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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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The effect of urate transporter polymorphisms on uric acid excretion
Mančíková, Andrea ; Krylov, Vladimír (advisor) ; Novotný, Jiří (referee) ; Ježek, Petr (referee)
Uric acid excretion disorders are the most common cause of primary dysuricemia. The kidneys eliminate two-thirds of uric acid production and the other third is eliminated in the gastrointestinal tract. Renal reabsorption and secretion occur through the polarised epithelial cells in the proximal tubules. Uric acid transporters are expressed on these cell membranes. Reabsorption deficiency leads to hypouricemia and elevated fraction excretion associated with urolithiasis, nephrolithiasis or acute renal injury. Decreased uric acid secretion in the kidneys and small intestine leads to hyperuricemia, which develops into gout in 10% of individuals. Genome wide association studies detected a strong effect of SLC22A12 (URAT1), SLC2A9 (GLUT9) reabsorbing transporters and ABCG2 (ABCG2) secreting transporter on uric acid serum concentration variability. This thesis aimed to map out urate transporter allelic variants in a cohort of primary dysuricemia patients and identification of the variants causing defective uric acid excretion. Six non-synonymous variants were described in SLC22A12 (URAT1) and SLC2A9 (GLUT9) genes in hypouricemic individuals, which had not been identified previously in any population studies. Significant decreases in uric acid transport have been demonstrated experimentally in vitro,...
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The effect of urate transporter polymorphisms on uric acid excretion
Mančíková, Andrea
Uric acid excretion disorders are the most common cause of primary dysuricemia. The kidneys eliminate two-thirds of uric acid production and the other third is eliminated in the gastrointestinal tract. Renal reabsorption and secretion occur through the polarised epithelial cells in the proximal tubules. Uric acid transporters are expressed on these cell membranes. Reabsorption deficiency leads to hypouricemia and elevated fraction excretion associated with urolithiasis, nephrolithiasis or acute renal injury. Decreased uric acid secretion in the kidneys and small intestine leads to hyperuricemia, which develops into gout in 10% of individuals. Genome wide association studies detected a strong effect of SLC22A12 (URAT1), SLC2A9 (GLUT9) reabsorbing transporters and ABCG2 (ABCG2) secreting transporter on uric acid serum concentration variability. This thesis aimed to map out urate transporter allelic variants in a cohort of primary dysuricemia patients and identification of the variants causing defective uric acid excretion. Six non-synonymous variants were described in SLC22A12 (URAT1) and SLC2A9 (GLUT9) genes in hypouricemic individuals, which had not been identified previously in any population studies. Significant decreases in uric acid transport have been demonstrated experimentally in vitro,...
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Maturation of brown adipose tissue
Csomová, Martina ; Žurmanová, Jitka (advisor) ; Mančíková, Andrea (referee)
Brown adipose tissue (BAT) is activated under the influence of the adrenergic system and thyroid hormones in response to a cold stimulus. It's main task is to cover the body heat loss and maintain the stability of the internal environment . BAT is in most cases found in new-borns accounting for 5% of the whole body. Cells found in BAT contain a high number of mitochondria with high respiratory capacity but low ATP-synthase activity which allows the production of heat instead of ATP in process of glucose oxidation. The result is non-shivering thermogenesis. The task of my work is to summarize the current knowledge about the development of BAT and to point out the markers for its characterization. The work will also include differences in adipose tissue maturation in selected model organisms. Key words: brown adipose tissue, white adipose tissue, beige adipose tissue, non-shivering thermogenesis, uncoupling protein 1
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The effect of urate transporter polymorphisms on uric acid excretion
Mančíková, Andrea ; Krylov, Vladimír (advisor) ; Novotný, Jiří (referee) ; Ježek, Petr (referee)
Uric acid excretion disorders are the most common cause of primary dysuricemia. The kidneys eliminate two-thirds of uric acid production and the other third is eliminated in the gastrointestinal tract. Renal reabsorption and secretion occur through the polarised epithelial cells in the proximal tubules. Uric acid transporters are expressed on these cell membranes. Reabsorption deficiency leads to hypouricemia and elevated fraction excretion associated with urolithiasis, nephrolithiasis or acute renal injury. Decreased uric acid secretion in the kidneys and small intestine leads to hyperuricemia, which develops into gout in 10% of individuals. Genome wide association studies detected a strong effect of SLC22A12 (URAT1), SLC2A9 (GLUT9) reabsorbing transporters and ABCG2 (ABCG2) secreting transporter on uric acid serum concentration variability. This thesis aimed to map out urate transporter allelic variants in a cohort of primary dysuricemia patients and identification of the variants causing defective uric acid excretion. Six non-synonymous variants were described in SLC22A12 (URAT1) and SLC2A9 (GLUT9) genes in hypouricemic individuals, which had not been identified previously in any population studies. Significant decreases in uric acid transport have been demonstrated experimentally in vitro,...
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The structure and function of transmembrane proteins ABCG2
Vávra, Jiří ; Mančíková, Andrea (advisor) ; Novotný, Marian (referee)
ABCG2 (ABCP/MXR/BCRP) transporters create homodimers through the plasma membrane. They play an important role in transmembrane transport of a wide spectrum of biological substrates. They are essential for renal, intestinal, placental and haematoencephalic barrier function. In particular they perform an excretory function, protect cells against toxic compounds and xenobiotic cumulation. They are also involved in metabolic regulation of stem cells. This bachelor thesis summarizes information about ABCG2 protein function, their physiological role in humans and other mammals. Keywords: ABCG2, BCRP, membrane transporters, multidrug resistention (MDR), ATP binding cassette family (ABC)
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The role of SGK1 in heart
Havlíková, Nikola ; Horníková, Daniela (advisor) ; Mančíková, Andrea (referee)
Serum and glucocorticoid-regulated kinase 1 (SGK1) is an enzyme which is encoded by the sgk1 gene. This is a dimer. Generally, SGK1 belongs into the protein kinases, but its structure is somehow different from the other protein kinases, especially in the reaction center, which is related to its activity. SGK1 belongs to the subfamily of serine/threonine kinases. This kinase is activated by insulin or growth factors via phosphatidylinositol-3-kinase (PI3K) and mammalian rapamycin mTORC2. SGK1 plays an important role in inflammatory processes, the proliferation and apoptosis. In heart it helps to increase the abundance of proteins, which has affect on the morphology of ion channels and Na+ /K+ -ATPase. The sgk1 gene plays an important role in cellular stress response. This kinase activates potassium, sodium, chloride and calcium channels, which suggests about the involvement in the regulation of processes such as the cell survival, neuronal excitability and renal sodium excretion. Currently, the most discussed roles of SGK1 are in the heart, kidneys, brain, lungs and gastrointestinal tract. In recent years, it was found that SGK1 has different expression and regulation during the developmental stages and pathological conditions such as hypertension, diabetic neuropathy, ischemic trauma 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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