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The role of mTOR complexes in immunophenotype of leukemia cells
Kořánová, Tereza ; Kuželová, Kateřina (advisor) ; Krulová, Magdaléna (referee)
Acute myeloid leukemia (AML) is a cancerous disease of hematopoiesis characterised by accumulation of immature cells (blasts) of the myeloid lineage. AML blasts utilise a range of mechanisms to escape the immune system including alteration of their metabolism or expression of inhibitory molecules. Activation of these mechanisms is not yet fully understood. One of the pathways used to regulate a great number of cellular processes is the mammalian target of rapamycin (mTOR) pathway. mTOR kinase forms two complexes, mTORC1 and mTORC2, each regulating different substrates and cellular functions. The aim of this thesis was to analyze the influence of inhibition of each of the mTOR complexes on the metabolism (oxidative phosphorylation and glycolysis) and expression of immune escape markers (HLA-I, HLA-DR, CLIP, PD-L1, TIM-3) was analysed. The inhibitor JR-AB2-011 (an mTORC2 inhibitor) reduced the mitochondrial respiration rate in the majority of the cell lines, but its impact on the cell immunophenotype was only weak. Importantly, we found that the effect on the cell metabolism did not stem from the inhibition of mTORC2. Rapamycin (an mTORC1 inhibitor) decreased both metabolic rates, as well as glucose uptake. At the same time, CLIP, PD-L1, and TIM-3 expression was reduced in all the studied cell lines,...
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Effect of maternal obesity on postnatal development of circadian clocks
Sejrková, Veronika ; Sumová, Alena (advisor) ; Spišská, Veronika (referee)
This thesis focuses on the synchronizing effect of obesity in mothers on ontogenesis of the circadian system in their offspring during gestation and postnatal life. Additionally, the work summarizes its impact on health of offspring in adulthood. During postnatal life, the central clock oscillator (SCN) is synchronized with external conditions through alternating period of light and darkness, but during prenatal ontogenesis of the main oscillator and peripheral oscillators, the SCN is synchronized with maternal signals, both behavioral, metabolic and hormonal. In the event of disruption of the maternal circadian and metabolic systems due to obesity, the circadian clocks of the offspring are incorrectly synchronized during gestation and breastfeeding, which may have a long-term effect on their health later during postnatal life. Maternal obesity is considered the main trigger for obesity occurring later.
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Screening of selected alkaloids of Fumariaceae and Amaryllidaceae families on Farnesoid X receptor and the G protein-coupled bile acid receptor 1
Hutníková, Miriama ; Pávek, Petr (advisor) ; Chlebek, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Miriama Hutníková Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of diploma thesis: Screening of selected alkaloids of Fumariaceae and Amaryllidaceae families on the farnesoid X receptor and the G protein coupled receptor 1 Farnesoid X receptor (FXR) and bile acid receptor associated with G protein 1 (TGR5) significantly affect metabolic processes in the human body. The role of FXR in neuronal apoptosis in Alzheimer's disease (AD) has also been discovered. The possible structural similarity of the small lipophilic molecules binding to these receptors and the alkaloids found in the plants Corydalis cava and Narcissus pseudonarcissus, as well as the richoften use of these plants in traditional medicine, represent a potential therapeutic intervention for these molecules. In our screening methods, we performed tests using a luciferase gene reporter assay to determine the ability of the alkaloids to interact with FXR and TGR5 in the HepG2 cell line. Many derivatives have shown a strong ability to antagonize FXR and TGR5 activated by obethicholic (OCA) or litocholic (LCA) acids in this assay. Some of the compounds also demonstrated the ability to potentiate the effects of OCA or LCA. Cytotoxicity...
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Mitochondrial transfer-mediated modulatory action of stem cells on immune cells
Somova, Veronika ; Krulová, Magdaléna (advisor) ; Balounová, Jana (referee)
Stem cells use different mechanisms of intercellular communication to modulate an immune response. Mitochondrial transfer is one of the mechanisms which induce metabolic changes, support cell survival, and change the phenotype of immune cells. Nevertheless, little is known about the mechanism used for transfer of mitochondria between different cell populations and the faith of mitochondria inside the acceptor cell. This thesis aims to describe the mechanism of transfer and the provided modulation. Factors that could affect mitochondrial transfer including reactive oxygen species production, apoptosis and mitochondria function were analyzed. And the impact of mitochondrial transfer on cell survival and mitophagy was described. The next aim was to compare the ability of mesenchymal stem cells (MSC) and Sertoli cells (SC) to transfer mitochondria, with MSC being more productive in the transfer of mitochondria than SC. Significant differences in the presence of mitochondria from donor MSC or SC in individual populations of immune cells were also detected. To explain these findings, the impact of reactive oxygen species on the transfer of mitochondria was analyzed in detail, although it wasn't confirmed. However, it needs to be highlighted that mitophagy plays an important role before and after...
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High grade serous ovarian carcinoma: molecular background and platinum-based chemotherapy challenges
Ivančinová, Jana ; Heneberg, Petr (advisor) ; Brábek, Jan (referee)
Ovarian carcinoma (O.C.) represent a group of various disease entities derived from ovaries. The most common malignant gynaecological cancer is high-grade serous ovarian carcinoma (HGSOC). HGSOC is associated with a high mortality rate due to its aggressive behaviour and insufficient early-stage detection. The survival rate has not been significantly improved since 1970s. The most effective treatment of HGSOC patients is by cytoreductive surgery (for early stages I/II) and followed by platinum-based chemotherapy (HGSOC presented in advanced stage III/IV) combined with taxane or potentially with PARP inhibitors (for BRCA1/2 mutation carriers). Multiple factors affect the patient's outcome and prognosis. Chemoresistance, molecular mutational patterns, stage at presentation of HGSOC are one of the clinical challenges contributing to common relapses even though patients often initially respond well to the HGSOC chemotherapy. This thesis overviews the fundamental biology of HGSOC, the major obstacles in clinical management and its improvements by implementing of multitherapy approaches. Key words: CA-125; platinum−based chemotherapy treatment; homologous recombination deficiency; ovarian carcinoma; resistance; Tp53; mortality; survival rate
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Importance of glycolysis and oxidative phosphorylation in the metabolism of mesenchymal stem cells
Fráňová, Markéta ; Krulová, Magdaléna (advisor) ; Rohlenová, Kateřina (referee)
Mesenchymal stem cells (MSCs) are classified as multipotent stem cells. They possess the ability to differentiate into many cell types, promote angiogenesis, increase cell survival in damaged tissue and modulate the immune response. These functions of MSCs are used in the treatment of various injuries and some diseases. This work characterizes MSCs, with a focus on their energy metabolism, specifically on the switch in their metabolic phenotype between glycolysis and oxidative phosphorylation in different states of MSCs, during cell culture and after transplantation. Finally, two modulations of MSC metabolism are presented, including cultivation in a hypoxic environment and quiescence induced by serum deprivation, which increase cell survival under the ischemic conditions that MSCs enter after transplantation. Key words: mesenchymal stem cells, metabolism, glycolysis, oxidative phosphorylation
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Factors influencing intraspecific scaling of metabolic rate
Trubelová, Zuzana ; Starostová, Zuzana (advisor) ; Storch, David (referee)
The relationship between metabolic rate and animal body size of the animal has been studied for more than hundred years. Recently, attention of scientists moved from the interspecific to the intraspecific level. The work focuses on the intraspecific scaling of metabolism. When plotting the metabolic rate against body mass during ontogeny the resulting line often exhibits one or more breaks. Why these breaks (and thus reduction the metabolic rate) occur hasn't been fully explained. It is assumed that can be due to certain factors that affect an individual during development. Some of these factors came from the most famous of several hypotheses attempting to explain the scaling of metabolic rate. These hypotheses include the Metabolic Theory of Ecology (MTE), the Metabolic Level Boundaries (MLB), the Cell model and the Dynamic Energy Budget (DEB) hypothesis. There are several factors that could affect individuals during ontogeny. These include internal factors, which result from the internal processes within the body. These factors are often interrelated with each other in different ways; therefore, it is unlikely to choose only one particular factor which affects metabolic rate. The most frequently studied factors are changes of cell size and changes in the proportion of metabolically active...
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Comparison of methods of basal metabolism determination
Kosková, Martina ; Coufalová, Klára (advisor) ; Hráský, Pavel (referee)
Title: Comparison of individual methods of basal metabolism determination Objectives: The aim of the work is to compare the individual methods of basal metabolism. These values were measured by indirect calorimetry, plethysmography, bioelectric impedance and predictive equations. Methods: The research was attended by 31 people, including eight men and twenty-three women. All participants of my research were aged 21-30 years. None of the participants was a professional athlete, they were all healthy and none of the women were pregnant or had menstruation. The indirect calorimetry, bioelectronics impedance device Tanita MC - 980 and BOD POD were used to collect the data. Basal metabolic rates were calculated from the prediction equations by Harris & Benedict, Fleisch's equation and Schofield's equation using measured anthropometric values. Results: The results of the methods that have been used for this group of people vary, but the difference is not significant. If we choose as a reference method indirect calorimetry, we can't replace it by any other method. The results for other methods are not significantly different, so we can replace one method with another, except indirect calorimetry. From calculations, we also found out that fat free mass greatly influences the results of basal metabolic rate...
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Metabolic alterations in cancer cells and their implications in the therapy of acute leukemias
Harárová, Alžbeta ; Starková, Júlia (advisor) ; Mrvová, Silvia (referee)
Cancer metabolism differs from that of the healthy cells in several aspects. Aerobic glycolysis (e.g. converting pyruvate to lactate under normoxic conditions) was the first described metabolic alteration of cancer cells. Metabolic alterations have since been described in the tricarboxylic acid cycle, oxidative phosphorylation, in the metabolism of amino acids (especially glutamine, asparagine and serine) and also in the metabolism of fatty acids and cholesterol. The common feature of these changes is the tendency to prefer anabolic pathways, thus enabling fast proliferation of cancer cells. The study of cancer metabolism is particularly important in the case of cancer cells that show resistance to treatment, as their aberrant metabolism is not only a potential diagnostic marker but also a potential therapeutic target. The majority of metabolic alterations have been described for the first time in solid tumors, whereas only recently has the metabolism of acute leukamias gained more attention. Asparaginase is an example of a chemotherapeutic agent that targets a metabolic alteration of leukemic cells. Distinct metabolic profile is also associated with the glucocorticoid resistance. Detailled study of the metabolic alterations of leukemic cells has elucitated the mechanisms of the asparaginase and...
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Metabolism of uric acid during mammalian evolution
Mančíková, Andrea ; Krylov, Vladimír (advisor) ; Stibůrková, Blanka (referee)
Uric acid is the end product of purine metabolism of humans and some higher primates. In other mammals enzyme urate oxidase is capable to further convert uric acid to allantoin. During evolution of primates several mutations in urate oxidase gene had occured, led the enzyme to decrease its activity or to complete loss of function. What was the initial impetus for the utilization of uric acid and what biochemical traits of uric acid led to a tendency to retain a major of this metabolite production in the bloodstream? Uric acid has antioxidant capabilities and it is scavanger of free radicals. Increased levels of uric acid in blood has an effect on acute and chronic elevations of blood pressure. It is possible that hyperuricemia helped to maintain blood pressure under low-salt dietary conditions of primates during the Miocene. This mechanism probably have allowed to stabilize bipedalism our ancestors. Uric acid has an important role as a neuroprotector. As inhibitor the permeability blood-brain barrier, uric acid limits the infiltration of undesirable substances to the neurons and prevents central nervous system against the formation of inflammatory diseases. Such as neurodegenerative diseases may be caused by reduced serum uric acid levels. Uric acid protects against peroxinitrite damage tissues in the...
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