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Induction of lipid catabolism and mitochondrial biogenesis in white adipose tissue as therapeutic target for obesity and associated metabolic disorders
Adamcová, Kateřina ; Janovská, Petra (advisor) ; Tencerová, Michaela (referee) ; Cahová, Monika (referee)
Adipose tissue is not only crucial in the storage of excessive fat and its release but also plays important role in the secretion of endo/para- and autocrine factors, thus influencing energy metabolism on the whole body level. The incapability of adipose tissue to meet its responsibilities leads to whole-body metabolic problems resulting in type 2 diabetes, storing of fat in the liver, coronary disease, and other diseases. How to prevent development of obesity and its consequences and/or completely reverse it, is a subject of great scientific interest. Activation of brown adipose tissue (BAT) and brite cells via induction of uncoupling protein 1 (UCP1) and/or stimulation of UCP1-independent energy-dissipating metabolic pathways such as futile cycles in white adipose tissue may be a promising path to fulfill this goal. This thesis is based on results from experiments with two cold-exposed inbred murine strains differing in the propensity to obesity and murine experiments with diet-induced obesity prevented by n-3 polyunsaturated fatty acids (PUFA). Mice resistant to diet-induced obesity (A/J mice) showed higher induction of triacylglycerol (TAG)/fatty acid (FA) futile cycle in epididymal white adipose tissue by cold exposure in comparison to obesity-prone B6 mice. Interestingly, the level of both...
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Functional analysis of posttranscriptional gene regulation by TENT5A in biomineralization and metabolism
Aranaz Novaliches, Goretti ; Sedláček, Radislav (advisor) ; Hovořáková, Mária (referee) ; Tencerová, Michaela (referee)
Non-canonical poly-A polymerases, such as TENT5A, belong to the Terminal nucleotidyl transferases (TENTs) family and are crucial for mRNA protection, stability, and translation. A Tent5a knock-out (KO) mouse model was generated in our laboratory, which exhibited a phenotype in teeth, skeleton structure, and metabolism. In my PhD project, I aimed to characterize the molecular mechanism underlying these phenotypes and explore their potential connection to rare human diseases. I focused on the biological function of Tent5a gene in enamel development (amelogenesis) and mRNA stabilization. Micro-computed tomography and scanning electron microscopy revealed that Tent5a KO mice displayed thin, hypomineralized enamel with disrupted microstructure, a condition known as Amelogenesis imperfecta. Direct mRNA sequencing demonstrated that TENT5A is responsible for polyadenylation of amelogenin (AmelX) and other secreted proteins, leading to a shortened poly-A tail in Tent5a KO ameloblasts. Moreover, Tent5a KO mice disclosed impaired self- assembly of enamel matrix proteins (EMPs) such as AMELX and ameloblastin (AMBN), leading to compromised hydroxyapatite deposition and enamel formation. In addition to its role in teeth, I investigated the physiological functions of EMPs in other tissues, considering that EMP...
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Circulating tumor cells in personalized cancer therapy
Jakabová, Anna ; Kološtová, Katarína (advisor) ; Svoboda, Bohuslav (referee) ; Tencerová, Michaela (referee)
Circulating tumor cells (CTC) have showed great potential to become both prognostic and predictive biomarker in various types of oncological diseases. CTC can help detect patients in higher risk of shorter overall survival, progression-free survival or relapse. They can be also helpful in therapy selection as in current clinical practice treatment is chosen based on primary tumor characteristics. Regular CTC counts and features monitoring can be real-time indication of therapy response and can be used to guide-targeted treatment. This information can be implemented to personalized medicine and each cancer patient can be treated based on individual profile. However, patients' sample with CTC is easily accessible, their detection has remained challenge due to low CTC number in the circulation and heterogeneous nature. CTC can circulate in blood in the form of single cells or in clusters that usually represent minority in comparison with single CTC but their metastatic potential is significantly greater than of single CTC. Apart from CTC count, the molecular character showed dynamic development and heterogeneous nature not only between patients but also within the individual patient's tumor tissue itself. Character of primary tumor, CTC and metastasis are not always consistent and has been changing...
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Molecular adaptations of adipose tissue in relation to dietary treatment of obesity in human
Tencerová, Michaela ; Štich, Vladimír (advisor) ; Flachs, Pavel (referee) ; Kazdová, Ludmila (referee) ; Kunešová, Marie (referee)
The general goal of this work was to investigate the molecular adaptations of human AT in relation to DIs with respect to its secretory activity as well as cellular composition focused on macrophages population. Specifically, we studied the role of novel adipokines, such as visfatin and RBP4, related to insulin resistance and AT metabolism. Furthermore, we wanted to characterize the effect of the dietary-induced changes on the content of ATM together with metabolic amelioration. In our studies, we found that lifestyle modifications had a beneficial effect on metabolic and biochemical parameters depending on the duration and type of DI. Regarding both of the investigated adipokines, visfatin and RBP4, we revealed modifications at the transcriptional and cirulating levels during DI. However, we did not find any association with the pattern of evolution of insulin resistance. Our findings do not support a clear hypothesis on the role of these adipokines in the diet-induced improvement of insulin sensitivity and other obesity-related metabolic disturbances. In respect to the changes of ATM content during long-term DI, we demonstrated using flow cytometry that the AT composition was changed at the end of the whole dietary intervention (i.e. after WM phase). This diet-induced AT remodelling was expressed by a...
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Role of inflammation in pathologic bone resorption in axial spondyloarthritis
Šebová, Eva ; Daňková, Pavlína (advisor) ; Tencerová, Michaela (referee)
Introduction: Axial spondyloarthritis (ax-SpA) is an inflammatory rheumatic disease. It is a unique model of bone remodeling disorders because, although one of the main diagnostic parameters is the rate of bone formation, inflammation present in patients' bodies increases the risk of pathological bone resorption, which can lead to osteoporosis. The processes of pathological resorption in ax-SpA have not been fully investigated, both in the disease as such and in the individual forms of the disease, i.e. non-radiographic (nr-axSpA), radiographic axial spondyloarthritis (r-axSpA) and ankylosing spondylitis (AS). This work deals with the influence of inflammatory serum of patients on the process of osteoclast differentiation from peripheral precursors of patients and healthy donors. Material and methods: Monocytes separated from the peripheral blood of either axSpA patients or healthy donors were stimulated for 14 days in vitro with serum from patients and in parallel with serum of age and sex of the corresponding healthy donors. Osteoclasts were evaluated as multinucleated, TRAP positive cells. Their numbers were statistically processed. Results: The inflammatory serum environment of patients with axSpA stimulated the osteoclastogenesis of axSpA monocytes significantly more (P <0,05) than the...
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Molecular adaptations of adipose tissue in relation to dietary treatment of obesity in human
Tencerová, Michaela ; Štich, Vladimír (advisor) ; Flachs, Pavel (referee) ; Kazdová, Ludmila (referee) ; Kunešová, Marie (referee)
The general goal of this work was to investigate the molecular adaptations of human AT in relation to DIs with respect to its secretory activity as well as cellular composition focused on macrophages population. Specifically, we studied the role of novel adipokines, such as visfatin and RBP4, related to insulin resistance and AT metabolism. Furthermore, we wanted to characterize the effect of the dietary-induced changes on the content of ATM together with metabolic amelioration. In our studies, we found that lifestyle modifications had a beneficial effect on metabolic and biochemical parameters depending on the duration and type of DI. Regarding both of the investigated adipokines, visfatin and RBP4, we revealed modifications at the transcriptional and cirulating levels during DI. However, we did not find any association with the pattern of evolution of insulin resistance. Our findings do not support a clear hypothesis on the role of these adipokines in the diet-induced improvement of insulin sensitivity and other obesity-related metabolic disturbances. In respect to the changes of ATM content during long-term DI, we demonstrated using flow cytometry that the AT composition was changed at the end of the whole dietary intervention (i.e. after WM phase). This diet-induced AT remodelling was expressed by a...
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