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Possible changes of endoglin expression in endothelial cells.
Tripská, Katarína ; Nachtigal, Petr (advisor) ; Mladěnka, Přemysl (referee) ; Vohnout, Branislav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Doctoral Degree Program: Pharmacology and Toxicology Candidate: Mgr. Katarína Tripská Supervisor: prof. PharmDr. Petr Nachtigal, Ph.D. Title of Doctoral Thesis: Possible changes of endoglin expression in endothelial cells Endoglin (Eng) is a co-receptor for ligands of the Transforming Growth Factor β superfamily. Multiple studies have demonstrated that Eng is associated with metabolic syndrome-related pathological conditions, such as hypercholesterolemia, hyperglycemia, hypertension, or obesity. However, the exact role of Eng in these pathologies is still unknown. Therefore, the main purpose of this thesis was to elucidate and summarize the role of membrane and soluble Eng in the selected pathologies associated with metabolic syndrome. We demonstrated that soluble Eng (sEng) levels, together with plasma lipids and markers of inflammation, were reduced after every lipoprotein apheresis in patients with familial hypercholesterolemia. This result, in combination with knowledge acquired by the review article, indicates that increased sEng levels are associated with cardiometabolic disorders. Regarding the role of membrane Eng, we showed that blockage of Eng expression by TRC105 results in a decrease...
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Search for an efficient cobalt chelator
Nosková, Karolína ; Mladěnka, Přemysl (advisor) ; Smutný, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Karolína Nosková Supervisor: prof. Přemysl Mladěnka, PharmD., Ph.D. Consultant: Monika Moravcová, MSc. Title of diploma thesis: Search for an efficient cobalt chelator Cobalt, as part of vitamin B12, is an essential trace element for human organism. However, long-term exposure to high doses leads to toxicity. Chronic cobalt intoxication is currently most commonly observed after the implantation of cobalt-containing prostheses, which in some cases do not work properly and cobalt is released from them by mechanical friction or corrosion. That not only leads to a local reaction, but cobalt ions also enter the blood and lymphatic circulation and thus cause a systemic reaction. The intoxication is then manifested by neurological, cardiovascular and endocrine symptoms, which can lead to irreversible changes or even to the death. However, a chelator that would be able to effectively and selectively bind cobalt and thus effectively treat intoxication is not available in clinical practice. The aim of this thesis was a search for an efficient cobalt chelator among known metal chelators. Chelation was measured in vitro by a method based on spectrophotometric detection of unchelated cobalt ions at...
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The copper - chelating activity of xanthen-3-ones derivates
Uramová, Daniela ; Mladěnka, Přemysl (advisor) ; Smutná, Lucie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Daniela Uramová, MSc. Supervisor: Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title: The copper - chelating activity of xanthen-3-ones derivates As a biogenic element, copper participates in many metabolic processes in the human body, it is a part of several enzymes, and its presence is therefore essential for life. On the other hand, free atoms of copper increase the formation of free radicals, and hence copper can be toxic to the body. Therefore, current research has being testing several substances that could be able to interact with copper ions and thus affect its dyshomeostasis in the body. Polyphenolic xanthones seem interesting, as they possess in addition to these properties also show other positive effects. The aim of this work was to evaluate the copper-chelating activity of ten closely structurally related synthetic derivates of xanthen-3-ones. The spectrophotometric measurement was carried out in vitro using the hematoxylin and bathocuproine method. 2,6,7-trihydroxy-xanthene-3-one derivates were shown to be able to chelate copper at all tested pH conditions (5.5; 6.8 and 7.5). However, in a more competitive environment, the resulting complexes are unstable. In some cases, it was...
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Natural drugs in the treatment of dry cough
Vojtechovská, Daniela ; Pourová, Jana (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Daniela Vojtechovská Supervisor: doc. PharmDr. Jana Pourová Ph.D. Title of diploma thesis: Natural drugs in the treatment of dry cough. Cough is a natural protective reflex of the airways. It is one of the universal symptoms and one of the major reasons to see a general practitioner. The main causes of cough include inflammatory diseases of upper and lower airways of viral or bacterial origin. However, cough can arise as a consequence of more serious diseases. Antitussives used in conventional therapy of cough are reliable, but they have many restrictions and adverse effects. Phytotherapy, including the therapy of dry cough, is a current trend. Unlike conventional antitussives, using natural drugs in therapy has several advantages, such as treating the main cause of cough, better safety, fewer adverse effects (natural drugs lack central adverse effects). In addition, natural drugs do not induce drug dependence, have fewer drug interactions, the duration of their use is not so limited, and they are easily available. The aim of this Thesis was to summarize available information on the use of natural drugs in the therapy of dry cough, and to supply reliable pharmacological data which would support...
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Interactions of rifampicin derivatives with pregnane X receptor and OATP1B1 transporter
Krajníková, Zdeňka ; Smutný, Tomáš (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Zdeňka Krajníková Supervisor: PharmDr. Tomáš Smutný, Ph.D. Title of diploma thesis: Interactions of rifampicin derivatives with pregnane X receptor and OATP1B1 transporter Pregnane X receptor (PXR) is a ligand-activated transcription factor, which regulates gene expression in the liver. Among PXR target genes, cytochrome P450 3A4 (CYP3A4) is the most important enzyme responsible for metabolism of clinically used drugs. Rifampicin (RIF) is a prototype PXR ligand. It enters hepatocytes across the basolateral membrane by OATP1B1 transporter. Noteworthy, RIF is a chemically unstable molecule. Additionally, it is also metabolized in the human body. In this diploma thesis, we decided to determine the affinity of RIF derivatives (i.e. rifampicin quinone, rifampicin N-oxide, 25-desacetylrifampicin, and 3-formylrifamycin SV) to PXR and OATP1B1, which has not been explored in details so far. For this, two hybrid and gene reporter assays were employed. As revealed by two hybrid assay, rifampicin quinone, rifampicin N-oxide, and 3- formylrifamycin SV (10 µM) activated PXR at a level comparable with RIF (positive control). Contrary, 25-desacetylrifampicin showed a lower affinity to PXR than that...
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The toxicity of vitamin D
Drouliskou, Eleftheria ; Mladěnka, Přemysl (advisor) ; Janoušek, Jiří (referee)
Vitamin D has essential role in skeletal health, however studies over the recent years have outlined its implication in many other physiological functions. The importance of vitamin D for health has, on one hand, raised needs for supplementation but may, on the other hand, lead to excessive administration. Vitamin D toxicity or hypervitaminosis D due to excess of vitamin D is a medical condition manifested mainly as hypercalcemia, with mostly gastrointestinal and neuropsychiatric symptoms. Long-term administration of large doses of vitamin D can result in vascular calcification and hence by associated with a cardiovascular risk. Hypervitaminosis D is extremely rare likely due to high therapeutic index of vitamin D. The clinical research shows an administration of 10.000 IU/day of vitamin D, which meets the criteria for the tolerable upper intake level, even for extended period, is probably not associated with adverse effects in almost all individuals in general population. However there are case studies globally showing vitamin D toxicity can occur due to misuse of over-the-counter vitamin D supplements, inappropriate prescribing or uncontrolled administration of high dose unlicensed preparations.
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Search for an efficient cobalt chelator
Nosková, Karolína ; Mladěnka, Přemysl (advisor) ; Smutný, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Karolína Nosková Supervisor: prof. Přemysl Mladěnka, PharmD., Ph.D. Consultant: Monika Moravcová, MSc. Title of diploma thesis: Search for an efficient cobalt chelator Cobalt, as part of vitamin B12, is an essential trace element for human organism. However, long-term exposure to high doses leads to toxicity. Chronic cobalt intoxication is currently most commonly observed after the implantation of cobalt-containing prostheses, which in some cases do not work properly and cobalt is released from them by mechanical friction or corrosion. That not only leads to a local reaction, but cobalt ions also enter the blood and lymphatic circulation and thus cause a systemic reaction. The intoxication is then manifested by neurological, cardiovascular and endocrine symptoms, which can lead to irreversible changes or even to the death. However, a chelator that would be able to effectively and selectively bind cobalt and thus effectively treat intoxication is not available in clinical practice. The aim of this thesis was a search for an efficient cobalt chelator among known metal chelators. Chelation was measured in vitro by a method based on spectrophotometric detection of unchelated cobalt ions at...
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Comparison of Iron-chelating Effects of Clinically Used Peroral Iron Chelators and 8-hydroxyquinolines
Zárubová, Pavla ; Mladěnka, Přemysl (advisor) ; Pávek, Petr (referee)
in English Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Candidate: Pavla Zárubová Consultant: Přemysl Mladěnka, Ph.D. Name of thesis: Comparison of iron-chelating effects of clinically used peroral iron chelators and 8-hydroxyquinolines Iron is an essentials element, which takes part in many vital processes. However, excessive iron can be toxic for the organism by catalyzing production of free radicals. Long-term administration of blood transfusions in the therapy of various anaemias is the most common cause of iron overload. Each transfuzion represents an intake of 200-250 mg iron in the organism, which due to low daily elimination (only 1-2 mg) leads to iron overload. As a result, complications like cardiovascular impairment or liver fibrosis can emerge. The risk of these severe complications can be reduced by administration of iron chelators. Deferoxamine has been traditionally used for the chelation therapy of chronic iron overload, but to his disadvantages belong frequent parenteral applications. In these days we can also use modern orally acive chelators (deferipron, deferoxamin). Furthermore, there is a wide range of potentially new indications (inflammation, tumor, cardiovascular and neurodegenerative diseases). In all these...
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Iron-chelating properties of fruit extracts of various elderberries
Gorová, Barbora ; Mladěnka, Přemysl (advisor) ; Kašparová, Marie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Barbora Gorová Supervisor: Assoc Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of thesis: Iron-chelating properties of fruit extracts of various elderberries Inorganic iron is the major food source of iron in humans. It plays role in many biochemical reactions. Thus, iron metabolism disorders can lead to different diseases associated with lack of iron or iron overload. One of the possible treatment modalities of the latter represents the administration of iron chelators. Elderberry, Sambucus nigra L. (Adoxaceae), has been used in traditional medicine. The fruits of elderberry are a rich source of cyanidin-based anthocyanins as the main component. There are important differences, both in chemical and physical properties between several cultivars of elderberry. Anthocyanins might interact with metals in the gastrointestinal tract by formation of chelates. However, data on metal interactions with anthocyanins are sparse. The main aim of this study was to perform the analysis of interaction of iron with elderberry fruit extracts as a rich and cheap source of anthocyanins with cyanidin as the aglycon. In this in vitro study ten elderberry fruit exctracts were tested for iron chelating activities...
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The influence of pH on iron chelation
Hrabalíková, Jitka ; Mladěnka, Přemysl (advisor) ; Hrdina, Radomír (referee)
v angličtině Iron is one of essential elements which are necessary for life of cells. Many important processes are connected with it and its insufficiency can lead to cell death. Iron excess can be dangerous, too; such situation can be triggered not only by acute intoxication, but it appears also chronically due to genetic abnormalities (hereditary hemochromatosis) or by frequent blood transfusions during treatment of thalassaemia, sideroblastic anemia or myelodysplastic syndrome. Iron chelators are used to cure these pathological states, but there have been currently analysed for the treatment of tumors or acute myocardial infarction as well. In pathogenesis of both of these disorders, iron and change of pH play significant roles. In this study, influence of pH on iron chelation abilities of various substances (deferoxamine, synthetic chelator SIH, flavonoids and synthetic coumarin 7,8-dihydroxy-4- methylcoumarin) was measured with the use of ferrozine as an indicator. The stability of complex chelator - iron in various pH was also tested. It was found that chelation activity of all tested substances and the stability of iron- chelator complex is increased with increasing pH. Strong chelators SIH and deferoxamine kept their effectiveness within pH from 7.5 to 5.5, whereas chelating activity of...
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