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

Abstract

Meglumine 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.
Author Marina A. Plotnikova
Marina A. Plotnikova,,
-
, Sergey A. Klotchenko
Sergey A. Klotchenko,,
-
, Artem A. Kiselev
Artem A. Kiselev,,
-
, Andrey N. Gorshkov
Andrey N. Gorshkov,,
-
, Anna-Polina S. Shurygina
Anna-Polina S. Shurygina,,
-
, Kirill A. Vasilyev
Kirill A. Vasilyev,,
-
, Urszula Uciechowska-Kaczmarzyk (FCh/DTCh/LMM)
Urszula Uciechowska-Kaczmarzyk,,
- Laboratory of Molecular Modeling
, Sergey Samsonov (FCh/DTCh/LMM)
Sergey Samsonov,,
- Laboratory of Molecular Modeling
, Alexey L. Kovalenko
Alexey L. Kovalenko,,
-
, Andrey V. Vasin
Andrey V. Vasin,,
-
Journal seriesScientific Reports, ISSN 2045-2322, (N/A 140 pkt)
Issue year2019
Vol9
Pages1-16
Publication size in sheets0.75
Article number18240
Keywords in Englishmeglumine acridone acetate, CMA, RNA-seq, intrinsic (mitochondrial) apoptosis pathway, immunosuppressive effect
ASJC Classification1000 Multidisciplinary
DOIDOI:10.1038/s41598-019-54208-9
Languageen angielski
LicenseRepository; published final; Uznanie Autorstwa (CC-BY); with publication
File
Plotnikova_Marina_Meglumine_acridone_acetate_2019.pdf Plotnikova_Marina_Meglumine_acridone_acetate_2019.pdf 2,4 MB
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 05-05-2020, ArticleFromJournal
Publication indicators WoS Citations = 0.000; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.401; WoS Impact Factor: 2018 = 4.011 (2) - 2018=4.525 (5)
Citation count*
Cite
busy
Share Share

Get link to the record


* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
Back
Confirmation
Are you sure?