These are likely caused by variations in type, composition, size, shape, surface charge, and modifications of nanoparticles employed; use of various in vivo and in vitro models (the cell death mode may be also cell type dependent); experimental procedures (different methods to evaluate cell death; nanomaterials dose, concentrations and efficiency of cellular uptake, and time of exposure). This paper aims to give a critical overview concerning the different cell death modalities induced by nanomaterials. Figure 1 Deregulated cell death is a common element of several Inhibitors,research,lifescience,medical human

diseases, including cancer, stroke, and neurodegeneration, and the modulation of this cellular response can be an optimal target for an effective therapeutic strategy. Many cytotoxic agents are potent anticancer therapeutics, whereas cytoprotective compounds may be used to elude inhibitor Idelalisib unwanted cell death in the context of

stroke, myocardial infarction or neurodegenerative disorders [36, 37]. The complex molecular mechanisms and Inhibitors,research,lifescience,medical signalling pathways that control cell death are increasingly becoming understood, and it is now clear that different cell death subroutines play a critical role in multiple diseases. In many instances, the modality by which cells die is crucial to the cell death achievement at the organism level. The Nomenclature Committee on Cell Death (NCCD) has recently Inhibitors,research,lifescience,medical formulated a novel systematic classification of cell death based on morphological characteristics, measurable biochemical features and functional considerations [38]. We will consider Inhibitors,research,lifescience,medical these definitions of cell death in order to summarize and organize the molecular mechanisms underlying the nanomaterials toxicity. We could not report all the studies, and we apologize for this; we will describe the most recently, accurate, and representative ones in term of the described molecular mechanisms. 2. Nanomaterials and Apoptosis Apoptosis is a form of cellular suicide

that can be classified into Inhibitors,research,lifescience,medical extrinsic and intrinsic apoptosis. Extrinsic apoptosis indicates the cell death, caspase dependent, stimulated by extracellular stress signals that are sensed and propagated by specific transmembrane receptors. Three major lethal signalling cascades have been reported: (i) death receptor signalling and activation of the caspase-8 (or -10) and then caspase-3 cascade; (ii) death receptor Cilengitide signalling and activation of the caspase-8 then BH3-interacting domain death agonist (BID), mitochondrial outer membrane permeabilization (MOMP), caspase-9 and caspase-3 pathways; and (iii) ligand deprivation-induced dependence receptor signalling followed by (direct or MOMP-dependent) activation of the caspase-9 and after caspase-3 cascade [38]. Intrinsic apoptosis can be triggered by a plethora of intracellular stress conditions, such as DNA damage, oxidative stress, and many others.