title: Up-regulation of NF-kB-sensitive miRNA-125b and miRNA-146a in metal sulfate-stressed human astroglial (HAG) primary cell cultures.
abstract: Micro RNAs (miRNAs) constitute a unique class of small, non-coding ribonucleic acids (RNAs) that regulate gene expression at the post-transcriptional level. The presence of two inducible miRNAs, miRNA-125b and miRNA-146a, involved in respectively, astroglial cell proliferation and in the innate immune and inflammatory response, is significantly up-regulated in human neurological disorders including Alzheimer's disease (AD). In this study we analyzed abundances miRNA-125b and miRNA-146a in magnesium-, iron-, gallium, and aluminum-sulfate-stressed human-astroglial (HAG) cells, a structural and immune-responsive brain cell type. The combination of iron- plus aluminum-sulfate was found to be significantly synergistic in up-regulating reactive oxygen species (ROS) abundance, NF-кB-DNA binding and miRNA-125b and miRNA-146a expression. Treatment of metal-sulfate stressed HAG cells with the antioxidant phenyl butyl nitrone (PBN) or the NF-кB inhibitors curcumin, the metal chelator-anti-oxidant pyrollidine dithiocarbamate (PDTC), or the resveratrol analog CAY10512, abrogated both NF-кB signaling and induction of these miRNAs. Our observations further illustrate the potential of physiologically relevant amounts of aluminum and iron sulfates to synergistically up-regulate specific miRNAs known to contribute to AD-relevant pathogenetic mechanisms, and suggest that antioxidants or NF-кB inhibitors may be useful to quench metal-sulfate triggered genotoxicity.
authors.affiliation: Neuroscience Center, Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112 USA.
authors.forename: Aileen I
authors.initials: AI
authors.lastname: Pogue
authors.forename: Maire E
authors.initials: ME
authors.lastname: Percy
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Cui
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: James M
authors.initials: JM
authors.lastname: Hill
authors.forename: Theodore P A
authors.initials: TP
authors.lastname: Kruck
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Zhao
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Lukiw
mesh_terms: D000534:Alum Compounds / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000633:toxicity*; D005296:Ferrous Compounds / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000534:Alum Compounds; D003497:Cyclic N-Oxides; D004785:Environmental Pollutants; D005296:Ferrous Compounds; D016166:Free Radical Scavengers; D005904:Glial Fibrillary Acidic Protein; C531888:MIRN125 microRNA, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C041524:aluminum sulfate; C020748:ferrous sulfate; C029217:phenyl-N-tert-butylnitrone; D003474:Curcumin
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