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Effect of lipophilic cation on the toxicity of phosphonium salts in parasitic protists
Čadková, Aneta ; Mach, Jan (advisor) ; Trnka, Jan (referee)
The mitochondrion is an essential organelle responsible for energy metabolism and maintaining cellular homeostasis. Disruption of their function can have serious consequences for the entire cell and organism. Given their key role in the organism, they become an attractive target for drugs. In this thesis, we examine the impact and significance of phosphonium salts as potential mitochondrial-targeted therapeutics. The investigated compounds have modified anchors based on the commonly used triphenylphosphonium cation (TPP+ ). These substances have the ability to permeate the phospholipid bilayer and accumulate on the inner mitochondrial membrane. Our research focuses on selected model organisms of the class Kinetoplastida and opportunistic pathogenic fungi. These pathogenic organisms are responsible for severe infectious diseases in humans. Our aim is to compare the effectiveness of phosphonium salts with different anchor modifications against these organisms and attempt to elucidate their mechanism of action. We have found that the modified salts are capable of inhibiting the growth of parasitic protists at nM concentrations, affecting mitochondrial respiration, membrane potential, and mitochondrial integrity. However, there is no increase in the level of oxygen radicals. We are assuming that the...
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Selective screening of antiparasitic substances
Wernerová, Klára ; Mach, Jan (advisor) ; Kovářová, Julie (referee)
The mitochondrion is the key organelle of the cell. It is involved in energy metabolism, the Krebs cycle, the respiratory chain, and the formation of Fe-S clusters, which form the structure of many proteins. Therefore, disruption of the mitochondria is usually fatal to the cell, especially if it contains only one mitochondrion, as is the case in Trypanosoma brucei brucei. The T. b. brucei parasite has become the primary model organism for our study because its basic biochemical processes are already well described, including mitochondrial metabolism, and it is also easy to cultivate in the laboratory. Other model organisms we used in this study were Leishmania mexicana, Cryptococcus neoformans and Candida albicans. All these organisms are causative agents of serious diseases, and although there are drugs against them, new drugs need to be developed due to the frequent emergence of resistances. Mitochondria-targeting drugs are promising for the pharmaceutical industry. In this work, we investigate the efficacy of compounds whose structure is composed of a mitochondrial phosphonium anchor linked to a carbon chain. These substances are capable of incorporation into the mitochondrial membranes. The work not only focuses on comparing the potency of the tested substances in selected model organisms, but...
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Use of RNAi and CRISPR systems in genetic modifications of parasitic protists
Kaiserová, Veronika ; Votýpka, Jan (advisor) ; Stojanovová, Darja (referee)
In organisms, RNA interference serves as a defence mechanism against foreign nucleic acids. RNAi has a negative effect on translation, via the binding of small non-coding molecules to the complementary region of mRNA, resulting in its degradation. CRISPR, a new method of genetic engineering, is based upon modulating genetic expression via creating double-stranded breaks in target DNA, aided by a ribonucleoprotein complex, consisting of the prokaryotic endonuclease Cas9 and sgRNA. Both of the aforementioned methods can be utilised in functional analysis of proteins and the characterisation of metabolic pathways in organisms of interest. This work summarises the current state of knowledge regarding RNAi and CRISPR and their use in genome editing of parasitic protists.
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Iron as a factor of virulence of parasitic protists
Glavanakovová, Marie ; Šuťák, Róbert (advisor) ; Smutná, Tamara (referee)
Iron is an essential nutrient for metabolism in almost all living organisms. Its importance for many crucial cellular processes originates primarily from the flexibility of available redox potentials. However, the high toxicity of free iron ions is well known. For most organisms, iron is simultaneously and paradoxically essential and toxic. Iron acquisition is crucial for parasitic organisms because it is needed for multiplication in hosts. Many studies have examined the relationship between iron availability and parasite development as a primary factor of virulence. These experiments commonly use chelators, chemical compounds that bind specifically and with high affinity iron ions, and are especially used for iron overload treatment. This thesis summarizes the influence of iron overload or deprivation in the host on the development of parasitic organisms and the impact of chelating agents on the virulence of selected parasitic protists, including the Plasmodium, Leishmania, Trypanosoma, Trichomonas and Tritrichomonas genuses.
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