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Redox homeostasis of pancreatic beta cells upon insulin secretion and its GLP-1 amplification
Berounská, Anna ; Ježek, Petr (advisor) ; Saudek, František (referee)
The regulation of pancreatic hormone secretion, specifically of insulin and glucagon, is a fundamental mechanism by which the body maintains a stable supply of energy substrates to our cells. Glucose acts as the primary trigger for insulin release, though other nutrients also influence this endocrine response. Oxidation of glucose leads to the production of ATP, which ensures depolarization of the cytoplasmic membrane, rise in calcium ion concentration in the cytosol, and subsequent exocytosis of insulin secretory vesicles from beta cells into the systemic circulation. Recent findings highlight the significance of redox signaling in this process, particularly the role of H2O2 as an essential factor for insulin secretion, which is produced by the activity of the enzyme NADPH oxidase 4. Insulin then influences target cells such as myocytes, hepatocytes, and adipocytes to promote the synthesis of energy-rich molecules. Dysregulation of this process can lead to the onset of diabetes mellitus. The incretin glucagon-like peptide 1 is secreted from enteroendocrine L-cells after food intake. Its direct effect on beta cells, along with other mechanisms, effectively reduces postprandial hyperglycemia, making its synthetic analogs an important therapeutic tool for diabetic patients. Moreover, these agents...
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Selected aspects of redox metabolism in leukemogenesis
Myšáková, Michaela ; Pimková, Kristýna (advisor) ; Kuželová, Kateřina (referee)
Blood cancers are caused by the accumulation of mutations in haematopoietic stem cells. This creates a malignant clone that has a selection advantage due to improved survival and unrestricted proliferation, a process of leukaemia development called leukemogenesis. Leukemogenesis is a complex process and it is difficult to identify a single mutation that is responsible for the transformation of haematopoietic cells. In addition to transcriptional deregulation caused by oncogenic fusion proteins, mutations in specific genes that regulate critical signaling pathways play a critical role in leukemogenesis. Examples of such genes include mutations in the isocitrate dehydrogenase 1 and 2 genes (mutIDH1/2). These genes are thought to play an important role in the development of leukaemia, as indicated by their increasing frequency in the progression of myelodysplastic syndrome to acute myeloid leukaemia. The functions of mutIDH1/2 include epigenetic regulation, changes in metabolism and redox homeostasis. It has been shown that regulation of reactive oxygen species (ROS) production and elimination, so-called redox homeostasis, is important for the proper function of haematopoietic stem cells and its disruption is a frequent phenomenon accompanying malignant transformation of these cells. Some mutations,...
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Proteins demaged by oxidative stress, their role in physiology and ageing of yest cells
Mikešová, Jana ; Palková, Zdena (advisor) ; Borčin, Kateřina (referee)
Reactive oxygen species (ROS) are regularly produced in cells as a by-product of aerobic metabolism. Hence, organisms developed various defence mechanisms, which are able to avoid molecular damages caused by ROS under physiological conditions. In stress conditions, however, such defence mechanisms are not sufficient to avoid molecular damages. Accumulation of oxidized proteins is supposed to be a reason for ageing and many diseases including Friedreich's ataxia, Amylotrophic lateral sclerosis, Alzheimer's disease and many others. During oxidative stress, reactive oxygen species are reflected in oxidation of cystein residues in transcription factors, regulation proteins and active canters centers of enzymes. Oxidative modifications however could lead also to changes in transcription factor activity and activation of specific pathways, including changes in gene expression, cell cycle and proteolysis. This work shows defence mechanisms, ROS and proteins altered by reactive oxygen species that may function as important signalling molecules, which are essential for many cellular processes.
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The role of NADPH oxidase in architecture and function of β cells and Langerhans Islets
Tučková, Štěpánka ; Plecitá, Lydie (advisor) ; Bardová, Kristina (referee)
Local production of reactive oxygen species (ROS) and changes in the redox environment influence the metabolism and function of β cells of the Langerhans islets (LO). Changing the ratio between NAD(P)H / NAD(P)+ redox partners significantly affects sensitive proteins and ROS production. ROS are able to reversibly modify some amino acid residues (eg Cys, Met) of antioxidant enzymes and their interaction partners. Such a signaling cascade allows the transmission of a signal over longer distances and can also interfere with the influence of gene expression. The unique enzyme NADPH oxidase 4 (NOX4) is present on membranes within β cells and constitutively produces H2O2 depending on the presence of NAD(P)H. After glucose stimulation, both NAD(P)H and Nox4 mRNA levels increase. As previously observed in our laboratory, C57BL/6J mice with a specific Nox4 deletion in β cells have a disrupted biphasic insulin release and exhibit insulin resistance in fat and muscle tissue. We found that the absence of NOX4 in C57BL/6J mice affects LO architecture. Wildtype (WT) mice on a normal, predominantly carbohydrate diet (ND) have the majority of small LO with an area of up to 5 000 μm2 (measured on histological sections). High-fat diet (HFD) feeding of WT for 8 weeks leads to the development of diabetic phenotype and...
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Proteins demaged by oxidative stress, their role in physiology and ageing of yest cells
Mikešová, Jana ; Palková, Zdena (advisor) ; Borčin, Kateřina (referee)
Reactive oxygen species (ROS) are regularly produced in cells as a by-product of aerobic metabolism. Hence, organisms developed various defence mechanisms, which are able to avoid molecular damages caused by ROS under physiological conditions. In stress conditions, however, such defence mechanisms are not sufficient to avoid molecular damages. Accumulation of oxidized proteins is supposed to be a reason for ageing and many diseases including Friedreich's ataxia, Amylotrophic lateral sclerosis, Alzheimer's disease and many others. During oxidative stress, reactive oxygen species are reflected in oxidation of cystein residues in transcription factors, regulation proteins and active canters centers of enzymes. Oxidative modifications however could lead also to changes in transcription factor activity and activation of specific pathways, including changes in gene expression, cell cycle and proteolysis. This work shows defence mechanisms, ROS and proteins altered by reactive oxygen species that may function as important signalling molecules, which are essential for many cellular processes.
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