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Alterations in gene expression of hepatobiliary transporters as potential mechanisms for drug-induced cholestasis by amoxicillin and clavulanic acid
Řepová, Veronika ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Řepová Supervisor: Prof. PharmDr. Petr Pávek, Ph.D., Prof. Ramiro Jover Atienza, Ph.D. Title of diploma thesis: Alterations in gene expression of hepatobiliary transporters as potential mechanisms for drug-induced cholestasis by amoxicillin and clavulanic acid The combination of amoxicillin and clavulanic acid (AMO/CLA) represents one of the most frequent causes of the idiosyncratic type of drug-induced liver injury (DILI) nowadays. Despite difficulties in diagnosis and causality assessment, the clinical features have already been reported and in most of the cases categorized as cholestatic damages. Number of descriptions of the molecular mechanisms of drug-induced cholestasis has been rising recently and the role of hepatobiliary transporters has turned out to be crucial in the pathogenesis. However, the mechanisms of AMO/CLA-induced DILI at the molecular level still remain indistinct. In order to investigate the hepatotoxic effects of AMO/CLA and AMO alone in vitro, HepG2 and human Upcyte hepatocytes were used as hepatocellular models. The mRNA levels of key bile acid (BA) transporters, enzymes and nuclear receptors (NRs) were measured by quantitative real-time polymerase chain...
Alterations in gene expression of hepatobiliary transporters as potential mechanisms for drug-induced cholestasis by amoxicillin and clavulanic acid
Řepová, Veronika ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Řepová Supervisor: Prof. PharmDr. Petr Pávek, Ph.D., Prof. Ramiro Jover Atienza, Ph.D. Title of diploma thesis: Alterations in gene expression of hepatobiliary transporters as potential mechanisms for drug-induced cholestasis by amoxicillin and clavulanic acid The combination of amoxicillin and clavulanic acid (AMO/CLA) represents one of the most frequent causes of the idiosyncratic type of drug-induced liver injury (DILI) nowadays. Despite difficulties in diagnosis and causality assessment, the clinical features have already been reported and in most of the cases categorized as cholestatic damages. Number of descriptions of the molecular mechanisms of drug-induced cholestasis has been rising recently and the role of hepatobiliary transporters has turned out to be crucial in the pathogenesis. However, the mechanisms of AMO/CLA-induced DILI at the molecular level still remain indistinct. In order to investigate the hepatotoxic effects of AMO/CLA and AMO alone in vitro, HepG2 and human Upcyte hepatocytes were used as hepatocellular models. The mRNA levels of key bile acid (BA) transporters, enzymes and nuclear receptors (NRs) were measured by quantitative real-time polymerase chain...
miRNAs as diagnostic markers after treatment with glucocorticoids in rheumatology
Tripská, Katarína ; Pávek, Petr (advisor) ; Doseděl, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Katarína Tripská Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: miRNAs as diagnostic markers after treatment with glucocorticoids in rheumatology MicroRNAs are important class of non-coding RNAs that play important role in modulation of expression of multiple genes at a post-transcriptional level. Their deregulation contributes to many immune disorders including rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. This thesis represents the most recent knowledge about functions of microRNAs in pathogenesis of these disorders and results were obtained by review of scientific literature published on PubMed database. The most perspective microRNAs in rheumatoid arthritis seem to be miR-16, miR-21, miR- 146a, miR-150 a miR-223. In lupus miR-148, miR-126, miR-21, miR-155, miR-125a a miR- 146 will probably find their useage as biomarkers. Systemic sclerosis is less examined diseases and we know most about miR-29 in the disease. Since the research of microRNA as diagnostic biomarkers is only at the beginning, it is most likely, that with the time there will be more and more of new microRNAs helping us clarify pathogenesis of each disorder. We can suppose...
Ames test in the drug development
Klaučová, Martina ; Pávek, Petr (advisor) ; Konečná, Klára (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Martina Klaučová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Consultant: PharmDr. Ivona Pávková, Ph.D. Diploma thesis title: Ames test in the drug development Background: Thesis objective is the determination of potential genotoxicity of newly developed drugs within primary testing and the introduction of the Ames microfluctuation test which can be used in common laboratory conditions. Methods: I used commercially supplied kit based on the principles of Ames test which detects reverse mutation through colour changes of the samples using bacterial strains S. typhimurium. At first I had to study literary sources and then I could design the procedures of the Ames microfluctuation test, preparation of the chemicals and storage of the strains which are optimal for all laboratories. Results: The drug samples T6445 and T6447 with 30 µM concentration tested by metabolic activation S9 on bacterial strain ST TA 98 show genotoxicity. The sample UOCHB1 with 30 µM concentration tested without activation shows possible genotoxicity on both strains ST TA 98 and ST TA 100. Other samples do not show any toxicity. I used 3 different procedures during the designation of assay. The most suitable version of the...
Introduction of cellular NFkappa-B model
Čečrle, Michal ; Pávek, Petr (advisor) ; Červený, Lukáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Michal Čečrle Supervisor: Prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Introduction of cellular NF-κB model NF-κB is the most important transcription factor involved in cell signaling of inflammatory processes. It participates in the inflammatory reaction in the distinct compartments of the living organism. As a transcription factor, it controls the gene expression of many genes, especially cytokines (tumor necrosis factor alfa, interleukins: IL-1β, IL-2, IL-6, IL-12; chemokines etc.). NF-κB is also a key factor in the activation of monocytes and macrophages In this diploma thesis I focused on the role of NF-κB in the monocyte cell line THP-1. This line is an important model of human macrophages in which the THP-1 line can be differentiated. Using available literature, I summarized all the available knowledge on this issue. At the same time, I conducted several experiments on NF-κB activation in the THP- 1 line as a potential model in the research and development of therapeutic intervention in NF-κB signaling to suppress inflammation.
Ames test in the drug development
Klaučová, Martina ; Pávek, Petr (advisor) ; Konečná, Klára (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Martina Klaučová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Consultant: PharmDr. Ivona Pávková, Ph.D. Diploma thesis title: Ames test in the drug development Background: Thesis objective is the determination of potential genotoxicity of newly developed drugs within primary testing and the introduction of the Ames microfluctuation test which can be used in common laboratory conditions. Methods: I used commercially supplied kit based on the principles of Ames test which detects reverse mutation through colour changes of the samples using bacterial strains S. typhimurium. At first I had to study literary sources and then I could design the procedures of the Ames microfluctuation test, preparation of the chemicals and storage of the strains which are optimal for all laboratories. Results: The drug samples T6445 and T6447 with 30 µM concentration tested by metabolic activation S9 on bacterial strain ST TA 98 show genotoxicity. The sample UOCHB1 with 30 µM concentration tested without activation shows possible genotoxicity on both strains ST TA 98 and ST TA 100. Other samples do not show any toxicity. I used 3 different procedures during the designation of assay. The most suitable version of the...
Pharmacotherapy of breast cancer: Novel approaches, overcoming of multidrug resistance
Menelaou, Pavlina ; Čečková, Martina (advisor) ; Pávek, Petr (referee)
Pavlina Menelaou: Pharmacotherapy of breast cancer: Novel approaches, overcoming of multidrug resistance. (Diploma thesis) ABSTRACT Breast cancer arises when there is an uncontrolled growth of abnormal cells in the breast. Most often the tumor involves glandular breast cells in the ducts or lobules. The most common sign of breast cancer is a new lump or mass. Other possible signs can be redness, swelling, nipple discharge and more. Some risk factors of breast cancer can be alcohol, obesity, oral hormonal contraceptives, radiation, gender, age, hereditary/genetic aspects, estrogen and progesterone receptors. Breast cancer can be treated by surgery including mastectomy, lymphedema surgery and lumpectomy, by radiation therapy or chemotherapy. The novel methods include hormonal therapy using selective estrogen receptor modulators like tamoxifen, raloxifene, aromatase inhibitors like anastrozole and letrozole. One of the promising therapies is immune therapy with the use of interferons and other cytokines, dendritic cells and vaccines. Another novel approach is represented by the targeted therapy that is using monoclonal antibodies, tyrosine kinase inhibitors and more promising ways. The gene therapy that is made to correct specific molecular defects that contributes to the cause or progressions of breast cancer...
The role of Wnt pathway in nociception
Pospíšilová, Blanka ; Skálová, Lenka (advisor) ; Pávek, Petr (referee)
Charles University in Prague University Roma Tre Faculty of Pharmacy in Hradec Králové Department of Biology Department of Biochemical Sciences Candidate: Veronika Staňková Supervisor: PharmDr. Iva Boušová, Ph.D. Prof. Sandra Incerpi, Prof. Jens Z. Pedersen, Prof. Luciano Saso Title of diploma thesis: Biological activity of antioxidant compounds in L-6 myoblasts from rat skeletal muscles. This work was carried out in the laboratory of physiology at University Roma Tre in Rome, under the supervision of Prof. Sandra Incerpi. The team of this laboratory studies the antioxidants of different structures and evaluates their ability to prevent the production of reactive oxygen species and oxidative stress. The reactive oxygen and nitrogen species play an important role as regulatory mediators of physiological responses. However, they can be also very harmful because they can damage DNA and proteins, cause peroxidation of lipids and injure other biomoleculs. In my work, I tested the antioxidant effect of different polyphenols (baicalein, 5,6-dihydroxyflavone, negletein, mosloflavone, gallic acid and its derivative) in the cell culture (L-6 myoblasts from rat skeletal muscles) and in the in vitro test. The state of oxidative stress was induced by cumene hydroperoxide (generator of cumene hydroperoxide...
Pharmacogenetics in rheumatoid arthritis
Kobrlová, Martina ; Pávek, Petr (advisor) ; Doseděl, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martina Kobrlová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Pharmacogenetics in rheumatoid arthritis Based on scientific progress in the research of human genome and the discovery of polymorphisms, which are involved in the interindividual differences in human population, there is also a growing interest in pharmacogenetics. It is a field combining pharmacology and genetics with the aim of identifying specific features that could explain the different responses of patients to treatment by clinically used drugs. Applying this knowledge could contribute to a simpler choice of medication for a particular patient and it could reduce the risk of side effects or poor response. In this diploma thesis I dealt with the latest scientific knowledge on pharmacogenetics in rheumatology, in particular the rheumatoid arthritis. From available studies, reviews, and meta-analyzes that have been published, I summarized current data on the relationship between polymorphisms and disease modifying drugs (DMARDs) used for the treatment of this disease. The largest amount of data was found on the most commonly used methotrexate. Further, the work examines the leflunomide and other...
Pharmacogenetics in rheumatology - role of miRNAs
Vicherková, Petra ; Pávek, Petr (advisor) ; Doseděl, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Candidate: Bc. Petra Vicherková Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of master thesis: Pharmacogenetics in rheumatology - role of miRNA Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that causes progressive joint damage and can result in to life-long depreciation of life. The influence on the onset and course of the disease is not only genetic, but due to the heterogeneous character of the disease, it is also strongly influenced by lifestyle. This disease, based on the malfunction of our immune system in RA, is still incurable. The treatment of RA uses conventional synthetic drugs as well as biological treatment. To diagnose the effect of anti-rheumatic therapy, monitoring and evaluating the response to treatment is necessary. Important indicators of RA activity, functional status, quality of life, and structural progression of the disease are important. In clinical practice, we use DAS 28 composite system according to recommendation of ČRS. Recent discoveries in the area of diagnostics raise the question of whether some miRNAs could be appropriate biomarkers of RA progression. In my diploma thesis, I summarize available knowledge in this field, obtained from...

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