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Sesquiterpenes in cancer therapy
Ambrož, Martin ; Skálová, Lenka (advisor) ; Hodek, Petr (referee) ; Souček, Pavel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Martin Ambrož Supervisor: Prof. RNDr. Lenka Skálová, Ph.D. Title of Doctoral Thesis: Sesquiterpenes in cancer therapy. Chemotherapy is an important part of treatment of cancer. Currently, the use of several anticancer drugs in combination seem to be more advantageous. This combination therapy prevents drug resistance development and make it possible to lower the doses of single drugs, which prevents the side effects in non-cancerous tissues. Large pool of potential drugs for combination therapy can be found among natural compounds, for example among sesquiterpenes. Our project was designed to evaluate the effect of Myrica rubra essential oil (MEO) and selected sesquiterpenes in combination cancer therapy. We focused on the potential ability of MEO and sesquiterpenes to increase the antiproliferative efficacy of classical cytostatics (doxorubicin, oxaliplatin, 5-fluorouracil). In addition, we also studied the possible interaction of sesquiterpenes with other drugs in combination therapy, which could be caused by sesquiterpene-mediated modulation of drug-metabolizing enzymes. For these purposes, a panel of various cell lines (both cancerous and non-cancerous) and primary culture of hepatocytes...
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Drug Interactions with Nuclear Receptors in the Regulation of Drug Metabolizing Enzymes and Drug Transporters
Nová, Alice ; Pávek, Petr (advisor) ; Skálová, Lenka (referee) ; Souček, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Pharmacology and Toxicology Candidate: Alice Nová, MSc Supervisor: Assoc. Prof. PharmDr. Petr pávek, Ph.D. Title of Doctoral Thesis: Drug interactions with nuclear receptors in the regulation of drug metabolizing enzymes and drug transporters Drug metabolizing enzymes play a key role in metabolism, elimination and detoxification of xenobiotics exposed to the body and protect the organism from potentially harmful effect of xenobiotics as well as certain endobiotics. Phase I and II drug metabolizing enzymes and drug transporters are expressed in most tissues in basal level or may be induced after exposure to xenobiotics. Affecting of expression or activity of drug metabolizing enzymes and drug transporters may result in unpredictable tissue and systemic drug distribution, to side effects or therapy failure. Up-regulation of drug metabolizing enzymes and drug transporters mediates mainly orphan nuclear receptors - pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and transcription factor aryl hydrocarbon receptor (AhR). This doctoral thesis presents the results of three studies dealing with the gene regulation of drug metabolizing enzymes and drug transporters via nuclear receptors. In the first part of...
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METABOLISM AND EFFECTS OF NEW ANTHELMINTIC DRUG IN HELMINTHS AND ITS HOSTS
Stuchlíková, Lucie ; Skálová, Lenka (advisor) ; Kučera, Radim (referee) ; Machala, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate Mgr. Lucie STUCHLÍKOVÁ Supervisor prof. RNDr. Lenka SKÁLOVÁ, Ph.D. Title of Doctoral Thesis METABOLISM AND EFFECTS OF NEW ANTHELMINTIC DRUG IN HELMINTHS AND ITS HOSTS Diseases caused by helminths, called helminthoses, are one of the most serious problems in veterinary and human medicine. These diseases are treated by anthelmintics but their effectiveness is often not sufficient due to resistance of helminths against common anthelmintics. The global anthelmintic resistance encouraged the developing of new drugs with a different mode of action. Monepantel (MOP) belongs to a new class of anthelmintic drugs known as amino- acetonitrile derivatives (AADs) that act on the nicotinic acetylcholine receptors. In 2011, MOP was approved for the treatment of gastrointestinal diseases caused by nematodes in the veterinary practice in the Czech Republic. It is produced commercially under the trade name Zolvix® (Novartis AG). The aim of this doctoral thesis was to study metabolism and effects of MOP and other AADs in order to contribute to the global research in this field. For this purpose, adults nematodes Haemonchus contortus (the sensitive strain ISE and the resistant strain WR) and its hosts Ovis...
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Testing of the efficacy and toxicity of new potential anthelmintics OMK3 AND OMK4
Žáková, Barbora ; Skálová, Lenka (advisor) ; Szotáková, Barbora (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical sciences Candidate: Bc. Barbora Žáková Supervisor: prof. RNDr. Lenka Skálová, Ph.D. Title of diploma thesis: Testing of the efficacy and toxicity of new potential anthelmintics OMK3 and OMK4 Haemonchus contortus is a parasite of smaller ruminants, mainly sheep and goats. It causes a disease called haemonchosis, the main symptom of which is anemia, whitch can lead to the death of the animal. Anthelmintics are used to treat this disease. However, these drugs have become ineffective due to resistance developing against them. Haemonchosis is thus becoming a significant global problem. Therefore, it is necessary to search for new anthelmintics with a new mechanism of action. In this study, the potential anthelmintic effects of new derivates of benzhydroxamic acide, OMK3 and OMK4, were investigated. The aim of this study was to determine whether these substances have an effect on eggs, larvae and adults of H. contortus, and to compare their effects on sensitive and resistant strains of H. contortus and to test their potential toxicity on sheep livers. For this purpose, eggs, larvae and adults of H. contortus were isolated, precision-cut liver slices from sheep were prepared, and the following tests were used: egg hatch...
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The effect of GP46 on function of HU protein of Francisella tularensis
Sokolová, Eliška ; Szotáková, Barbora (advisor) ; Skálová, Lenka (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Science Candidate: Bc. Eliška Sokolová Supervisor: prof. Ing. Barbora Szotáková, Ph.D. Supervisor - consultant: RNDr. Petra Špidlová, Ph.D. Title of diploma thesis: The effect of Gp46 on function of HU protein of Francisella tularensis Francisella tularensis is a highly virulent bacteria and the DNA binding HU protein is one of its important virulence factors. Recently, it was reported that the Gp46 protein inhibits the function of the Bacillus subtilis HU protein (Zhang et al., 2022). The main goal of the presented diploma thesis was to find out if the Gp46 protein of the B. subtilis bacteriophage SPO1 also works as an inhibitor of the F. tularensis HU protein. Given the high conservation of HU proteins, Gp46 might function as a universal inhibitor of all HU proteins. At the Department of Molecular Pathology and Biology (Military Faculty of Medicine, University of Defense) neither bacteriophage SPO1 nor its DNA were available, thus, it was initially necessary to acquire the gp46 gene, which encodes the Gp46 protein, using the overlap PCR method. Subsequently, the Gp46 protein was purified from the E. coli expression system using affinity chromatography. In both in vivo and in vitro conditions, we studied...
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Testing of the efficacy and toxicity of new potential anthelmintics OMK1 and OMK2
Junková, Kateřina ; Skálová, Lenka (advisor) ; Raisová Stuchlíková, Lucie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Kateřina Junková Supervisor: prof. RNDr. Lenka Skálová, Ph.D. Consultant: Mgr. Josef Krátký, PharmDr. Thuy Linh Nguyen, Ph.D. Title of diploma thesis: Testing of the efficacy and toxicity of new potential anthelmintics I Haemonchus contortus, a blood-feeding nematode of ruminants, causes significant economic losses in livestock production worldwide. Despite anthelmintic therapy being crucial for haemonchosis control, the emergence of anthelmintic resistance in H. contortus is increasingly compromising the efficacy of available drugs. Therefore, there is an urgent need for novel anthelmintics effective against resistant H. contortus strains. The theoretical part of this thesis provides a concise overview of current treatment options for haemonchosis, including the mode of action of commonly used anthelmintics. Alternative measures for haemonchosis prevention and control, including plant-derived anthelmintics, vaccines, and biological control, are also presented in the context of their potential to replace or supplement anthelmintic therapy and thereby mitigate the risk of resistance development. The experimental part of this thesis evaluated the efficacy of two novel potential anthelmintics,...
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Metabolism and efficacy of new potential anthelmintics
Zajíčková, Markéta ; Skálová, Lenka (advisor) ; Várady, Marián (referee) ; Vadlejch, Jaroslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Markéta Zajíčková Supervisor: Prof. RNDr. Lenka Skálová, Ph.D. Consultant: PharmDr. Ivan Vokřál, Ph.D. Title of Dissertation Thesis: Metabolism and efficacy of new potential anthelmintics Overpopulation of gastrointestinal nematodes represents global health and economical problem. Therefore, suitable solution in the form of effective anthelmintic treatment is needed. Several anthelmintics with distinct mechanism of action are available on the market, however, the widespread resistance limits their efficacy. As a consequence, finding a new possible alternative becomes important. In present dissertation thesis, the novel anthelmintic candidates were selected and their effect against model parasitic nematode Haemonchus contortus was examined. The studies encompassed three approaches within the field of drug discovery: new molecular entity identification and structure modification, drug repurposing, and medicinal plants screening. Newly synthesized compounds designated as BLK127, HBK4 and BLK127 derivatives, already known antipsychotic drug sertraline (SRT) and the extracts from eight European ferns species from genus Dryopteris, Athyrium and Blechnum were the subjects of our interests. Two...
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