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Molecular mechanisms of drug-induced liver injury (DILI)
Vašků, Markéta ; Smutný, Tomáš (advisor) ; Pávek, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Markéta Vašků Supervisor: PharmDr. Tomáš Smutný, Ph.D. Title of diploma thesis: Molecular mechanisms of drug-induced liver injury (DILI) Drug-induced liver injury is a common reason for halting the development of new drugs and has led to the withdrawal of several drugs from the market in the past. This diploma thesis aims to describe the molecular mechanisms responsible for drug hepatotoxicity and present both methods of preclinical and clinical testing of drugs to detect potential hepatotoxicity and examples of hepatotoxicity. Five mechanisms are currently known to cause DILI, namely mitochondrial damage, formation of reactive oxygen species, endoplasmic reticulum stress, lysosomal damage, inhibition of bile acid transport, and activation of the immune response. However, these mechanisms have not fully been explored yet and require further research. Unfortunately, even testing still falls short of perfection. Neither preclinical in vitro models nor animal models are completely satisfactory and cannot reliably detect DILI. The same applies to clinical testing. DILI is very complex and usually requires the interplay of multiple factors, which may not be reflected in clinical testing. Particulary,...
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Vplyv vybraných endokrinných disruptorov na metabolismus lipidov v pečeňových bunkových modeloch
Konopová, Veronika
Endocrine Disrupting Compounds (EDCs) are exogenous compounds that interfere with the endocrine system and consequently elicit toxic outcomes. One of their possible consequences in the organism is their negative impact on metabolic processes linked with development of metabolic diseases, including liver steatosis. In this research area, it is important to develop suitable in vitro cellular models. In this thesis, we evaluated the possibility of using of cell model of immortalized human hepatocytes, MIHA cell line, for detection of activation of nuclear receptors, PXR, LXRa a PPARa, which might be targeted by some EDC. We studied in particular the induction of expression of target genes of these receptors, CYP3A4, SCD, PDK4, CPTT1A, with the aim to compare the sensitivity of MIHA cells with a commonly used of liver cells, HepaRG cell line. The results showed that although some EDC (or model ligands of nuclear receptors) may induce the expression of target genes of nuclear receptors in MIHA cells, in general, this cell model appears to be less suitable for studying the impact of EDC than HepaRG cell line. The MIHA cell line, though, allows to study the compounds activating PPARa, which is an important regulator of metabolism of fatty acids in the liver tissue.
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Pharmacological perspectives and clinical benefits of SIRT1 and AMPK activators and inhibitors in inflammatory and oxidative stress in the liver
Njeka Wojnarová, Lea ; Kutinová Canová, Nikolina (advisor) ; Hodek, Petr (referee) ; Votava, Martin (referee)
Introduction: Liver diseases represent a significant cause of morbidity and mortality worldwide. Previous experimental studies have shown that polyphenolic compound, resveratrol, as a less specific activator of sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) can effectively attenuate acute liver injury. Although SIRT1 and AMPK have been widely studied for many years, further evidence for a mutual SIRT1/AMPK signaling mechanism and how it is modulated by drugs of small molecules had not been fully clarified at start of our experimental work. Goal: The main objective of the presented research was to investigate the relationship of SIRT1 and AMPK in process of hepatotoxicity/hepatoprotection in in vivo and in vitro animal model of acute drug-induced liver injury. Methods: Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by a single dose of D-Galactosamine (GalN)/lipopolysaccharide (LPS) or acetaminophen (APAP). Some rats and cultured hepatocytes were treated by resveratrol, synthetic selective activator or inhibitor of SIRT1 and AMPK. Biochemical markers of liver injury (aminotransaminases, total bilirubin), oxidative stress (nitrites) and lipid peroxidation (conjugated dienes, TBARS) were measured in the plasma, medium or liver homogenate. Liver...
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