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Regulation of triglyceride metabolism in circulation in postprandial phase.
Zemánková, Kateřina ; Kovář, Jan (advisor) ; Kazdová, Ludmila (referee) ; Zlatohlávek, Lukáš (referee)
Increased triglyceride (TG) concentration has been generally accepted as a risk factor for ischemic heart disease and, therefore, lowering TG is therapeutic target that should reduce cardiovascular disease risk. Traditionally, concentration of TG is measured in the fasting state (8-12 hours after an overnight fasting) mainly because the rise in TG levels after meal leads to the high variation in TG values. However, human beings spend larger portion of the day in a postprandial state and postprandial hypertriglyceridemia may then play a substantial role in determination of cardiovascular disease risk. The increased and prolonged postprandial lipemia has been found in patients with coronary heart disease. Moreover, recent data from Copenhagen Heart Study point out that the non-fasting TG concentration is associated with cardiovascular disease risk more tightly than the fasting TG concentration. Importantly, concentration of non-fasting TG is substantially affected by individual behavioural habits such as diet composition and physical activity. It remains to be determined whether it would be appropriate to identify individuals at higher risk of cardiovascular disease due to increased postprandial TG using tolerance test analogous to glucose tolerance test. The protocol of standardized fat tolerance...
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Role of phospholipases A2 in the mechanism of cardioprotection induced by adaptation to chronic hypoxia
Míčová, Petra ; Novotný, Jiří (advisor) ; Kuda, Ondřej (referee) ; Kazdová, Ludmila (referee)
Cardiovascular diseases, particularly acute myocardial infarction, are the leading causes of death in developed countries including the Czech Republic. One of the ways to increase cardiac resistance against acute ischemia/reperfusion (I/R) injury is adaptation to chronic hypoxia. However, changes at the molecular level associated with this adaptation have still not been fully explored. It is obvious that the myocardial function depends on maintaining membrane integrity and cellular homeostasis of cardiomyocytes. From this perspective, phospholipases A2 (PLA2) are the key enzymes that take part in the remodeling and repairing of the cell membranes. Moreover, PLA2 are also involved in generation of lipid signaling molecules - free long chain fatty acids (FA) and 2-lysophopholipids. In myocardium, members of three major PLA2 classes are present: cytosolic PLA2 (cPLA2), calcium-independent PLA2 (iPLA2) and secretoric PLA2 (sPLA2). This thesis aimed to determine the following in the left ventricular myocardium of adult male Wistar rats: 1) The effect of intermittent hypobaric hypoxia (IHH; 8 hours/day, 5 days/week, 5 weeks, ~ 7000 m) on the expression of total cPLA2α and its phosphorylated form (p-cPLA2α, Ser505 ), and further iPLA2 and sPLA2IIA, as well as signaling proteins activating cPLA2α enzyme...
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Genetic determination of cholesterolemia regulation
Vlachová, Miluše ; Kovář, Jan (advisor) ; Vrablík, Michal (referee) ; Kazdová, Ludmila (referee)
Most types of hypercholesterolemia are of polygenic origin. Some genes related to hypercholesterolemia are known, although all genes responsible for cholesterolemia regulation have not been characterised yet. To identify these new genes, animal models with spontaneous defects in cholesterol metabolism could be very useful. Moreover, a number of variations and polymorphisms have been found to influence blood cholesterol levels in humans. Some may also affect cholesterolemia responsiveness to dietary fat. The Prague hereditary hypercholesterolemic (PHHC) rat is a unique model of hypercholesterolemia induced by dietary cholesterol alone (without administration of cholic acid or thyrotoxic drugs). It exhibits modestly increased cholesterolemia when fed chow and responds to a diet containing cholesterol with a several-fold increase of cholesterolemia to concentrations comparable to those observed in hypercholesterolemic patients. Hypercholesterolemia in this model is characterised by accumulation of very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) enriched by cholesterol. In an experiment with tyloxapol (an inhibitor of lipoprotein lipase) we found that PHHC rats on a cholesterol diet incorporated twice as much cholesterol into VLDL as Wistar rats, although liver...
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Metabolism of fatty acids in pancreatic diseases
Macášek, Jaroslav ; Tvrzická, Eva (advisor) ; Stožický, František (referee) ; Kazdová, Ludmila (referee)
Introduction: Chronic pancreatitis (ChP) is a progressive inflammatory disorder characterized by the destruction of parenchyma that is replaced by fibrous tissue. Pancreatic cancer (PC) is a serious oncologic disease with poor prognosis. There is evidence that deregulation of fatty acid (FA) metabolism is connected with a number of diseases. We decided to analyze profile of FA in plasma lipid classes in patients with ChP, with 2 type diabetes mellitus (DM), with PC and healthy people. Pattern of FA is affected by many factors including starvation, dietary intake and various pathological states. The aim of the study was to analyze FA pattern in all lipid classes in all groups of patients, to elicit eventual deficiency of essential FA and to detect relationship between clinical or biochemical disturbances and FA profile. Material and methods: Patients with ChP (n= 39, 30/9 M/F), patients with ChP+DM (n=39, 30/9 M/F), patients with 2 type DM (n=38, 30/8 M/F) and healthy persons paired by the sex and age (n=39, 30/9 M/F) were included in the first group. Second group consisted of 84 patients with pancreatic adenocarcinoma (47/37 M/F) and 68 healthy volunteers (36/32 M/F). Anthropometric and biochemical parameters were examined by conventional methods. Profile of FA in plasma lipids was determined by...
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Importance of adipose tissue metabolism for whole-body energy balance
Zouhar, Petr ; Flachs, Pavel (advisor) ; Rossmeislová, Lenka (referee) ; Kazdová, Ludmila (referee)
Adipose tissue plays a crucial role in nutrient and energy homeostasis. At the time of worldwide pandemy of obesity and consequent metabolic syndrome, a great effort is made to find new treatments with potential to preserve insulin sensitivity, or even counteract development of obesity and type 2 diabetes. There are three principal possibilities how the adipose tissue biology can contribute to this goal: 1) induction of UCP1-dependent energy dissipation in brown adipose tissue; 2) conversion of white adipose depots to brown-like tissue (i.e. "browning"); and 3) stimulation of UCP1-independent thermogenesis in white adipose tissue. This thesis is based on two published works and one article under preparation. Generaly, it is focused on three different approaches targeting the above mentioned processes in adipose tissue of laboratory mouse: 1) diet supplementation with bile acids; 2) combination treatment of ω-3 polyunsaturated fatty acids and calorie restriction; and 3) cold exposure. In the experiments with administration of bile (specifically chenodeoxycholic) acid to mice, we confirm specific induction of UCP1 in both brown and subcutaneous white adipose tissue, as well as reversion of obesity in the response to the treatment. Nevertheless, most of the acute beneficial effects are mediated by...
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Interaction between adipocytes and immune cells in pathogenesis of obesity related pro-inflammatory state of adipose tissue
Mališová, Lucia ; Rossmeislová, Lenka (advisor) ; Flachs, Pavel (referee) ; Kazdová, Ludmila (referee)
Obesity is considered to be a worldwide epidemic disease characterized by an accumulation of AT. Increased adiposity can perturb normal metabolic functions and lead to the development of diseases like insulin resistance and other metabolic disorders. A large amount of clinical studies have been shown that changes in inflammatory signaling in adipose tissue cells, increased infiltration of immune cells into AT as well as stress of endoplasmic reticulum belong to the key molecular steps leading to the development of metabolic disturbances associated with this disease. Adverse metabolic effects of AT accumulation can be diminished by calorie restriction resulting in weight loss. In addition, stress of endoplasmic reticulum could be alleviated by chemical chaperones including bile acids. These two approaches for the treatment of obesity or the obesity-associated disturbances were basis for this PhD thesis. In the first part of this work, we studied inflammation status of gluteal in comparison with abdominal AT and differentiation and secretory capacity of adipocytes after weight loss in obese patients. We revealed that inflammatory profile of gluteal AT, estimated by mRNA level of macrophages and cytokines as markers of inflammatory status of the body, did not explain the different clinical impact of...
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Glutathion a glutathion dependentní enzymy za různých patofyziologických stavů.
Kodydková, Jana ; Tvrzická, Eva (advisor) ; Kazdová, Ludmila (referee) ; Vejražka, Martin (referee)
Backround: Oxidative stress (OS) has been implicated in pathogenesis of human disorders such as depressive disorder, sepsis, cardiovascular disease, acute and chronic pancreatitis, and cancer. Increased OS is result of imbalance between increased reactive oxygen and nitrogen species (RONS) production and / or insufficient activity of antioxidant defence system. Antioxidant system, which is composed of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidases (GPX), glutathione reductase (GR) and non- enzymatic antioxidant reduced glutathione (GSH) plays an important role in the protection of cells against enhanced OS. The aim of this study was to assess the OS markers and antioxidant enzymes in different pathophysiological states. Materials and methods: Activities of erythrocyte glutathione peroxidase (GPX1), GR and concentration of GSH as well as levels of OS markers were analysed in six different pathophysiologic states. These parameters were measured in 35 women with depressive disorder (DD), 40 patients with metabolic syndrome (MetS), 30 septic patients (S) followed up in the course of sepsis; 15 non-septic critically ill patients (NC), 13 patients with acute pancreatitis (AP), 50 with chronic pancreatitis (CP) and 50 patients with pancreatic cancer (PC), compared to...
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Possibilities to Influence Atherogenesis in Experimental Animal Models and Endothelial Cells
Stráský, Zbyněk ; Nachtigal, Petr (advisor) ; Blaha, Vladimír (referee) ; Kazdová, Ludmila (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Candidate: Mgr. Zbyněk Stráský Supervisor: Doc. PharmDr. Petr Nachtigal, Ph.D. Title of Doctoral Thesis: Possibilities to influence atherogenesis in experimental animal models and endothelial cells. This guided final thesis studied the Endoglin and Spirulina platensis in the process of atherosclerosis both in vivo and in vitro and their effects on specific pro- or anti-atherogenic markers, particularly with regard to the vascular endothelium. Endoglin (CD 105, TGF-β receptor III ENG) is a homodimeric membrane glycoprotein, which plays a regulatory role in TGFβ signaling. The relation between endoglin and endothelial NO synthase (eNOS) is essential for our study. Endoglin increases eNOS expression and promotes the production of NO, which affects the function of vascular endothelium. Changes in the expression of eNOS and endoglin could thus be associated with the development of endothelial dysfunction, a key step in atherogenesis. In our studies, we investigated the effects of cholesterol (1% cholesterol diet) and statins (atorvastatin) with respect to endoglin expression and soluble endoglin levels in a mouse model of atherosclerosis. Hypercholesterolemia increased levels of soluble...
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Regulation of adiponectin and its isoforms production in human obesity
Kováčová, Zuzana ; Štich, Vladimír (advisor) ; Hainer, Vojtěch (referee) ; Kazdová, Ludmila (referee) ; Rossmeisl, Martin (referee)
It is apparent that the imbalance in energy intake and expenditure coming hand-to-hand with the "westernisation" of our lifestyle leads to an elevated number of overweight and obese individuals that are commonly in a greater risk of developing chronic complications (e.g. insulin resistance, type 2 diabetes and cardiovascular diseases) with increased mortality. The development of obesity-related complications closely relate with dysfunction of adipose tissue leading to the peripheral insulin resistance and metabolic disruption of insulin sensitive organs (e.g. muscle, liver) subsequently inducing whole body insulin resistance. Since adipose tissue is the biggest endocrine organ in the human body producing many hormones influencing functions of adipose tissue itself or other organs, alteration of their spectrum has been revealed as one of the possible inductors or contributors disturbing body energy homeostasis. Adipose tissue serves as a major site for storage of surplus nutritions, however, long-term positive energy imbalance and high dose calorie intake lead not only to expansion of fat mass but mainly to the pathological changes of the tissue. In states of obesity, adipose tissue is under constant metabolic stress, resulting in the activation of the stress and inflammatory response. It leads to...
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