The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.

The severe pain caused by oral ulcers seriously affects food intake and speech, bringing great inconvenience in daily life. Drug-loaded patches are mostly used to treat oral mucosal diseases such as oral ulcers and oral lichen planus, but their effects are limited because of the influences of saliva and muscle movement. To enhance the adhesion of drug-loaded patches used in the oral cavity, we designed antimicrobial peptides (AMPs)-modified polycaprolactone (PCL)–collagen nanosheets (APCNs). The internal layer is a bioactive and antibacterial collagen layer modified with antimicrobial peptides. The backing layer is a hydrophobic PCL layer with good mechanical strength that can reduce external influences. We have characterized and tested the APCNs. First, the APCNs exhibited continuous and strong adhesion to irregular buccal mucosa surfaces under wet conditions and external force action. Antibacterial experiments showed that the APCNs had high antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. Moreover, the APCNs showed good biocompatibility and promoted the adhesion of fibroblasts in vitro. Furthermore, APCNs treatment accelerated ulcer healing in a Sprague Dawley rat oral ulcer model. Our study developed antibacterial, wet-adhesive, and healing-promoting PCL-collagen nanosheets and demonstrated that these nanosheets could be promising adhesive therapeutic agents for the treatment of oral mucosal ulcers.

Mucosal immunity plays a critical role in the pathogenesis of inflammatory immune diseases. This study leverages single-cell RNA sequencing, spatial transcriptomics, and spatial proteomics to compare the cellular mechanisms involved in periodontitis between humans and mice, aiming to develop precise strategies to protect the gingival mucosal barrier. We identified key conserved and divergent features in cellular landscapes and transcriptional profiles across the two species, underscoring the complexity of inflammatory responses and immune dynamics in periodontitis. Additionally, we revealed a novel regulatory mechanism by which epithelial cells modulate macrophage behavior and inflammation through the JAG1–Notch pathway. Validation through animal experiments revealed that JAG1 inhibition reduces inflammation in epithelial cells, mitigating periodontitis. Our findings advance the understanding of periodontal disease pathogenesis and highlight the importance of integrating human and animal model data to develop treatments aligned with human physiology, offering potential therapeutic targets for controlling inflammation and enhancing tissue regeneration.

To explore the mechanism underlying autophagy disruption in gingival epithelial cells (GECs) in diabetic individuals. Bone marrow-derived macrophages (BMDMs) and GECs were extracted from C57/bl and db/db mice, the exosomes (Exo) were isolated from BMDMs. qRT‒PCR and Western blotting were performed to analyse gene expression. The AnimalTFDB database was used to identify relevant transcription factors, and miRNA sequencing was utilised to identify relevant miRNAs with the aid of the TargetScan/miRDB/miRWalk databases. A dual-luciferase assay was conducted to verify intermolecular targeting relationships. Similar to BMDMs, BMDM-derived Exos disrupted autophagy and exerted proinflammatory effects in GEC cocultures, and ATG7 may play a vital role. AnimalTFDB database analysis and dual-luciferase assays indicated that NR5A2 is the most relevant transcription factor that regulates Atg7 expression. SiRNA-NR5A2 transfection blocked autophagy in GECs and exacerbated inflammation, whereas NR5A2 upregulation restored ATG7 expression and ameliorated Exo^DM-mediated inflammation. MiRNA sequencing, with TargetScan/miRDB/miRWalk analyses and dual-luciferase assays, confirmed that miR-381-3p is the most relevant miRNA that targets NR5A2. MiR-381-3p mimic transfection blocked autophagy in GECs and exacerbated inflammation, while miR-381-3p inhibitor transfection restored ATG7 expression and attenuated Exo^DM-mediated inflammation. BMDM-derived Exos, which carry miR-381-3p, inhibit NR5A2 and disrupt autophagy in GECs, increasing periodontal inflammation in diabetes.