Neuroscience Center, Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112 USA.
J Inorg Biochem. 2011 Nov;105(11):1434-7. doi: 10.1016/j.jinorgbio.2011.05.012. Epub 2011 May 27.
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.
微小 RNA（miRNA）是一类独特的非编码小 RNA，可在转录后水平调控基因表达。两种诱导型 miRNA（miRNA-125b 和 miRNA-146a）的存在分别涉及星形胶质细胞增殖以及固有免疫和炎症反应，在包括阿尔茨海默病（AD）在内的人类神经疾病中显著上调。在这项研究中，我们分析了镁、铁、镓和硫酸铝应激下人星形胶质细胞（HAG）中 miRNA-125b 和 miRNA-146a 的丰度，HAG 细胞是一种结构和免疫反应性脑细胞类型。发现铁加铝硫酸盐的组合在显著上调活性氧（ROS）丰度、NF-кB-DNA 结合以及 miRNA-125b 和 miRNA-146a 的表达方面具有显著协同作用。用抗氧化剂苯丁基硝酮（PBN）或 NF-кB 抑制剂姜黄素、金属螯合剂抗氧化剂吡咯烷二硫代氨基甲酸盐（PDTC）或白藜芦醇类似物 CAY10512 处理金属硫酸盐应激的 HAG 细胞，均可阻断 NF-кB 信号转导和这些 miRNA 的诱导。我们的观察结果进一步说明了生理相关量的铝和铁硫酸盐协同上调已知有助于 AD 相关发病机制的特定 miRNA 的潜力，并表明抗氧化剂或 NF-кB 抑制剂可能有助于抑制金属硫酸盐触发的遗传毒性。
