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The multinucleation effect of silicananoparticles (SiNPs) hadbeen determined in our previous studies, but the relative mechanismsof multinucleation and how the multinucleated cells are generatedwere still not clear. This extensional study was conducted to investigatethe mechanisms underlying the formation of multinucleated cells afterSiNPs exposure. We first investigated cellular multinucleation, thenperformed time-lapse confocal imaging to certify whether the multinucleatedcells resulted from cell fusion or abnormal cell division. Our resultsconfirmed for the first time that there are three patterns contributingto the SiNPs-induced multinucleation in HepG2 cells: cell fusion,karyokinesis without cytokinesis, and cytokinesis followed by fusion.The chromosomal passenger complex (CPC) deficiency and cell cyclearrest in G1/S and G2/M checkpoints may be responsible for the cellaberrant cytokinesis. The activated MAPK/ERK1/2 signaling and decreasedmitosis related proteins might be the underlying mechanism of cellcycle arrest and thus multinucleation. In summary, we confirmed thehypothesis that aberrant cytokinesis and cell fusion resulted in multinucleationin HepG2 cells after SiNPs exposure. Since cell fusion and multinucleationwere involved in genetic instability and tumor development, this studysuggests the potential ability of SiNPs to induce cellular geneticinstability. These findings raise concerns with regard to human healthhazards and environmental risks with SiNPs exposure. [ABSTRACT FROM AUTHOR]

Epidemiological studies demonstrate that fine particulate matter (PM2.5) promotes the development of atherosclerosis. However, the mechanism insight of PM2.5-induced atherosclerosis is still lacking. The aim of this study was to explore the biological effects of hypoxia-inducible factor 1a (HIF-1α) on PM2.5-triggered atherosclerosis. The vascular stiffness, carotid intima-media thickness (CIMT), lipid and atherosclerotic lesion were increased when von Hippel-Lindau (VHL)-null mice were exposed to PM2.5. Yet, knockout of HIF-1α markedly decreased the PM2.5-triggered atherosclerotic lesion. We firstly performed microarray analysis in PM2.5-treated bone morrowderived macrophages (BMDMs), which showed that PM2.5 significantly changed the genes expression patterns and affected biological processes such as phagocytosis, apoptotic cell clearance, cellular response to hypoxia, apoptotic process and inflammatory response. Moreover, the data showed knockout of HIF-1α remarkably relieved PM2.5-induced defective efferocytosis. Mechanistically, PM2.5 inhibited the level of genes and proteins of efferocytosis receptor c-Mer tyrosine kinase (MerTK), especially in VHL-null BMDMs. In addition, PM2.5 increased the genes and proteins of a disintegrin and metallopeptidase domain 17 (ADAM17), which caused the MerTK cleavage to form soluble MerTK (sMer) in plasma and cellular supernatant. The sMer was significantly up-regulated in plasma of VHL-null PM2.5-exposed mice. Moreover, PM2.5 could induce defective efferocytosis and activate inflammatory response through MerTK/IFNAR1/STAT1 signaling pathway in macrophages. Our results demonstrate that PM2.5 could induce defective efferocytosis and inflammation by activating HIF-1α in macrophages, ultimately resulting in accelerating atherosclerotic lesion formation and development. Our data suggest HIF-1α in macrophages might be a potential target for PM2.5-related atherosclerosis. [ABSTRACT FROM AUTHOR]