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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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Mechanisms of action of bisphenol A with emphasis on metabolism and fertility
Houška, Jakub ; Daňková, Pavlína (advisor) ; Novák, Jan (referee)
Bisphenol A is an endocrine disruptor, a chemical which is found in environment and also in water and food consumed by people and which disrupts endocrine system of humans and other organisms. Being endocrine disruptor it has a wide scale of negative effects on human health. I have attempted reviewing the molecular mechanism of its action with special respect to obesity and reproduction in this paper including interactions of bisphenol with specific receptors, its impact on enzyme synthesis and also on epigenetic mechanisms as DNA methylation or changes in miRNA expression. Possible ways of elimination of bisphenol A effects are examined in the end of this work. Keywords bisphenol A, molecular mechanisms, obesity, fertility, receptor, epigenetic mechanisms, elimination of effects
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Autophagy as a key mediator of beneficial effects of caloric restriction
Kačinská, Irena ; Novotný, Jiří (advisor) ; Funda, Jiří (referee)
Caloric restriction has long been known in the scientific world as a life-prolonging condition, and there is growing evidence that the effect of activation of non-selective autophagy is responsible for these effects. In this thesis, the molecular mechanisms of autophagy in the state of caloric restriction will be described, as well as its beneficial effects on the aging of the organism and various health problems associated with aging and the modern way of life will be summarized. Some risks that could result from unprofessional intervention in one's own body will also be mentioned. It is hypothesized that practicing caloric restriction under the supervision of an expert brings prevention of diseases of civilization diseases and diseases associated with aging and prolongs quality of life, which would, among other things, help reduce the cost of health and social care. Keywords: Autophagy, caloric restriciton, molecular mechanisms
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Remote ischemic conditioning: principles and mechanisms
Chmelířová, Kateřina ; Novotný, Jiří (advisor) ; Vebr, Pavel (referee)
Ischemic remote conditioning is an experimental treatment method serving for the protection of heart (or other organs) against ischemia-reperfusion injury. In comparison with the regular conditioning, where the process is initiated by sequence of short ischemias performed directly on the target organ, protective function of the remote conditioning is activated via sequence of short ischemias and following reperfusions executed on a remote tissue - usually by strangulating an upper limb. Transmission of the signal from the remote organ to the target organ is mediated via neuronal and humoral routes. Method can be applied as pre-conditioning, before the presumed long-term ischemia, and per-conditioning, during long-term ischemia, or as post-conditioning after a long-term ischemia. It is quite safe, non- invasive, inexpensive and easily feasible method. This thesis describes the so far identified molecular mechanisms involved in the development of cardioprotection mediated by remote conditioning.
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