Bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor and inhibits angiogenesis, can cause hypertension. Although blood pressure generally rises in winter and falls in summer, seasonal patterns of bevacizumab-related hypertension (BRHT) remain unclear. We investigated these patterns using Japanese Adverse Drug Event Report data from July 2007 to June 2025. Cases where bevacizumab was reported as a “suspected drug” were identified using the Medical Dictionary for Regulatory Activities preferred terms “hypertension,” “blood pressure increased,” or “systolic blood pressure increased.” Monthly relative BRHT frequencies were calculated by dividing BRHT reports by the total adverse event reports and compared with mean monthly temperatures obtained from the Japan Meteorological Agency. Seasons were defined as spring (March–May), summer (June–August), autumn (September–November), and winter (December–February), and were visualized using mosaic plots. Between April 2004 and September 2025, 985,999 reports were registered, of which 956 met the BRHT criteria. The median time-to-onset (TTO) was 21.0 days (interquartile range, 7.0–45.0). The Weibull scale parameter (α) was 40.8 (95% confidence interval [CI]: 37.4–44.5), and the shape parameter (β) was 1.06 (95% CI: 0.99–1.13). BRHT reports peaked in September and October and were least frequent in summer. No significant differences were observed in either TTO or clinical outcomes across seasons of adverse event onset. BRHT occurred more frequently in autumn, particularly in September and October, than in winter. Healthcare professionals should be aware of this seasonal risk and ensure appropriate blood pressure monitoring and preventive measures during autumn.

Progression of metabolic dysfunction-associated steatotic liver disease leads to insulin resistance, a condition driven by the induction of specific hepatokines. We previously developed an in vitro steatotic liver model, PXB-cells LA (Lipid Analysis), derived from fresh human hepatocytes (PXB-cells^®) isolated from humanized mouse livers. In the present study, we investigated its utility as a screening system for insulin-sensitizing agents. Our results demonstrated that metformin and rosiglitazone, well-known treatments for type 2 diabetes, reduced the expression of the prodiabetic hepatokines leukocyte cell-derived chemotaxin 2 and fetuin-A in PXB-cells LA. Furthermore, while fibroblast growth factor 21 enhances systemic insulin sensitivity, both agents upregulated fibroblast growth factor 21 production at both the mRNA and protein levels in this model.

Insomnia is highly prevalent among older adults, and hypnotics are widely prescribed in Japan. As older individuals are vulnerable to hypnotic-related adverse events, such as falls and cognitive impairment, monitoring national prescription trends is essential for safer pharmacotherapy. Using the National Database Open Data from fiscal years 2019–2023, we examined nationwide prescription trends of hypnotics indicated for insomnia (or insomnia with pre-anesthetic medication). We calculated the annual total dispensed quantity, the dispensed quantity attributable to adults aged ≥65 years, and the proportion (%) of dispensed quantity among older adults. Conventional hypnotics (benzodiazepines and Z-drugs) and newer agents, including dual orexin receptor antagonists (DORAs), were evaluated. Zolpidem remained the most frequently used hypnotic, increasing from 506 million dispensed dosage units in 2019 to 685 million in 2023. However, the proportion of dispensed quantity attributable to adults aged ≥65 years declined from 64.7% to 60.2%. Brotizolam exhibited a similar utilization trend, with stable overall use but a reduction from 66.6% to 62.1% in the older adult population. In contrast, lemborexant, introduced in 2020, demonstrated a rapid uptake, reaching 504 million dispensed dosage units in 2023, whereas its proportion of use among older adults increased from 38.9% to 51.1%. Insomnia medication prescription trends are shifting in Japan, with the increasing adoption of DORAs along with a relative decline in conventional hypnotics among older adults. Continued monitoring is warranted to support safer prescription practices in geriatric insomnia care.

High mobility group box 1 (HMGB1) is a critical pro-inflammatory damage-associated molecular pattern (DAMP), and ribosomal protein L9 (RPL9) has been identified as a potential “regulatory DAMP” that can suppress HMGB1’s activity. However, it is unclear how pro-inflammatory DAMP signaling is initiated when these opposing molecules are released together. We hypothesized that the release kinetics of HMGB1 and RPL9 are differentially regulated depending on the cell type. To test this, we compared the release of HMGB1 and RPL9 from human macrophage (THP-1), liver (HepG2), and endothelial (EA.hy926) cell lines following stimulation with lipopolysaccharide and nigericin. In THP-1 macrophages, classical pyroptosis induced a rapid, sequential release of HMGB1 followed by RPL9. In contrast, HepG2 cells showed slower, apoptosis-like cell death, and RPL9 was released several hours before HMGB1. EA.hy926 cells were highly resistant to the stimulus. Notably, RPL9 release was closely associated with phosphatidylserine externalization in both THP-1 and HepG2 cells, regardless of their primary cell death pathway. Our findings demonstrate that the balance between pro-inflammatory and regulatory DAMPs is governed by a complex, cell-type-specific temporal control system intrinsically linked to the mode of cell death. Furthermore, we propose the existence of a novel, selective release pathway for RPL9. A deeper understanding of this time-dependent regulation may contribute to the development of new therapeutic strategies for inflammatory diseases.

Mitochondria play essential roles in cellular redox homeostasis and viability, and oxidative stress is known to impair mitochondrial function. In this study, we examined the effects of pyridoxine hydrochloride (vitamin B₆) on mitochondrial responses in normal human dermal fibroblasts (NHDFs) exposed to hydrogen peroxide (H₂O₂). Pre-treatment with pyridoxine hydrochloride was associated with changes in mitochondrial responses, including increased cell viability, higher PCR-based mtDNA amplifiability (an indirect indicator of mtDNA integrity), and maintenance of mitochondrial membrane potential under oxidative stress conditions. These observations indicate that pyridoxine hydrochloride influences mitochondrial responses to oxidative stress in this in vitro model, and suggest its utility for evaluating small-molecule antioxidants.

Objective: In October 2024, the Selected Medical Care System, a patient cost-sharing scheme for off-patent brand-name drugs, was introduced to promote the use of generic drugs (GEs). To clarify the impact of introducing this system on the rate of GE usage, we examined the degree of change following its implementation. Methods: We analyzed the volume share of GEs (September 2019 to March 2025) using an interrupted time-series design with a linear mixed model, and assessed the deviations of individual insurers from historical trends by calculating 95% prediction intervals using linear regression. Results: The median GE volume share of all 1,877 organizations increased from 0.854 in September 2024, immediately prior to introduction of the Selected Medical Care System, to 0.902 in March 2025, revealing that the median half-year-on-half-year rate of change increased from +0.021 to +0.057. Linear mixed modeling confirmed the positive impact of the system on GE volume share among professional subgroups, even after controlling for pre-existing trends, whereas trend analysis revealed that 92.4% (146/158) of the analyzed organizations showed deviations from their historical trends during the post-implementation period. Conclusions: The system for selected medical care coverage has had a notable effect regarding the promotion of GE use and can be considered an effective measure for encouraging behavioral change, even in groups for which the rate of GE usage is generally relatively low.

Objective: There is increasing research interest on the impact of ischemic stroke on organs beyond the central nervous system, and it is now widely recognized that cerebral ischemia induces multiple alterations in peripheral systems. Therefore, it is necessary to elucidate the systemic consequences of cerebral ischemia. Serine protease inhibitor a3 (SERPINA3), a secretory immune-related molecule produced primarily in the liver and brain under normal conditions, is upregulated in response to inflammation. Here, we examined Serpina3n gene expression in the brain and liver and evaluated plasma SERPINA3N protein concentrations following cerebral ischemia using a mouse model. Methods: We examined changes in SERPINA3N levels in the brain, liver, and blood over time using a mouse model of focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion for 4 h followed by reperfusion. Brain, liver, and blood samples were collected on days 1, 3, and 7 after MCA occlusion (MCAo). Serpina3n gene expression levels in the brain and liver were measured by quantitative real-time polymerase chain reaction (qPCR), and plasma SERPINA3N levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Serpina3n gene expression levels in the brain and liver were increased on day 1 after MCAo. Plasma SERPINA3N protein levels were increased and peaked on day 1 after MCAo. Conclusion: A mouse model of cerebral ischemia showed increased Serpina3n gene expression in the liver and SERPINA3N protein level in plasma. This is the first study of the effects of plasma SERPINA3N protein levels using a mouse model of cerebral ischemia.

Moderate midazolam sedation is often used in gastrointestinal endoscopy to induce stress-free conscious sedation. Conversely, flumazenil can reverse midazolam-induced sedation and cause temporary awakening and resedation. However, the effects of flumazenil disuse on the incidence of inpatient falls are unknown. In this study, we performed a retrospective cohort analysis of the incidence of falls in inpatients who underwent gastrointestinal endoscopy under midazolam-induced sedation with or without flumazenil. This study included 1,424 procedures, of which 559 involved flumazenil use. The frequency of inpatient falls did not significantly differ between the flumazenil and nonflumazenil use groups (2/559 episodes [0.36%] vs. 2/865 episodes [0.23%], P = 0.648). The inverse probability of treatment weighting analysis could not determine the association of flumazenil disuse with the incidence of inpatient falls (odds ratio, 0.57; 95% confidence interval, 0.08-4.14; P = 0.58). Our results indicate that the association between flumazenil disuse and the incidence of inpatient falls remain unclear.

As part of our ongoing study on verification of helium–alternative carrier gases in the official test method using gas chromatography–mass spectrometry (GC–MS) for chemicals in indoor air, we examined the applicability of hydrogen and nitrogen to thermal desorption (TD)–GC–MS. A comparison of the signal–to–noise ratios of standard solutions of volatile organic compounds (VOC) and Phthalate esters showed that detection sensitivities of hydrogen and nitrogen analyses were sufficient for the official test method. Measurements using these alternative carrier gases showed good linearity and could quantify less than 1/100^th of Japanese guideline values for indoor air concentrations. Therefore, hydrogen and nitrogen gases can be applied to the official test method using TD–GC–MS for VOC and Phthalate esters in indoor air as alternative carrier gases to helium.

Benzotriazole-based ultraviolet absorbers (BUVs) are widely used in polymers due to their high thermal and photo stability. However, their environmental persistence and bioaccumulation potential have raised concerns, and some have become subject to regulation. BUVs have been detected in water, air, road dust, biota, and indoor products such as plastics and paints. They have also been frequently found in household dust (HD), which accumulates semi-volatile organic compounds; however, no studies to date have investigated the presence of BUVs in Japanese HD. This study established an LC–MS/MS method with atmospheric pressure chemical ionization (APCI) to quantify eight BUVs in HD and evaluate their occurrence in Japanese residences. Here, eight BUVs were selected for analysis, including UV-320—classified as a Class I specified chemical substance under Japan’s Chemical Substances Control Law—and UV-328, newly listed in 2024. Sample preparation was optimized by evaluating six solid-phase extraction methods, among which basic alumina-based cartridges demonstrated selective BUV retention. High recoveries ranging from 86.9 to 100% were achieved using a back-flush elution approach. Using the developed method, HD samples collected in 2023 and 2024 were analyzed. Six compounds, excluding UV-320 and UV-PS, were detected in 100% of the samples. Although the maximum and minimum concentrations varied considerably between the two years, the median values and detection frequencies showed generally consistent trends. These findings reveal the contamination status of BUVs in Japanese HD and demonstrate that the developed APCI–LC–MS/MS method is a reliable approach for indoor pollution monitoring.

Telomeric repeat-containing RNA (TERRA), a long non-coding RNA (lncRNA), is transcribed from both chromosomal ends and regulates gene expression at telomeres as well as within internal chromosomal regions. Although chromosomal dysfunction has been implicated in depression, the relationship between TERRA expression and depressive symptoms remains poorly understood. In this study, we developed a quantitative reverse transcription PCR (RT-qPCR) method to measure TERRA expression from 10 loci on chromosomes 3, 8, 11, 12, 16, and 22, which have been associated with depressive disorder. Using this method, we examined the association between TERRA expression in peripheral blood and depressive symptoms in 18 patients with major depressive disorder. TERRA expression levels at 8p and 11p exhibited limited correlation with those at other chromosomal loci. Moreover, when patients were stratified into two groups based on depressive symptom severity, TERRA expression at 8p was significantly lower in the group with severe depressive symptoms compared with those with mild symptoms (P = 0.043). This study established a method for quantifying chromosome-specific TERRA expression and provided insights into its potential association with depressive symptoms. The findings suggest that aberrant TERRA expression at 8p may contribute to the pathophysiology of depression. Further studies involving larger cohorts are warranted to validate these results.