National Repository of Grey Literature 159 records found  1 - 10nextend  jump to record: Search took 0.00 seconds. 
Study on impact of selected protein kinase inhibitors on drug resistance mediated by cytochromes P450
Janoušková, Adéla ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Janoušková Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study on impact of selected protein kinase inhibitors on drug resistance mediated by cytochromes P450 Pharmacokinetic drug resistance often leads to failure of an anticancer therapy. One of the mechanisms is increased efflux of drugs from tumour cells, whereas some studies suggest that increased drug conversion to an inactive metabolite might be another contributing mechanism. The aim of this work was to define the possible role of CYP3A4 and CYP2C8 enzymes in the phenomenon of pharmacokinetic resistance and to investigate the possibility of its modulation by new targeted drugs. In the first part, we used the MTT proliferation method together with HepG2 cells stably transduced with particular human enzymes and demonstrated significant involvement of CYP3A4 in docetaxel resistance. In the following part, we examined the inhibitory effects of four selected tyrosine kinase inhibitors on the CYP3A4 activity in intact cells using a commercial kit. Cobimetinib and dabrafenib showed significant inhibitory activity, while osimertinib and brivanib did not. In the final part, we demonstrated the ability of the first two...
Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases
Odvárková, Anna ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Anna Odvárková Supervisor: RNDr. Jakub Hofman, Ph.D. Consultants: Carina Lemke Prof. Dr. Michael Gütschow Title of diploma thesis: Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases Cysteine cathepsins are proteases which are naturally present in the human body, taking part in various physiological processes such as cell signaling, proliferation or bone remodeling. However, their dysregulation leads to serious disorders. An aberrant activity of cysteine cathepsins is present in diseases like cancer, osteoporosis, neurodegenerative disorders or autoimmune diseases. Therefore, these enzymes can serve as valuable diagnostic or therapeutic targets. Rhodesain is a parasitic protease produced by Trypanosoma brucei rhodesiense and essential for its survival. This enzyme shares a high homology with human cysteine cathepsin L. Inhibition of rhodesain can be a potential treatment of African trypanosomiasis, also known as sleeping sickness. Inhibitory potency of several compounds against the target enzymes was assayed spectrophotometrically or fluorometrically and the results were evaluated by using linear or non-linear regression. Determination of a Michaelis- Menten constant...
Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases
Odvárková, Anna ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Anna Odvárková Supervisor: RNDr. Jakub Hofman, Ph.D. Consultants: Carina Lemke Prof. Dr. Michael Gütschow Title of diploma thesis: Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases Cysteine cathepsins are proteases which are naturally present in the human body, taking part in various physiological processes such as cell signaling, proliferation or bone remodeling. However, their dysregulation leads to serious disorders. An aberrant activity of cysteine cathepsins is present in diseases like cancer, osteoporosis, neurodegenerative disorders or autoimmune diseases. Therefore, these enzymes can serve as valuable diagnostic or therapeutic targets. Rhodesain is a parasitic protease produced by Trypanosoma brucei rhodesiense and essential for its survival. This enzyme shares a high homology with human cysteine cathepsin L. Inhibition of rhodesain can be a potential treatment of African trypanosomiasis, also known as sleeping sickness. Inhibitory potency of several compounds against the target enzymes was assayed spectrophotometrically or fluorometrically and the results were evaluated by using linear or non-linear regression. Determination of a Michaelis- Menten constant...
The detection of protein covalent complexes with DNA using fluorescent microscopy
Melicharová, Růžena ; Jirkovská, Anna (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department od Biochemical Sciences Candidate: Růžena Melicharová Supervisor: PharmDr. Anna Jirkovská, Ph.D. Title of thesis: The detection of protein covalent complexes with DNA using fluorescent microscopy Anthracycline antibiotics are present one of the most potent antineoplastic drugs. The mechanism of their action is complex. They are reported to intercalate to DNA, form DNA adducts and interact with topoisomerase II (TopII) as its poisons. Catalytic cycle of TopII is interrupted when anthracyclines stabilize the covalent complex of DNA and TopII and that causes cell damage. However, using of anthracyclines is limited by several adverse effects e. g. myelotoxicity and cardiotoxicity. The mechanism of cardiotoxicity is still unclear but may be associated with poisoning of the TopIIβ isoform. Unlike the TopIIα, TopIIβ is present mostly in quiescent cells as cardiomyocytes. Furthermore, the only clinically approved cardioprotective drug dexrazoxane belongs to TopII catalytic inhibitors. Nevertheless, the details of the dexrazoxane-afforded protection are unclear. This thesis was aimed to optimize the TARDIS (trapped in agarose DNA immunostaining) assay to detect and quantify covalent cleavage complexes, compare different ways for analysis of...
The effect of acalabrutinib and ibrutinib on the efficacy of daunorubicin in cancer cells.
Čermáková, Lucie ; Novotná, Eva (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Lucie Čermáková Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: The effect of acalabrutinib and ibrutinib on the efficacy of daunorubicin in cancer cells Leukemia presents malignant diseases of hematopoiesis, which essence is the malignant transformation of a hematopoietic stem cell at various levels of maturation and increased proliferative activity. Chemotherapy is the gold standard in the treatment of leukemia. One of the many treatments is the use of anthracycline chemotherapeutics, especially daunorubicin (DAU). Anthracyclines are widely used in clinical practice but have high cardiotoxic effects that limit their dosage. One of the main causes of side effects is the reduction of an anthracycline chemotherapeutic to the appropriate toxic metabolite, which accumulates in the heart. Carbonyl, reducing enzymes from the superfamily aldo-ketoreductase (AKR), and short-chain dehydrogenase/reductase (SDR) are involved in this reduction. At the same time, carbonyl reducing enzymes, has been shown to be involved in the mechanisms that cause tumor cells to be resistant to anthracyclines, thereby reducing the inhibition of the growth of these cells. In the diploma thesis we found that...
Study on the role of selected cytochrome P450 isoforms in cytostatic resistance at apoptosis level
Moriová, Magdalena ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradci Králové Departement of Pharmacology & Toxicology Student: Magdalena Moriová Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study on the role of selected cytochrome P450 isoforms in cytostatic resistance at apoptosis level Cytostatic resistance is one of the most problematic obstacles in oncological treatment. Beside pharmacodynamic mechanisms, pharmacokinetic factors play an important role in drug resistance as well. Enzymatic transformation of active substance to inactive metabolite in tumor cells probably belongs to these mechanisms, however, evidences concerning the relevance of this phenomenon are predominantly either indirect and/or affected by interference elements. Using comparative experiments with HepG2 cell lines with/without CYP3A4 overexpression, we focused on the evaluation of the role of this clinically important enzyme in the resistance against docetaxel. Methodologically, it was the assessment of apoptosis induction (activation of caspases 3/7, 8 and 9) using commercial luminescent kits. Our results suggest significant participation of CYP3A4 enzyme on the reduction of docetaxel anticancer efficacy after 48 h from treatment, whereas this effect was not recorded in earlier intervals. These findings perfectly correlate...
The effect of alisertib and brigatinib on the activity of selected human carbonyl reducing enzymes.
Lakomá, Petra ; Novotná, Eva (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Petra Lakomá Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: The effect of alisertib and brigatinib on the activity of selected human carbonyl reducing enzymes Key words: brigatinib, alisertib, daunorubicin, inhibition, carbonyl-reducing enzymes Protein kinases are enzymes, whose main function is based on a transfer of phosphate group from ATP to protein substrate. This common posttranslational modification is involved in the regulation of intracellular processes and cell signaling. Altered expression of protein kinases is often coupled with a development of cancer. Inhibition of protein kinases may prevent cancer cell proliferation and induce their cell death. The main aim of the diploma thesis was to measure inhibition potential of protein kinase inhibitors, alisertib and brigatinib, against carbonyl-reducing enzymes. Overexpression of carbonyl-reducing enzymes in cancer cells may cause resistance to drugs followed by failure of chemotherapeutic therapy. In case of antracyclin chemotherapeutic daunorubicin, carbonyl-reducing enzymes reduce the carbonyl in C-13 giving rise a primary metabolite daunorubicinol, which has lower cytotoxic effect but higher cardiotoxicity. The effort to...
The detection of protein covalent complexes with DNA using fluorescent microscopy
Melicharová, Růžena ; Jirkovská, Anna (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department od Biochemical Sciences Candidate: Růžena Melicharová Supervisor: PharmDr. Anna Jirkovská, Ph.D. Title of thesis: The detection of protein covalent complexes with DNA using fluorescent microscopy Anthracycline antibiotics are present one of the most potent antineoplastic drugs. The mechanism of their action is complex. They are reported to intercalate to DNA, form DNA adducts and interact with topoisomerase II (TopII) as its poisons. Catalytic cycle of TopII is interrupted when anthracyclines stabilize the covalent complex of DNA and TopII and that causes cell damage. However, using of anthracyclines is limited by several adverse effects e. g. myelotoxicity and cardiotoxicity. The mechanism of cardiotoxicity is still unclear but may be associated with poisoning of the TopIIβ isoform. Unlike the TopIIα, TopIIβ is present mostly in quiescent cells as cardiomyocytes. Furthermore, the only clinically approved cardioprotective drug dexrazoxane belongs to TopII catalytic inhibitors. Nevertheless, the details of the dexrazoxane-afforded protection are unclear. This thesis was aimed to optimize the TARDIS (trapped in agarose DNA immunostaining) assay to detect and quantify covalent cleavage complexes, compare different ways for analysis of...
Evaluation of Efficiency and Risks of Private Construction Project
Čičmanec, Juraj ; Novotná, Eva (referee) ; Hromádka, Vít (advisor)
The diploma thesis deals with the evaluation of the effectiveness and risks of a private construction project. This work is divided into two parts. The first part is a theoretical part, which defines the basic concepts associated with investment as such, but also directly with investment in real estate and construction investment. In the second part, this work deals with risk assessment, determination of their size and finally risk management. The end of the theoretical part is the elaboration of methodology for the practical part. The beginning of the practical part the work is devoted to the description of the construction area and specification of the building itself. In the next part are set investment costs, operating income and expenses. Operating income consists of the lease itself. This was determined on the basis of similar investments in the area. Operating expenses are divided into fixed and variable where only fixed are included in the evaluation. Subsequently, the work establishes the profit and loss statement and therefrom the cash flows. The second part defines the risks associated with the construction of the project. The switching value is then calculated for critical project risks. The end of the practical part is devoted to risk management. The conclusion summarizes the results of individual parts of the thesis and a written recommendation for the investor whether to realize the project or not.
Effect of selected tyrosine kinase inhibitors on the activity of human carbonyl reducing enzymes
Tomanová, Alžbeta ; Novotná, Eva (advisor) ; Matoušková, Petra (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Alžbeta Tomanová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Effect of selected tyrosine kinase inhibitors on the activity of human carbonyl reducing enzymes Key words: tyrosin kinases, screening, carbonyl, daunorubicin, inhibition Tyrosine kinases are a subclass of protein kinases, catalysing the transfer of ATP phosphate residue to a protein, thereby playing an important role in cellular signaling. Abnormal tyrosine kinase activity is present in various malignancies. In certain cases, inhibition of their function can prevent tumor cell proliferation and eventually induce apoptosis. At the same time, some tyrosine kinase inhibitors have demonstrated the ability to inhibit efflux transporters, which are often involved in the development of resistance to anticancer treatment. In this diploma thesis, the inhibitory effect of imatinib, nilotinib, dasatinib and acalabrutinib (tyrosine kinase inhibitors) has been studied on carbonyl reducing enzymes, whose overexpression by tumor cells may lead to resistance to chemotherapy. In particular, in the case of anthracyclines, the reduction of carbonyl group on C-13 results in not only lower cytotoxic activity, but also increased...

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