Aquaporin-4 (AQP4) depolarization-mediated glymphatic system (GS) dysfunction is a critical pathological mechanism in diabetic cognitive impairment (DCI). However, its underlying mechanism has not been clarified. The Zhimu-Huangbo (ZMHB) herb pair, a classic formulation historically employed in traditional Chinese medicine, demonstrates neuroprotective effects, including the amelioration of cognitive dysfunction. Emerging evidence suggests that the exosomal pathway may regulate abnormalities in diabetes-induced AQP4 polarization. Nevertheless, whether the neuroprotective effects of ZMHB mediate the restoration of AQP4 polarity through the exosomal pathway remains to be elucidated. This study takes the exosomal pathway as the entry point to elucidate the mechanism of AQP4 depolarization in DCI and determine how ZMHB restores AQP4 polarization and improves cognitive function. ZMHB significantly improved cognitive function, effectively restored GS function and maintained AQP4 polarization. Pharmacological blockade of exosomal pathways partially reduced the therapeutic effects of ZMHB, demonstrating that its efficacy depends on exosome-mediated signaling; proteomics combined with western blotting validation revealed tissue inhibitor of metalloproteinase 3 (TIMP3) as a pivotal protein modulated by ZMHB, which restored AQP4 polarization by inhibiting matrix metalloproteinase-9 (MMP9) activity and blocking β-dystroglycan (β-DG) cleavage in astrocytes. In vitro studies further demonstrated that both ZMHB-treated serum exosomes (ZMHB-sExos) and the TIMP3 agonist MPT0B390 restored astrocytic AQP4 polarization by modulating the MMP9/β-DG pathway. We demonstrated that ZMHB restored AQP4 depolarization in DCI rats by modulating the exosomal TIMP3-MMP9/β-DG pathway.

The enteral administration of drugs as suspensions is a potential alternative route for patients with dysphagia. The simple suspension method is commonly used in Japan; however, nationwide data are lacking. This study aimed to investigate the real-world use and potential impact of oral anticancer agent (OAA) suspensions in patients with dysphagia in Japan. A large Japanese administrative claims database was used in this retrospective study (April 2014 to August 2023). Patients with cancer who had nasogastric, gastrostomy, or jejunostomy tubes and received OAAs during non-oral intake periods were included. These periods were defined using procedural codes, and it was assumed that the prescribed drugs were suspended. Three frequently used drugs (temozolomide, lenvatinib, and osimertinib) were analyzed. Patients were divided into suspension and non-suspension groups using propensity score matching, and overall survival (OS) was compared using the Kaplan–Meier method. Among 25,252 patients with feeding tubes, 126 received OAAs during the non-oral period. The median age was 76 years, and 62% had gastrostomy tubes. Temozolomide was the most common drug suspension, followed by lenvatinib and osimertinib. No significant difference in OS was observed between the temozolomide and lenvatinib groups. However, OS of the osimertinib suspension group was shorter than that of the non-suspension group (p = 0.047). This large-scale study of OAA suspensions in Japan suggests that drug suspensions may support continued anticancer treatment in patients with dysphagia. However, drug stability and exposure risks should be considered. Further evidence and more specific guidelines are required to ensure safe and effective use.

Drug-induced weight gain is a clinically important adverse event that can lead to obesity, metabolic syndrome, cardiovascular disease, and reduced treatment adherence. Although several drug classes are known to cause weight gain, the onset timing and underlying mechanisms remain incompletely understood. This study aimed to investigate signals and evaluate time to onset of drug-induced weight gain using the Japanese Adverse Drug Event Report (JADER) database. We analyzed JADER data from April 2004 to June 2025, and in the disproportionality analysis reporting odds ratios with 95% confidence intervals were calculated. Time to onset was also assessed, and Weibull distribution analysis was applied to evaluate onset patterns. Among 975,869 reports, 814 cases of drug-induced weight gain were identified. Signals were detected for known drugs such as antipsychotics, pregabalin, and pioglitazone, as well as for drugs without weight gain listed in their package inserts, including benzodiazepines. Pregabalin showed the earliest median onset at 19 days (early failure), followed by olanzapine and risperidone at 1–2 months, pioglitazone at 2 months, and clozapine at 6 months, all classified as random failure types. This study demonstrated that drug-induced weight gain varies by drug class in both onset timing and mechanisms. These findings underscore the need for careful weight monitoring during treatment, particularly early with pregabalin and long-term with clozapine and pioglitazone. Prospective studies are warranted to clarify causal relationships and clinical implications.

This pilot study investigated the protective effect of transfecting brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (bcl-2) genes in retinal ganglion cells (RGCs) using in vivo electroporation in an adult rat optic nerve transection model. Sprague-Dawley rats were randomly divided into five groups: BDNF(+)/bcl-2(+), BDNF(+), bcl-2(+), empty plasmid (EP), and no surgery (NS). The plasmids were intravitreally injected and electroporated into the left eye. Seven days later, optic nerve transection was performed in all groups except the NS group. Protein expression was examined using Western blotting, RGC survival was quantified using 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) retrograde labeling, and apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) at multiple time points (7, 14, and 28 d after transfection). A significantly higher number of DiI (+) RGCs and lower number of apoptotic cells were observed in the BDNF(+)/bcl-2(+), BDNF(+), and bcl-2(+) groups compared to those in the EP group at all time points. The number of DiI (+) RGCs in the three treatment groups was significantly lower than that in the NS group. However, there were no significant differences among the three treatment groups. The protective effects of gene transfection tended to be strongest in the BDNF(+)/bcl-2(+) group, followed by the BDNF(+) group and then the bcl-2(+) group. Thus, all gene transfection treatments had a protective effect against the loss of DiI(+) RGCs induced by optic nerve transection but did not result in full recovery. This study also confirmed the value of in vivo electroporation. The findings of this pilot study provide a working base for the development of gene therapy for blinding optic nerve disorders.

The aim of this study is to evaluate the efficacy and safety of 5-aminolevulinic acid hydrochloride/sodium ferrous citrate (5-ALA-HCl/SFC) in patients with adult-onset Still's disease (AOSD) refractory to glucocorticoids during the maintenance treatment period of a phase II investigator-initiated randomized, double-blind, parallel-group clinical trial. This multicenter, open-label, continuous trial was limited to participants from the preceding study, which was planned for 30 enrollees but was stopped early after four enrollees because of slow recruitment. The current trial maintained a 16-week treatment period and remained double-blind until the previous study database was locked and unblinded. Two dose groups were used: 5-ALA-HCl/SFC 100 and 300 mg. Participants previously assigned to placebo were re-randomized 1:1 to either dose group. The dosage and administration were identical to those of the previous protocol. The primary endpoint was the achievement of adapted ACR 30 at week 16. All four participants achieved the primary endpoints. Secondary outcomes, including the adapted ACR 90/100 and the change in serum ferritin levels, showed numerically greater improvement in the participant who received the high-dose compared with the other. Eleven adverse events occurred in three participants, including one serious event and one discontinuation; all were deemed unrelated to the study drug, and no deaths were reported. This study identified potential efficacy signals, particularly in the high-dose group. However, because of premature termination and a very limited sample size, the data were insufficient to establish the efficacy and safety profile of 5-ALA-HCl/SFC in refractory AOSD. Larger studies are required to confirm these findings.

This study compared the diagnostic value of contrast-enhanced ultrasound (CEUS) and contrast-enhanced computed tomography (CECT) for differentiating benign and malignant gallbladder (GB) lesions. A retrospective analysis was performed on 151 hospitalized patients with GB lesions: 74 underwent CEUS alone, 25 CECT alone, and 52 both examinations preoperatively. Histopathology served as the reference standard. Imaging features of benign/malignant lesions were compared using t-test or chi-square (χ²) test; CEUS quantitative parameters were analyzed via t-test. Diagnostic efficacy of the two modalities was compared by χ² test. Of 151 patients, 57 (37.7%) had malignant and 94 (62.3%) benign lesions. Statistically significant differences between benign and malignant groups were observed in CEUS/CECT features (vascular enhancement morphology, contrast distribution, GB wall integrity, ill-defined borders with adjacent liver) and CEUS washout time (WT) (all P < 0.05). In the entire cohort, no significant differences existed between CEUS and CECT in sensitivity (89.2% vs. 85.7%), specificity (78.8% vs. 74.3%), accuracy (84.9% vs. 80.5%), positive predictive value (PPV) (85.7% vs. 80.0%) and negative predictive value (NPV) (83.7% vs. 81.2%) (all P > 0.05). Similar non-significant differences were noted in the 52-patient subgroup (sensitivity: 65.0% vs. 80.0%; specificity: 62.5% vs. 80.0%; accuracy: 63.5% vs. 76.9%; PPV: 40.6% vs. 50.0%; NPV: 51.3% vs. 66.7%; all P > 0.05). CEUS is effective for differentiating benign and malignant GB lesions, with diagnostic efficacy comparable to CECT.

Rapid postprandial elevations in interstitial glucose contribute to the progression of type 2 diabetes and associated vascular complications. Nutritional sequencing strategies, such as consuming dietary fiber or protein before carbohydrate intake, have been proposed to attenuate glucose excursions by delaying gastric emptying, stimulating incretin secretion, and enhancing insulin responsiveness. However, observational evidence under real-world conditions remains scarce in both healthy individuals and those with diabetes. We performed an observational study including healthy participants and individuals with type 2 diabetes. All participants were equipped with a continuous glucose monitoring system (FreeStyle Libre™) for 14 days to capture interstitial glucose profiles under daily living conditions. Participants simultaneously recorded dietary intake and meal timing. Postprandial glucose excursions were evaluated by comparing carbohydrate ingestion alone with ingestion preceded by fiber and/or protein. Preceding carbohydrate intake with dietary fiber or protein was associated with significant attenuation of postprandial glucose excursions compared with carbohydrate alone. This effect was particularly evident within the first 120 minutes after eating and was most pronounced when fiber and protein were consumed in combination. Attenuation occurred in both healthy individuals and participants with type 2 diabetes, though the magnitude of suppression varied across groups. Our findings indicate that consuming fiber and protein prior to carbohydrate intake can substantially mitigate rapid postprandial glucose rises. These results support the physiological rationale for macronutrient sequencing and underscore the potential of simple, practical dietary strategies to improve glycemic control in daily life among both healthy individuals and those with diabetes.

We aimed to evaluate the clinical significance of imeglimin in older patients with type 2 diabetes. Prescription trends were analyzed using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (2021–2023). Prescriptions for imeglimin increased, with the highest usage among patients in their 70s, followed by those in their 60s, and a clear upward trend in those aged ≥ 80 years. We present the case of an 80-year-old woman with diabetes who repeatedly discontinued treatment. After initiating imeglimin (2000 mg/day), she continued therapy successfully, achieving stable HbA1c levels at approximately 7% over 30 months. Muscle mass indices (creatine kinase, creatinine, and estimated glomerular filtration rate), nutritional status (albumin), and inflammation (C-reactive protein) remained stable, and independent walking and quality of life were preserved. These findings suggest that imeglimin may support glycemic control and may help attenuate frailty and sarcopenia progression in older adults with diabetes.

Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by tafazzin mutations that impair cardiolipin remodeling, leading to mitochondrial dysfunction and symptoms such as cardiomyopathy, myopathy, and neutropenia. On September 19, 2025, the U.S. Food and Drug Administration (FDA) granted accelerated approval to elamipretide, the first therapy directly targeting the mitochondrial etiology of BTHS. Elamipretide binds to cardiolipin on the inner mitochondrial membrane, stabilizing respiratory chain supercomplexes, enhancing electron transport efficiency, and reducing reactive oxygen species production. In a randomized, double-blind, placebo-controlled, crossover trial, elamipretide resulted in no significant improvement in the 6-minute walk test or fatigue scores; however, sustained benefits were observed during a 168-week open-label extension. The most common adverse events were mild injection-site reactions. As a condition of accelerated approval, a confirmatory trial is required. Elamipretide represents a promising therapy addressing an unmet medical need in BTHS and provides a foundation for future mitochondria-targeted treatments.

The World Health Organization (WHO) has approved a new diagnostic code, "5B72 Undernutrition in Adults", in the 11th Revision of the International Classification of Diseases (ICD-11). Prior to this update, undernutrition in adults was represented only by the code "5B54 Underweight in Adults". However, the increasing diversity of causes of undernutrition in adults and the accompanying rise in associated diseases have been recognized as global health challenges in recent years. The approval of the "5B72 Undernutrition in Adults" category signifies its formal recognition as a distinct disease entity and is expected to improve data collection and research, enhance clinical diagnosis and interventions, and support policy development and nutritional education.