Biology subjects

Sebastijanovic, A.

Publications and source records attributed to Sebastijanovic, A..

3 recordsLinked to original sources

bioRxiv2024

Particulate matter constituents trigger the formation of extracellular amyloid beta and Tau-containing plaques and neurite shortening in vitro

IntroductionAir pollution is an environmental factor associated with Alzheimers disease, characterized by decreased cognitive abilities and memory. The limited models of sporadic Alzheimers disease fail to replicate all pathological hallmarks of the disease, making it challenging to uncover potential environmental causes. Environmentally driven models of Alzheimers disease are thus timely and necessary. MethodsWe used live-cell confocal fluorescent imaging combined with high-resolution stimulated emission depletion (STED) microscopy to follow the response of neuron-like cells to nanomaterial exposure. Here, we report that a high dose rate in vitro exposure of neuron-like cells to particulate matter constituents reproduces neurodegenerative phenotype, including extracellular amyloid-{beta} containing plaques and decreased neurite length. ResultsConsistent with the existing in vivo research, we observed detrimental effects, specifically a substantial reduction in neurite length and formation of amyloid beta plaques, after exposure to iron oxide and diesel exhaust particles. Conversely, after exposure to engineered cerium oxide nanoparticles, the lengths of neurites were maintained, and almost no extracellular amyloid beta plaques were formed. DiscussionAlthough the exact mechanism behind this effect remains to be explained, the high dose rate in vitro model, comprising wild-type neuron-like cells, could serve as an alternative environmentally driven model of Alzheimers disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/586796v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@63faf1org.highwire.dtl.DTLVardef@1eff3cdorg.highwire.dtl.DTLVardef@6f3365org.highwire.dtl.DTLVardef@973a78_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO High dose rate in vitro exposure of neuron-like cells to particulate matter constituents, like diesel exhaust and iron oxide nanoparticles, reproduces neurodegenerative phenotype, including extracellular amyloid--containing plaques and reduction in neurite length and density. C_FIG

pharmacology and toxicology↗

bioRxiv2024

Binucleated cell formation and oncogene expression after particulate matter exposure is preceded by microtubule disruption, dysregulated cell cycle, prolonged mitosis, and septin binding

Several biopersistent high aspect ratio nanomaterials show pronounced pathogenic effects, from chronic lung inflammation and fibrosis to cancer. For example, asbestos fibers are classified as carcinogens, whereas the carcinogenicity of highly inflammatory multi-wall carbon nanotubes (MWCNTs), and TiO2 nanomaterials is still being evaluated. The exact early mechanisms of their pathogenicity towards inflammation and cancer remains uncertain, but it is likely not due to genotoxic or mutagenic activity. A proposed early mode of action that might lead to the formation of cancerous cells for asbestos fibers is the formation of binucleated and multinucleated cells, resulting in genetic instability. Here, we show that two high aspect ratio nanomaterials, MWCNTs and TiO2 nanotubes, which both induce chronic lung inflammation, induce very different cancer-related changes in vitro. TiO2 nanotubes - but not low aspect-ratio nanocubes of the same crystalline structure - disrupt microtubule organization and prolong mitosis, as well as deform nuclear shape, induce the formation of binucleated cells, and downregulate the tumour suppressor protein p53, whereas only the MWCNTs activate the stimulator of the interferon genes (STING) pathway, a hallmark of lung cancer. The observed differences in cellular responses to different high aspect ratio materials imply the need for assessing each nanomaterial individually with a broad range of tests rather than relying solely on a single marker or pathway, or even morphological or bulk chemical properties to infer possible carcinogenic properties.

cancer biology↗

bioRxiv2020

Towards predictive nanotoxicology: from roundabout of molecular events to chronic inflammation prediction

Nanomaterial-induced diseases cannot be reliably predicted because of the lack of clearly identified causal relationships, in particular between acute exposures and chronic symptoms. By applying advanced microscopies and omics to in vitro and in vivo systems, together with in silico molecular modelling, we have here determined that the long-lasting response to a single exposure originates in the counteracting of a newly discovered nanomaterial quarantining and nanomaterial cycling among different lung cell types. This allows us to predict the nanomaterial-induced spectrum of lung inflammation using only in vitro measurements and in silico modelling. Besides its profound implications for cost-efficient animal-free predictive toxicology, our work also paves the way to a better mechanistic understanding of nanomaterial- induced cancer, fibrosis, and other chronic diseases.

molecular biology↗