Ultrasound has attracted considerable attention not only as a diagnostic imaging modality but also as a physical trigger for drug delivery system (DDS). Ultrasound irradiation applied in combination with gas-filled bubbles can induce cavitation and transiently increase the permeability of cellular membranes, thereby enhancing the intracellular delivery of therapeutic molecules. Our research group has developed ultrasound-responsive gas-containing lipid nanoparticles, initially termed bubble liposomes (BLs) and later referred to as nanobubbles (NBs), as carriers for nucleic acid delivery. Early studies indicated that BLs facilitated the efficient cytoplasmic delivery of small interfering RNA under ultrasound irradiation. Subsequent investigations expanded the platform to include diverse nucleic acids, including plasmid DNA and microRNA, and revealed therapeutic efficacy in disease models such as hindlimb ischemia. Further developments include strategies for brain-targeted gene delivery mediated via blood–brain barrier modulation and the design of stable anionic NBs with the capacity to load nucleic acids via cationic intermediates. More recently, polysaccharide-coated NBs and microfluidic preparatory methods have been assessed with a view to improving delivery performance and particle uniformity. These advances highlight the potential utility of nucleic acid-loaded NBs as theranostic platforms for the integration of ultrasound imaging and gene delivery. The continued development of this technology may contribute to the advancement of next-generation ultrasound-mediated DDS.

The optimization of infectious disease treatment requires a multilevel perspective linking individualized pharmacotherapy with population-level evaluation. Clinical questions arising from bedside practices provide a starting point to improve treatment via therapeutic drug monitoring, pharmacogenomics, and pathophysiology-based dose optimization. For example, patient-specific factors, such as hepatic dysfunction and CYP3A5 genotype, substantially influence drug exposure and infection risk in transplant recipients. However, patient-level optimization alone is insufficient to determine whether antimicrobial therapy is practiced appropriately across institutions, regions, or healthcare systems. Therefore, antimicrobial surveillance systems are critical for quantifying antimicrobial use using standardized metrics and providing a measurable foundation for stewardship. In Japan, nationwide surveillance studies have enabled quantitative assessment of antimicrobial consumption and resistance patterns at both hospital and national levels. Furthermore, the increasing availability of large healthcare databases, including administrative claims data and pharmacy dispensing information, has expanded the scope of evaluation to prescribing behavior, guideline adherence, stewardship interventions, and impacts of healthcare policies. These developments allow antimicrobial stewardship to be assessed at both individual institution and national healthcare system levels. In this evolving landscape, clinical pharmacists are uniquely positioned to contribute to both individualized therapy and broader evidence generation. This review builds on our accumulated research findings and discusses how bedside clinical questions can be extended to surveillance infrastructure and big data analysis, thereby linking patient care to health policies and public health strategies against antimicrobial resistance.

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.

Hot flashes are a common vasomotor symptom (VMS) experienced by postmenopausal women. In rodents, VMS-like symptoms can be assessed by monitoring tail skin temperature (TST), which reflects thermoregulatory changes. However, because the TST is highly sensitive to handling and environmental stresses, a reliable assessment requires continuous monitoring under low-stress and unrestrained conditions. In this study, we established a monitoring system for aged Wistar rats and evaluated hot flash-like symptoms using a within-subjects design across four physiological states: intact, ovariectomized (OVX), 17β-estradiol (E2) treatment, and E2 withdrawal. E2 treatment significantly decreased dark-phase TST (26.63 ± 0.26°C) compared with OVX (29.39 ± 0.18°C), and this effect was reversed upon pellet removal. We also quantified ΔTST, defined as the difference between light- and dark-phase TST, and found that E2 treatment markedly increased ΔTST, indicating an estrogen-dependent restoration of circadian TST amplitude. Because aged rats exhibit irregular estrous cycles and reduced ovarian steroidogenesis, yet remain underutilized in VMS research, this model provides a physiologically relevant platform for studying menopausal vasomotor dysfunction. By repeatedly monitoring the same individuals, inter-individual variability is minimized and reliable detection of within-subject changes is achieved with a small number of animals. These findings demonstrate that our method enables reliable long-term TST monitoring under unrestrained conditions and offers a practical and validated approach for investigating the pathophysiology of menopausal vasomotor dysfunction and for screening candidate compounds targeting hot flash-like symptoms in rodents.

In addition to the 23-valent pneumococcal polysaccharide vaccine (PPSV23), the 13-valent and 15-valent pneumococcal conjugate vaccines (PCV13 and PCV15, respectively) are currently utilized as optional vaccines for adults. Although PCV15 provides broader serotype coverage than PCV13, comparative evidence regarding their immunogenicity, safety, and optimal clinical application remains limited. This systematic review and meta-analysis evaluated the immunogenicity and safety of PCV13 and PCV15, both as monotherapy and in combination with PPSV23. We conducted a comprehensive systematic search of PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) published through September 15, 2023. Eligible studies included those comparing PCV13 and PCV15, as well as their respective sequential schedules with PPSV23, in adults. Outcomes included opsonophagocytic activity geometric mean titer ratios (OPA GMTRs), immunoglobulin G geometric mean concentration ratios (IgG GMCRs), and adverse event incidence. Risk ratios and 95% confidence intervals were calculated using the inverse variance–weighted method and DerSimonian–Laird random-effects model. Six RCTs (n = 6460) comparing PCV13 and PCV15 monotherapy demonstrated significantly higher OPA GMTRs and IgG GMCRs for the six shared serotypes in the PCV15 group. Injection-site pain and myalgia were more common with PCV15, whereas other adverse events showed no differences. Three RCTs (n = 2279) comparing PPSV23/PCV13 with PPSV23/PCV15 demonstrated higher immune responses for several serotypes in the PPSV23/PCV15 group, with comparable safety profiles. Overall, PCV15 provides broader serotype coverage and elicits robust immunogenicity while maintaining a safety profile comparable to that of PCV13, whether administered as monotherapy or in sequential vaccination with PPSV23.

Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor kappa B ligand, can cause hypocalcemia, necessitating calcium and vitamin D supplementation, and serum calcium monitoring. We examined the effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on denosumab-induced hypocalcemia. Data were collected from Fukuoka University Hospital between January 1, 2018, and March 31, 2023. Data of patients who were prescribed denosumab were extracted and categorized into three groups: denosumab monotherapy, denosumab + PPI, and denosumab + H2RA. Each group was followed up for 30 d after initial administration. Data from 335 patients were analyzed, which revealed a higher incidence of hypocalcemia with PPIs (37/129 patients, 28.7%) and H2RAs (6/14 patients, 42.9%) than with denosumab monotherapy (34/192 patients, 17.7%). A Cox regression analysis indicated a significantly higher risk of hypocalcemia with PPIs (hazard ratio [HR] = 1.78, 95% confidence interval [CI]: 1.12–2.84) and H2RAs (HR = 2.94, 95% CI: 1.23–7.00) than with denosumab monotherapy. This study highlights the need for careful monitoring of serum calcium levels when denosumab is combined with gastric acid suppressants in patients treated with PPIs or H2RAs.

Intracerebral hemorrhage (ICH) is a lethal stroke subtype characterized by secondary injury resulting from pathological intracellular Ca²⁺ signaling. Bioactive molecules such as ATP and thrombin activate multiple receptor subtypes. Thus, targeting a common downstream molecular mechanism may be more effective than inhibiting individual receptors. One potential candidate is transient receptor potential canonical 3 (TRPC3), a Ca²⁺-permeable nonselective cation channel activated via Gq/phospholipase C signaling. However, its role in ICH remains unclear. Thus, this study aimed to investigate the role of TRPC3 in neurological dysfunction after ICH by using TRPC3 knockout (KO) mice and astrocyte-specific knockdown approaches. The TRPC3-KO mice exhibited significantly lower neurological deficit scores and performed better on the rotarod test than the wild-type mice at 1 and 3 d after ICH, suggesting that TRPC3 plays a critical role in functional impairment. However, the astrocyte-specific knockdown of TRPC3 using an adeno-associated virus vector did not significantly improve neurological dysfunction. These results indicate that TRPC3 contributes to neurological dysfunction after ICH, but that its pathological role cannot be explained by astrocytic TRPC3 alone, indicating the involvement of multiple cell types. In conclusion, TRPC3 is a key channel involved in neurological dysfunction after ICH, suggesting that targeting TRPC3 may provide a new therapeutic strategy for attenuation of neurological dysfunction after ICH.

Voriconazole (VRCZ) exhibits highly variable pharmacokinetics. Although CYP2C19 poor metabolizers are common in Japan, routine genetic testing is rarely performed in daily clinical practice. Consequently, existing population pharmacokinetic (Pop-PK) models that lack genetic data require external validation in Japanese clinical settings. This study aimed to identify the most accurate nongenetic Pop-PK model for this population and elucidate the factors influencing prediction errors. We retrospectively analyzed 174 adult inpatients who received VRCZ within the first 14 d of therapy. Eight Pop-PK models were evaluated using prediction error metrics and specific clinical criteria. For the best-performing model, normalized prediction distribution error (NPDE) analysis was conducted. Subsequently, a classification and regression tree (CART) analysis with leave-one-out cross-validation (LOOCV) was performed to identify factors associated with prediction accuracy. Model H, incorporating the albumin–bilirubin (ALBI) score, performed best (relative root mean square error 2.97, criteria 33.91%, median prediction error (MDPE) −29.06%). However, NPDE analysis (mean 0.774, variance 2.394) revealed residual systematic underprediction and substantial unmodeled variability. CART analysis identified C-reactive protein (CRP) as the primary determinant of accuracy. While the best model (age, platelet count, serum creatinine, and CRP) achieved a training accuracy of 69.5%, internal validation via LOOCV yielded an accuracy of 56.9% and a multi-class area under the receiver operating characteristic curve of 0.568. While the ALBI-score–based Model H is the most accurate, predictions remain limited in high-inflammation states due to inherent stochastic variability. Stratifying patients by baseline CRP level is crucial for optimizing the initial VRCZ dosing.

Prolonged or high-dose administration of nonsteroidal anti-inflammatory drugs (NSAIDs) can induce gastric mucosal injury (GMI), potentially progressing to gastric ulcer (GU). Studies have shown that oxidative stress and necroptosis were closely associated with GU. Vladimiria souliei, a traditional Chinese herb, has been used to treat digestive disorders, particularly GU, but its pharmacological mechanisms remain unidentified. This study aimed to investigate the pharmacological mechanisms of GMI treatment in this herb. Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to analyze blood-enterable components. Aspirin (ASP) was orally administered to induce GMI in mice. After intervention with Vladimiria souliei extract (VSE), the morphology of gastric tissues was observed, and the levels of pepsin and prostaglandin E2 (PGE2) were detected. Further therapeutic evaluation of VSE in GMI was performed using hematoxylin and eosin (H&E) and periodic acid-schif (PAS) staining. Serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were measured, while immunohistochemistry and Western blot were used to assess nuclear factor erythroid 2-related factor 2 (Nrf2) and receptor interacting protein kinase 1 (RIP1)-related signaling. Six prototype components were identified in the drug-containing serum of the VSE. Moreover, VSE mitigated ASP-induced GMI with shrunken areas of ulcers and promoted gastric mucin secretion, increased the levels of SOD and PGE2, and decreased the levels of pepsin, MDA, IL-1β, IL-6, and TNF-α. Pharmacological studies revealed that VSE upregulated the expression of Nrf2, NAD (P) H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1) and down-regulated the expression of kelch-like ECH-associated protein-1 (Keap1), RIP1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphoglycerate mutase 5 (PGAM5), and dynamin-related protein 1 (Drp1) in the gastric mucosa. Therefore, VSE alleviated oxidative stress and necroptosis by regulating Nrf2 and RIP1 signaling in ASP-induced GMI mice, providing a theoretical basis for GU treatment and for the development of medicinal resources with this herb.

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.

Cisplatin (cis-diammineplatinum (II) dichloride [CDDP]) induces acute kidney injury (AKI), and repeated dosing may lead to incomplete recovery and progression to chronic kidney disease (CKD). However, the quantitative dynamics underlying the AKI-to-CKD transition remain unclear. This study aimed to develop a mathematical model to characterize the CDDP-induced AKI-to-CKD transition during repeated administration. Rats received three cycles of CDDP at 21-d intervals under different dosing regimens, but with an identical cumulative dose (9 mg/kg). Plasma creatinine (Cr) was measured longitudinally as a marker of renal function, and values from Days 15 to 21 after each dosing cycle were used to evaluate the extent of recovery following AKI. A toxicodynamic model based on Cr mass balance was developed. The model incorporated a Hill-type function to describe CDDP-induced toxic effects and evaluated alternative structural assumptions in which toxicity progression across cycles was modeled as either additive or multiplicative. Renal function progressively decreased in a dose-dependent manner across cycles. Although Cr profiles differed among regimens during individual cycles, Cr levels converged by the end of the third cycle. The additive toxicity model, in which CDDP accumulates in a virtual kidney compartment and the toxic signal decays slowly (half-life: 79 d), best described the data (CDDP dose per body weight producing 50% inhibition: 5.11 mg/kg). To our knowledge, this study presents the first mathematical model describing the dynamics of the AKI-to-CKD transition following repeated CDDP administration. The proposed modeling approach may facilitate prediction of the AKI-to-CKD transition and support the optimization of safer CDDP treatment strategies.

The environmental and human health implications of microplastics (MPs) and nanoplastics (NPs) have become a growing concern, particularly as increasing evidence demonstrates their accumulation in human tissues and association with disease. However, most toxicological studies rely on spherical polystyrene particles, which poorly represent environmentally relevant MPs and NPs that exhibit irregular morphologies and undergo surface oxidative degradation. In this study, we developed fragmented polyethylene NPs (PE-NPs) with physicochemical properties that better mimic environmental particles. PE-NPs were synthesized via a precipitation-based method and subsequently subjected to vacuum UV irradiation to induce surface oxidation and generate degraded PE-NPs (dPE-NPs). Structural and chemical characterizations confirmed the irregular morphology and successful introduction of carbonyl functional groups without altering the particle shape. Fluorescent labeling using Nile Red enabled the visualization of PE-NPs and revealed oxidation-dependent shifts in fluorescence properties. Using phorbol 12-myristate 13-acetate-differentiated THP-1 macrophage-like cells, we investigated cellular interaction behavior, including particle uptake and particles localized near the cell membrane. Confocal microscopy demonstrated a significantly enhanced cellular interaction of dPE-NPs, including both uptake and particle-associated signals localized near the cell membrane. Quantitative analysis confirmed that surface oxidation markedly increased the particle-associated area per cell. These findings highlight the critical role of surface oxidative modification in governing NP–cell interactions and uptake kinetics. Our results emphasize that physicochemical properties, particularly environmentally induced surface changes, must be considered for realistic risk assessment of NPs. This study provides an environmentally relevant experimental framework and advances our understanding of how NP aging influences biological behavior and potential health risks.

Atherosclerosis (AS), a primary contributor to cardiovascular disease, is driven by hyperlipidemia, chronic inflammation, and gut dysbiosis. Although Salvia miltiorrhiza Bunge (Danshen) has long been used to treat atherosclerotic disorders, its most potent anti-inflammatory constituent remains unclear. Screening 12 constituents from Danshen revealed that dihydrotanshinone I (DHT) was the most potent inhibitor of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in vitro. In an atherosclerotic mouse model, DHT treatment effectively attenuated dyslipidemia and reduced atherosclerotic plaque burden in the aorta and aortic sinus. Mechanistically, DHT significantly downregulated the aortic mRNA expression of key inflammasome components (NLRP3, ASC, Caspase-1, and IL-1β) and significantly suppressed the aortic protein levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Furthermore, gut microbiota analysis indicated that DHT alleviated high-fat diet-induced gut dysbiosis by restoring gut microbial diversity. This was characterized by a decrease in pathobionts (Rikenellaceae_RC9_gut_group, Muribaculum, and [Eubacterium]_ventriosum_group) and an increase in beneficial genera (Akkermansia and Allobaculum). Fecal microbiota transplantation (FMT) confirmed that these atheroprotective effects were transferable via the gut microbiota, highlighting the key role of microbial modulation. Collectively, DHT exerts its anti-atherosclerotic effects by simultaneously improving lipid metabolism, inhibiting NLRP3 inflammasome activation, and restoring gut microbial homeostasis.

The optimal choice between sedating histamine H₁ antagonists (sAHs) and non-sedating histamine H₁ antagonists (nsAHs) for preventing infusion-related reactions (IRRs) during daratumumab subcutaneous (DARA-SC) therapy remains unclear. Here, we aimed to compare the efficacy and safety of nsAH and sAH as premedication for DARA-SC therapy. Patients with multiple myeloma or light-chain amyloidosis who received DARA-SC therapy at eight hospitals were enrolled in this prospective, multicenter, observational study. Patients were categorized into nsAH and sAH groups based on their premedication. IRRs and drowsiness were assessed using patient-reported questionnaires, including the Stanford Sleepiness Scale (SSS) and the Japanese Epworth Sleepiness Scale (JESS), at baseline, post-administration (Q2), and before bedtime (Q3). Overall, 104 patients (nsAH, n = 49; sAH, n = 55) were analyzed. No significant differences were observed in the IRR incidence between the nsAH and sAH groups at Q2 (8.2 vs. 9.1%) or Q3 (13 vs. 17%). Conversely, the incidence of new-onset drowsiness at Q2 was significantly lower in the nsAH group (13%) than in the sAH group (32%, p < 0.05). Additionally, the increase in SSS from baseline to Q2 was significantly lower in the nsAH group than in the sAH group (p < 0.05). No significant differences were observed in JESS scores. Thus, nsAH was associated with reduced early post-administration drowsiness and there were no statistically significant differences in IRR preventive effects compared to that for sAH, suggesting that nsAH may reduce sedation without a significant increase in the incidence of IRRs; however, these hypothesis-generating findings warrant verification through future prospective comparative trials.

4-[4-(Bis(2-(nitrooxy)ethyl)amino)phenyl]butanoic acid (NPB), a phenylbutyrate-derived nitric oxide (NO) donor, has been developed as a potential anticancer agent for pancreatic cancer. In the present study, we investigated the cytotoxic effects of NPB under cellular stress conditions and examined its effects on autophagy-related pathways and hypoxia-inducible factor-1α (HIF-1α) signaling. NPB-induced cell death was enhanced under nutrient-deprived conditions in PANC-1 cells. In addition, NPB induced greater cell death under hypoxic conditions than under normoxic conditions in PANC-1 cells, whereas in BxPC-3 cells, NPB-induced cell death was slightly but significantly lower under hypoxic conditions than under normoxic conditions. Using GFP-LC3-RFP-LC3ΔG reporter cells, NPB suppressed starvation-induced autophagic flux. In pancreatic cancer cells, NPB decreased DAPGreen fluorescence, an indicator of autophagy-related vesicular activity, and increased propidium iodide-positive cells under hypoxic conditions. Western blot analysis showed that NPB induced the accumulation of p62 and LC3 under both normoxic and hypoxic conditions. Under hypoxic conditions, NPB also reduced HIF-1α expression. Under cobalt chloride (CoCl₂)-induced HIF-1α-accumulating conditions, NPB and the NO donor NONOate suppressed HIF-1α expression, whereas OH-PB, a non-NO-releasing analog, showed little effect. Furthermore, the proteasome inhibitor MG132 restored HIF-1α accumulation in NPB-treated cells. Time-course analysis under CoCl₂-treated conditions showed that NPB reduced HIF-1α expression concomitantly with p62 accumulation. These findings suggest that NPB induces pancreatic cancer cell death, particularly under nutrient-deprived and hypoxic conditions, accompanied by impairment of autophagy-related pathways and NO-dependent, proteasome-associated reduction of HIF-1α.

An increased salt taste sensitivity threshold may lead to high salt intake in patients with chronic kidney disease (CKD). The present study aimed to evaluate whether community pharmacist-led dietary salt restriction guidance improved salt taste sensitivity; its association with salt intake in outpatients with CKD was quantified. A multicenter, prospective, open-label, single-arm study was conducted with a before-and-after comparison design in six community pharmacies. Eligible patients (n = 14) with an estimated glomerular filtration rate <60 mL/min/1.73 m² received salt restriction guidance from pharmacists, and a sodium-impregnated strip test, a tool for assessing salt taste sensitivity, was conducted in community pharmacies. Daily estimated salt intake was calculated from spot urine samples collected at the hospital. The primary outcome was the change in the threshold of taste recognition at 12 weeks post-intervention. The association between changes in the taste recognition threshold and estimated salt intake was evaluated using regression analysis. The median taste recognition threshold significantly decreased from 1.20 (interquartile range [IQR]: 0.80–1.35) to 1.00 (IQR: 0.80–1.00) (p = 0.033). Seventy-one percent of patients with a baseline threshold ≥0.8% showed improvement, with an effect size of −0.57. A greater reduction in the threshold was associated with a decreasing trend in the estimated salt intake. In conclusion, this pilot study suggests that community pharmacist-led dietary salt restriction guidance may improve salt taste recognition thresholds in outpatients with CKD. The sodium-impregnated strip test may be useful in promoting awareness of dietary salt restriction and in reflecting changes related to salt intake in community pharmacy settings.

Curcumin is a naturally occurring bioactive compound with well-characterized anti-inflammatory and antitumor properties; however, its clinical utility is limited by poor bioavailability and chemical instability. To overcome these limitations, various curcumin analogs have been developed. In this study, we investigated the antitumor and antimetastatic effects of 3,5-bis(2′-ethoxybenzylidene)-piperidine-4-one (E145), a monocarbonyl curcumin analog, with a particular focus on its ability to inhibit nuclear factor-kappaB (NF-κB) signaling in breast cancer cells. We first evaluated the effects of E145 on cell proliferation in murine 4T1 and human MDA-MB-231 breast cancer cell lines. E145 inhibited cell proliferation in a dose-dependent manner and suppressed phosphorylation of the NF-κB p65 subunit. Furthermore, E145 blocked tumor necrosis factor alpha–induced NF-κB activation by inhibiting both p65 phosphorylation and nuclear translocation. Consistently, E145 reduced the expression of NF-κB–regulated pro-tumorigenic factors, including vascular endothelial growth factor, matrix metalloproteinase-9, interleukin-1β (IL-1β), and IL-6. Functional assays demonstrated that E145 markedly suppressed the migration and invasion of breast cancer cells in vitro. In addition, experimental lung metastasis assays revealed that E145 treatment significantly reduced metastatic colonization of 4T1 cells in vivo. Collectively, these findings indicate that E145 exerts potent antimetastatic effects by inhibiting cell-intrinsic NF-κB activation and downstream inflammatory mediators. These results suggest that E145 is a promising therapeutic candidate for targeting NF-κB–driven breast cancer progression and metastasis.

Metabolic dysfunction-associated steatohepatitis (MASH) is frequently accompanied by metabolic comorbidities that require long-term pharmacotherapy. Because the liver plays a central role in drug metabolism, disease-associated alterations in hepatic drug-metabolizing enzyme expression may substantially affect drug disposition and increase the risk of drug–drug interactions. However, comprehensive and systematic analyses of hepatic drug-metabolizing enzyme expression during metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH progression remain limited. In this study, we performed a comprehensive stage-dependent analysis of hepatic drug-metabolizing enzyme expression using a choline-deficient l-amino acid-defined high-fat diet mouse model of MASLD/MASH. Transcript-level expression profiles of 102 CYP, 22 uridine diphosphate glucuronosyltransferase (UGT), and 21 sulfotransferase (SULT) isoforms were analyzed, of which 75 CYPs, 20 UGTs, and 17 SULTs were significantly expressed in the liver during disease progression. MASLD/MASH progression was associated with widespread but isoform-specific alterations in hepatic drug-metabolizing enzyme expression. Several major CYP isoforms, including members of the CYP2C and CYP3A subfamilies, exhibited sustained or transient downregulation, whereas other isoforms exhibited selective induction or no significant change. Similarly, multiple UGT and SULT isoforms exhibited sustained or transient downregulation, while selective induction was observed in specific isoforms such as Sult4a1, indicating that MASLD/MASH progression induces selective remodeling of hepatic drug-metabolizing enzyme expression rather than uniform suppression. This comprehensive expression profiling provides important insights into disease-associated alterations in hepatic drug metabolism and establishes a basis for improved prediction of drug disposition and safer, more individualized pharmacotherapy in patients with MASLD/MASH.

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.

Beta cell dysfunction is a critical factor contributing to decreases in insulin secretion. A growing body of evidence suggests the involvement of endoplasmic reticulum (ER) stress in beta cell dysfunction, which leads to the development of diabetes. On the other hand, oxidative stress also plays a role in the development of diabetes with beta cell dysfunction. Transient receptor potential melastatin 2 (TRPM2) is a Ca²⁺-permeable channel activated by oxidative stress and is highly expressed in beta cells. Some studies have claimed that Ca²⁺ influxes via TRPM2 in response to oxidative stress are involved in beta cell dysfunction accompanied by cell death. Although ER stress and oxidative stress form a mutually reinforcing cycle, the relationship in diabetes development between ER stress and the oxidative stress-sensitive TRP channel, TRPM2, has yet to be investigated. Therefore, we herein examined this relationship using Akita mice. Akita mice develop diabetes by ER stress-induced beta cell dysfunction accompanied by cell death. We found that increases in blood glucose in Akita mice were attenuated by the disruption of Trpm2. Additionally, in a glucose tolerance test, abnormal blood glucose increases with glucose loading in Akita mice were attenuated by the disruption of Trpm2. The results of this study using Akita mice suggest that the oxidative stress-sensitive channel, TRPM2, contributes to diabetes progression associated with ER stress.