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.