BACKGROUND: Olfactory dysfunction is a pathology associated with viral infections, toxic damage, aging, and neurodegenerative diseases. Damage to the olfactory epithelium impairs olfactory function and related neurological behaviors. This study evaluated the restorative effects of Scutellaria baicalensis Georgi (SBG) extract and baicalein in a methimazole-induced olfactory dysfunction model. METHODS: Olfactory epithelial damage was induced in mice with methimazole, followed by treatment with SBG extract or baicalein. Olfactory and neurobehavioral functions were assessed using odor-finding, novel object recognition (NOR), Morris water maze (MWM), open field (OFT), and elevated plus maze tests (EPM). Histological, immunohistochemical, and in vitro analyses were performed to evaluate epithelial regeneration, mature olfactory sensory neurons (OSNs) expressing olfactory marker protein (OMP), and proliferative activity. RESULTS: Methimazole induced severe olfactory epithelial damage, impairing olfactory behavior and reducing learning and memory. Treatment with SBG extract and baicalein significantly improved olfactory and cognitive functions. Histological and immunohistochemical analyses confirmed restoration of epithelial structure and olfactory neurons. In vitro, SBG extract increased epithelial cell density and modulated proliferative activity. CONCLUSIONS: SBG extract and baicalein promote recovery of olfactory function and improve neurobehavioral outcomes, indicating their potential as therapies for olfactory dysfunction.

BACKGROUND: Therapeutic resistance limits durable survival in advanced/metastatic renal cell carcinoma (RCC) treated with first-line tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI). We sought to define key resistance drivers and actionable targets. METHODS: Integrated RNA sequencing of cabozantinib-resistant RCC cells, lipid metabolomics, and PD-L1 correlation analyses identified ENPP2 as a candidate driver. Its role in TKI resistance and survival signaling was validated by apoptosis, CCK-8, and colony formation assays in vitro and by nude-mouse xenograft models in vivo. ELISA, flow cytometry and tumor cell-T-cell co-culture assays were used to dissect ENPP2-dependent CD8+ T-cell dysfunction. The therapeutic benefit of pharmacologic ATX inhibition combined with standard TKI-ICI regimens was tested in RCC patient-derived xenograft models. RESULTS: The ATX-LPA axis conferred TKI resistance via constitutive AKT/mTOR activation and promoted immune evasion by upregulating PD-L1 through TBK1/IRF3 signaling, thereby impairing intratumoral CD8+ T-cell function. ENPP2 enhanced PD-L1 transcription by facilitating IRF3 nuclear translocation and its direct recruitment to the CD274 promoter. ATX inhibition improved the antitumor efficacy of TKI-ICI therapy in preclinical models. CONCLUSIONS: Targeting the ATX-LPA axis represents a promising strategy to overcome resistance to current TKI-ICI combinations.

Mammalian hearing loss is typically permanent due to the inability to replace damaged cochlear hair cells. However, the neonatal mice inner ear demonstrates regenerative capacity, with cochlear floor cells proliferating and differentiating into organoids containing new hair cells and supporting cells, yet the governing molecular mechanisms remain poorly understood. Here, we isolated extracellular vesicles (EVs) from inner ear organoids at proliferation and differentiation stages, characterized their EV miRNA profiles through sequencing, and validated findings using public transcriptomic datasets to elucidate miRNA-mediated regulatory mechanisms during inner ear development. Inner ear organoids were successfully developed from cochlear duct cells, expressing otic progenitor marker SOX2 and hair cell marker Myo7A and demonstrating functional mechano-transduction activity through FM1-43 uptake. Small RNA sequencing identified 35 differentially expressed EV miRNAs between developmental stages. Integrated analysis with public transcriptome datasets revealed 18 genes with significant differential expression, leading to identification of three key regulatory genes—Trp53, Ezh2, and Zbtb4—that exhibited dynamic spatiotemporal expression during inner ear maturation. Pathway analysis demonstrated that these genes are associated with DNA Repair, P53, and Wnt/β-Catenin signaling with remarkable cell-type specificity. Our results demonstrate that EV miRNAs are temporally regulated during organoid development, with predominant downregulation during differentiation. These findings provide crucial insights into developmental mechanisms that could optimize organoid-based models and guide EV miRNA-based therapeutic strategies for hearing restoration.