Articles

• Medicines for influencing the posttranslational modifications of histones – a tutorial review

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  Miklós Bege

  Anikó Borbás

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  31

  Epigenetic therapy is a relatively novel, but undoubtedly a promising area of pharmacology. Most epigenetic drugs act by affecting enzymes and play a role in post-translational modifications of histones. The molecular targets of these medicines include histone methyltransferases, histone demethylases, isocitrate dehydrogenases, histone acetyltransferases and histone deacetylases. Since histone modifications are important regulatory signals, abnormalities in this process often lead to tumorigenesis, therefore these medicines constitute an important class of antitumor therapy. In this tutorial review, we would like to briefly overview the medicines that affect histone modifications, focusing on the currently approved ones, and briefly mention other interesting examples.

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• Toward synthesis of thioglycosyl-phosphonate analogues of lipid ll

  Viktor Kelemen

  Milán Csiszár

  Anikó Borbás

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  Although a multitude of epidemics have already been eradicated with the use of modern antibiotics, in the 20th century, a new and increasingly serious phenomenon has arisen - the resistance against antibiotic therapies, necessiting the need for the development of novel antibiotic compounds. Transglycosylases are key enzymes in the biosynthesis of the bacterial cell wall, and currently there is no approved drug in human use against them, so they are an excellent target for further antibiotic development. During our research, the main goal was to synthesize compounds that are structurally similar to lipid ll, the substrate of bacterial transglycosylases, however, with significant modifications, such as the incorporation of an α-thioglycosidic unit instead of the α-O-glycosidic bond and an alkylphosphonate unit instead of the pyrophosphate part, making the molecules suitable to act as enzyme inhibitors. The key step of our work is the stereoselective construction of the 1,2-cis-α-thioglycosidic bond by photoinitiated thiol ene coupling reaction. ln this paper, the novel synthesis route is described which can be applied to furnish different lipid ll analogues, on example synthesis of a D-glucose derivative.

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• The Role of KRAS in Macropinocytosis and its Implications of Multi-Drug Resistance in Cancer

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  Ferenc Fenyvesi

  Zeinab Ibrahim

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  KRAS is one of the most frequently mutated oncogenes in cancer and is involved in various tumorigenic processes. Among its diverse roles, KRAS mutations have been shown to upregulate macropinocytosis, a form of endocytosis that allows cells to engulf extracellular fluid and its contained solutes, subsequently supporting the increased need for cancer cells' growth and proliferation. The nutrient uptake function of macropinocytosis was initially described within the framework of KRAS-driven pancreatic tumors. Although constitutive macropinocytosis can be induced by activating mutations of proteins that are commonly found in cancer, KRAS-induced macropinocytosis constitutes a fundamental area of research due to the high occurrence of mutated KRAS in cancer (~1/3 of all cancers).  Furthermore, KRAS-mutated macropinocytosis not only contributes to tumorigenesis but also plays a critical role in developing resistance to treatments, as it was found to be implicated in Multi-Drug Resistance (MDR) in cancer cells. This mini-review aims to synthesize current knowledge of mechanisms of KRAS-mutated macropinocytosis briefly and examines the relationship between KRAS and macropinocytosis in the light of its role in cancer progression and drug resistance, highlighting therapeutic implications, targeting potential vulnerabilities and outlining clinical advancements in pertinent therapies.

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• To be or not to be manipulated by our bacteria?

  Marc LE BORGNE

  Marina Le Borgne

  Kézia Sossou-Echavidre

  Christine Janssen

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  8

  The gut microbiota has become a central focus of research since its intricate connection with the brain was identified. Notably, the gut microbiota can influence mental health, opening new prospects for improving the management of psychiatric disorders. Understanding the bidirectional interactions between the brain, gut, and microbiome is crucial for evaluating the true impact of gut microbiota on mental health and its subsequent implications for psychiatry. Currently, the brain-gut-microbiome axis communicates through five interconnected pathways: the immune system, the vagus nerve, the enteric nervous system, the neuroendocrine system, and the circulatory system. The development of microbiota-based therapeutics signals significant changes in current clinical practices. Furthermore, microbiome-based therapeutics are expected to undergo substantial regulatory transformations in Europe in the coming years. This mini-review aims to explore these aspects to evaluate the potential of gut bacteria to shape mental health interventions.

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