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 (Ca2+) 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 Ca2+/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 Ca2+-dependent mechanism in SH-SY5Y cells. The Ca2+/CaMKKβ/AMPK/mTOR pathway is involved in autophagy. Orally administered silver nanoparticles induce ER stress-mediated autophagy and apoptosis in rats.

中文翻译：

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银纳米颗粒通过SH-SY5Y细胞和大鼠大脑中的Ca2 + /CaMKKβ/ AMPK / mTOR途径诱导保护性自噬。

银纳米颗粒（AgNPs）被广泛用于制造含有抗菌剂的产品，以及可食用薄膜和食品包装等食品技术。AgNPs暴露的途径主要是通过与某些医用喷雾剂，食品，牙膏和纯化产品接触而得出的。先前，我们表明AgNPs诱导内质网（ER）应激并促进SH-SY5Y细胞凋亡。然而，AgNP诱导的内质网应激是否能够在体内和体外触发自噬，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，我们发现由AgNP诱导的内质网应激引起的细胞内钙（Ca2 +）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'的激活。-单磷酸激活的蛋白激酶（AMPK），下调雷帕霉素（mTOR）的哺乳动物靶标水平，并上调Beclin-1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抑制自噬显着增强了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，我们表明连续28天口服AgNPs可通过激活CaMKKβ和AMPK诱导大鼠内质网应激介导的细胞凋亡和自噬。总而言之，这项研究是第一个报道AgNP在体内和体外通过Ca2 + /CaMKKβ/ AMPK / mTOR途径诱导保护性自噬的研究。因此，公众接触AgNPs应该引起人们对环境安全和人类健康的关注。突出显示银纳米颗粒诱导的内质网应激通过SH-SY5Y细胞中的Ca2 +依赖性机制引起保护性自噬。Ca2 + /CaMKKβ/ AMPK / mTOR途径参与自噬。口服银纳米颗粒诱导大鼠内质网应激介导的自噬和细胞凋亡。