Violence, runaway, and suicide attempts among people living with schizophrenia in China: Prevalence and correlates.

Excessive and chronic inflammation can cause osteogenic dysfunction and disrupt the balance of the osteoimmune microenvironment, thereby increasing the risk of fracture non-union. Urolithin A (UA), a gut microbiota-derived metabolite produced from dietary sources, has been reported to inhibit RANKL-induced osteoclastogenesis and alleviate postmenopausal osteoporosis. However, the effect of UA on osteogenesis, particularly under pathogenic inflammatory conditions, remains unclear. In this study, mouse bone marrow-derived mesenchymal stromal cells (mBMSCs) were used to evaluate osteogenesis in vitro, and RAW 264.7 cells were used as macrophages in vitro. Tumour necrosis factor (TNF)-α was used to establish an inflammatory environment. In vivo, a mouse femur fracture model with local TNF-α injection was established, and UA or vehicle was administered by intragastric gavage. The UA showed no obvious effect on cell viability at concentrations ranging from 0 to 10 μM and had no direct effect on the osteogenic differentiation of mBMSCs. TNF-α treatment significantly decreased the expression of osteogenesis-related genes and proteins and inhibited calcium deposition, whereas UA reversed this inhibitory effect in a dose-dependent manner. Mechanistically, UA inhibited activation of the TNF-α-induced nuclear factor-κB signalling pathway. Furthermore, UA reduced pro-inflammatory cytokine levels and inhibited type-1 macrophage polarisation under TNF-α-induced inflammatory conditions. Conditioned medium derived from RAW 264.7 cells stimulated with TNF-α after UA treatment promoted the osteogenic differentiation of mBMSCs. In vivo, local administration of TNF-α significantly impaired bone fracture healing in the mouse femur fracture model, whereas intragastric supplementation with UA improved fracture healing and reduced pro-inflammatory responses. Collectively, these findings demonstrated that UA alleviates osteogenic dysfunction through inhibition of the nuclear factor-κB signalling pathway and regulation of macrophage-mediated inflammation under TNF-α-induced inflammatory conditions, thereby promoting osteogenesis and fracture healing.