National Repository of Grey Literature 139 records found  1 - 10nextend  jump to record: Search took 0.00 seconds. 
Biochemical and molecular studies of cytochrome c oxidase and ATP synthase deficiencies
Fornůsková, Daniela ; Zeman, Jiří (advisor) ; Hyánek, Josef (referee) ; Stiborová, Marie (referee)
Mgr. Daniela Fornuskova PhD thesis Biochemical and molecular studies of cytochrome c oxidase and ATP synthase deficiencies ABSTRACT The mammalian organism fully depends on the oxidative phosphorylation system (OXPHOS) as the major energy (ATP) producer of the cell. Disturbances of OXPHOS may be caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). One part of the thesis is focused on the role of early and late assembled nuclear-encoded structural subunits of cytochrome c oxidase (CcO) as well as Oxa1l, the human homologue of the yeast mitochondrial Oxa1 translocase, in the biogenesis and function of the human CcO complex using stable RNA interference of COX4, COX5A, COX6A1 and OXA1L, as well as expression of epitope-tagged Cox6a, Cox7a and Cox7b, in HEK (human embryonic kidney)- 293 cells. Our results indicate that, whereas nuclear- encoded CcO subunits Cox4 and Cox5a are required for the assembly of the functional CcO complex, the Cox6a subunit is required for the overall stability of the holoenzyme. In OXA1L knockdown HEK-293 cells, intriguingly, CcO activity and holoenzyme content were unaffected, although the inactivation of OXA1 in yeast was shown to cause complete absence of CcO activity. In addition, we compared OXPHOS protein deficiency patterns in mitochondria from skeletal...
Biochemical and molecular studies of the congenital disorders of glycosylation
Ondrušková, Nina ; Hansíková, Hana (advisor) ; Stiborová, Marie (referee) ; Hřebíček, Martin (referee)
Congenital disorders of glycosylation (CDG) represent a rapidly growing group of rare inherited metabolic diseases with estimated prevalence as high as 1:20 000, which are caused by genetic defects that impair the process of glycosylation, i.e. the enzymatic addition of a specific saccharide structure onto a protein or lipid backbone. Due to non-specificity and variability of clinical symptoms in the patients, the medical diagnosis of CDG remains extremely challenging and significantly relies on accurate biochemical and genetic analyses. The overall goal of the present dissertation thesis was to study CDG at the biochemical and molecular genetic level in the context of the Czech and Slovak Republic, which involved three specific aims: A.) to introduce and optimize laboratory screening methods for CDG detection in a group of clinically suspected patients, B.) to determine the corresponding genetic defect in the positive patients selected via CDG screening and to study the pathobiochemical aspects of specific CDG types at the cellular level, and C.) to analyze glycosylation disturbances of non- CDG etiology. Contributions of this work include optimization of isoelectric focusing of apolipoprotein C-III (ApoC-III) as a screening method for O-glycosylation abnormalities, as well as the description of...
Nanoparticle forms of anticancer drugs and the mechanisms influencing their efficiency
Urbanová, Tereza ; Stiborová, Marie (advisor) ; Hýsková, Veronika (referee)
Currently, cancer is one of the major diseases of civilization. The disadvantage of conventional chemotherapy, which began in the 1940s, is its non-specific effect, so the cytostatics are toxic to healthy cells. However, if the cytostatic is inserted into a nanotransporter, it increases its specific efficacy and reduces the negative side effects. One of the possible nanotransporters is protein called apoferritin (a protein component of ferritin, an iron-carrying protein) that contains light and heavy subunits differing in their function in iron uptake. In this bachelor thesis, the ability of apoferritin to encapsulate two cytostatics (ellipticine and doxorubicin), depending on its origin and the proportion of light and heavy apoferritin subunits, was studied.
Telomere Length in Colorectal Cancer
Tomášová, Kristýna ; Stiborová, Marie (advisor) ; Liška, Václav (referee)
Telomeres are non-coding nucleoprotein structures that make up the very end of each linear chromosome. They stabilize chromosome structure and thus prevent the ends from being recognized by DNA damage response machinery. Telomere shortening in the synthesis phase of the cell cycle is related to the loss of protective ability and the finite replicative potential of the cell. The environmental factors, impaired DNA repair pathways, and loss of telomeric DNA-binding proteins exert negative effects on telomere function. Telomere dysfunction instigates chromosomal rearrangements and together with telomere erosion precedes tumorigenesis. Extension of telomeric DNA is catalyzed by the enzyme telomerase, whose activity is repressed in most adult somatic cells, except for stem cells, lymphocytes, and some cancer cell types. Colorectal cancer comprises malignant tumors of the colon and rectum. It is the second most common cancer in both sexes in the Czech Republic, with over 81,000 cases diagnosed in 2013 and 55.2% overall survival at 5 years. This study focuses on the association of telomere length to clinico-pathological features of the colorectal cancer patients and investigates also the effect of cancer treatment on telomere length. Further, it compares two methods of telomere length measurement; the...
Inhibitors of tyrosine kinases, the anticancer drugs of a new generation, modulate metabolism of ellipticine
Kolárik, Matúš ; Stiborová, Marie (advisor) ; Lengálová, Alžběta (referee)
8 Abstract Ellipticine is a cytotoxic alkaloid that exhibits multiple mechanisms of action such as intercalation into DNA, inhibition of topoisomerase II and activation of apoptosis due to changes in protein p53. The main mechanism of its action is formation of covalent adducts of ellipticine metabolites with DNA. Inhibitors of tyrosine kinases vandetanib, lenvatinib and cabozantinib are anticancer drugs, approved for treatment of advanced metastatic thyroid gland cancer. Mechanism of their action is modulation of cell signalization pathways in cancer cells. The aim of this thesis was investigation whether tyrosine kinase inhibitors can modulate metabolism of ellipticine in vitro, because metabolic activation of ellipticine dictates its pharmacological efficacy. The formation of ellipticine metabolites catalyzed by human and rat microsmes was found. Superosomes™ containing human or rat recombinant cytochromes P450 (CYP) were used to resolve, whether tyrosine kinase inhibitors affect oxidation of ellipticine by these enzymes. Other enzymes tested for possible alteration of formation of metabolites of ellipticine were peroxidases, including thyreoperoxidase. Ellipticine metabolites were separated by HPLC and quantified. Oxidation of ellipticine by human or rat microsomal enzyme systems was inhibited by tested...
Study of action of anticancer drugs tyrosine kinase inhibitors in a form of nanotransporters
Takácsová, Paulína ; Stiborová, Marie (advisor) ; Černá, Tereza (referee)
Tyrosine kinase inhibitors (TKI) are small organic molecules designed for the targeted cancer therapy. They perform the inhibition of activated receptor tyrosine kinases in tumor cells, that defeats tumor growth, proliferation, metastasis and angiogenesis in tumor tissue. Two TKI, lenvatinib and vandetanib, are used in thyroid cancer treatment. This thesis investigates the ways leading to enhancement of efficiency of these anticancer drugs for therapy. One of the studied anticancer drug - lenvatinib - was investigated to be prepared in a nanoform. Nanoparticles were based on protein apoferritin as well as on lipids. Theoretical model of lenvatinib interaction with an apoferritin cavity, as well as the model of its encapsulation obtained by computer modeling indicated that lenvatinib seems not to be suitable for preparation of apoferritin nanoparticles. Since lenvatinib occurs in its neutral form during preparation of nanoparticles, it does not interact with nanoparticle. The unsuccessful experimental preparation of lenvatinib-loaded apoferritin nanoparticles confirmed that lenvatinib is not suitable for its preparation. However, the theoretical model can serve for screening of other potentially suitable drugs before the experimental nanoparticle preparation. Since the experimental preparation of...
Study on metabolism of plant carcinogen aristolochic acid I
Dedíková, Alena ; Stiborová, Marie (advisor) ; Eckschlager, Tomáš (referee)
Aristolochic acids (AA) are natural compounds present in plant species of Aristolochiaceae. These plant alkaloids exhibit nephrotoxic effects and are human carcinogens. The extract of plants species Aristolochiaceae contains various kinds of substances, including aristolochic acids. Aristolochic acid I (AAI) and aristolochic acid II (AAII) are mainly present. AA compounds are associated with two diseases, Aristolochic Acid Nephropathy (ANN), previously known as Chinese Herbs Nephropathy (CHN) and Balkan Endemic Nephropathy (BEN). Both these diseases are accompanied by renal failure and the formation of tumors in urothelial tissue, which are caused by AA. However, the same clinical manifestations do not occur in both diseases. This is propably due to the variability in enzymes involved in AA biotransformation, but also depends on AA doses. In organisms, AA are metabolized by activation and/or detoxification reactions. These thesis is directed on the activating metabolism of AAI, precisely to clarify the formation of reducing metabolites of AAI. Reduction of AAI is the activation pathway responsible for the genotoxic effect of AAI. During this reaction AAI is enzymatically reduced to the cyclic acylnitrenium ion that is capable of binding to the exocyclic amino groups of adenine and guanine in DNA...
Study of metabolism carcinogenic and nephrotoxic natural compound aristolochic acid II
Martináková, Lenka ; Stiborová, Marie (advisor) ; Moserová, Michaela (referee)
Aristolochic acids (AA) have been considered as toxicants of plants which were found in plants of the family Aristolochiaceae. The most abundant acids in mentioned plants are aristolochic acid I (AAI) and aristolochic acid II (AAII). AA have been considered as causes kidney disease called Aristolochic acid nephropathy (AAN). AAN was initially discovered in patients of one Belgian clinic in Brussels specialized on treatment of patients leading to a decrease in their body weight. The first name of this disease was Chinese herb nephropathy (CHN). Later, it was discovered that one component of herbal preparation was changed by a mistake with the Aristolochiaceae plant. The second type of renal disease caused by AA was discovered in populations of countries along the Danube river, called as Balkan endemic nephropathy (BEN), which was probably caused by the contamination of grains with plants containing AA. These renal diseases (AAN and BEN) are often associated with development of upper urothelial cancer (UUC). AA (AAI + AAII) in organisms are subject to biotransformation leading to its reductive activation or oxidative detoxification. Both cytosolic enzymes [NAD(P)H:quinone oxidoreductase] and microsomal enzymes [cytochromes P450, NADPH:cytochrome P450 reductase] participate in their reduction. The...
Study of the mechanism of anticancer drug action on neuroblastomas
Černá, Tereza ; Stiborová, Marie (advisor) ; Souček, Pavel (referee) ; Mrízová, Iveta (referee)
Despite advances in cancer diagnosis and therapy, cancer is the second leading cause of death globally. The improvements of cancer treatment are the major challenge in this research. The aim of the thesis was studying of effects of two anticancer drugs ellipticine (Elli) and doxorubicin (DOX) on some cancer and healthy cell lines. Specific consideration was given to expand current knowledge about the metabolism and cytostatic effects of Elli in neuroblastoma cell lines. Another part of this study was focused on mechanisms contributing to the development of ellipticine-resistance in cancer cells and influence of histone deacetylase inhibitors on anticancer therapy was investigated. Moreover, the aim was to develop apoferritin (Apo) nanocarrier suitable for the active transport of cytostatics to cancer cells. Several essential data were found in this doctoral thesis. Anticancer efficiency of Elli depends on the CYP3A4-mediated metabolism in cancer. The CYP3A4 enzyme encapsulated into two nanoparticle forms, liposomes and SupersomesTM , was tested to activate ellipticine to its reactive species forming covalent DNA adducts. The formation of adducts seems to be dependent on concentrations of CYP3A4 in nanoparticle systems. A higher effectiveness of CYP3A4 in SupersomesTM than in liposomes to form...

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See also: similar author names
1 Stiborová, Marie Luisa
1 Stiborová, Markéta
2 Stiborová, Martina
2 Stiborová, Milada
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