a Department of Pharmacology , Shenyang Pharmaceutical University , Shenyang , P.R.China.
b Department of Pharmacy, The First Affiliated Hospital of College of Medicine , Zhejiang University , Hangzhou , P.R. China.
Nanotoxicology. 2019 Apr;13(3):369-391. doi: 10.1080/17435390.2018.1550226. Epub 2019 Feb 7.
Silver nanoparticles (AgNPs) are widely used for manufacturing products containing antibacterial agents, as well as food technologies such as edible films and food packaging. Routes of AgNPs exposure are principally derived by contacting with certain medical sprays, food, toothpaste, and purification products. Previously, we showed that AgNPs induce endoplasmic reticulum (ER) stress and promote apoptosis progression in SH-SY5Y cells; however, whether AgNP-induced ER stress is able to trigger autophagy in vivo and in vitro, and the role of autophagy in AgNP-induced cytotoxicity remain unclear. In the present study, we found that increased intracellular calcium (Ca) levels arising from AgNP-induced-ER stress resulted in activation of calmodulin-dependent protein kinase kinase β (CaMKKβ) and adenosine 5'-monophosphate-activated protein kinase (AMPK), which downregulated the level of mammalian target of rapamycin (mTOR) and upregulated Beclin-1 to activate autophagy in SH-SY5Y cells. Specifically, inhibition of autophagy by the addition of chloroquine (CQ) or silencing of Beclin-1 significantly enhanced the cytotoxicity of AgNPs, suggesting that autophagy plays a protective role in AgNP-induced cell apoptosis. Furthermore, we showed that oral administration of AgNPs for 28 continuous days induced ER stress-mediated apoptosis and autophagy in rats via activation of CaMKKβ and AMPK. In summary, this study is the first to report that AgNPs induce protective autophagy via a Ca/CaMKKβ/AMPK/mTOR pathway in vivo and in vitro. Therefore, public exposure to AgNPs should arouse concerns regarding environmental safety and human health. Highlight Silver nanoparticle-induced ER stress elicits protective autophagy via a Ca-dependent mechanism in SH-SY5Y cells. The Ca/CaMKKβ/AMPK/mTOR pathway is involved in autophagy. Orally administered silver nanoparticles induce ER stress-mediated autophagy and apoptosis in rats.
银纳米粒子（AgNPs）广泛用于制造含抗菌剂的产品，以及食品技术，如可食用薄膜和食品包装。AgNPs 的暴露途径主要来自于接触某些医疗喷雾、食品、牙膏和净化产品。之前，我们表明 AgNPs 在 SH-SY5Y 细胞中诱导内质网（ER）应激并促进细胞凋亡进展；然而，AgNP 诱导的 ER 应激是否能够在体内和体外引发自噬，以及自噬在 AgNP 诱导的细胞毒性中的作用尚不清楚。在本研究中，我们发现 AgNP 诱导的 ER 应激引起的细胞内钙离子（Ca）水平升高导致钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）和腺苷 5'-单磷酸激活蛋白激酶（AMPK）的激活，从而下调雷帕霉素哺乳动物靶标（mTOR）的水平并上调 Beclin-1 以激活 SH-SY5Y 细胞中的自噬。具体而言，通过添加氯喹（CQ）或沉默 Beclin-1 抑制自噬显著增强了 AgNPs 的细胞毒性，表明自噬在 AgNP 诱导的细胞凋亡中起保护作用。此外，我们表明，AgNPs 的口服给予 28 天连续诱导通过 CaMKKβ 和 AMPK 的激活导致大鼠 ER 应激介导的细胞凋亡和自噬。总之，这项研究首次报道了 AgNPs 通过体内和体外的 Ca/CaMKKβ/AMPK/mTOR 途径诱导保护性自噬。因此，公众对 AgNPs 的暴露应该引起对环境安全和人类健康的关注。
重点 AgNPs 通过 Ca 依赖性机制在 SH-SY5Y 细胞中诱导 ER 应激引发保护性自噬。Ca/CaMKKβ/AMPK/mTOR 途径参与自噬。口服给予银纳米粒子诱导大鼠 ER 应激介导的自噬和凋亡。
