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Epitranscriptomics and cardioprotective interventions
Benák, Daniel ; Hlaváčková, Markéta (advisor) ; Štengl, Milan (referee) ; Bohuslavová, Romana (referee)
1 Ischemic heart disease stands as the foremost global cause of mortality. Myocardial ischemia results in damage to cardiomyocytes which can further lead to impaired heart function. However, the extent of ischemic injury hinges not only on the intensity and duration of the ischemic stimulus but also on cardiac tolerance to ischemia. Therefore, it is extremely important to unravel the molecular basis of cardioprotective interventions such as adaptation to chronic hypoxia or fasting. We focused on the novel epitranscriptomic mechanisms around RNA modifications - N6 -methyladenosine (m6 A) and N6 ,2'-O-dimethyladenosine (m6 Am). Our findings revealed that while most epitranscriptomic modifiers displayed differential regulation in the heart following hypoxic adaptation and fasting, demethylases (ALKBH5 and FTO) were consistently upregulated after these cardioprotective interventions. Furthermore, we detected a discernible reduction in cardiac total RNA methylation levels after fasting. On the contrary, transcripts Nox4 and Hdac1, both of which play a role in the cytoprotective action of ketone bodies, exhibited increased methylation in hearts of fasting rats. Finally, inhibition of epitranscriptomic demethylases ALKBH5 and FTO decreased the hypoxic tolerance of adult rat primary cardiomyocytes isolated from...
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The m6A pathway at the molecular level and its role in neurological diseases
Švendová, Aneta ; Černá, Barbora (advisor) ; Čočková, Zuzana (referee)
N6-methyladenosine is the most abundant modification in eukaryotic messenger RNA. This modification is reversible, thanks to a complex of methyltransferases and demethylases. The biological effects of m6 A are mediated through reader proteins. This complex mechanism of proteins contributes to many molecular processes such splicing, translation and transport. It also plays a role in many serious neurological diseases, such as Alzeheimer's disease, Parkinson's disease, major depressive disorder and attention deficit hyperactivity disorder. The purpose of this thesis is to describe the m6 A pathway, its regulation at the molecular level and to put it into context with neurological diseases of today. Key words: mRNA, mRNA metabolism, N6-methyladenosine, m6 A regulation, FTO, METTL, ALKBH5, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, major depressive disorder, ADHD
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