Lukiw Walter J, Pogue Aileen I
Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
J Inorg Biochem. 2007 Sep;101(9):1265-9. doi: 10.1016/j.jinorgbio.2007.06.004. Epub 2007 Jun 13.
Iron- and aluminum-sulfate together, at nanomolar concentrations, trigger the production of reactive oxygen species (ROS) in cultures of human brain cells. Previous studies have shown that following ROS induction, a family of pathogenic brain genes that promote inflammatory signalling, cellular apoptosis and brain cell death is significantly over-expressed. Notably, iron- and aluminum-sulfate induce genes in cultured human brain cells that exhibit expression patterns similar to those observed to be up-regulated in moderate- to late-stage Alzheimer's disease (AD). In this study we have extended our investigations to analyze the expression of micro RNA (miRNA) populations in iron- and aluminum-sulfate treated human neural cells in primary culture. The main finding was that these ROS-generating neurotoxic metal sulfates also up-regulate a specific set of miRNAs that includes miR-9, miR-125b and miR-128. Notably, these same miRNAs are up-regulated in AD brain. These findings further support the idea that iron- and aluminum-sulfates induce genotoxicity via a ROS-mediated up-regulation of specific regulatory elements and pathogenic genes that redirect brain cell fate towards progressive dysfunction and apoptotic cell death.
硫酸铁和硫酸铝共同作用，在纳摩尔浓度下可引发人脑细胞培养物中活性氧（ROS）的产生。先前的研究表明，在ROS诱导后，一类促进炎症信号传导、细胞凋亡和脑细胞死亡的致病性脑基因会显著过度表达。值得注意的是，硫酸铁和硫酸铝可在培养的人脑细胞中诱导出一些基因，这些基因的表达模式与在阿尔茨海默病（AD）中晚期观察到的上调模式相似。在本研究中，我们进一步扩展了研究范围，分析了原代培养的经硫酸铁和硫酸铝处理的人神经细胞中微小RNA（miRNA）群体的表达情况。主要发现是，这些产生ROS的神经毒性金属硫酸盐还上调了一组特定的miRNA，其中包括miR-9、miR-125b和miR-128。值得注意的是，在AD脑中这些相同的miRNA也会上调。这些发现进一步支持了以下观点：硫酸铁和硫酸铝通过ROS介导的特定调控元件和致病基因的上调来诱导基因毒性，从而使脑细胞命运转向进行性功能障碍和凋亡性细胞死亡。
