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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Study of selected flavonoids as modulators of cytochrome P450 3A4
Skotnicová, Aneta ; Hodek, Petr (advisor) ; Koblihová, Jitka (referee)
Flavonoids are secondary metabolites of plants exhibiting a wide range of biological activities. Special attention is paid to them mainly because of their antioxidant properties. Consumption of these natural substances is currently increasing especially in the form of dietary supplements. In addition, these compounds exhibit antiviral, anti-inflammatory or hepatoprotective effects and some of them also exhibit mutagenic and/or pro-oxidative properties. The study of flavonoid interactions with biotransformation enzymes such as cytochromes P450 are important because of their possible interference with the metabolism of drugs or carcinogenesis processes. In this bachelor thesis the influence of selected flavonoid compounds, dihydromyricetin and myricetin, on the expression and activity of cytochrome P450 3A4 was studied. The flavonoid premedication of rats did not resulted in induction of CYP3A4. However, dihydromyricetin and myricetin inhibit CYP3A4. IC50 were determined as 25 M for dihydromyricetin and 24 M for myricetin. Key words: Immunodetection, HPLC, inhibition, induction (In Czech)
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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Preparation of mutated forms of fosfatidylinositol kinase IIα
Gregor, Jiří ; Šulc, Miroslav (advisor) ; Košek, Dalibor (referee)
Phosphatidylinositol 4-kinases (PI4K) are enzymes that form phosphatidylinositol-4- phosphate, which is an important regulatory molecule and precursor for the synthesis of other regulatory molecules. PI4K are interesting from medical aspect, because of connection between their function and viral, malignant, metabolic and neurodegenerative diseases. PI4K type II are inhibited by calcium cations, whereas PI4K type III aren't. The goal of this thesis was to elucidate the relationship between structure and regulation of function of PI4K IIα, specifically regulation by calcium cations. We failed in preparation of mutated forms of PI4K IIα that wouldn't be inhibited by calcium cations. However, the results obtained suggest, how aminoacids N313, D346 and E193 affect the kinase activity of PI4K IIα. (In Czech)
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Self-control: disentanling inhibition and initiation
Kucharský, Šimon ; Vranka, Marek (advisor) ; Lukavský, Jiří (referee)
Self-control is usually defined as a unit in a regulatory cycle process. As such, it can be used for inhibition of urgent need or overriding impulsive responses, but it can also mean that person can engage in a behavior which is aversive at the moment. Contemporary the most influential is strength model of self-control that envisages one general and limited source of energy for every act of self-control. According to this model, after depleting this energy, one's ability to control his or her behavior or thought is impaired, even in domains that does not relate to the cause of the depletion. However, there has been substantial criticism of this model recently - regarding theoretical implausibility, possible bias in literature (or even manipulated results) and also growing body of evidence that is not in line with the model. Because of that, there are attempts to alter or dismiss the model. One of the possible updates is distinguishing between two domains of self-control (inhibition and initiation). This thesis overviews body of recent findings about self-control and proposes experimental design which could serve to verify hypothesis of existence of two independent domain of self- control. Limits of this approach and suggestions for future research are also discussed. Keywords: Self-control, ego...
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Succession of insect communities inhabiting carcasses of small vertebrates, with emphasis on the beetles
Kadlec, Jakub ; Šípek, Petr (advisor) ; Růžička, Jan (referee)
This master thesis deals with succession and succession mechanisms of beetles (Coleoptera) on carrions of small vertebrates. As a model sample of small carrion a small mouse of weight 20 grams was chosen. In 2014 two experiments occurred. The first one studied the succession of a beetle community in dependence on seasonality and time of death of the sample. The second experiment was aimed to survey the blocking effect of an early insect succession on the final beetle community composition on carrions. It turned out, that during decomposition of the carrion the overall amount of beetles raised equally to the guild of necrophagous beetles. Change of the species spectrum during succession was not statistically confirmed. On the other hand, the effect of seasonality was clear as during the season the abundance and the amount of species increased. The proportion of trophic guilds changed significantly, necrophagous beetles were the most dominant part of the community towards the end of the season. Equally, the taxonomic composition of the community also changed during the season. The seasonal dynamics of carrion beetles was clear; Nicrophorus vespillo (Linnaeus, 1758) and N. investigator Zetterstedt, 1824 showed their peaks in spring and summer while N. humator (Gleditsch, 1767) and N. vespilloides...
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Vliv vybraných potravních doplňků na metabolismus karcinogenů přítomných v potravě
Fousová, Petra ; Hodek, Petr (advisor) ; Burdová, Kamila (referee)
The consumption of dietary supplements such as flavonoids may reduce risk of many civilization diseases. Flavonoids are able to modulate the activity of cytochromes P450 (CYPs), xenobiotic-metabolising phase I enzymes of biotransformation that are involved in the activation and detoxification of food-derived carcinogens. Inhibition of CYP activities by flavonoids has been extensively studied because of their potential use as agents blocking the initiation stage of carcinogenesis. On the other hand, flavonoids have been shown to enhance the activation of carcinogens and/or influence their metabolism via induction of specific CYPs. In the first part of this study, flavonoids dihydromyricetin and α-napthoflavone were explored for their possible effects on CYP1A1 expression and activity when administered in combination with carcinogen benzo[a]pyrene (BaP). For this purpose, liver, small intestine and colon microsomal fractions were isolated from treated rats and induction of CYP1A1 was evaluated by immunodetection and EROD activity measurements. In liver and small intestine, all combinations of BaP and flavonoids led to strong induction of CYP1A1 expression. Moreover, the CYP1A1 protein levels were almost identical to levels observed when the rats were treated with BaP alone. However, in comparison...
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Testing of the sensitivity of bacteria on selected substances in school environment
Švehlová, Vendula ; Pavlasová, Lenka (advisor) ; Skýbová, Jana (referee)
The aim of this bachelor thesis lies in describing and executing of methods which are determining the resistance of various types of bacteria to antibiotics and selected common household disinfectants and also selected products for oral hygiene. Due to the structure of these methods they can be used f.e. in practical classes in grammar or high schools. Antibiotic discs and other supplies are used when examining resistence of bacteria towards antibiotics which are affordable for aforementioned schools. We can see the efficiency of various antibiotics and disinfectants and we can easily decide which ones are worth of purchase and which ones are not very functional alltogether. Last items tested are samples of mouthwashes and toothpastes. The mechanisms behind the efficiency of all these substances and the sensitivity of bacteries will be described either in practical and theoretical part of this thesis. Key words: Antimicrobials substances, resistance, inhibition, agar soil, bacteria
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The effect of secondary metabolites (essential oils) on endophytic fungi from leaves of Rhododendron tomentosum
Koudelková, Barbora ; Koukol, Ondřej (advisor) ; Žabka, Martin (referee)
Rhododendron tomentosum is an evergreen shrub with a high content of secondary metabolites, particularly essential oils with antimicrobial effects. Diversity of endophytic fungi in this species and their possible adaptation to growth in the essential oil environment is not much explored. Therefore, the first aim of this thesis was to reveal the diversity of endophytic fungi colonising leaves of R. tomentosum on seven localities in the Czech Republic and one in Estonia. I isolated and determined (using comparison of ITS1 and ITS2 rDNA with the sequences from GenBank and morphological signs) 37 species of endophytic fungi. Among them the ubiquitous species colonising the most of the plants as endophytes were dominant. The second aim of my thesis was to explore whether the essential oil from R. tomentosum influences its endophytic fungi. The hypothesis that the strains obtained from R. tomentosum would be adapted to growth in the environment of the essential oil was postulated. I supposed that they would grow better on mediums with different concentrations of these chemical compounds added, in comparison with strains of the same species obtained from different substrates. Within four of seven species tested, the strains obtained from R. tomentosum grew better, but also on the medium without the...
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Modulation of HIV-1 Protease Activity
Pokorná, Jana ; Konvalinka, Jan (advisor) ; Šedo, Aleksi (referee) ; Ruml, Tomáš (referee)
HIV-1 protease plays a crucial role in the late state of the life cycle of HIV virus when it cleaves the viral polyprotein precursors into the structural and functional proteins. If it is effectively inhibited, HIV particles remain immature and noninfectious. The application of highly active antiretroviral therapy (HAART) including protease inhibitors can reduce plasma HIV-1 levels below the detection limit in adherent patients and thus dramatically change their life expectancy. The clinical utility of the first inhibitors was limited by severe side effects, low bioavailability, high pill burdens, and rapid development of viral resistance under the selection pressure of HIV antiretrovirals. To overcome these difficulties, second-generation inhibitors were developed. Despite an indisputable improvement they brought to antiretroviral therapy, the development of new highly active HIV-1 protease inhibitors with optimal pharmacokinetic properties, higher metabolic stability, little off-target activity, and particularly, more favorable resistance profiles is still of high importance. This thesis provides an overview of anti-HIV- drugs including development of substituted metallacarboranes, a new class of potent, unusual, nonpeptidic HIV protease inhibitors with therapeutic potential. Next, the impact of...
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