Biology subjects

Vogel, U.

Publications and source records attributed to Vogel, U..

6 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

Cell circuits underlying nanomaterial specific respiratory toxicology

Nanomaterials emerged as boundless resource of innovation, but their shape and biopersistence related to respiratory toxicology raise longstanding concerns. The development of predictive safety tests for inhaled nanomaterials, however, is hampered by limited understanding of cell type-specific responses. To advance this knowledge, we used single-cell RNA-sequencing to longitudinally analyze cellular perturbations in mice, caused by three carbonaceous nanomaterials of different shape and toxicity upon pulmonary delivery. Focusing on nanomaterial-specific dynamics of lung inflammation, we found persistent depletion of alveolar macrophages by fiber-shaped nanotubes. While only little involvement was observed for alveolar macrophages during the initiation phase, they emerged, together with infiltrating monocyte-derived macrophages, as decisive factors in shifting inflammation towards resolution for spherical nanomaterials, or chronic inflammation for fibers. Fibroblasts, central for fibrosis, sensed macrophage and epithelial signals and emerged as orchestrators of nanomaterial-induced inflammation. Thus, the mode of actions identified in this study will significantly inspire the precision of future in vitro testing. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/579746v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1d6f061org.highwire.dtl.DTLVardef@3fabb1org.highwire.dtl.DTLVardef@21040eorg.highwire.dtl.DTLVardef@1915c3b_HPS_FORMAT_FIGEXP M_FIG 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↗

bioRxiv2023

Pulmonary maternal immune activation does not extend through the placenta but leads to fetal metabolic adaptation

Maternal immune system activation (MIA) during pregnancy can disrupt the fetal environment, causing postnatal susceptibility to disorders. How the placenta and the fetus respond to acute MIA over time is unknown. Here, we characterized the response to acute maternal pulmonary inflammation across time in maternal and fetal organs using multi-omics. Unlike maternal organs which mounted strong innate immune responses, the placenta upregulated tissue-integrity genes, likely to prevent fetal exposure to infections, and downregulated growth-associated genes. Subsequently, the placenta upregulated biosynthesis and endoplasmic reticulum stress genes in order to return to homeostasis. These responses likely protected the fetus, since we observed no immune response in fetal liver. Instead, likely due to nutrient depletion, the fetal liver displayed metabolic adaptations, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. Our study shows, for the first time, the integrated temporal response to pulmonary MIA across maternal and fetal organs.

genomics↗

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↗

bioRxiv2018

Intake of red and processed meat, use of non-steroid anti-inflammatory drugs, genetic variants and risk of colorectal cancer; a prospective study of the Danish \"Diet, Cancer and Health\" cohort

Red and processed meat have been associated with increased risk of colorectal cancer (CRC), whereas long-term use of non-steroid anti-inflammatory drugs (NSAIDs) may reduce the risk. The aim was to investigate potential interactions between meat intake, NSAID use, and gene variants in fatty acid metabolism and NSAID pathways in relation to the risk of CRC. A nested case-cohort study of 1038 CRC cases and 1857 randomly selected participants from the Danish prospective \"Diet, Cancer and Health\" study encompassing 57,053 persons was performed using the Cox proportional hazard models. Gene variants in SLC25A20, PRKAB1, LPCAT1, PLA2G4A, ALOX5, PTGER3, TP53, CCAT2, TCF7L2, BCL2 were investigated. CCAT2 rs6983267 was associated with risk of CRC per se (p<0.01). Statistically significant interactions were found between intake of red and processed meat and CCAT2 rs6983267, TP53 rs1042522, LPCAT1 rs7737692, SLC25A20 rs7623023 (pinteraction=0.04, 0.04, 0.02, 0.03, respectively), and use of NSAID and alcohol intake and TP53 rs1042522 (pinteraction=0.04, 0.04, respectively) in relation to risk of CRC. No other consistent associations or interactions were found. This study replicated an association of CCAT2 rs6983267 with CRC and an interaction between TP53 rs1042522 and NSAID in relation to CRC. Interactions between genetic variants in fatty acid metabolism and NSAID pathway and intake of red and processed meat were found. Our results suggest that meat intake and NSAID use affect the same carcinogenic mechanisms. All new findings should be sought replicated in independent prospective studies. Future studies on the cancer-protective effects of aspirin/NSAID should include gene and meat assessments.\n\nAuthor SummaryIntake of red and processed meat has been associated with risk of cancer and in particular colorectal cancer. However, the underlying biological mechanisms are only incompletely understood. Gene-environment interaction analysis may be used for identifying underlying mechanisms for e.g. meat carcinogenesis. In this work, we have analyzed the interaction between the intake of red and processed meat, use of non-steroid anti-inflammatory drugs (including the anti-carcinogenic drug aspirin) and genetic variants. Our results suggest that meat intake and non-steroid anti-inflammatory drug use affect the same carcinogenic mechanisms. These results need to be replicated in other cohort studies with lifestyle information. If replicated, these results may have future implications for developing new strategies for preventing colorectal cancer and other cancers that share similar pathways.

genetics↗