PDF(Pubmed)
Abstract：
Manganese (Mn) is an essential heavy metal in the human body, while excess Mn leads to neurotoxicity, as observed in this study, where 100 µM of Mn was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to Mn exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at p < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate Mn-induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, Mn activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated Mn-losses of viability in SH-SY5Y cells. We discuss Mn as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. Mn induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc.
摘要：
锰(Mn)是人体必需的重金属,而过量的锰会导致神经毒性，正如在这项研究中观察到的那样，其中将100µM的Mn施用于神经退行性疾病中多巴胺能神经元的人类神经母细胞瘤（SH-SY5Y）细胞模型。我们定量了基于稳态细胞对Mn暴露的适应中的途径和基因变化。利用基因表达综合，我们访问GSE70845数据集作为Gandhi等人发表的SH-SY5Y细胞微阵列。(2018)，并在p<0.05时应用统计学意义截止。我们报告了74个通路和10个基因的变化具有统计学意义。ReactomeGSA分析表明，组蛋白（10个诱导基因中的5个）和组蛋白脱乙酰酶的上调是重塑/减轻Mn诱导的DNA/染色质损伤的神经保护性反应。神经退行性相关通路发生改变。NF-κB通过Sirtuin-1发出保护性反应信号以减轻神经炎症。严重的,Mn激活了嘌呤代谢缺陷的三种途径。因此,我们验证了尿酸盐，嘌呤和抗氧化剂，减轻SH-SY5Y细胞中Mn-活力的损失。我们讨论Mn作为HIF-1α的缺氧模拟物和反式激活剂，血管缺氧线粒体功能障碍的中枢反式激活剂。Mn诱导抗氧化剂金属硫蛋白III的mRNA水平增加3倍，缺氧模拟物去铁胺和锌诱导了100倍。
