Duan Wei-Xia, He Min-Di, Mao Lin, Qian Feng-Hua, Li Yu-Ming, Pi Hui-Feng, Liu Chuan, Chen Chun-Hai, Lu Yong-Hui, Cao Zheng-Wang, Zhang Lei, Yu Zheng-Ping, Zhou Zhou
Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing 400038, People's Republic of China.
Toxicol Appl Pharmacol. 2015 Jul 15;286(2):80-91. doi: 10.1016/j.taap.2015.03.024. Epub 2015 Apr 1.
With application of nano-sized nickel-containing particles (Nano-Ni) expanding, the health concerns about their adverse effects on the pulmonary system are increasing. However, the mechanisms for the pulmonary toxicity of these materials remain unclear. In the present study, we focused on the impacts of NiO nanoparticles (NiONPs) on sirtuin1 (SIRT1), a NAD-dependent deacetylase, and investigated whether SIRT1 was involved in NiONPs-induced apoptosis. Although the NiONPs tended to agglomerate in fluid medium, they still entered into the human bronchial epithelial cells (BEAS-2B) and released Ni(2+) inside the cells. NiONPs at doses of 5, 10, and 20μg/cm(2) inhibited the cell viability. NiONPs' produced cytotoxicity was demonstrated through an apoptotic process, indicated by increased numbers of Annexin V positive cells and caspase-3 activation. The expression of SIRT1 was markedly down-regulated by the NiONPs, accompanied by the hyperacetylation of p53 (tumor protein 53) and overexpression of Bax (Bcl-2-associated X protein). However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs-induced apoptosis and activation of p53 and Bax. Our results suggest that the repression of SIRT1 may underlie the NiONPs-induced apoptosis via p53 hyperacetylation and subsequent Bax activation. Because SIRT1 participates in multiple biologic processes by deacetylation of dozens of substrates, this knowledge of the impact of NiONPs on SIRT1 may lead to an improved understanding of the toxic mechanisms of Nano-Ni and provide a molecular target to antagonize Nano-Ni toxicity.
随着纳米级含镍颗粒（Nano-Ni）应用范围的扩大，人们对其对肺部系统不良影响的健康担忧日益增加。然而，这些材料的肺毒性机制仍不清楚。在本研究中，我们聚焦于氧化镍纳米颗粒（NiONPs）对sirtuin1（SIRT1，一种NAD依赖性脱乙酰酶）的影响，并研究SIRT1是否参与NiONPs诱导的细胞凋亡。尽管NiONPs在液体介质中倾向于团聚，但它们仍可进入人支气管上皮细胞（BEAS-2B）并在细胞内释放Ni(2+)。5、10和20μg/cm(2)剂量的NiONPs抑制细胞活力。通过凋亡过程证明了NiONPs产生的细胞毒性，Annexin V阳性细胞数量增加和caspase-3激活表明了这一点。NiONPs显著下调SIRT1的表达，同时伴有p53（肿瘤蛋白53）的超乙酰化和Bax（Bcl-2相关X蛋白）的过表达。然而，通过白藜芦醇处理或转染过表达SIRT1可明显减轻NiONPs诱导的细胞凋亡以及p53和Bax的激活。我们的结果表明，SIRT1的抑制可能是NiONPs通过p53超乙酰化及随后的Bax激活诱导细胞凋亡的基础。由于SIRT1通过对数十种底物进行脱乙酰化参与多种生物学过程，了解NiONPs对SIRT1的影响可能有助于更好地理解Nano-Ni的毒性机制，并提供一个对抗Nano-Ni毒性的分子靶点。
