AG-1478

Concerns that airborne micro- and nanoplastics (MNPs) may impair human respiratory health are rising. However, the specific effects of MNPs on allergic asthma remain insufficiently explored. This study developed an allergic asthma model using house dust mite (HDM), and mice were exposed to 50 μg polystyrene nanoparticles (PS-NPs) at three-days interval. Additionally, the effects and potential mechanisms of PS-NPs exposure (25, 50 and 100 μg/mL) on lung epithelial barrier dysfunction were explored using mouse lung epithelial type II (MLE-12) and A549 cells. The pathological changes of airway tissue and the increase of inflammatory response confirmed that exposure to PS-NPs significantly aggravated allergic asthma in mice. Importantly, in the presence of HDM sensitization, the accumulation of PS-NPs in the alveolar region was increased, leading to lung epithelial barrier dysfunction and more Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-13, immunoglobulin E (Ig E) and eosinophils. The activation of the epidermal growth factor receptor (EGFR) pathway and its downstream extracellular regulating kinase (ERK) was investigated using transcriptomic sequencing to elucidate the effects of PS-NPs exposure on lung epithelial barrier dysfunction. Furthermore, an EGFR-specific inhibitor AG1478 was employed to confirm the role of the EGFR/ERK pathway in lung epithelial barrier dysfunction and asthma exacerbation in vitro and in vivo experiments. In conclusion, the molecular mechanism by which PS-NPs aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PS-NPs and lays a theoretical foundation for addressing the health risks posed by PS-NPs.

Vertebrates vary greatly in their abilities to regenerate injured hearts. Zebrafish possess a remarkable capacity for cardiac regeneration, making them an excellent model for regeneration research. Recent studies have reported the activation and underlying regulatory mechanisms of leptin b (lepb) and the leptin b-linked enhancer (LEN) in injured hearts. However, the regenerative response activity of the leptin receptor (lepr) and its regulatory mechanisms still warrant further exploration.

We identified a novel lepr-linked enhancer (leprEnh) and generated a stable transgenic zebrafish line for validation. We also employed a genetic ventricle ablation system to elucidate the mechanisms governing its activation. Immunofluorescence, in situ hybridization and confocal imaging of larvae treated with various inhibitors during ventricle regeneration were performed.

Our results revealed that both lepr expression and leprEnh-directed EGFP fluorescence were weakly expressed in the ventricle during early heart development but displayed a sharp increase after ventricle ablation. Strong injury response activity was also observed in the atrium. Furthermore, the regeneration-responsive activity was attenuated by hemodynamic force alteration and was modulated by Notch, ErbB2 and BMP signaling pathways.

Our study sheds light on the regulation of lepr and leprEnh during heart regeneration and provide a basis for screening for novel therapeutic targets for myocardial infarction.