatory reaction. Inflammation is also one of the risk factors of preterm deliveries and it can be therefore assumed that these pathological states are accompanied by changes in expression of placental transporters. This study was performed using 51 placentas obtained from Faculty hospital in Hradec Králové from women who underwent preterm delivery and on 15 placentas delivered in term. The study employed quantitative RT-PCR approach. The mRNA expression of membrane transporters ABCB1, ABCG2, OATP1A2, OATP1B3, OATP2A1, OATP2B1, OATP3A1, OATP4A1 was assessed and the results were compared to...
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CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION
Jirkovský, Eduard ; Štěrba, Martin (advisor) ; Kolář, František (referee) ; Hrdina, Radomír (referee)
- CARDIOTOXICITY OF ANTHRACYCLINE ANTINEOPLASTIC DRUGS AND POSSIBILITIES OF PHARMACOLOGICAL CARDIOPROTECTION Chronic anthracycline (ANT) cardiotoxicity is an important clinical problem which can have a substantial impact on morbidity and mortality of cancer survivors. Dexrazoxane (DEX) is the only agent with clearly evidenced cardioprotective effects in both experimental models and clinical trials. Despite intensive research, precise pathogenesis of chronic ANT cardiotoxicity and molecular mechanisms of cardioprotective effects of DEX remain unknown. Current clinical guidelines recommend not using DEX from the beginning of ANT therapy, but instead only from the cumulative ANT dose of 300 mg /m2. The aim of this work was to study functional, morphological and molecular changes associated with induction of chronic ANT cardiotoxicity and their further development in the post-exposure (follow up) period. Special attention was paid on the role of oxidative stress and possible response of protective antioxidant pathway regulated by Nrf2 as well as on mitochondrial impairment and response of mitochondrial biogenesis pathway. Chronic ANT cardiotoxicity was induced in rabbits by repeated intravenous injections of daunorubicin (DAU, 3 mg/kg, once weekly for 10 weeks). At the end of the treatment, the animals...
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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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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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Expression and funkction of placental drug transpoters in health and disease
Umanová, Barbora ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Barbora Umanová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Expression and function of placental drug transporters in health and disease There are many physiological changes during pregnancy. Placenta is a crucial organ which mediates exchange of nutrients, metabolites and respiratory gases, provides endocrine functions and fetal protection. A pregnant woman and her fetus may be exposed to various potentially harmful substances during pregnancy, including drugs that may endanger fetal health. Protection of the fetus from xenobiotics is enabled by drug transporters. Drug transporters are membrane proteins expressed in most tissues of the human body. In the placenta, they are localized in the placental syncytiotrophoblast and occur also in the endothelial cells of the fetal vessels. They belong into two large superfamilies of transporter proteins: ATB-binding cassette (ABC) and solute carrier (SLC). While ABC transporters mediate exclusively efflux of their substrates, SLC are predominantly influx transporters. Therefore, these transport proteins play a key role in the disposition of drugs, some of which facilitate drugs entry into a fetus, and others actively...
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Localisation of FUBP3 protein in human cervical cancer cell line
Kunrt, Josef ; Jirkovský, Eduard (advisor) ; Macháček, Miloslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Josef Kunrt Supervisor: Eduard Jirkovský, PharmD, PhD.; Assist. Prof. Nika Lovšin, M.Chem., PhD Title of Diploma Thesis: Localisation of FUBP3 Protein in Human Cervical Cancer Cell Line Osteoporosis is a skeletal disorder characterised by an impaired bone mass, strength and microarchitecture which leads to a higher risk of fracture. The disease is predominant in postmenopausal women but also affects older men and other risk groups, such as oncological patients. To ascertain the genetic basis of osteoporosis, multiple genome-wide association studies have been performed with the aim to identify genes with a role in the diseases. These studies discovered multiple genetic loci associated with a higher risk of osteoporotic fractures, one of which was far upstream element-binding protein 3 (FUBP3). Works studying the properties of this protein such as cellular localisation are scarce. Therefore, we focused on establishing a protocol for visualisation of FUBP3 and its co-localization with other cellular structures in a human cervical cancer cell line (HeLa). The visualisation was done using immunostaining of FUBP3 and GM130, a matrix protein of Golgi apparatus, and subsequent imaging with...
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Expression of selected membrane transporters in placentas of pregnant women diagnosed for preterm rupture of membranes
Michalská, Martina ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martina Michalská Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Expression of selected membrane transporters in placentas of pregnant women diagnosed for preterm rupture of membranes Placenta is a key organ for pregnancy maintenance. One of its main functions is transport of compounds between mother and her fetus. The transplacental penetration is ensured due to membrane transporters that are present in the apical or basal side of trophoblast. Their expression level is affected by many physiological and pathological factors, among others it can be influenced by infection and inflamatory reaction. Inflammation is also one of the risk factors of preterm deliveries and it can be therefore assumed that these pathological states are accompanied by changes in expression of placental transporters. This study was performed using 51 placentas obtained from Faculty hospital in Hradec Králové from women who underwent preterm delivery and on 15 placentas delivered in term. The study employed quantitative RT-PCR approach. The mRNA expression of membrane transporters ABCB1, ABCG2, OATP1A2, OATP1B3, OATP2A1, OATP2B1, OATP3A1, OATP4A1 was assessed and the results were compared to...
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