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Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Podhorná, Pavla ; Vokřál, Ivan (advisor) ; Ambrož, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Pavla Podhorná Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of dexamethasone on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices Dexamethasone is a corticosteroid that has anti-inflammatory, immunosuppressive, and anti-allergic effects. The mechanism of dexamethasone action involves its ability to bind to intracellular glucocorticoid receptors, which are present in many types of cells, including intestinal mucosal cells. Upon binding to these receptors, it translocates to the nucleus of the cells and affects gene expression. This mechanism also affects the expression of genes important for the metabolism and transport of xenobiotics in the intestinal mucosa. The most important such genes include ABCB1, an important intestinal transporter, and CYP3A4, a significant biotransformationenzyme.Their localizationinthe wall of the small intestine can significantlyaffect the absorptionof orallyadministereddrugs.Studyingdrug interactions with this transporter and biotransformation enzyme is important for safe and effective pharmacotherapy. To determine whether dexamethasone affects the expression of these genes in the intestinal barrier,we used the method of...
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Fotoiniciovaná degradace vybraných léčiv (dexametazonu, prednisolonu, fluoxetinu) a testování toxicity léčiv a produktů jejich fotodegradace na vodní organismy (\kur{Daphnia magna})
DOKOUPILOVÁ, Eliška
This diploma thesis investigates kinetics of photoinitiated degradation of selected drugs (dexamethasone, prednisolone, fluoxetine) under conditions relevant to surface waters and provides results of toxicity tests of original compounds and their photodegradation products mixtures for a representant of aquatic organisms, cladoceran Daphnia magna. The theoretical part describes the basic characteristics, mechanism of action and therapeutic usage of selected drugs. Toxicological studies related to adverse effects of these substances on aquatic organisms are also briefly outlined. The experimental part presents first the results of photochemical degradation kinetics of the studied compounds and second the findings of chronic toxicity tests of the selected drugs and their photoproducts mixtures on Daphnia magna, namely on the number of juveniles, on the number of clutches and on the body size.
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Functional genomic and pharmacogenomic analysis of metabolic syndrome aspects
Krupková, Michaela ; Šeda, Ondřej (advisor) ; Haluzík, Martin (referee) ; Polák, Jan (referee)
Metabolic syndrome is a prevalent disease characterized by concurrent manifestation of insulin resistance, obesity, dyslipidemia, hypertension and other hemodynamic and metabolic disorders. It has multifactorial type of inheritance and its resultant phenotype is determined by both environmental and genetic factors as well as their interactions. That is the main reason why comprehensive analysis of the genetic component of this syndrome is complicated in human population. Genetically designed experimental animal models are significant tools for analysis of genetic architecture of human complex conditions including the metabolic syndrome. The aim of this Thesis is utilization of functional and comparative genomic tools to uncover pathogenesis of metabolic syndrome aspects and their genetic determinants. We also studied pharmacogenetic interactions of these genetic determinants with drugs affecting particular components of the metabolic syndrome. Establishing and utilizing several genetically designed congenic rat strains, we undertook four different research projects focusing on pharmacogenetic interaction of all-trans retinoic acid and ondansetron with differential segment of rat chromosome 8, pharmacogenetic interaction of differential segment of rat chromosome 4 and dexamethasone, determining Plzf...
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Coaxial nanofibers with incorporated suplements for regulated chondrogenic differentiation
Korbelová, Gabriela ; Rampichová, Michala (advisor) ; Vištejnová, Lucie (referee)
In the field of regenerative medicine, regeneration of cartilage defects (caused either by injury or age-related degeneration) has become a widely discussed topic. Nanofibrous scaffolds provide a suitable environment for cell adhesion, proliferation, differentiation, and also for the local involvement of bioactive substances. Nanofibrous scaffolds mimic the extracellular matrix (ECM) of hyaline cartilage. These scaffolds are seeded with autologous chondrocytes. After having been isolated from the patient, the cells must be cultivated in vitro in order to obtain a sufficient amount of chondrocytes. Scaffolds with cultivated chondrocytes are later implanted back into the pacient. Chondrocytes, however, when grown on a 2D tissue culture plastic rapidly de-differentiate and thus lose the ability to synthesize ECM molecules. The aim of the work was modulation of chondrogenic differentiation medium through finding the ideal concentration of chondrogenic supplements, composed of L-ascorbate-2-phosphate (A2P) and dexamethasone (DEX), in the culture of primary chondrocytes seeded on a nanofibrous polycaprolactone (PCL) scaffold. The effect of different concentrations of the chondrogenic supplements on chondrocyte adhesion to the scaffold and their proliferation and differentiation was studied. The influence...
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Coaxial nanofibers with incorporated supplements for regulated chondrogenic differentiation
Korbelová, Gabriela ; Rampichová, Michala (advisor) ; Vištejnová, Lucie (referee)
In the field of regenerative medicine, regeneration of cartilage defects (caused either by injury or age-related degeneration, such as osteoporosis) has become a widely discussed topic. Nanofibrous scaffolds provide a suitable environment for cell adhesion, proliferation, differentiation, and also local involvement of bioactive substances. Nanofibrous scaffolds mimic the extracellular matrix (ECM) of hyaline cartilage and thus have the potential to treat cartilage defects. The aim of the work was modulation of chondrogenic differentiation medium through finding the ideal concentration of chondrogenic supplements, composed of ascorbate-2- phosphate and dexamethasone, in the culture of primary chondrocytes of pig origin seeded on a nanofibrous polycaprolactone (PCL) scaffold. The effect of different concentrations of the chondrogenic supplements on chondrocyte adhesion to the scaffold and their proliferation and differentiation was studied. Firstly, the influence of each of the supplements alone in the medium was studied, followed by study of effects of their combinations. Then, the supplements were incorporated into the nanofibers and their effect upon their release from the nanofibers was investiaged. The supplements were studied in 21-day experiments. The chondrogenic re- differentiation was best...
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Functional genomic and pharmacogenomic analysis of metabolic syndrome aspects
Krupková, Michaela ; Šeda, Ondřej (advisor) ; Haluzík, Martin (referee) ; Polák, Jan (referee)
Metabolic syndrome is a prevalent disease characterized by concurrent manifestation of insulin resistance, obesity, dyslipidemia, hypertension and other hemodynamic and metabolic disorders. It has multifactorial type of inheritance and its resultant phenotype is determined by both environmental and genetic factors as well as their interactions. That is the main reason why comprehensive analysis of the genetic component of this syndrome is complicated in human population. Genetically designed experimental animal models are significant tools for analysis of genetic architecture of human complex conditions including the metabolic syndrome. The aim of this Thesis is utilization of functional and comparative genomic tools to uncover pathogenesis of metabolic syndrome aspects and their genetic determinants. We also studied pharmacogenetic interactions of these genetic determinants with drugs affecting particular components of the metabolic syndrome. Establishing and utilizing several genetically designed congenic rat strains, we undertook four different research projects focusing on pharmacogenetic interaction of all-trans retinoic acid and ondansetron with differential segment of rat chromosome 8, pharmacogenetic interaction of differential segment of rat chromosome 4 and dexamethasone, determining Plzf...
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Synchronization of peripheral circadian clocks during ontogenesis.
Paušlyová, Lucia ; Sumová, Alena (advisor) ; Hock, Miroslav (referee)
The circadian system is an important coordinator of physiological functions of a mammalian organism. It comprises of a central oscillator represented by cells in the suprachiasmatic nuclei of hypothalamus (SCN) and peripheral oscillators in most if not all cells of peripheral tissues. The peripheral oscillators, similarly to the central ones, generate circadian oscillations at the level of so called clock genes and their protein products. In peripheral tissues, oscillations in expression of the individual clock genes are autonomous, however, they need to be synchronized to ensure their robust rhythmic expression. The peripheral clocks are synchronized mainly by rhythmical signals from the SCN, including signals regulating food intake. Disturbances in the clock gene expressions, as well as impaired synchronization signals, can result in various pathophysiological states. Spontaneously hypertensive rat (SHR) strain is a convenient animal model to study potential connection between the disturbed circadian system and progressive development of hypertension and metabolical diseases in mammals. Various studies have shown differences in the rhythmical expression of clock genes between SHR strain and normotensive Wistar/Wistar-Kyoto strain. The aim of this thesis is to provide insight into the early...
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Effect of environmentally relevant concentration of dexamethasone to fish organism
BOŘÍK, Adam
Pharmaceutical pollutants have been aim of many recent aquatic environment studies. Due to human activities surface waters are polluted with plenty of substances, including products of personal care, which are ranked among a number of pharmaceuticals. The main goal of this work is to assess the impact of environmentally relevant concentrations of the synthetic glucocorticoid dexamethasone on aquatic organisms through biomarkers of oxidative stress. The principle of this experiment was chronic in vivo exposure model organisms (rainbow trout) to doses of this drug and the subsequent monitoring activities of antioxidant enzyme system in the liver and gill tissues. Experimental results have demonstrated a response enzymatic protection mechanism on the increased production of reactive oxygen species induced by the drug at environmentally relevant concentrations especially in gill tissue. Our results illustrate a real risk that this xenobiotic represents to aquatic organisms.
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