Zinc oxide nanoparticles effectively regulate autophagic cell death by activating autophagosome formation and interferin
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RESEARCH
Open Access
Zinc oxide nanoparticles effectively regulate autophagic cell death by activating autophagosome formation and interfering with their maturation Zixuan Liu, Xuying Lv, Lei Xu, Xuting Liu, Xiangyu Zhu, Erqun Song and Yang Song*
Abstract Background: With the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ZnO NPs neurotoxicity remain obscure. In an attempt to address concerns regarding neurotoxicity of ZnO NPs, we explored the relationship between free zinc ions, reactive oxygen species (ROS) and neurotoxic mechanisms in ZnO NPs-exposed PC12 cells. Result: This study demonstrated the requirement of free zinc ions shed by ZnO NPs to over generation of intracellular ROS. Next, we identified autophagic cell death was the major mode of cell death induced by ZnO NPs, and autophagosome accumulation resulted from not only induction of autophagy, but also blockade of autophagy flux. We concluded that autophagic cell death, resulting from zinc ions-ROS-c-Jun N-terminal kinase (JNK)-autophagy positive feedback loop and blockade of autophagosomal-lysosomal fusion, played a major role in the neurotoxicity of ZnO NPs. Conclusion: Our study contributes to a better understanding of the neurotoxicity of ZnO NPs and might be useful for designing and developing new biosafety nanoparticles in the future. Keywords: ZnO nanoparticles, Autophagic cell death, Autophagic flux, JNK, Autophagosomal-lysosomal fusion
Background Nanoparticles (NPs) have been widely used in recent years, and the global market for nanotechnology products was estimated to reach 64.2 billion in 2019. Zinc oxide nanoparticles (ZnO NPs) are one of the most abundantly used metal oxide NPs, and global annual output of ZnO NPs was estimated at 0.1–1.2 million tons [1]. Due to the optical properties that combine broad-spectrum UV filtering with transparency to visible light, ZnO NPs are widely formulated into sunscreens * Correspondence: [email protected] Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People’s Republic of China
[2]. ZnO NPs are also used for dental fillers [3] or food packaging materials to prevent bacterial contamination, because of their excellent antibacterial performance [4]. In addition, ZnO NPs have been utilized in semiconductors, coatings, and nanopiezotronics [5]. Although, the toxicities of ZnO NPs in mammalian organs, e.g. stomach, kidney, liver, spleen, and pancreas, have been widely studied [6], their potential hazardous effects on the central nervous system (CNS) are still limited. ZnO NPs may transfer to the CNS through blood brain barrier (BBB) [7], placental barrier [8], olfactory bulb or taste nerve pathways [9], leading to various neurotoxic effects. There are three inducers engaged in toxicity activities of ZnO NPs: the release of zinc io
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