Meglumine acridone acetate, the ionic salt of CMA and N-methylglucamine, induces apoptosis in human PBMCs via the mitochondrial pathway
Marina A. Plotnikova , Sergey A. Klotchenko , Artem A. Kiselev , Andrey N. Gorshkov , Anna-Polina S. Shurygina , Kirill A. Vasilyev , Urszula Uciechowska-Kaczmarzyk , Sergey Samsonov , Alexey L. Kovalenko , Andrey V. Vasin
AbstractMeglumine acridone acetate (MA) is used in Russia for the treatment of influenza and other acute respiratory viral infections. It was assumed, until recently, that its antiviral effect was associated with its potential ability to induce type I interferon. Advanced studies, however, have shown the failure of 10-carboxymethyl-9-acridanone (CMA) to activate human STING. As such, MA’s antiviral properties are still undergoing clarification. To gain insight into MA’s mechanisms of action, we carried out RNA-sequencing analysis of global transcriptomes in MA-treated (MA+) human peripheral blood mononuclear cells (PBMCs). In response to treatment, approximately 1,223 genes were found to be differentially expressed, among which 464 and 759 were identified as either up- or down-regulated, respectively. To clarify the cellular and molecular processes taking place in MA+ cells, we performed a functional analysis of those genes. We have shown that evident MA subcellular localizations are: at the nuclear envelope; inside the nucleus; and diffusely in perinuclear cytoplasm. Postulating that MA may be a nuclear receptor agonist, we carried out docking simulations with PPARα and RORα ligand binding domains including prediction and molecular dynamics-based analysis of potential MA binding poses. Finally, we confirmed that MA treatment enhanced nuclear apoptosis in human PBMCs. The research presented here, in our view, indicates that: (i) MA activity is mediated by nuclear receptors; (ii) MA is a possible PPARα and/or RORα agonist; (iii) MA has an immunosuppressive effect; and (iv) MA induces apoptosis through the mitochondrial signaling pathway.
|Journal series||Scientific Reports, ISSN 2045-2322, (N/A 140 pkt)|
|Publication size in sheets||0.75|
|Keywords in English||meglumine acridone acetate, CMA, RNA-seq, intrinsic (mitochondrial) apoptosis pathway, immunosuppressive effect|
|License||Repository; published final; ; with publication|
|Score||= 140.0, 05-05-2020, ArticleFromJournal|
|Publication indicators||= 0.000; : 2016 = 1.401; : 2018 = 4.011 (2) - 2018=4.525 (5)|
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