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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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Adipose tissue metabolism and genetically modified murine models
Irodenko, Ilariia ; Bardová, Kristina (advisor) ; Železná, Blanka (referee)
Adipose tissue plays an important role in energy and glucose homeostasis. Adipose tissue metabolism includes lipolysis and lipogenesis processes which control lipid mobilization, storage and distribution in the body. In addition to that adipose tissue is recognized as an endocrine organ which generates cytokines and adipokines for communication with other organs and tissues. The major process of lipogenesis is triacylglycerol synthesis which comprises such enzymes as monoacylglycerol acyltransferase and diglyceride acyltransferase for triacylglycerol storage in a form of lipid droplets. The other way around main enzymes of lipolysis adipose triglyceride lipase and hormone-sensitive lipase produce sufficient amount of energy for other tissues. Lipid combustion in brown adipose tissue produces heat in the body through the function of uncoupling protein 1. Signaling pathways of lipolysis and thermogenesis comprise adrenergic receptors. Study of thermogenic function of uncoupling protein and adipose tissue metabolism can be useful for the treatment of obesity and metabolic disorders.
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The role of adipose tissue in the whole-body energy metabolism in mice with different genetic background
Funda, Jiří ; Janovská, Petra (advisor) ; Pecina, Petr (referee) ; Žurmanová, Jitka (referee)
Adipose tissue greatly contributes to the maintenance of the whole-body energy homeostasis. White adipose tissue (WAT) is the most important storage of metabolic energy in the body, while brown adipose tissue (BAT) enables the body to survive in cold environment by transforming metabolic energy to heat. Both WAT and BAT have a critical role in the control of systemic levels of fatty acids, which is necessary for the maintenance of the energy homeostasis and for the prevention of lipotoxic damage of non-adipose tissues. Abundant lipid accumulation can lead to the development of obesity, which is often accompanied by metabolic disorders such as type 2 diabetes and by the impairment of adipose tissue metabolic functions. Healthy adipose tissue prevents from the development of metabolic disorders associated with obesity by buffering the excess of nutrients. The key processes for efficient buffering of fatty acids are futile triacylglycerols/fatty acid cycling (TAG/FA cycling) and fatty acid oxidation. These processes occur in both WAT and BAT and their rates are largely affected by a set of transcriptional regulators, especially peroxisome proliferator-activated receptors (PPARs) and their coactivators. Bioactive molecules such as hormones, polyunsaturated fatty acids (PUFA) or pharmaceutics such as...
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Applications of chiral and achiral chromatography in pharmacology and toxicology
Chytil, Lukáš ; Slanař, Ondřej (advisor) ; Bultas, Jan (referee) ; Coufal, Pavel (referee)
Development and validation of methods for analysis of several drugs or their metabolites are decribed in this thesis. The document is presented as a commentary to the original papers, which were published in peer reviewed journals. Discussion on the optimization of each method is presented and covers also method development and influence of preanalytical aspects. Additionally, examples of the application of the developed methods in clinical pharmacology and toxicology are shown. This dissertation consists of three parts: enantiomeric determination of tramadol and its metabolite, determination of some antihypertensive drugs, and qualitative analysis of benzodiazepines. Development of a method for chiral analysis of tramadol and its desmethylated metabolite O- desmethyltramadol (ODT) in human urine and plasma is described in the first part of the thesis. Tramadol is a centrally acting analgetic drug, which is used as racemate in clinical practise. Each enantiomer displays different binding properties for various receptors: (+)-tramadol preferentially inhibits serotonin reuptake while (-)-tramadol mainly inhibits noradrenalin reuptake. (+)-tramadol is considered 10-times more potent than (-)-tramadol. Major active metabolite (ODT), which is considered to be the main agent responsible for the...
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Biogenesis of mitochondria in parasitic protist Trypanosoma brucei
Mach, Jan
In last decade, investigations of mitochondria including their various reduced forms such as hydrogenosomes and mitosomes revealed unexpected diversity of this indispensable organelle. Interestingly, the single mitochondrion of parasitic protist Trypanosoma brucei is able to undergo remarkable functional and structural changes reflecting available carbon sources. Moreover, it was proposed that trypanosomes belong among the most ancient eukaryotes and as such, their mitochondria raised high attention of biologists. To contribute to the knowledge of mitochondrial biogenesis and function, we focused on studies of two key mitochondrial processes, the processing of preproteins that are imported to the mitochondria, and mechanism of pyruvate transport to these organelles. Moreover, we also investigated uptake of iron by T. brucei. This metal is essential for function of numerous proteins, particularly for iron-sulfur proteins in mitochondria. Evolutionary history of trypanosomes and their mitochondrion is a question of debates. According to some reports, mitochondrion of trypanosomes represent an ancient form of this organelle, which is supported by identification of putative "archaic" translocase of the outer mitochondrial membrane (ATOM) and finding of only a single type of translocation pore in...
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Chemical and biochemical transformation of bioactive compounds
Šimášková, Ema ; Sokolová, Romana (advisor) ; Martínková, Markéta (referee)
Xenobiotics, such as pharmaceuticals, food additives, environmental pollutants, and dietary bioactive compounds in organism are metabolized by various enzymes, resulting in their bioactivation or detoxification. Identification of structure of resulting metabolites is important for their detection in bodily fluids and tissues for diagnostic and forensic purposes. This thesis reviews known biochemical processes and enzymes involved in xenobiotic metabolism, including cytochromes 450 (CYP) and flavine monooxygenases (FMO). Given that biochemical reactions are to a major extent composed of electron-transfer reactions (i.e. oxidation and reduction), the thesis includes a section dealing with the practical approaches to determination of the oxidative or reductive mechanism of bioactive compounds.
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Adipose tissue metabolism and genetically modified murine models
Irodenko, Ilariia ; Bardová, Kristina (advisor) ; Železná, Blanka (referee)
Adipose tissue plays an important role in energy and glucose homeostasis. Adipose tissue metabolism includes lipolysis and lipogenesis processes which control lipid mobilization, storage and distribution in the body. In addition to that adipose tissue is recognized as an endocrine organ which generates cytokines and adipokines for communication with other organs and tissues. The major process of lipogenesis is triacylglycerol synthesis which comprises such enzymes as monoacylglycerol acyltransferase and diglyceride acyltransferase for triacylglycerol storage in a form of lipid droplets. The other way around main enzymes of lipolysis adipose triglyceride lipase and hormone-sensitive lipase produce sufficient amount of energy for other tissues. Lipid combustion in brown adipose tissue produces heat in the body through the function of uncoupling protein 1. Signaling pathways of lipolysis and thermogenesis comprise adrenergic receptors. Study of thermogenic function of uncoupling protein and adipose tissue metabolism can be useful for the treatment of obesity and metabolic disorders.
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Biogenesis of mitochondria in parasitic protist Trypanosoma brucei
Mach, Jan ; Tachezy, Jan (advisor) ; Yurchenko, Vyacheslav (referee) ; Hashimi, Hassan (referee)
In last decade, investigations of mitochondria including their various reduced forms such as hydrogenosomes and mitosomes revealed unexpected diversity of this indispensable organelle. Interestingly, the single mitochondrion of parasitic protist Trypanosoma brucei is able to undergo remarkable functional and structural changes reflecting available carbon sources. Moreover, it was proposed that trypanosomes belong among the most ancient eukaryotes and as such, their mitochondria raised high attention of biologists. To contribute to the knowledge of mitochondrial biogenesis and function, we focused on studies of two key mitochondrial processes, the processing of preproteins that are imported to the mitochondria, and mechanism of pyruvate transport to these organelles. Moreover, we also investigated uptake of iron by T. brucei. This metal is essential for function of numerous proteins, particularly for iron-sulfur proteins in mitochondria. Evolutionary history of trypanosomes and their mitochondrion is a question of debates. According to some reports, mitochondrion of trypanosomes represent an ancient form of this organelle, which is supported by identification of putative "archaic" translocase of the outer mitochondrial membrane (ATOM) and finding of only a single type of translocation pore in...
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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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Biogenesis of mitochondria in parasitic protist Trypanosoma brucei
Mach, Jan
In last decade, investigations of mitochondria including their various reduced forms such as hydrogenosomes and mitosomes revealed unexpected diversity of this indispensable organelle. Interestingly, the single mitochondrion of parasitic protist Trypanosoma brucei is able to undergo remarkable functional and structural changes reflecting available carbon sources. Moreover, it was proposed that trypanosomes belong among the most ancient eukaryotes and as such, their mitochondria raised high attention of biologists. To contribute to the knowledge of mitochondrial biogenesis and function, we focused on studies of two key mitochondrial processes, the processing of preproteins that are imported to the mitochondria, and mechanism of pyruvate transport to these organelles. Moreover, we also investigated uptake of iron by T. brucei. This metal is essential for function of numerous proteins, particularly for iron-sulfur proteins in mitochondria. Evolutionary history of trypanosomes and their mitochondrion is a question of debates. According to some reports, mitochondrion of trypanosomes represent an ancient form of this organelle, which is supported by identification of putative "archaic" translocase of the outer mitochondrial membrane (ATOM) and finding of only a single type of translocation pore in...
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