Noriaki Maeshige

Background: Electrical stimulation (ES) is recommended as an adjunctive therapy for pressure injuries (PIs), but adoption requires implementation-relevant estimates of facility-level budget impact, including delivery costs. Methods: We conducted a model-based financial consequence analysis (provider perspective, Japan) using a 14-day randomized double-blind crossover trial (n = 12). Baseline time to heal under placebo (T_placebo) was imputed from published median healing times stratified by DESIGN-R category and PI depth. A ratio-based healing acceleration parameter (r; treated as a secondary translation parameter) was used to estimate time to heal under ES (T_ES = T_placebo/r) and days saved. Days saved were valued as a modeled gross offset using JPY 4000/day as a healing-related monetary value proxy; ES implementation costs comprised device allocation, consumables, and incremental staff time; and uncertainty was propagated via 10,000 patient-level bootstrap resamples. Results: The primary crossover effect was Δ = 0.128 cm²/day (ES minus placebo; p = 0.008), and r was 3.52 (95% uncertainty interval [UI] 1.53–13.67). Under the base-case modeled translation, mean T_placebo was 177.3 days and mean T_ES was 50.4 days, yielding 126.9 days saved (95% UI 63.5–164.9). The modeled gross offset (proxy-based) was JPY 507,723/case (95% UI 253,854–659,434). Mean implementation cost was JPY 47,794/case, giving a net financial impact (proxy-based) of JPY 459,929/case (95% UI 158,459–640,086). Conclusions: Under the base-case-modeled assumptions, ES may be cost offsetting when healing-related care is valued using a monetary value proxy. However, prospective studies directly measuring time to heal and resource use are warranted.

Skeletal muscle-derived extracellular vesicles (SkM-EVs) are promising candidates for non-invasive, systemically delivered therapies, but their functional specificity relative to clinically advanced mesenchymal stem cell-derived EVs (MSC-EVs) remains unclear. We reanalyzed public miRNA-seq datasets of SkM-EVs and MSC-EVs and integrated validated miRNA–mRNA interactions to infer pathway-level repression potential of EV miRNA cargo. Two complementary approaches were used: a differential-expression-based relative evaluation with RBiomirGS, and an abundance-weighted absolute evaluation that converts miRNA profiles into gene-level Impact Scores followed by preranked KEGG enrichment. Despite their different formulations, both approaches converged on a shared pattern. SkM-EV miRNAs showed a predicted repression bias in FoxO, TGF-β and ErbB signaling pathways linked to muscle atrophy, metabolic homeostasis and pro-proliferative signaling. By contrast, MSC-EV miRNAs showed a predicted repression bias in immune signaling pathways. These source-dependent pathway signatures provide hypothesis-generating evidence that SkM-EVs may be better suited for muscle-, metabolic-, and cancer-related indications, whereas MSC-EVs may be more appropriate for immunomodulatory indications, pending experimental validation. Our miRNA–target-based framework provides a general strategy to benchmark EV sources at the pathway level directly from miRNA profiles.

Aged skeletal muscle satellite cells (MuSCs) exhibit impaired autophagy-related activity, reduced proliferative capacity, and compromised myogenic differentiation, which collectively contribute to defective muscle regeneration during aging. However, whether hypoxia-driven modulation of autophagy-related activity can improve aged MuSC function and the underlying molecular mechanisms remain incompletely understood. In this study, aged MuSCs were divided into three groups: normoxia, hypoxia, and hypoxia combined with an autophagy inhibitor. Aged MuSCs exhibited a decreased LC3B-II/LC3B-I ratio and Beclin-1 expression, together with elevated p62 levels, indicating altered autophagy-related activity. Hypoxic culture was associated with enhanced autophagy-related activity in aged MuSCs, accompanied by HIF-1α stabilization, BNIP3 upregulation, and reduced p62 accumulation. Functionally, hypoxia significantly promoted the proliferation and myogenic differentiation of aged MuSCs. Pharmacological inhibition of autophagy using 3-methyladenine, as well as BNIP3 suppression, markedly attenuated these hypoxia-induced functional improvements. Collectively, these findings suggest that hypoxia is associated with improved proliferative and myogenic capacities of aged MuSCs, potentially involving autophagy-related activity regulated by the HIF-1α/BNIP3 pathway. This study provides insight into the relationship between hypoxic signaling and autophagy in aged MuSCs and may inform future strategies aimed at improving muscle regeneration during aging.

Diabetes mellitus severely impairs skeletal muscle regeneration after injury, limiting satellite cell activation and angiogenesis and disrupting barrier integrity while increasing fibrosis. Hypobaric hypoxia has been proposed to improve the regenerative microenvironment through hypoxia-responsive signaling, but its temporal effects and the coordination between vascular and myogenic programs in diabetic muscle remain unclear. To clarify these processes, adult male mice were divided into five groups: diabetes mellitus control (DM), cardiotoxin-injured (CTX) diabetes assessed on days 7 and 14 (CTX7, CTX14), and hypobaric-hypoxia-treated diabetic injury assessed on days 7 and 14 (H+CTX7, H+CTX14). Animals in the hypoxia groups were exposed to a hypobaric hypoxia chamber for 8 h per day for 14 days. Fibrosis, angiogenic and myogenic markers, and endothelial junctional genes were examined using histology, immunofluorescence, immunoblotting, and qRT-PCR (Quantitative Real-Time PCR). Hypobaric hypoxia on day 7 enhanced HIF-1α (hypoxia-inducible factor 1 alpha), VEGF (vascular endothelial growth factor), eNOS (endothelial nitric oxide synthas), Kdr (kinase insert domain receptor, VEGFR-2), and Angpt2 (angiopoietin-2) expression, accompanied by simultaneous endothelial sprouting and early myogenic stimulation compared to CTX7. Improvements were observed in Angpt1 (angiopoietin-1), Cdh5 (cadherin-5, VE-cadherin), Emcn (endomucin), the Angpt1/Angpt2 ratio, and CD31 density. Myogenin and MyHC (myosin heavy chain) were induced with a reduction in eMyHC (embryonic myosin heavy chain) in accordance with stabilization of endothelium and maturation of fibers, which occurred by day 14. A decrease in fibrosis and an increase in the myofiber cross-sectional area occurred. These findings suggest that hypobaric hypoxia modulates HIF-1α signaling, which in turn induces the VEGF-Kdr-eNOS pathway and the angiopoietin–Tie2–VE-cadherin pathway. Together, these pathways coordinate vascular remodeling and myogenic regeneration, ultimately improving the structural and functional recovery of diabetic muscle.

Introduction: Excessive inflammatory responses in macrophages lead to increased oxidative stress, and the excessive production of reactive oxygen species (ROS) causes tissue damage, contributing to the development of chronic diseases and tissue deterioration. Therefore, controlling the inflammatory response and ROS production is crucial for human health. Electrical stimulation (ES) has been shown to have antioxidant and anti-inflammatory effects on macrophages. However, the key pathway underlying these effects remains unclear. Methods: In this study, ES was applied to Lipopolysaccharide (LPS)-stimulated macrophages, and the production of ROS and 8–hydroxy–2′–deoxyguanosine (8-OHdG), inflammatory cytokine expression, and intracellular metabolites were analyzed in a glucose-6-phosphate dehydrogenase (G6PD) knockdown experiment, the rate-limiting enzyme of the Pentose Phosphate Pathway(PPP). Results: ES significantly increased sedoheptulose 7-phosphate (S7P), an intermediate metabolite in PPP, and reduced ROS and 8-OHdG production and the expression of inflammatory cytokines in LPS-stimulated macrophages. Meanwhile, ES did not exert antioxidant effects in G6PD-knockdown macrophages. Discussion: These findings indicate that the antioxidant effects of ES are mediated by PPP in LPS-stimulated macrophages.

Skeletal muscle, the largest secretory organ, regulates distant organs through the secretion of various factors. Among these are extracellular vesicles (EVs), which play a significant role in mediating communication between muscle and other tissues and hold therapeutic potential due to their target specificity and anti‐inflammatory properties. Enhancing the release of EVs from skeletal muscle into the circulation is crucial for eliciting their diverse effects, including anti‐inflammatory actions; however, effective strategies to increase the levels of muscle‐derived EVs in the bloodstream have not yet been developed. While exercise is the most studied method to increase blood EV levels, its efficacy in enhancing skeletal muscle‐derived EVs remains unclear. This study reveals that a brief, 5‐min ultrasound (US) treatment of skeletal muscle robustly elevates circulating levels of muscle‐derived EVs, introducing a novel, non‐invasive stategy to modulate EV release. US‐induced EVs showed altered miRNA profiles enriched with anti‐inflammatory miRNAs that target pathways involved in inflammatory responses. Additionally, transient upregulation of reactive oxygen species and activation of the endoplasmic reticulum stress pathway were observed in US‐treated muscle, suggesting a mechanism for enhanced EV release. Our findings establish US as the first non‐invasive and rapid method to selectively enhance skeletal muscle‐derived EV release into the circulation, highlighting its potential for therapeutic applications through its anti‐inflammatory effect.

Objectives: Wheelchair seat sagging is hypothesized to increase pressure and shear forces, potentially leading to pressure injuries. The objective of this study was to assess the impact of correcting wheelchair seat sagging on ischial pressure, shear force, and posture in a population of healthy adults. Methods: A total of twenty-two participants who met the study requirements were included in the study. Participants were evaluated under two conditions: with seat base correction (With Correction) and without it (No Correction). Correction was achieved using insert panels. Ischial pressure was measured using a pressure-mapping system (CONFORMat), shear force with a specialized sensor (iShear), and posture with accelerometers (TSND151). The primary analysis compared peak pressure index (PPI), shear force, slide, and postural changes between conditions. The subgroup analysis was conducted as an exploratory approach to assess potential variation among participants with elevated shear forces. Results: There was no statistically significant difference in ischial pressure between the No Correction and With Correction conditions (p = 0.37). However, shear force and slide were significantly reduced when seat sagging was corrected (p < 0.05). Accelerometer data showed no significant difference in postural changes between conditions (p ≥ 0.05), although the With Correction condition displayed a slight trend toward greater positional variability over time. Conclusions: These findings indicate that correcting seat sagging can reduce shear force and slide, potentially lowering the risk of pressure injuries. However, because this study targeted healthy adults, further research involving older or at-risk populations is necessary. Addressing seat sagging could be an important component of comprehensive pressure injury prevention strategies.