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.

Patient-derived tumor organoids are widely used in cancer research, yet the biological impact of tissue processing during model generation remains unclear. Fragment-based and dissociation-based (DIS) approaches are commonly assumed to trade fidelity for uniformity, but their molecular consequences remain incompletely defined. To address this gap, we performed a proteome-wide comparison of fragment-based (cut-and-culture [CUT]) and DIS glioblastoma organoid protocols using quantitative mass spectrometry. Organoids from multiple patient tumors were cultured under growth factor-free or growth factor-supplemented conditions and compared with matched primary tissue. Results show that both protocols produced technically robust glioblastoma organoids when maintained in their native media. However, CUT organoids matched the reproducibility of DIS cultures while preserving a broader extracellular matrix (ECM) repertoire and networks linked to collagen assembly, vascular support, and cell-matrix signaling. DIS cultures were biased toward exogenous basement membrane components and proliferative, growth factor-responsive states. Across tumors, CUT organoids consistently showed greater proteomic similarity to matched primary tissue, retaining neural, glial, stromal, and extracellular features largely absent from DIS models. Taken together, fragment-based glioblastoma organoids can be both reproducible and biologically faithful. Tissue dissociation acts as a major perturbation that reshapes ECM organization, cellular states, and tumor identity, making protocol choice a critical determinant of model fidelity and translational relevance.