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Summary: Impaired bone quality and increased fracture risk are cardinal features of the skeleton in diabetes mellitus. Hyperglycemia-induced oxidative stress is proposed as a potential underlying mechanism, but the precise pathogenic mechanism remains incompletely understood. In this investigation, osteoblasts under high glucose exhibited heightened levels of reactive oxygen species, impaired mitochondrial membrane potential, and profound inhibition of late-stage osteoblast differentiation. Further analyses uncovered that high glucose resulted in the downregulation of the PINK1/Drp1 pathway in osteoblasts, consequently leading to impaired mitophagy. Conversely, the upregulation of PINK1/Drp1 pathway activated mitophagy, which restored the differentiation capacity of osteoblasts. Notably, in an STZ-induced diabetic mouse model, BMP9 upregulated the expression of PINK1/Drp1 in the bone tissue, leading to an improvement in bone quality and bone mineral density. These findings suggest that the PINK1/Drp1 pathway might be a potential therapeutic target to enhance osteogenic differentiation and treat diabetic osteoporosis.

Ruscogenin (RUS), first isolated from Ruscus aculeatus, also a major steroidal sapogenin of traditional Chinese herb Radix Ophiopogon japonicus, has been found to exert significant anti-inflammatory and anti-thrombotic activities. Our previous studies suggested that ruscogenin remarkably inhibited adhesion of leukocytes to a human umbilical vein endothelial cell line (ECV304) injured by tumor necrosis factor-Α (TNF-Α) in a concentration-dependent manner. Yet the underlying mechanisms remain unclear. In this study, the in vivo effects of ruscogenin on leukocyte migration and celiac prostaglandin E2 (PGE2) level induced by zymosan A were studied in mice. Furthermore, the effects of ruscogenin on TNF-Α-induced intercellular adhesion molecule-1 (ICAM-1) expression and nuclear factor-κB (NF-κB) activation were also investigated under consideration of their key roles in leukocyte recruitment. The results showed that ruscogenin significantly suppressed zymosan A-evoked peritoneal total leukocyte migration in mice in a dose-dependent manner, while it had no obvious effect on PGE2 content in peritoneal exudant. Ruscogenin also inhibited TNF-Α-induced over expression of ICAM-1 both at the mRNA and protein levels and suppressed NF-κB activation considerably by decreasing NF-κB p65 translocation and DNA binding activity. These findings provide some new insights that may explain the possible molecular mechanism of ruscogenin and Radix Ophiopogon japonicus for the inhibition of endothelial responses to cytokines during inflammatory and vascular disorders. Keywords:: ruscogenin, endothelial cell, adhesion, intercellular adhesion molecule-1 (ICAM-1), nuclear factor-κB (NF-κB)