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The role of toll-like receptors in the pathogenesis of liver diseases
Petrášek, Jan ; Jirsa, Milan (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Červinková, Zuzana (referee)
Identifikační záznam: PETRÁŠEK, Jan. ÚLOHA TOLL-LIKE RECEPTORŮ V PATOGENEZI JATERNÍCH ONEMOCNĚNÍ. [The role of toll-like receptors in the pathogenesis of liver diseases]. Praha, 2010. 198s., Disertační práce. Univerzita Karlova v Praze, 1. lékařská fakulta, Laboratoř Experimentální Hepatologie IKEM. Vedoucí práce: Milan Jirsa. Abstrakt Společným jmenovatelem nejčastějších onemocnění jater je aktivace mechanismů vrozené imunity, které přispívají k rozvoji zánětu a poškození jaterního parenchymu. Klíčovou úlohu v rozvoji jaterního poškození hrají Toll-like receptory, jejichž charakterizace v posledním desetiletí vedla přehodnocení patofyziologie některých jaterních onemocnění. Předkládaná práce studuje význam alelických variant v genech kódujících proteiny Toll-like receptorové signální kaskády a mezibuněčné signalizace v patogenezi alkoholické nemoci jater, přináší nový pohled na probiotika v léčbě nealkoholické steatohepatitidy a nové poznatky o protizánětlivém působení interferonů I. typu u některých jaterních chorob. Abstract Recent reports suggest that majority of chronic and acute liver diseases share a significant degree of liver inflammation and injury attributable to innate immunity, activated through Toll-like receptors. Detailed characterization of Toll-like receptor sigaling cascades in the last...
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The study of the changes of hepatocyte energy metabolism: the effect of oxidative stress and triiodthyronine
Endlicher, René ; Červinková, Zuzana (advisor) ; Kalous, Martin (referee) ; Rauchová, Hana (referee)
Changes of energy metabolism of hepatocytes: The effect of oxidative stress and triiodothyronine Liver is a vital organ performing numerous essential functions. Due to its position in the blood circulation, liver is the first organ incessantly exposed to a great number of toxic substances. Respiratory chain located in mitochondria is a frequent target of toxic action of these substances. There are various mechanisms that participate in hepatocyte damage, nevertheless the most important mechanism of hepatotoxic effect is oxidative stress induced by increased production of free radicals. Impact of oxidative stress on hepatocytes is very complex and still not fully elucidated. The aim of my thesis was to investigate the effect of oxidative stress on energy metabolism of rat hepatocytes using isolated hepatocytes and isolated mitochondria. We evaluated the effect of oxidative stress on the activity of mitochondrial enzymes and function of mitochondrial permeability transition pore (MPTP), respectively. Opening of this pore induces activation of apoptotic and necrotic processes. Our results document selective action of oxidative stress on the activity of various mitochondrial enzymes. Tert-butylhydroperoxide (t-BHP) causes significant inhibition of NADH-dependent substrates, while oxidation of...
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Pharmacological and metabolic influence on liver mitochondrial functions
Sobotka, Ondřej ; Červinková, Zuzana (advisor) ; Kuncová, Jitka (referee) ; Žurmanová, Jitka (referee)
Liver mitochondria play a crucial role in intermediary metabolism and main metabolic pathways. We evaluated the pharmacological effect on liver mitochondria in vitro using two novel anticancer drugs: 3-bromopyruvate and α-tocopheryl succinate. Metabolic influence on liver mitochondria was performed in vivo by high fat and high cholesterol diet. Toxicity of both drugs was evaluated in cell cultures of hepatocytes isolated from rat and mouse liver. The effect of anticancer drugs on liver mitochondrial functions in vitro was studied on suspensions of isolated liver mitochondria, tissue homogenate and permeabilized hepatocytes. Mitochondrial respiration was measured using high-resolution respirometry. 3-bromopyruvate caused morphological and functional damage of primary rat and mouse hepatocytes in cell cultures; this toxic effect was accompanied by an increase of reactive oxygen species production and mitochondrial dysfunction. 3-bromopyruvate decreased the oxygen consumption of mitochondria energized by substrates for complex I and complex II. α-Tocopheryl succinate caused a decrease of succinate-dependent respiration in all experimental models both in coupled and in uncoupled states. The most pronounced effect of α-tocopheryl succinate was apparent in isolated mitochondria and the least pronounced...
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Characterization of blackthorn products
Červinková, Zuzana ; Veselá, Mária (referee) ; Kovalčík, Adriána (advisor)
This bachelor thesis deals with the preparation and the chemical characterization of ethanolic extracts and products from the blackthorn (Prunus spinosa L.) fruit. The theoretical part of the work contains the characterization of the blackthorn and describes the chemical composition of the fruit. Furthermore, the theoretical part states possible effects and possible uses of the Prunus spinosa L. fruit in the food industry, folk medicine and pharmacy. The experimental part describes the preparation of the extracts (40% ethanol) and the products (i.e., homemade sloe wine and homemade blackthorn liqueur). The content of reducing sugars, polyphenols and flavonoids was quantified in samples of wine, liqueur, juice and ethanol extracts. Furthermore, the antioxidant activity of individual samples was determined. Two spectrophotometric methods for the determination of reducing sugars were used and compared, namely the Somogyi-Nelson (SN) assay and the 3,5-dinitrosalicylic acid (DNS) assay. The DNS assay provided slightly overestimated results, while the results from the SN assay were closer to the actual content of reducing sugars. Polyphenols and flavonoids are substances that have antioxidant properties. A strong correlation was observed between antioxidant activity and the concentration of flavonoids.
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Effect of Selected Pathological States on Mitochondrial Function in Mammalian Cells and Tissues
Kohoutová, Michaela ; Kuncová, Jitka (advisor) ; Červinková, Zuzana (referee) ; Ferko, Miroslav (referee)
Sepsis, or life-threatening organ dysfunction caused by deregulated host response to the presence of infection, is one of the most significant causes of death caused by infection diseases worldwide. 31.5 million patients get sick with sepsis annually and 5.3 million of them die. Sepsis is characterised by homeostatic dysbalance, which can lead to septic shock or even to death. Sepsis may also result in development of multiorgan dysfunction or damage to several organs at the same time. Especially heart, kidneys, liver, lungs, central nervous system and blood elements belong among the organs affected by sepsis. One of the most affected organs is the heart, impairment of which is accompanied with the development of myocardial depression, which contributes to the increase of mortality from sepsis. The precise mechanisms leading to septic myocardial depression have not been fully explained yet, nevertheless mitochondria appear to play an important role in this process. Due to sepsis, many mitochondrial functions are disrupted, which is subsequently manifested by the depletion of cellular energy stores, resulting in myocardial depression. In our laboratories, we managed to create a clinically relevant model of sepsis and septic shock, specifically sepsis caused by fecal peritonitis in domestic pigs, that...
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Functional characterisation of new components of mitochondrial proteome.
Kovalčíková, Jana ; Vrbacký, Marek (advisor) ; Červinková, Zuzana (referee) ; Ješina, Pavel (referee)
1 Abstract It has been estimated that the mammalian mitochondrial proteome consists of ~1500 distinct proteins and approximately one quarter of them is still not fully characterized. One of these proteins is TMEM70, protein involved in the biogenesis of the eukaryotic F1Fo-ATP synthase. TMEM70 mutations cause isolated deficiency of ATP synthase often resulting in a fatal neonatal mitochondrial encephalocardiomyopathies in patients. To understand the molecular mechanism of TMEM70 action, we generated constitutive Tmem70 knockout mice, which led to embryonic lethal phenotype with disturbed ATP synthase biogenesis. Subsequently generated inducible Tmem70 mouse knockout was lethal by the week 8 post induction. It exhibited primarily impaired liver function, which contrasts with the predominantly cardiologic phenotype at disease onset in humans. Liver mitochondria revealed formation of labile ATP synthase subcomplexes lacking subunit c. Thus, in case of TMEM70 deficiency c-oligomer was not incorporated into ATP synthase, which led to critical impairment of mitochondrial energy provision, analogous to TMEM70 dysfunction in humans. In TMEM70 deficient models, the ATP synthase deficiency reached the 'threshold' for its pathologic presentation, which we quantified at 30 %. We observed compensatory increases in the...
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Pharmacological and metabolic influence on liver mitochondrial functions
Sobotka, Ondřej ; Červinková, Zuzana (advisor) ; Kuncová, Jitka (referee) ; Žurmanová, Jitka (referee)
Liver mitochondria play a crucial role in intermediary metabolism and main metabolic pathways. We evaluated the pharmacological effect on liver mitochondria in vitro using two novel anticancer drugs: 3-bromopyruvate and α-tocopheryl succinate. Metabolic influence on liver mitochondria was performed in vivo by high fat and high cholesterol diet. Toxicity of both drugs was evaluated in cell cultures of hepatocytes isolated from rat and mouse liver. The effect of anticancer drugs on liver mitochondrial functions in vitro was studied on suspensions of isolated liver mitochondria, tissue homogenate and permeabilized hepatocytes. Mitochondrial respiration was measured using high-resolution respirometry. 3-bromopyruvate caused morphological and functional damage of primary rat and mouse hepatocytes in cell cultures; this toxic effect was accompanied by an increase of reactive oxygen species production and mitochondrial dysfunction. 3-bromopyruvate decreased the oxygen consumption of mitochondria energized by substrates for complex I and complex II. α-Tocopheryl succinate caused a decrease of succinate-dependent respiration in all experimental models both in coupled and in uncoupled states. The most pronounced effect of α-tocopheryl succinate was apparent in isolated mitochondria and the least pronounced...
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Liver regeneration after partial hepatectomy in rats suffering from non-alcoholic fatty liver disease
Garnol, Tomáš ; Červinková, Zuzana (advisor) ; Pantoflíček, Tomáš (referee) ; Šiller, Jiří (referee)
1. SUMMARY Liver regeneration after partial hepatectomy in rats suffering from non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) is currently the most frequent chronic liver disease in economically developed countries with prevalence of about 30 %. Liver resection from different reasons is nowadays common surgical procedure. Successful recovery and renewal of liver functions depend on regenerative capacity of liver remnant. The course of liver regeneration could be profoundly influenced by concomitant liver pathological processes including NAFLD. The aim of this work has been study of early phase of liver regeneration after partial hepatectomy (PHx) in rats with nutritionally induced simple steatosis. At the beginning we introduced a model of NAFLD by a high-fat diet giving to Wistar or Sprague-Dawley rats for 3 and 6 weeks, resp. This regimen induced simple steatosis without signs of inflammation, necrosis or fibrotic changes in both strains. In the second part of our study we followed if liver regeneration after PHx in rats with NAFLD is altered. Liver regeneration was assessed by bromodeoxyuridin incorporation into DNA of hepatocytes. Regeneration of liver with simple steatosis induced by 2/3 PHx was not significantly influenced in comparison to non-steatotic liver. The only...
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The US Supreme Court, its, formation and first key decisions
Červinková, Zuzana ; Seltenreich, Radim (advisor) ; Horák, Záboj (referee)
These days, the Supreme Court of the United States represents a very important and irreplaceable role in its home land: protection of constitutionality, explanation of federal laws, as well as appellate court of last resort within the framework of American courts. Today there is no doubt about its jurisdiction, but there were doubts. In the beginning of its existence no one was sure if the Court could overcome the initial obstacles which were in the way. This diploma thesis deals with the initial existence of the Supreme Court of the United States, its role within the framework of the US federal power system, and its progressive integration as equal with the legislative branch and executive power - The United States Congress and the President, respectively. The main objective of this thesis is to introduce the federal judiciary of the United States, show its differences from the continental system, and accentuate the importance of precedents. First, I focus on the history of the United States; colonization by British citizens, the American War for Independence, The Declaration of Independence, and the formation of American statehood in the 1780s, which resulted in the acceptance of one of the longest- lasting written constitutions in the world. After the historical excurse, the thesis focuses on...
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