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The study of the role of biotransformational enzymes in chemical carciogenesis
Kondrová, Eliška ; Souček, Pavel (advisor) ; Skálová, Lenka (referee) ; Vobořilová, Jana (referee) ; Bořek Dohalská, Lucie (referee)
In vitro biotransformation studies are an integral part of both toxicological research and drug development. They allow for a significant reduction of tests on human volunteers and provide detailed information about the metabolism of a given compound. Due to limited availability of human liver tissue, it is necessary to make use of alternative model systems and model animal species in the study of the interactions between biotransformation enzymes and xenobiotics. Since the activities of the most important human biotransformation enzymes are absent in the most commonly used laboratory species, rat, information gained in experiments with minipigs is very valuable. Recombinant human biotransformation enzymes expressed in bacteria can be used in biotransformation studies in the form of isolated bacterial membranes. These model systems provide information about the metabolism of a given xenobiotic by a defined enzyme and thein advantages compared to purified enzymes include low cost and quicker and easier preparation with lower loss of enzymatic activity during isolation. The aims of this study were: 1) To prepare a model system with recombinant human biotransformation enzymes expressed in bacterial membranes and to compare the properties of this system with minipig liver microsomes. To assess the usefulness of...
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Role of selected ABC transporters in breast cancer development
Perglerová, Karolína ; Stiborová, Marie (referee) ; Souček, Pavel (advisor)
Breast cancer is a leading cause of death among women in many countries. In the treatment of the breast cancer cytotoxic drugs (chemotherapy) are often used. Interindividual differences of drug response are an important cause of treatment failures. Bioavailability also depends on a major extent from the expression and activity of drug transport across biomembranes. In particular efflux transporters of the ATP-binding cassette family such as ABCB1, ABCC1 and ABCC2 have been identified as major determinants of chemoresistance in tumor cells. It was hypothesized that variance in the gene expression of membrane transporters and their genetic variance could explain at least in part interindividual differences of pharmacokinetics and clinical outcome of a variety of drugs. This thesis focuses on the functional significance of gene expression of ABCB1, ABCC1 and ABCC2 and single nucleotide polymorphisms in ABCC1 gene.
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Study of alternatively spliced variants of estrogen receptor alpha in breast cancer cell lines
Lhota, Filip ; Kleibl, Zdeněk (advisor) ; Souček, Pavel (referee)
Filip Lhota: Study of alternatively spliced variants of estrogen receptor alpha in breast cancer cell lines Abstract: Estrogen receptor α (ER-α) is a transcription factor responsible for mediation of the activities of its natural ligand 17-β-estradiol (E2), the hormone that together with progesterone belongs to the key regulators of mammary epithelial as well as breast cancer cells proliferation. Except to the major gene product consisting of all eight coding exons of ER-α, numerous qualitatively and quantitatively different spliced variants originated from primary transcript by activity of alternative splicing is expressed. Despite that some of these spliced variants have been functionally characterized, their precise role on final ER-α cellular activity remains to be elucidated. The functional characterization of individual alternative forms of ER-α and description of its participation on the overall ER-α activity is important for our understanding of their biogenesis and is also critical for the delineation of molecular bases for ER-α regulation during anti cancer chemotherapy. This work aimed to study the influence of alternatively spliced ER-α variants on the growth characteristics of clones constructed from stable mammary tissue cell lines in regulation to cultivation conditions and cellular...
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The effect of histone deacetylase inhibitor vaplroate on activity and expression of cytochromes P450 and peroxidases oxidizing ellipticine
Göttlicherová, Markéta ; Souček, Pavel (referee) ; Stiborová, Marie (advisor)
Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and inhibition of topoisomerase II. Ellipticine was also found to form covalent DNA adducts mediated by its enzymatic activation with cytochromes P450 (CYP) and peroxidases. The next study demonstrated increasing formation of these ellipticine-DNA adducts by histone deacetylase inhibitor valproate (VPA) in neuroblastoma cells. This phenomenon correlates with increasing cytotoxicity of ellipticine induced by this histone deacetylase inhibitor. This observation can be explained by several mechanisms. One of them can be loosening the structure of chromatine, which leads to accessing DNA for modification. Another one is the effect of VPA on activities and expression of enzymes metabolizing ellipticine. This study was aimed to test the second hypothesis. Since VPA has been shown to be metabolized by similar enzymes as ellipticine is, we have studied the effect of VPA (i) on oxidation of ellipticine by cytochromes P450 and peroxidases, (ii) on activities of the CYP enzymes, which significantly participate in oxidation of ellipticine (CYP1A, CYP3A) and (iii) on expression of enzymes oxidizing ellipticine (CYP1A1, CYP3A4, lactoperoxidase). Oxidation of ellipticine in vitro by model...
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Age related macular degeneration - modern diagnostic and therapeutic preventive approach
Gogelová, Blanka ; Souček, Petr (advisor)
Age-related macular degeneration (AMD) is a disease associated with aging that gradually destroys sharp, central vision. Central vision is needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD affects the macula, the part of the eye that alows seeing of fine details. AMD occurs in two form: dry and wet. In dry AMD, the light sensitive cells in the macula slowly break down. As fewer cells in the macula are able to function, people will see details less clearly in front of them, such as faces or words in book. Dry AMD often occurs in just one eye at first. Later the other eye can be affected. The most common early sign is blurred vision. The dry form is much more common. More than 85 % of all people have thy dry form. Once dry AMD reaches the advanced stage, no form of treatment can prevent vision loss. The National Eye Institute's Age-Related Eye Disease Study (AREDS) found that taking a specific high-dose formulation of antioxidants and zinc significantly reduces the risk of advanced AMD and it's associated vision loss. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. Damage to the macula occurs rapidly. With wet AMD, loss of central vision can occur quickly. The classic early symptom is that straight lines appear crooked...
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The position of creditors in reorganization
Souček, Petr ; Zoulík, František (referee) ; Smolík, Petr (advisor)
Act No. 182/2006 Coll., the Insolvency Act, represented big changes on the field of the Czech bankruptcy law. One of these changes was introduction of a new way of dealing with bankruptcy - the reorganization. It provides the debtor, who is in a difficult financial situation, with a chance to save his business. Reorganization represents a sanation form of bankruptcy proceedings and it is thus an alternative to a typical liquidation form of dealing with bankruptcy. The Insolvency Act strengthened the position of creditors in the bankruptcy proceedings. They have new powers and a greater influence on the ongoing proceedings. This thesis deals with the position of creditors in the reorganization. It analyzes their rights and obligations through the whole process of reorganization. The thesis begins with a definition of creditors and special creditors' bodies in general and defines basic terminology used in the thesis. This is followed by a description of the process of reorganization itself in chapter two. The foreign legislation as an inspiration of the Czech legislature is placed at the beginning of this part. A number of conditions have to be met that the court may authorize the reorganization. A bankruptcy of a debtor is a basic prerequisite. In chapter three, the attention is paid to the creditor...
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The study of activation and detoxication metabolism of the anticancer drug ellipticine by the cytochrome P450 system in vitro and in vivo…
Kotrbová, Věra ; Stiborová, Marie (advisor) ; Hansíková, Hana (referee) ; Souček, Pavel (referee)
Gen. Physiol. Biophys. (2006), 25, 245-261 245 Oxidation Pattern of the Anticancer Drug Ellipticine by Hepatic Microsomes - Similarity Between Human and Rat Systems M. Stiborová1 , L. Bořek-Dohalská1 , D. Aimová1 , V. Kotrbová1 , K. Kukačková1 , K. Janouchová1 , M. Rupertová1 , H. Ryšlavá1 , J. Hudeček1 and E. Frei2 1 Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic 2 Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany Abstract. Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of DNA adducts mediated by cytochrome P450 (CYP). We investigated the ability of CYP enzymes in rat, rabbit and human hepatic microsomes to oxidize ellip- ticine and evaluated suitable animal models mimicking its oxidation in humans. Ellipticine is oxidized by microsomes of all species to 7-hydroxy-, 9-hydroxy-, 12- hydroxy-, 13-hydroxyellipticine and ellipticine N2 -oxide. However, only rat micro- somes generated the pattern of ellipticine metabolites reproducing that formed by human microsomes. While rabbit microsomes favored the production of ellipticine N2 -oxide, human and rat microsomes predominantly formed 13-hydroxyellipticine. The species difference in...
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Dynamic Behaviours of the C Axis Drive for Multifunction Cutting Center
Křepela, Jan ; Marek, Jiří (referee) ; Souček, Pavel (referee) ; Brychta, Zdeněk (referee) ; Singule, Vladislav (advisor)
his Disertation thesis involves the creating of the simulation model of the C axis drive over mentioned machine and them verification on the prototype of this machine. C axis is controlled with position feedback. Simulation model was created before the realisation of the machine prototype for the preliminary identification of the dynamic behaviours in the working cycles and them opportunity of the realisation this conception. C axis is constructed with worm gear and is controlled with help of Master-Slave drive. This torque drive eliminates the production backlash in the worm gear. The multifunction turning center, where is used this C axis, is determinate for heavy duty roughing cutting of the forged peaces, where is problem with dynamic stability of the cutting process. Simulation model includes the problems with multi-body mass system, friction on the worm gear, self locking, damping on the worm gear and the optimization of the parametrs for many regulators. Simulation model was verified on the prototype of the machine. Achieved results bring the new knowledge, which are used for simulation complicated machine nodes and this knowledge is used for research and developing of the similar mechatronics system.
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Russian cinematographers of the 70`s and 80`s of the 20th century
Souček, Prokop ; SMUTNÝ, Vladimír (advisor) ; BERNARD, Jan (referee)
In this diploma thesis I summarize and analyze information about cinematographers of the 70`s and 80`s of the 20th century. I deal with the basics of theory in the context of the period, as well as artistic relationships, and detailed analysis of specific films, with the target to explain the innovative visual procedures established in this period in Russia. I aim to show the influence of the unique production of the period on todays work by analyzing given means of expression.
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