Kobe Pharmaceutical University

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is a central regulator of cellular defense mechanisms against oxidative stress. The pharmacological activation of this pathway has emerged as a promising strategy for the treatment of diseases such as neurodegeneration and inflammation. In this study, we performed a high-throughput luciferase reporter assay to screen the original compound library comprising small molecules synthesized at Kobe Pharmaceutical University. Initial screening identified KU-0016, KU-0017, and KU-0171 as moderate activators of the Nrf2 pathway. Furthermore, structural comparison revealed a common α,β-unsaturated imide motif, which led to the synthesis of KU-0017-based analogs for structure-activity relationship analysis. Among them, KU-0479 exhibited potent Nrf2 activation and low cytotoxicity. Further assays demonstrated that KU-0479 increased the intracellular glutathione (GSH) levels and protected cells from hydrogen peroxide-induced oxidative damage in a GSH-dependent manner. Moreover, LC-MS analysis confirmed the formation of mono-GSH adducts, and covalent docking simulations suggested covalent binding at the Cys151 residue of Keap1. These findings highlight KU-0479 as a synthetically accessible covalent Nrf2 activator with favorable redox-modulating properties and therapeutic potential.

To identify the postoperative mortality in patients requiring home oxygen therapy (HOT).

This descriptive study used a nationwide hospital-based database constructed by JMDC Inc. (Tokyo, Japan). Patients aged ≥ 18 years requiring HOT who underwent surgery between January 2014 and June 2022 were included. The study outcomes were in-hospital and 30-day postoperative mortality rates and other complications. We established a non-HOT group matched by age, sex, procedure, and surgical urgency for contrast and analyzed mortality in subgroups based on the reason for HOT, surgical department, and urgency.

Among the 3349 patients receiving HOT who underwent surgery, 293 (8.7%) in-hospital mortalities and 213 (6.4%) 30-day mortalities were reported. Postoperative pulmonary complications were observed in 359 (10.7%) patients, and 227 (6.8%) had non-respiratory complications. Furthermore, 123 (3.7%) in-hospital mortalities and 74 (2.2%) 30-day mortalities were also reported in the non-HOT group (3323 patients). The subgroup analysis indicated no significant differences in mortality or complications based on the reason for HOT. Higher mortality rates were reported in gastroenterology (9.3%), dermatology (14.7%), respiratory (11.8%), otolaryngology (36.5%), and neurosurgery (16.3%) departments. In-hospital and 30-day mortalities for emergency surgeries in the HOT group were 17.3 and 13.4%, respectively.

Among patients requiring HOT, in-hospital and 30-day mortalities were 8.7 and 6.4%, respectively. In addition, emergency surgeries may contribute to higher postoperative mortalities. Future research should identify specific mortality risk factors and develop perioperative management strategies to reduce these risks.

Oral cancers frequently metastasise to adjacent cervical lymph nodes (CLNs), leading to systemic dissemination and poor prognosis. Intranasal (i.n.) drug delivery provides direct access to cervical lymphatics, enabling high local drug concentrations while minimising systemic exposure. This study evaluated the pharmacokinetics (PK) and anti-metastatic efficacy of two vascular endothelial growth factor receptor (VEGFR)-3 inhibitors - cediranib maleate (CDNB) and pazopanib hydrochloride (PPNB) - administered i.n. in a mouse model of tongue cancer. Pharmacokinetic analysis showed that i.n. delivery yielded significantly higher CLN concentrations of both drugs than intravenous administration, despite lower plasma levels. In tumour-bearing mice, i.n. CDNB markedly reduced the incidence of CLN metastasis (0.167) versus controls (0.875, p < .01) and was more effective than intraperitoneal CDNB (0.571) or i.n. PPNB (0.500). Although less potent, PPNB significantly reduced the number of metastatic CLNs (0.438, p < .05). CDNB exhibited superior and more consistent efficacy. The reduced effect of PPNB may reflect its lower dose - limited by solubility - and possible differences in target specificity. These findings highlight the potential of i.n. administration to deliver VEGFR-3 inhibitors to CLNs, suppress lymphangiogenesis and lymphatic metastasis, and reduce systemic toxicity. This approach may offer a non-invasive alternative to neck dissection in oral cancer.