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Transcriptomic analysis of cutaneous inflammatory biomarkers in a mouse model of small fiber neuropathy
Benčová, Simona ; Mladěnka, Přemysl (advisor) ; Smutný, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Simona Benčová Supervisors: Dr. Claire Demiot, Dr. Aurore Danigo Assoc. Prof. Přemysl Mladěnka, Ph.D Title of diploma thesis: Transcriptomic analysis of cutaneous inflammatory biomarkers in a mouse model of small fiber neuropathy. Peripheral neuropathy is an expanding public health problem conditioned by various diseases and associated with several adverse effects such as the occurrence of chronic pain or increased risk of pressure ulcers (PUs). The aim of this study is to explore, whether the inflammatory state of the skin is modified during peripheral neuropathy and in the course of the formation of a pressure ulcer. The transcriptomic analysis was performed with two different models of mice: PU model and uninjured model, to determine genes that differ in expression and in particular, those involved in inflammation. Small fiber neuropathy was induced in young mice by intraperitoneal injection of resiniferatoxin (50 µg/kg, i.p.) - transient receptor potential vanilloid 1 (TRPV1) agonist. PUs were induced by applying two magnetic plates on the dorsal skin. Gene expression was obtained based on RNA microarray and the results were subsequently verified by qPCR. The transcriptomic analysis of PU...
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Ability of copper chelators to interact with iron and zinc
Hanuščinová, Lucia ; Mladěnka, Přemysl (advisor) ; Čonka, Patrik (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Lucia Hanuščinová Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmDr., PhD. Title of diploma thesis: Ability of copper chelators to interact with iron and zinc Copper plays in the human organism a role of an element with indispensable significance, whose biological influence and effects depend on its quantity. With elevated concentrations in the human body, copper becomes toxic, resulting in pathological conditions. The most well-known diseases is the Wilson's disease, whose treatment consists of oral administration of chelators, i.e. chemical compounds, which are capable of binding copper ions in various proportions and eliminating them from the organism. Chelation therapy is currently the first choice after confirmation of the diagnosis. Chelation toxicity results from several factors, e.g. inhibition of copper dependent enzymes or low selectivity to metals. And precisely the selectivity of chelators is being discussed in this diploma thesis. An ideal chelator should not interact with any of the other physiological ions, that are necessary for the proper functioning of the organism. Five of the most frequently therapeutically or experimentally used substances /trientine, D-penicillamine,...
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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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Determination of the stoichiometry of the coopper complexes with 7,8-dihydroxycoumarins
Mocová, Klára ; Mladěnka, Přemysl (advisor) ; Maixnerová, Jana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Klára Mocová, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of Thesis: Determination of the stoichiometry of the copper complexes with 7,8-dihydroxycoumarins Copper is an important element, which is necessary for right functioning of the organism because of its presence in wide range of enzymes. However, increased level of this element can cause various health complications. Coumarins are natural or synthetic substances, which contain 1,2-benzopyrone in their chemical structure. These compounds are known, among others, by their antioxidant activity, which includes the ability to chelate metals and hence form complexes with them. The stoichiometry of the complex is one of the important characteristics of metal complexes. The aim of this in vitro study was to assess the stoichiometry of 7,8- dihydroxycoumarins complexes with copper. We have been dealing with chelating activity of 7,8-dihydroxy-4-methylcoumarin and 7,8-dihydroxycoumarin with Cu+ and Cu2+ ions. Direct UV-Vis spectrophotometry was used to measure the complex formation at four physiologically or pathophysiologically relevant pH conditions (4,5; 5,5; 6,8 a 7,5). Both tested coumarins chelated Cu2+ ions in...
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Flavonoids and natural coumarins interactions with conventional medicine
Sigmundová, Tereza ; Tůmová, Lenka (advisor) ; Mladěnka, Přemysl (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Supervisor: doc. PharmDr. Lenka Tůmová, CSc. Student: Tereza Sigmundová Title of Thesis: Flavonoids and natural coumarins interactions with conventional medicine Keywords: medicinal plant, flavonoids, coumarins, interactions The aim of this diploma thesis is to give an overview of the interactions between conventional drugs and simultaneous use of flavonoids, coumarins or medicinal plants containing flavonoids and coumarins. Cited literature includes articles published since 2000 till 2018, that were collected mostly using online databases (Web of Science, Science Direct, PubMed, Google Scholar). Flavonoids can affect the metabolism of drugs through interaction with CYP450 enzymes, P-glycoprotein, ABC or SLC transporters. This type of interaction is particularly important for drugs with narrow therapeutic index such as cyclosporin, digoxin or warfarin. Furanocoumarins contained for example in grapefruit juice cause irreversible inhibition of CYP3A4 enzyme and affect the pharmacokinetics of many drugs. The major drug classes that have been reported to present pharmacodynamic interactions with flavonoids or natural coumarins are anticoagulants, cytostatics and central nervous system agents. The thesis also describes...
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Assessment of the complex stoichiometry of the active dexrazoxane metabolite ADR-925 with iron and copper by the standard Job's method
Szotáková, Tereza ; Mladěnka, Přemysl (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Tereza Morávková Supervisor: Assoc. Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of Thesis: Assessment of the complex stoichiometry of the active dexrazoxane metabolite ADR-925 with iron and copper by the standard Job'smethod Iron and copper are important trace elements which participate on many physiological processes in humans. Their kinetics in the organism is tightly regulated since both lack or excess of these elements are associated with pathological states. Free ions of iron and copper can catalyse reactive oxygen species (ROS) production and hence cause damage to proteins and DNA. Imbalance in these metals is linked with diabetes, cardiotoxicity, cirrhosis of the liver and neurodegenerative diseases as Alzheimer's disease or Parkinson's disease. Dexrazoxane is a drug with documented protecting effect against cardiotoxicity of anthracyclines. A former theory associated its protective effects against these cytotoxic drugs with the iron-chelating properties of its active metabolite ADR-925. The goal of this diploma thesis was to explore if ADR-925 is able to chelate Fe2+ , Fe3+ , Cu+ a Cu2+ ions at physiologically and pathophysiologically relevant pH values (4,5; 5,5; 6,8 and 7,5) and...
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Pharmacokinetics of flavanols
Sobolová, Dominika ; Mladěnka, Přemysl (advisor) ; Najmanová, Iveta (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Dominika Sobolová Supervisor: Assoc. Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of diploma thesis: Pharmacokinetics of flavanols This work is focusing on summarizing available information about the fate of flavanols in the organism. It is necessary to know the pharmacokinetics to explain their biological effects. In contrast to other flavonoids, they occur in the form of aglycones in plant foods. Galoylation, polymerization and optical isomerism have an important influence on the pharmacokinetics. Partial absorption of monomers begins in the small intestine after oral ingestion. In addition to the liver, the extensive metabolic changes take place even in the enterocytes. The resulting metabolites enter the circulation or they are effluxed back into the intestinal lumen, especially in the case of (epi)catechin sulfates. Epicatechin and catechin are present almost exclusively as glucuronides, sulfates or methylated compounds in the plasma. On the contrary, free unconjugated forms prevail within the gallates. The extent of their absorption is lower. They are excreted via biliary excretion, while other catechins are quickly eliminated by the kidneys in urine. The bioavailability of the parent...
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The pharmacokinetics of isoflavonoides
Ungerová, Lucie ; Pourová, Jana (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Ungerová Supervisor: PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: The pharmakokinetics of isoflavonoids The aim of this diploma thesis is to summarize currently available informations about the pharmacokinetics of the polyfenolic compounds from a large group of flavonoids, isoflavonoids. Isoflavonoids are coumpounds found in many plant families, but especially in some members of Fabaceae family. One of the main well-known sources are soy beans containing the most famous isoflavones - genistein and daidzein, their pharmakokinetics is the main theme of this diploma thesis. Since isoflavonoids are mainly contained in the diet, their oral administration is very relevant. Isoflanonoids in the human diet occurs predominantly in the form of glykosides and therefore, after ingestion, they have to be deglycosylated by β- glucosidase enzyme family to aglycones. After that they are able to pass through the intestine into the systemic circulation and they are available for action. This is already happening in the oral cavity and the absorption occurs in the small intestine. The intestinal bacterial microflora composition is also very important for pharmacokinetics, for example I can mention...
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Monitoring the effect of statins and soluble endoglin on markers of endothelial dysfunction in selected cell line and culture.
Vařejčková, Michala ; Nachtigal, Petr (advisor) ; Štěrba, Martin (referee) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Candidate: Mgr. Michala Vařejčková Supervisor: Prof. PharmDr. Petr Nachtigal, Ph.D. Title of Doctoral Thesis: Monitoring the effect of statins and soluble endoglin on markers of endothelial dysfunction in selected cell line and culture. This doctoral thesis studied the effect of soluble endoglin on endothelial dysfunction markers in vitro in primary cell culture HUVEC and cell line HEK293T. Some experiments included in this thesis were made in cooperation in the laboratory of prof. Carmelo Bernabeu in the research center Centro de Investigaciones Biológicas (CIB) in Madrid. Endothelial dysfunction is damage of endothelium when the balance between vasoconstrictor and vasodilatory mechanisms is disrupted, it's leading to platelet aggregation, leukocyte adhesion and increased permeability of the endothelium. All these events represent the first step in the development of atherosclerosis and they are part of other cardiovascular diseases such as preeclampsia, type 2 diabetes mellitus, familial hypercholesterolemia. An important role in these diseases play endoglin, eNOS and soluble endoglin (sEng), which is cleaved by MMP- 14 from the membrane endoglin and released into the circulation. It was found...
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Microglia control adenosine A2A-receptor mediated astrogliosis
Svobodová, Magdaléna ; Mladěnka, Přemysl (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Magdaléna Svobodová Supervisor: Assoc. Prof. Přemysl Mladěnka, Ph.D. Assoc. Prof. Maria da Glória Correia da Silva Queiroz, Ph.D. Title of diploma thesis: Microglia control adenosine A2A-receptor mediated astrogliosis In the central nervous system, astrocytes and microglia are the main cells coordinating the inflammatory response. During inflammation, dying or temporarily damaged cells release ATP, as a danger-associated signal molecule, that contributes to the induction of astrogliosis and promotes clearance of the debris by immune cells such as microglia. Adenosine that results from ATP metabolism also stimulates astrogliosis. However, the effects of adenosine on astrogliosis may be more complex, since it also modulates microglia phenotype and microglia have been shown to prevent excessive astroglial proliferation mediated by nucleotides. In this context, ATP and adenosine are assumed as relevant signalling molecules in the control of astrogliosis and its modulation by microglia. However, it is still unknown whether and how microglia modulate adenosine-mediated astrogliosis. The present study aims to clarify the impact of microglia in the control of adenosine-induced astrogliosis. Two...
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