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Effect of selected compounds on the reduction and toxicity of doxorubicine in the tumorous cellular line
Vildová, Lenka ; Skálová, Lenka (advisor) ; Szotáková, Barbora (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Title, Name, Surname of candidate: Mgr. Lenka Vildová Title, Name, Surname of tutor: Doc. RNDr. Lenka Skálová, Ph.D. Title, Name, Surname of tutor-specialist: Mgr. Martina Gavelová, Ph.D. Title of a diploma work: The effect of selected compounds on reduction and toxicity of doxorubicin in cancer cell line. The anthracycline antibiotic doxorubicin is widely used in the treatment of solid and haematologic malignancies, including breast cancer. The major metabolite of doxorubicin is 13-doxorubicinol that has a significantly lower antineoplastic potency compared to the parent drug and has been implicated as a potential mediator of chronic cardiotoxicity. The aim of the present study was to evaluate the effect of inhibitors of carbonyl reductase 1 (CBR1), such as quercitrin, rutin, and menadion, and prospective anticancer agent oracin on reduction and toxicity of doxorubicin in human breast cancer MCF-7 cells. Experiment performed with menadion revealed that CBR1 plays a important role in reduction of doxorubicin in cytosol of MCF-7 cells. The formation of 13-doxorubicinol was inhibited by oracin that acts as a competitive inhibitor of CBR1. The cytotoxic effect of doxorubicin was examined by the...
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The metabolism of anthelmintics for helminth
Cvilink, Viktor ; Skálová, Lenka (advisor) ; Holčapek, Michal (referee) ; Machala, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Viktor Cvilink Supervisor: Doc. RNDr. Lenka Skálová, Ph.D. Title of Doctoral Thesis: METABOLISM OF ANTHELMINTICS IN HELMINTHS Anthelminthic drugs are presently the principal method for the control of helminth diseases. Knowledge of detoxification mechanisms that helminths possess is important for understanding the processes that affect the drug concentration within a helminth organism and may be crucial in the treatment efficacy. When the drug concentration in a target organism does not reach the therapeutic level, it results in a decreased efficacy of pharmacotherapy which may further lead to the induction of helminth biotransformation enzymes and eventually issue in resistance development to the administered drug. Present knowledge of helminth biotransformation enzymes is insufficient. Often it is not known whether a given individual helminth species possesses such enzymes or whether it is capable of employing them in treatment evasion. In the presented thesis, the objective was to investigate the biotransformation pathways of selected anthelminthics in model helminth species, identify the formed metabolites and characterize biotransformation enzymes of the studied parasites. Our...
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Haemonchus contortus - metabolism of anthelmintics and other model xenobiotics in vitro
Kuběnová, Markéta ; Skálová, Lenka (advisor) ; Lamka, Jiří (referee)
Most economic losses in ruminant are associated with gastrointestinal parasite infections. Haemonchus contortus is one of the most pathogenic parasites of small ruminants (sheep, goat). H. contortus exhibits considerable adaptability to unfavourable conditions and its occurrence is world-wide. Today, the treatment of haemonchosis is complicated due to resistance of H. contortus to common anthelmintics, especially those with benzimidazole structure. Biotransformation enzymes, that protect parasite against toxic effect of anthelmintics, may contribute to development of resistance. The aim of this project was to study the biotransformation of benzimidazole anthelmintic flubendazole in H. contortus and to find out biotransformation of other model xenobiotics. The results showed that cytosolic NADPH-dependent enzymes of H. contortus deactivate flubendazole via reduction of its carbonyl group. Substantial reduction of other xenobiotics was also found. Significant activity of glutathion S- tranferases may aid to anthelmintics further deactivation. The new information about biotransformation enzymes of parasites contribute to understanding of mechanism of resistance.
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Assessment of activity and expression of selected isoforms of glutathione S-transferase in the in vivo model of glutamate-induced obesity
Košťáková, Šárka ; Boušová, Iva (advisor) ; Skálová, Lenka (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Šárka Košťáková Supervisor: doc. PharmDr. Iva Boušová, Ph.D. Title of diploma thesis: Assessment of activity and expression of selected isoforms of glutathione S-transferase in the in vivo model of glutamate-induced obesity Obesity is a chronic disease with an increasing prevalence worldwide. This disease is associated with many pathophysiological changes in the organism; a possible influence on the antioxidant defenses of the organism is one of them. The aim of this study was to determine specific activity, protein expression and mRNA level of selected isoforms of glutathione S-transferase (GST) in the cytosol obtained from kidney and heart of the male NMRI mice with the obesity induced by repeated subcutaneous administration of monosodium glutamate (MSG) and in healthy controls. The specific activities were assayed by spectrophotometric method using universal and specific substrates. Protein expression of GST isoforms from GSTA, GSTM and GSTP families was monitored using denaturing polyacrylamide gel electrophoresis and immunoblotting. The mRNA level of selected GST genes was determined by real-time PCR. In the cytosolic fraction of MSG mice kidney, increase in total GST specific...
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