Radiation therapy is widely used for cancer treatment; however, radioresistance remains a major obstacle, particularly in malignant melanoma. In this study, we investigated the effects of hypertonicity and activation of the mechanosensitive ion channel Piezo1 on the radiation response of B16 mouse melanoma cells. Hypertonic conditions significantly impaired radiation-induced DNA damage signaling and/or repair, as evidenced by reduced γH2AX and 53BP1 foci formation, and increased the number of unrepaired DNA damage sites at later time points. Consistently, hypertonicity enhanced radiation-induced reproductive cell death. These effects were attenuated by the Piezo1 inhibitor GsMTx4 and by Piezo1 knockdown, suggesting that Piezo1 partially mediates hypertonicity-induced radiosensitization. Pharmacological activation of Piezo1 using Yoda1 similarly impaired DNA damage responses and enhanced radiation-induced cell death. In addition, the combination of Yoda1 and irradiation significantly suppressed tumor growth in B16 melanoma-bearing mice. Collectively, these findings suggest that hypertonicity and activation of Piezo1 enhance the radiosensitivity of B16 melanoma cells, at least in part through impairment of DNA damage responses, and highlight Piezo1 as a potential target for improving radiotherapy efficacy.

Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is characterized by neuroinflammation and neurodegeneration. Both the innate and adaptive immune systems, with effector cells such as B and T lymphocytes, are critically involved in the pathogenesis of MS. Existing disease-modifying therapies have limited efficacy against progressive MS, and there is a strong need to identify new drug targets. Investigating how peripheral organs influence lymphocyte dynamics in the pathogenesis of MS may provide new insights for identifying novel therapeutic targets. The spleen is the largest secondary lymphoid organ with several immunological roles, including the activation of naïve CD4⁺ T cells. In this study, we investigated the contribution of the spleen to experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS, in splenectomized (SPX) mice. SPX mice exhibited more severe EAE symptoms and larger demyelinated areas than sham-operated controls. SPX mice showed enhanced T-helper type 1 (Th1) differentiation at the onset of the disease and increased activation of ionized calcium-binding adapter molecule 1 (Iba1)-immunopositive myeloid cells at the peak of the disease. Thus, we inferred that the spleen plays an important role in the pathology of EAE by regulating microglial activation and macrophage infiltration during the disease’s acute phase.

Area under the concentration–time curve (AUC)-guided dosing for vancomycin requires the measurement of both peak and trough concentrations. Recently, a novel population pharmacokinetic model (Bayesian-based, free-web application PAT version 4.0) was developed. The aim of the present study was to verify whether this optimized pharmacokinetic model improved the predictive accuracy of AUC calculated using trough-only data compared to data obtained using trough and peak sampling on Day 2. We conducted a single-center, cohort study to evaluate the agreement of AUC calculated using trough-only data compared to peak–trough sampling on Day 2, and to compare results obtained with the Yasuhara (previous) and Oda (updated) pharmacokinetic models. The proportion of trough/peak–trough AUC_24–48 ratios within a 5% difference was significantly higher with the Oda model than with the Yasuhara model (75 vs. 58.3%, p = 0.034). Furthermore, multivariate logistic regression analysis showed that implementation of the Oda model was a significant factor associated with deviation of trough/peak–trough AUC_24–48 within 5% (odds ratio 2.36, 95% confidence interval, 1.05–5.05, p = 0.027). The updated model offers enhanced predictive performance for AUC_24–48 estimation using trough-only data. Further development of strategies to improve the predictive accuracy of AUC_24–48 using trough-only data is warranted.

Cystic fibrosis (CF) airway disease is characterized by exaggerated inflammatory responses and progressive respiratory failure. Although interleukin-8 (IL-8) is a central mediator of neutrophilic inflammation in the CF airway, the upstream epithelial pathways that regulate cytokine production remain incompletely understood. Interleukin-17C (IL-17C) is an epithelial-derived IL-17 family cytokine that can promote inflammatory signaling in an autocrine/paracrine manner, but its regulation in CF-derived airway epithelial cells remains poorly defined. Here, we examined Toll-like receptor (TLR) ligand-induced IL-17C regulation in primary human airway epithelial cells derived from bronchial and small airway compartments, including normal human bronchial epithelial cells, CF-derived human bronchial epithelial cells, small airway epithelial cells (SAEC), and CF-derived SAEC (D-SAEC-CF). Among the ligands tested, polyinosinic–polycytidylic acid [poly(I:C)], a synthetic TLR3 ligand, consistently revealed differences in IL-17C and IL-8 induction between non-CF and CF-derived cells in both epithelial cell systems. Time-course analyses showed that poly(I:C)-induced IL-17C expression increased gradually and exhibited relatively delayed kinetics compared with the rapid interferon-β response, resembling IL-8 induction. Pharmacological inhibition indicated that c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB, but not extracellular signal-regulated kinase, were involved in poly(I:C)-induced IL-17C expression. Basal TLR3 and IL-17RE mRNA levels were elevated most clearly in D-SAEC-CF cells; however, IL-17RE knockdown did not significantly reduce poly(I:C)-induced IL-8 production in bronchial epithelial cells. Together, these findings suggest that poly(I:C)-induced IL-17C production may represent a TLR3-dependent epithelial inflammatory response in CF-derived primary airway epithelial cells.