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Chronic lead (Pb) exposure causes neurodysfunction and contributes to the development of neurodegenerative disease. However, the mechanism of Pb-induced neurological dysfunction have yet to be fully elucidated. This study determined the role pyroptosis plays in Pb-induced neurodysfunction in neurons. We used both in vitro and in vivo approaches to explore whether Pb exposure induces caspase-1-mediated pyroptosis in neurons and its relationship to Pb-induced neurological disorders. Our findings showed that caspase-1-mediated pyroptosis in Pb-exposed neurons activated glycogen synthase kinase 3 protease activity by disrupting Ca2+/calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, leading to neurological disorders. Moreover, the caspase-1 inhibition VX-765 or the non-steroidal anti-inflammatory drug sodium para-aminosalicylic acid (PAS-Na) attenuated the Pb-induced neurological disorders by alleviating caspase-1 mediated neuronal pyroptosis. Our novel studies suggest that caspase-1-mediated pyroptosis in neurons represents a potential mechanism for Pb-induced neurodysfunction, identifying a putative target for attenuating the neurodegenerative effects induced by this metal. [Display omitted] • Pb induces pyroptosis in neurons. • Caspase-1 mediates neuronal pyroptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] Precise modulation of immuno-inflammatory response is crucial to control periodontal diseases and related systemic comorbidities. The present nanosystem with the controlled-release and cell-penetrating manner enhances the inflammation modulation effects of baicalein in human gingival epithelial cells (hGECs) for better oral healthcare. We constructed a red-emissive mesoporous silica nanoparticle-based nanosystem with cell-penetrating poly(disulfide) (CPD) capping, through a facile in-situ polymerization approach. It was featured with a glutathione-responsive manner and instant cellular internalization capacity for precisely delivering baicalein intracellularly. Laboratory experiments assessed whether and how the nanosystem per se with the delivered baicalein could modulate immuno-inflammatory responses in hGECs. The in-situ polymerized CPD layer capped the nanoparticles and yet controlled the release of baicalein in a glutathione-responsive manner. The CPD coating could facilitate cellular internalization of the nanosystem via endocytosis and thiol-mediated approaches. Notably, the intracellularly released baicalein effectively downregulated the expression of pro-inflammatory cytokines through inhibiting the NF-κB signaling pathway. The nanosystem per se could modulate immuno-inflammatory responses by passivating the cellular response to interlukin-1β. This study highlights that the as-synthesized nanosystem may serve as a novel multi-functional vehicle to modulate innate host response via targeting the NF-κB pathway for precision healthcare. [ABSTRACT FROM AUTHOR]