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Background Osteoporosis, resulting from an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation, affects millions globally. Recent studies have identified type H vessels (CD31 hi EMCN hi ) as a specialized subset of bone blood vessels that positively regulate bone formation. This study aims to investigate the effects of metformin on bone mass, strength, and angiogenesis in osteoporotic mice, and to elucidate the underlying molecular mechanisms, particularly focusing on the YAP1/TAZ-HIF1α axis. Methods Osteoporotic mice were administered metformin, and bone mass and strength were measured. In vivo and in vitro angiogenesis assays were performed under hypoxic conditions. Expression levels of YAP1/TAZ and HIF1α were assessed in femoral metaphysis and hypoxia-cultured human microvascular endothelial cells (HMECs). Small interfering RNA was used to interfere with HIF1α or YAP1/TAZ expression in hypoxia-cultured HMECs. Additionally, we employed AAV-mediated overexpression of YAP1/TAZ in vivo to determine whether elevated YAP1/TAZ levels alter metformin’s effects on bone mass and angiogenesis. Results Metformin significantly enhanced bone mass and strength in osteoporotic mice. It also promoted angiogenesis under hypoxia conditions both in vivo and in vitro. Metformin reduced YAP1/TAZ expression while increasing HIF1α expression in both the femoral metaphysis of osteoporotic mice and hypoxia-cultured HMECs. Interference with HIF1α or YAP1/TAZ confirmed that metformin enhances HIF1α and its target genes primarily by inhibiting YAP1/TAZ. Furthermore, overexpression of YAP1/TAZ partially reversed the bone-protective effect of metformin, leading to reduced HIF1α levels and diminished type H vessel formation. Conclusion Our findings suggest that metformin holds promise as a therapeutic agent for osteoporosis by enhancing type H vessel formation through the inhibition of the YAP1/TAZ-HIF1α axis. Graphical abstract

Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, yet effective therapies are lacking. Here, we show that alternate-day intermittent fasting (IF1:1) attenuates vitamin D-induced VC in mice, whereas a 5:2 regimen is ineffective. The protective effect of IF1:1 is gut microbiota-dependent, particularly through enrichment of Akkermansia muciniphila ( Akk ). Microbiota-derived extracellular vesicles (EVs) function as nano-scale mediators that bypass the spatiotemporal constraints of bacterial survival to facilitate long-distance communication with host cells, providing a crucial pathway for downstream mechanistic investigation. Akk -derived EVs ( Akk -EVs) are internalized by vascular smooth muscle cells (VSMCs), suppressing osteogenic differentiation and calcification in vitro and in vivo. Proteomic analysis identified B2URF3 as a highly enriched functional protein in Akk -EVs and Akk , which interacts with Aldehyde Dehydrogenase 1 Family Member B1 (ALDH1B1) to inhibit VSMC osteogenic transdifferentiation. Clinically, reduced fecal Akk abundance and lower serum B2URF3 levels were observed in patients with coronary calcification. These findings define a gut-vascular axis by which IF1:1 mitigates VC and nominate Akk -EVs and B2URF3 as potential therapeutic targets and biomarkers. Graphical abstract

Acute kidney injury (AKI) is a life-threating syndrome characterized by sudden loss of kidney function, and its management is challenging and often suboptimal. Mesenchymal stem cells (MSCs) have shown promise in AKI therapy in pre-clinical and clinical trials; however, their clinical application still faces many challenges. MSC-derived small extracellular vesicles (sEV) may help overcome these challenges. In the current study, we overexpressed Klotho in MSCs and then isolated Klotho-loaded sEV (Klotho-sEV) using anion-exchange chromatography. Klotho-sEV displayed characteristics comparable to those of sEV in terms of size, morphology, conventional markers, and biosafety, as well as a higher abundance of Klotho protein. In rhabdomyolysis-induced AKI, sEV showed preferential tropism in injured kidneys. We found significantly and stably accelerated renal recovery, mitigated functional and histological abnormalities, stimulated tubular cell proliferation, reduced injury and inflammatory marker expression, and restored endogenous Klotho loss in mice after the administration of Klotho-sEV. In addition, Klotho-sEV treatment activated the mTOR and MEK1/2 signaling pathways. Proteomics and small RNA sequencing analyses of sEV and Klotho-sEV revealed abundant proteins and miRNAs involved in anti-inflammation and reno-protection, and Klotho-sEV showed characteristics that were different from those of sEV. In conclusion, Klotho-sEV may be a promising cell-free strategy for the treatment of AKI. Graphical abstract

本研究旨在探討旅遊網站使用者持續採用行為，以「期望確認理論」（Expectation Confirmation Theory，ECT）為基礎，並透過整理過去有關旅遊網站特性、科技採用與資訊系統成功的相關文獻，歸納出影響旅遊網站持續採用之相關因素，藉以提出一套能夠適用於旅遊網站情境之理論模式。在「期望確認理論」相關文獻中，尚未有研究以「背包客」（Backpackers）為研究對象來探討系統使用者之持續採用行為，本研究延伸期望確認理論之相關變數，以讓此理論應用在旅遊網站的情境上更臻完整。本研究以臺灣地區的背包客為研究對象，指非透過旅行社安排，曾經進行國內、外自助旅遊者為主，經由網路問卷的方式，共回收251份有效問卷，並使用LISREL軟體進行統計分析資料，結果顯示多數假說均獲得支持。本研究有以下發現：（1）旅遊網站品質特性（資訊品質、系統品質及服務品質）對「確認程度」有正向顯著之影響；（2）「確認程度」對旅遊網站使用特性（知覺有用性、知覺易用性）與「使用者滿意度」有正向顯著之影響；（3）旅遊網站使用特性（知覺有用性、知覺易用性）對「使用者滿意度」有正向顯著之影響；（4）旅遊網站使用特性（知覺有用性、知覺易用性）對「持續使用意願」沒有正向顯著之影響；（5）「使用者滿意度」對「持續使用意願」有正向顯著之影響。最後，根據研究結果提供旅遊網站業者一些有效管理旅遊網站系統營運之實務建議。