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Comparsion of iron reducing properties of flavonols and flavanones
Kyjovská, Veronika ; Mladěnka, Přemysl (advisor) ; Karlíčková, Jana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Veronika Kyjovská Supervisor: P emysl Mlad nka, Ph.D. Title of Thesis: Compare iron-reducing properties of flavanols and flavanons The aim of this thesis was to compare the iron-reducing properties of flavanons and flavonols in different concentrations, at different pathophysiological pHs and in non-buffered conditions. A spectrophotometric method with ferrozin, an indicator of ferrous ions, was used. Results at pH 4.5 and in non-buffered conditions were almost comparable, while at pH 5.5 flavonoids showed almost no reduction activity. At pH 6.8 and 7.5 flavonoids did not reduce ferric ions at all. Representatives with the highest reduction activity belonged mostly to the group of flavonols (quercetin, kaempferol, morin, myricetin). Only one representative of flavanons - taxifolin showed the same reduction activity as aforementioned representatives of flavonols. This is probably due to the presence of the 3-hydroxy group in C ring. Other representatives of flavonon do not contain this group and were associated with minimal capabilities of reduction. Lower reduction activity was also observed in case of a representantive of flavonols - rutin, which has the 3-hydroxy group substituted...
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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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Effect of Nicotinic Acid on infiltration of macrophages in the ischemic brain
Pokorná, Barbora ; Pávek, Petr (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Kralove Department of Pharmacology and Toxicology Candidate: Barbora Pokorna Supervisor: Doc. PharmDr. Petr Pavek Ph.D. Specialized supervisor: Prof. Dr. med. Markus Schwaninger Title of diploma thesis: Effect of Nicotinic Acid on infiltration of macrophages in the ischemic brain Stroke is one of the leading causes of death worldwide and its effective protective treatment is still missing. Nicotinic acid has been a widely used substance to modify lipid profiles for many years and it successfully prevents clinical cardiovascular diseases. Recently explored receptor, GPR109A, causes its effect and it was found to be expressed in spleen, adipose, and immune cells including macrophages. The aim of this work is to investigate the effect of nicotinic acid on the infarct size during cerebral ischemia and to determine the role of macrophages in its effect. We compared two groups in our experiments, transgenic CD11bDTR mice and control wild type (WT) mice. Both groups were treated with diphtheria toxin (DT), then a middle cerebral artery occlusion was performed and afterwards mice were treated with either nicotinic acid or vehicle. We have found depletion of macrophages in CD11bDTR group induced by DT treatment and depletion of macrophages in WT...
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Modulace exprese alfa-synukleinu pomocí působení 5-S-cysteinyldopaminu na buňky lidského neuroblastonu SH-SY5Y: možná úloha katecholthioetherů při neurodegeneraci
Hrabáková, Rita ; Štaud, František (advisor) ; Mladěnka, Přemysl (referee)
-Synuclein is a presynaptic protein which has been demonstrated to be involved in PD etiopathogenesis.It can regulate DA homeostasis by inhibition of TH activity, by regulation of the DAT activity and finally by potential role in vesicular storage. - Synuclein is a natively unfolded protein, which can undergo overexpression and aggregation due to toxic insults or oxidative stress. The aggregation of α-synuclein leads to a loss of function, which in PD neurons may determine a dysregulation of the DA pathways with subsequent excess of cytosolic DA, that can enhance the neurotoxic effect of α-synuclein aggregates. In recent years, a catecholthioether metabolite of DA, 5-S-cysteinyl-dopamine, has been identified in certain dopaminergic regions of the brain, notably the Substantia nigra. Cys-DA seems to have a possible significance as an index of oxidative stress in aging and in neurodegenerative processes and it was recently hypothesized that this substance or its metabolites may be the endogenous neurotoxins responsible for neurodegeneration in PD. Hence, the aim of this experimental work was to determine whether Cys-DA is able to cause overexpression of -synuclein both at transcriptional and translational levels in a cellular model of PD, the human neuroblastoma dopaminergic cell line SH-SY5Y....
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Identification and characterization of G protein-coupled nucleotide and nucleotide-like receptors P2Y13 and GPR17
Klenotič, Ondřej ; Doležal, Martin (advisor) ; Mladěnka, Přemysl (referee)
Identification and characterization of G protein-coupled nucleotide and nucleotide-like receptors P2Y13 and GPR17 Purinergic receptors are divided into three subfamilies, P1 (adenosine), P2 (nucleotide) and P0 (adenine) receptors. P2 receptors comprise ligand-gated ion channels - shortly LGICs, receptors P2X1-7, and class A, δ-branch GPCRs termed P2Y1,2,3,6,12-14. The P2Y13 receptor is physiologically activated by ADP and coupled to Gi whose activation results in an inhibition of adenylate cyclase. P2Y13 receptor activation has been reported to be neuroprotective. P2Y13 receptors also play a role in lipoprotein metabolism and cholesterol transport, making the receptor an interesting target for the potential treatment of atherosclerosis. The nucleotide-like orphan receptor GPR17, whose endogenous agonist remains still unknown, is also Gi-coupled. GPR17 appears to be involved in demyelinating diseases such as multiple sclerosis, and some inflammatory diseases. The development of potent, selective ligands, agonists and antagonists, for both P2Y13 and GPR17, is required to study their physiological and pathophysiological roles and for validating the receptors as future drug targets. In the present study, we aim to find out, if the approach via β-arrestin assay employing an enzyme complementation is...
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Copper chelating properties of flavanones
Kantorová, Tereza ; Mladěnka, Přemysl (advisor) ; Spilková, Jiřina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Departmet of Pharmacology and Toxicology Candidate: Tereza Kantorová, MSc. Consultant: Assoc. Prof. Přemysl Mladěnka, Pharm.D.,PhD. Title of the Rigorous Thesis: Copper chelating properties of flavanones Copper is an essential trace element playing an essential role in our body. As part of couproenzymes, it is involved in many physiological processes. However, at the same time, it also poses a certain risk to the human body. Free copper has the ability to potentiate the formation of reactive oxygen species and thus to promote oxidative stress. Therefore, copper homeostasis must be carefully regulated. Flavanones belong to one of the subclasses of flavonoids. These natural substances are very interesting from a scientific point of view due to their possible various pharmacological effects. In this work, we focused on their copper-chelating properties. Flavanones, which are expect to possess a low potential for side effects, could find application as copper chelators and thus expand the current therapeutic modalities for some diseases associated with copper imbalance (e.g. Wilson's disease, tumors). Four selected flavanones (hesperetin, hesperidin, naringenin and naringin) were tested for their ability to chelate copper ions using two...
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Search of effective cobalt chelators - 8-hydroxyquinolines
Pelnářová, Karolína ; Mladěnka, Přemysl (advisor) ; Carazo Fernández, Alejandro (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Karolína Pelnářová Supervisor: Prof. Přemysl Mladěnka, PharmD., Ph.D. Consultant: Václav Tvrdý, MSc.; Marcel Hrubša, MSc. Title of diploma thesis: Searching of effective cobalt chelators - 8-hydroxyquinolines Cobalt is one of the essential trace elements present in the human body. It forms a part of the organometallic complex of vitamin B12, which is essential for many physiological functions. Both overload and lack of cobalt in the body is associated with pathological conditions. Manifestations of deficiency can lead up to pernicious anemia or hypofunction of the thyroid gland. Cobalt intoxication can occur in an industrial environment, such as by cobalt metal dust during heavy metal processing, or by its release due to corrosion from orthopedic prostheses. Systemic toxicity is manifested by a number of endocrine, cardiovascular and neurological symptoms. The main aim of this diploma thesis was to find effective chelators of cobalt from the group of substances derived from 8-hydroxyquinoline. In vitro spectrophotometric measurement was used to determine the degree of chelation. The effect of chelation was also monitored ex vivo in rat erythrocytes. All tested chelators - 8-hydroxyquinoline,...
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Comparasion of interaction of cyanidin and cyanidin-3-glucoside with copper and iron
Gavurová, Lucie ; Mladěnka, Přemysl (advisor) ; Smutná, Lucie (referee)
Iron and copper are trace elements involved in many essential processes in the human body. Copper plays an important role in human metabolism, primarily as a cofactor of many metalloenzymes, like superoxide dismutase and ceruloplasmin. Copper is also essential for iron homeostasis. Iron is incorporated into many biomolecules like heme or enzymes, and is hence vital for cellular processes like oxygen transport, energy production and DNA synthesis. In biological systems, copper is present in both the oxidised form of cupric (Cu2+ ), and the reduced form as cuprous ion (Cu+ ). Iron as well exists in two stable oxidation states as ferrous (Fe2+ ) or ferric ion (Fe3+ ). Due to their strong redox potential, both elements can be potentially toxic to the body. Iron accumulates in vital organs such as the liver, heart and kidneys. Wilson's disease is an example of copper overload disease resulting from pathogenic mutations in gene ATP7B. The iron excess in the body is usually associated with iron overloading conditions, such as hereditary hemochromatosis or repeated treatments with blood transfusions (e.g. in thalassemia). In such cases, drugs with chelating or reducing effect are convenient for clinical use. The aim of this thesis was to compare the interaction of the chelating and reducing efficacy of two...
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Optimization of PEI based LbL capsules with pDNA
Ondrašáková, Petra ; Mladěnka, Přemysl (advisor) ; Hofman, Jakub (referee)
Ab rac Charle Uni er i Fac l of Pharmac in Hradec Kr lo Depar men of Pharmacolog and To icolog S den : Pe ra Ondra ko , MSc. S per i or: A oc. Prof. P em l Mlad nka, Pharm.D., Ph.D. Co- per i or: Dr. Haider Sami, Uni er i of Vienna, Di i ion of Clinical Pharmac and Diagno ic Ti le of rigoro he i : Op imi a ion of PEI ba e LbL cap le i h pDNA In hi he i , e foc ed on he de elopmen of pol e h lenimine (PEI) ba ed non- iral cap le , hich ill en er n cle of he cancer cell and lead o he e pre ion of he lacking pro ein, hich ca e di ea e. A fir , PEI ba ed la er-b -la er (LbL) pol mer cap le ere formed. PEI ha man ad an age - i ha pro onable amine , good abili and ran fec ion efficienc . When forming he cap le, I follo ed p on m diploma he i and con in ed o op imi e he mo i able combina ion of pol mer , ha ere la ered on he CaCO3core. The aim a o ob ain a biodegradable cap le and hen o incorpora e pla mid DNA (pDNA) herein. Fl ore cen l labelled PEI a ed a he la la er o i ali e par icle in fl ore cen micro cope. Then a canning elec ron micro cope (SEM) a ed o ob er e cap le in more de ail . UV-VIS and Dapi aining ere ed o ee he her here i pDNA bo nd in cap le . Ne ep ere i i cell e perimen on mo e mammar cancer cell - c o o ici and cell lar in ake. Vi ali a ion a pro ided i h fl ore cen micro cop . 2 pe of...
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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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