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Study of intestinal transporters and their role in drug absorption
Huličiak, Martin ; Červený, Lukáš (advisor) ; Mladěnka, Přemysl (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Training Workplace Department of Pharmacology and Toxicology Doctoral Degree Program Pharmacology and Toxicology Candidate Mgr. Martin Huliciak Supervisor Assoc. Prof. PharmDr. Lukas Cerveny, PhD. Advisor PharmDr. Ivan Vokral, PhD. Title of Doctoral Thesis Study of intestinal transporters and their role in drug absorption Oral drug administration is a widely accepted method due to its convenience and cost- effectiveness, with the small intestine playing a crucial role in drug absorption, thus affecting bioavailability and serving as a potential site for drug-drug interactions (DDIs). Efflux drug transporters such as P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), along with metabolizing enzymes such as cytochrome P450 3A4 (CYP3A4) at the intestinal barrier, significantly contribute to DDIs. Risk factors for DDIs include comorbidities, advanced age, and polypharmacotherapy. People living with HIV requiring antiretroviral therapy (ART) are particularly susceptible to DDIs, especially when co-infected with HCV. Antivirals, commonly used in ART and in the treatment of HCV infection, can interact with efflux transporters and CYP enzymes, affecting drug efficacy and safety. Therefore, this study mainly focuses on the DDIs of...
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Role of melatonin in the mammalian intestine and its interaction with the gut microbiome
Přiklopilová, Barbora ; Sumová, Alena (advisor) ; Mašín, Jiří (referee)
Melatonin is a hormone that primarily functions in regulating circadian rhythms in mammals. Independently of the pineal gland, it is also synthesized in the intestines, where it can interact with the gut microbiome and thus contribute to a wide variety of diverse functions. The aim of this paper is to describe the role of melatonin and summarize its functions across different organisms, with a particular focus on mammals. The work concentrates on explaining the proven effects of melatonin in the mammalian gut, its potential interactions with the gut microbiome, and the overall impact on the homeostasis of the intestinal environment.
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Knot unit for casing, device technical design and its automatic control
Šimeček, Jiří ; Marada, Tomáš (referee) ; Němec, Zdeněk (advisor)
My diploma work deals with the project and the construction of prototype machinery into food-processing industry which serves for knotting of frankfurther casings. This knot is make on uneatable frankfurther casing of which is shirring a peg. Diploma work I separated into several parst. In the firts part I inscribe to project of principle of knotting. In other part I prefer instrumentation components and automation function, algorithms of operating, solution to automation problems and realization of application program. This work is complete any program in Visilogic.
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Circadian regulation of digestive system function and its disturbances due to external factors
Běloušková, Klára ; Sumová, Alena (advisor) ; Balounová, Kateřina (referee)
Circadian clocks regulate the behavior of cells in living organisms in 24hour periods. They react to environmental influences and, by synchronizing with them, ensure optimal cell function and the overall health of the organism. Biological clocks in the gastrointestinal tract and their functions can be influenced by several factors, including the timing of food intake or the influence of the microbiome. The correct timing of food intake can be essential in maintaining the functional physiology of the organism as well as the appropriate composition of the gut microbiome. Disruption of the synchronization between these factors and the biological clock in the gastrointestinal tract leads to disharmony of the organism, its improper function and the development of disease. The timing of food intake and the cultivation of an appropriate microbiome is critical to maintaining optimal health and should not be neglected by the public.
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Wnt/β-catenin signalling in the development of the marine annelid Platynereis dumerilii
Žídek, Radim ; Kozmik, Zbyněk (advisor) ; Janečková, Lucie (referee) ; Macůrková, Marie (referee)
Radim Žídek "Wnt/β-catenin signalling in the development of the marine annelid Platynereis dumerilii" (dissertation) Abstract: Wnt/β-catenin signalling is absolutely crucial for the early embryonic development of metazoan animals from the establishment of body axes, through the specification of germ layers and tissues to the development of organ systems. I used pharmacological manipulations of the Wnt/β-catenin pathway activity in the planktonic larvae of the marine polychaete annelid Platynereis dumerilii, the representative of the clade Spiralia, to investigate the role of Wnt/β- catenin signalling in the development and evolution of three hallmarks of Bilateria: the central nervous system, the body segmentation and the digestive tube. Wnt proteins are produced in all three aforementioned systems in Platynereis where they trigger the Wnt/β-catenin pathway in neighbouring cells. I describe here, for the first time in Platynereis, a homologue of the endpoint transcription factor of the entire pathway, Pdu-Tcf, which is subjected to an alternative splicing and along with a Wnt target gene Pdu-Axin is expressed in tissues with the active Wnt signalling - in the brain ganglia, in the neuroectoderm along the ventral midline, in segments, in the posterior growth zone and in the gut. Pharmacological manipulations...
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Role of intestinal circadian clock in epithelial transport, proliferation, and tumourigenesis
Soták, Matúš ; Pácha, Jiří (advisor) ; Bendová, Zdeňka (referee) ; Herichová, Iveta (referee)
AABBSSTTRRAACCTT The molecular circadian clock enables anticipation of environmental changes. In mammals, clocks are ubiquitously present in almost all tissues and they are comprised of transcriptional-translational feedback loops of the so-called clock genes. The central clock represents the intrinsic pacemaker which is located in suprachiasmatic nuclei (SCN) of hypothalamus and synchronizes peripheral clocks. Clockwork system in alimentary tract and its regulatory link to intestinal functions are poorly understood. Therefore the objective of the thesis was to characterize molecular clock in particular parts of the rat intestine and to elucidate its link to the intestinal transport, regulation of cell cycle and neoplastic transformation in colonic tissue. We used quantitative RT-PCR (qPCR) to determine circadian profiles of mRNA expression of clock genes in the epithelium of duodenum, jejunum, ileum, and colon of rat. Furthermore, we analysed the expression of genes coding sodium chloride transporters and channels as well as cell cycle regulators in colon. To focus more precisely on different structures of intestinal epithelia we used laser capture microdissection. In addition, we performed Ussing chamber measurements to determine the colonic electrogenic transport. To study the contribution of circadian...
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In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters
Halodová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Halodová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters Tenofovir (TFV) is the first-line agent in the treatment of hepatitis B virus (HBV) infection for patients aged over 12 years and one of the first-line choices for the combination antiretroviral therapy (cART) of infections caused by human immunodeficiency virus (HIV). Two commercially available prodrugs have been developed for oral administration of TFV, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). These prodrugs increase TFV membrane permeability and oral bioavailability. One of the factors that can affect the bioavailability of orally administrated drugs is active transport mediated by efflux transporters, mainly by P-glycoprotein (ABCB1, P-gp) and Breast cancer resistance protein (ABCG2, BCRP). It has been already proved that TDF and TAF are substrates of both of these transporters. The goal of this diploma thesis was to use in vitro and ex vivo models of intestinal barrier to assess the impact of the efflux transporters on TDF and TAF transport in the intestine and on their...
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Effect of anthelmintics on the transport of drugs in the intestine
Štefanová, Anna ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Anna Štefanová Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of anthelmintics on the transport of drugs in the intestine Several classes of drugs are currently available for the treatment of helminthiasis in humans and animals, the so-called anthelmintics. Most of these drugs are administered by the oral route, where absorption into the systemic circulation occurs through the intestinal barrier. However, the course and extent of this absorption may be limited by biotransforming enzymes and transport proteins, in particular the family of so-called ATP-binding cassette transporters. These transporters are capable of returning many xenobiotics, including many drugs, back into the lumen of the gut and are the first line of defence against the entry of these substances into the body. An important representative of this group of transporters is P-glycoprotein, which is known for its broad substrate specificity. On this transporter, drugs can act as substrates but also as inhibitors and/or inducers, which may lead to the risk of drug-drug interactions. There is relatively little information about the effect of anthelmintics on P-glycoprotein inhibition. The most studied...
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In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters
Halodová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Halodová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters Tenofovir (TFV) is the first-line agent in the treatment of hepatitis B virus (HBV) infection for patients aged over 12 years and one of the first-line choices for the combination antiretroviral therapy (cART) of infections caused by human immunodeficiency virus (HIV). Two commercially available prodrugs have been developed for oral administration of TFV, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). These prodrugs increase TFV membrane permeability and oral bioavailability. One of the factors that can affect the bioavailability of orally administrated drugs is active transport mediated by efflux transporters, mainly by P-glycoprotein (ABCB1, P-gp) and Breast cancer resistance protein (ABCG2, BCRP). It has been already proved that TDF and TAF are substrates of both of these transporters. The goal of this diploma thesis was to use in vitro and ex vivo models of intestinal barrier to assess the impact of the efflux transporters on TDF and TAF transport in the intestine and on their...
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