title: Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy.
abstract: Safety concerns have been raised over the extensive applications of silver nanoparticles (AgNPs) because nano dimensions make them highly bioactive, being potentially harmful to the exposed humans. Surface physico-chemistry (shape, surface charge, chemical composition, etc.) that mainly dictates nano-bio interactions is relevant for influencing their biocompatibility and toxicity. Although the hazardousness of AgNPs has been demonstrated in vitro and in vivo, mechanistic understanding of the toxicity particularly at the molecular and organismal levels, in addition to oxidative stress and silver ion dissolution, has remained unclear. A growing body of research has elucidated that autophagy, being activated in response to exposure to various nanomaterials, may serve as a cellular defense mechanism against nanotoxicity. Recently, autophagy activation was shown to correlate with AgNPs exposure; however, the subsequent autophagosome-lysosome fusion was defective. As autophagy plays a crucial role in selective removal of stress-mediated protein aggregates and injured organelles, AgNPs-induced autophagic flux defect may consequently lead to aggravated cytotoxic responses. Furthermore, we suggest that p62 accumulation resulting from defective autophagy may also potentially account for AgNPs cytotoxicity. Intriguingly, AgNPs have been shown to interfere with ubiquitin modifications, either via upregulating levels of enzymes participating in ubiquitination, or through impairing the biological reactivity of ubiquitin (due to formation of AgNPs-ubiquitin corona). Ubiquitination both confers selectivity to autophagy as well as modulates stabilization, activation, and trafficking of proteins involved in autophagic clearance pathways. In this regard, we offer a new perspective that interference of AgNPs with ubiquitination may account for AgNPs-induced defective autophagy and cytotoxic effects.
authors.affiliation: a Department of Environmental and Occupational Health , College of Medicine, National Cheng Kung University , Tainan City , Taiwan .|b Department of Physiology , College of Medicine, National Cheng Kung University , Tainan City , Taiwan ROC .
authors.forename: Bin-Hsu
authors.initials: BH
authors.lastname: Mao
authors.affiliation: c Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University , Tainan City , Taiwan ROC .
authors.forename: Jui-Chen
authors.initials: JC
authors.lastname: Tsai
authors.affiliation: d Institute of Labor, Occupational Safety and Health Ministry of Labor , Sijhih District, New Taipei City , Taiwan ROC .
authors.forename: Chun-Wan
authors.initials: CW
authors.lastname: Chen
authors.affiliation: b Department of Physiology , College of Medicine, National Cheng Kung University , Tainan City , Taiwan ROC .
authors.forename: Shian-Jang
authors.initials: SJ
authors.lastname: Yan
authors.affiliation: a Department of Environmental and Occupational Health , College of Medicine, National Cheng Kung University , Tainan City , Taiwan .|e Department of Biomedical Informatics , Asia University , Wufeng District, Taichung City , Taiwan ROC .|f Department of Medical Research , China Medical University Hospital , Taichung City , Taiwan ROC.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D004705:Endocytosis; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D012834:Silver / Q000737:chemistry / Q000633:toxicity*; D013499:Surface Properties
chemical_list: D012834:Silver
keywords: AgNPs-ubiquitin corona; blockade of autophagosome–lysosome fusion; selective autophagy