Lead (Pb) exposure in children and adolescents poses a significant public health risk due to its potential neurotoxic effects. While high-level Pb exposure is known to impair learning and cognition, the behavioral and molecular consequences of low-level Pb exposure during developmental periods remain poorly understood. This study examined behavioral and neurochemical changes in mice exposed to Pb acetate exposure via drinking water from 4 to 8 weeks of age, corresponding to the juvenile through early adult developmental stages in mice. Mice exposed to 30 mg/L resulting in blood lead levels (BLLs) of 1.26 ± 0.089 µg/dL, while the 300 mg/L group, included as a neurotoxic reference, displayed BLLs exceeding 10 μg/dL. Behaviorally, exposure to 30 mg/L Pb did not affect locomotor activity, however, mice exposed to 300 mg/L exhibited hyperactivity and impaired nesting. Notably, impulsive and compulsive behaviors were significantly altered even at 30 mg/L. Neurochemically, qPCR and Western blotting analysis revealed downregulation of DOPA decarboxylase (Ddc), an enzyme crucial for dopamine synthesis, alongside decreased dopamine levels in the striatum. Pb exposure also disrupted striatal dopaminergic signals, including tyrosine hydroxylase (TH) and dopamine D2 receptors (D2R). These findings suggest that even low-level Pb exposure can lead to behavioral dysfunctions by disrupting striatal dopaminergic signaling, highlighting a previously underexplored mechanism of Pb neurotoxicity.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options and increasing global incidence, with a median survival of only 2–5 years. The clinical utility of macrophage polarization to regulate the progression of pulmonary fibrosis remains understudied. This study determined the efficacy of nintedanib and pexidartinib (PLX3397) combination therapy for treating IPF. Combination treatment effectively inhibited the progression of radiation-induced pulmonary fibrosis (RIPF) and prolonged survival in bleomycin-treated mice. Micro-CT analysis revealed a significant tissue repair efficacy. The therapy significantly normalized the abnormal vascular structure observed during RIPF and bleomycin-induced pulmonary fibrosis progression and was accompanied by a decrease in the M2 population. Polarized M1 macrophages enhanced normalized tube formation of irradiated endothelial cells (ECs) in vitro; M2 macrophages increased adhesion in irradiated ECs and abnormal tube formation. Single-cell RNA sequencing data from patients with IPF further supports colony stimulating factor (CSF) 1 upregulation in macrophages and downregulation of capillary EC markers. This study highlights a promising combination strategy to overcome the therapeutic limitations of monotherapy with nintedanib for the treatment of IPF.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3β at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the α-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3β inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3β-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD.