Jiansheng Su

The precise regulation of bone homeostasis and the balance between bone resorption and formation in periodontitis remain unclear. This study explores the role of long intergenic noncoding RNA-erythroid prosurvival (lincRNA-EPS) in inflammatory osteoclastogenesis and bone resorption. LincRNA-EPS knockout (KO) worsened LPS-induced alveolar bone resorption in vivo and osteoclast differentiation in vitro. Transcriptomics and protein sequencing showed dysregulated osteoclastogenesis and iron homeostasis without lincRNA-EPS, marked by increased expression of Lcn2 . Knockdown of Lcn2 in osteoclast precursors (OCPs) resulted in a reduction in the level of iron metabolism and osteoclastogenesis; however, the regulatory response was delayed in KO cells. Correspondingly, overexpression of lincRNA-EPS accelerated the regulation of iron metabolism. Further, reducing Lcn2 levels in wildtype mice alleviated periodontitis-related bone loss, but not in KO mice. Taken together, we identified the critical role of lincRNA-EPS in regulating osteoclastogenesis under inflammatory environment, by preventing excessive iron metabolism caused by Lcn2.

In the original publication [...].

Distinct clinical phenotypes of periodontitis are associated with specific microbiome profiles and diverse inflammatory conditions. Current drug delivery systems face challenges in precisely modulating this dynamic microenvironment. Effective inhibition of bone resorption can only be achieved through a strategic response to bacterial infections and inflammation within the periodontal pocket, followed by prompt treatment tailored to disease severity. In this study, tannic acid (TA) is loaded into hollow mesoporous silica nanoparticles (HMSNs) that are functionalized with positively charged polyarginines (R8) and negatively charged human serum albumin (HSA). These HMSNs‐R8@TA‐HSA (HRT) nanoparticles are then encapsulated within an injectable Nap‐Gly‐Phe‐Phe‐Tyr‐OH (NapGFFY) hydrogel (NHRT). The intermediate linker R8 can interact with both arginine gingipain A (RgpA) and reactive oxygen species (ROS), which serve as markers of bacterial infections and inflammation, respectively. HSA, arginine, TA, and nitric oxide are differentially released from the hydrogel in response to varying concentrations of RgpA and ROS, demonstrating excellent antibacterial, antioxidant, and anti‐inflammatory properties. This smart RgpA/ROS dual‐responsive and injectable hydrogel with multifunctional therapy provides new prospects for the management of periodontitis.

Temporomandibular joint osteoarthritis (TMJOA) is a multifaceted degenerative disease characterized by progressive cartilage degradation, chronic pain, and functional limitations of the TMJ, significantly affecting patients’ quality of life. Although metabolic homeostasis in chondrocytes is crucial for cartilage health, the mechanisms underlying metabolic dysregulation in TMJOA remain poorly characterized. This study aimed to investigate the metabolic imbalance in TMJOA cartilage and explore novel therapeutic strategies targeting metabolic reprogramming. RNA sequencing revealed a significant imbalance between glycolysis and oxidative phosphorylation (OXPHOS) in TMJOA cartilage, with a marked shift toward glycolysis, which is associated with inflammation and cartilage degradation. To counteract this imbalance, Laccase domain-containing 1 (Lacc1), a metabolic regulator involved in both inflammation and metabolic homeostasis, was selected for investigation, as its role in chondrocytes had not been explored. We engineered macrophage-derived extracellular vesicles (EVs) to overexpress Lacc1 (OE-EVs), aiming to restore metabolic balance and modulate inflammation in chondrocytes. In vitro, OE-EVs significantly reduced IL-1β-induced inflammation, inhibited glycolysis by decreasing key glycolytic enzymes, improved mitochondrial function by decreasing mitochondrial superoxide levels, and the restoration of normal mitochondrial structure. In vivo, micro-computed tomography (Micro-CT) and histological analyses demonstrated that OE-EVs effectively alleviated inflammation and promoted cartilage repair, as indicated by a 1.55-fold increase in toluidine blue-stained cartilage area compared to the TMJOA group, reflecting improved cartilage matrix integrity and proteoglycan retention. These findings highlight the therapeutic potential of Lacc1-engineered EVs to target mitochondrial metabolism, reestablish metabolic homeostasis, and reduce inflammation in TMJOA, offering a novel and promising strategy for improving clinical outcomes in TMJOA patients.

Periodontitis, a chronic inflammatory disorder primarily induced by bacterial infection and exacerbated by excessive oxidative stress, leads to the destruction of alveolar bone. Diabetes mellitus intensifies this oxidative stress in periodontal tissues and disrupts the oral microbiome, thereby aggravating periodontal conditions and complicating the management of periodontitis. The development of materials that possess comprehensive therapeutic effects, including antibacterial, antioxidant and osteogenic properties, for the treatment of diabetic periodontitis (DP) remains at the forefront of research. In this study, we introduced a copper hydrogen phosphate (CuHP) composite hydrogel, which exhibited multi-enzymatic activities at varying pH levels. This hydrogel was synthesized by encapsulating CuHP within a commercially available sodium alginate (SA) matrix. In vitro analyses explored the pH-responsive enzymatic activities, biocompatibility and the antioxidant, osteogenic and antibacterial properties of the resultant SA/CuHP composite hydrogel. At neutral pH, the hydrogel primarily exhibited catalase-like activity, providing it with antioxidant capabilities that reduced the inhibitory effects of oxidative stress on osteogenesis in bone marrow mesenchymal stem cells. In mildly acidic conditions, the hydrogel displayed peroxidase-like activity, catalysing the production of more potent reactive oxygen species and exhibiting significant antibacterial efficacy against Aggregatibacter actinomycetemcomitans. Furthermore, the SA/CuHP hydrogel continuously released copper ions, which synergistically enhance its osteogenic and antimicrobial efficacies. In vivo studies demonstrated that this composite hydrogel significantly inhibited bacterial growth and promoted bone regeneration in a rat model of DP. These findings suggest that the SA/CuHP hydrogel holds substantial potential for the treatment of periodontitis in patients with diabetes.

Background: The conventional treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is surgery; however, the efficacy of definitive chemoradiotherapy (CRT) remains controversial.Objective: This study aimed to evaluate the ability of deep learning (DL) models to identify patients with LA-HNSCC who can achieve organ preservation through definitive CRT and provide individualized adjuvant treatment recommendations for patients who are better suited for surgery.Methods: Five models were developed for treatment recommendations. Their performance was assessed by comparing the difference in overall survival rates between patients whose actual treatments aligned with the model recommendations and those whose treatments did not. Inverse probability treatment weighting (IPTW) was employed to reduce bias. The effect of the characteristics on treatment plan selection was quantified through causal inference.Results: A total of 7,376 patients with LA-HNSCC were enrolled. Balanced Individual Treatment Effect for Survival data (BITES) demonstrated superior performance in both the CRT recommendation (IPTW-adjusted hazard ratio (HR): 0.84, 95% confidence interval (CI), 0.72–0.98) and the adjuvant therapy recommendation (IPTW-adjusted HR: 0.77, 95% CI, 0.61–0.85), outperforming other models and the National Comprehensive Cancer Network guidelines (IPTW-adjusted HR: 0.87, 95% CI, 0.73–0.96).Conclusion: BITES can identify the most suitable treatment option for an individual patient from the three most common treatment options. DL models facilitate the establishment of a valid and reliable treatment recommendation system supported by quantitative evidence.

The primary pathology of periodontitis involves the gradual deterioration of periodontal tissues resulting from the inflammatory reaction triggered by bacterial infection. In this study, a novel drug for periodontal pocket injection, known as the Shed-Cu-HA hydrogel, was developed by incorporating copper ions (Cu²⁺) and Shed-derived exosomes (Shed-exo) inside the hyaluronic acid (HA) hydrogel. Suitable concentrations of Cu²⁺ and Shed-exo released from Shed-Cu-HA enhanced cell viability and cell proliferation of human periodontal ligament stem cells. Additionally, the Shed-Cu-HA demonstrated remarkable antibacterial effects against the key periodontal pathogen (Aa) owing to the synergistic effect of Cu²⁺ and HA. Furthermore, the material effectively suppressed macrophage inflammatory response via the IL-6/JAK2/STAT3 pathway. Moreover, the Shed-Cu-HA, combining the inflammation-regulating properties of HA with the synergistic osteogenic activity of Shed-exo and Cu²⁺, effectively upregulated the expression of genes and proteins associated with osteogenic differentiation. The experimental findings from a mouse periodontitis model demonstrated that the administration of Shed-Cu-HA effectively reduced the extent of inflammatory cell infiltration and bacterial infections in gingival tissues and facilitated the regeneration of periodontal bone tissues and collagen after 2 and 4 weeks of injection. Consequently, it holds significant prospects for future applications in periodontitis treatment.

To investigate the effects of long intergenic noncoding RNA‐erythroid prosurvival (lincRNA‐EPS) on periodontal inflammation mediated by inflammasomes and to explore its mechanism. Experimental periodontitis was induced in KO (lincRNA‐EPS^−/−) and WT (lincRNA‐EPS^+/+) mice to compare the periodontal bone loss and inflammation by using micro‐computed tomography, immunofluorescence staining and haematoxylin and eosin staining. The expression and activation of cysteinyl aspartate‐specific proteinase‐11 (caspase‐11) and NOD‐like receptor protein 3 (NLRP3) inflammasomes, as well as nuclear factor‐kappa B (NF‐κB) activation in mouse gingival fibroblasts (MGFs), were measured by real‐time quantitative polymerase chain reaction, Western blotting, enzyme‐linked immunosorbent and lactate dehydrogenase assays. MGFs were transfected with overexpression plasmids to assess the biological functions of lincRNA‐EPS. RNA pull‐down and immunoprecipitation experiments were performed to identify the interacting protein of lincRNA‐EPS. LincRNA‐EPS‐expressing lentivirus was locally administered to inflamed periodontal tissues to evaluate its salvage function in periodontitis. The absence of lincRNA‐EPS increased bone loss and expression of myeloperoxidase, interleukin‐1α (IL‐1α) and IL‐1β in the inflammatory periodontium. LincRNA‐EPS KO MGFs exhibited increased expression and activation of caspase‐11/NLRP3 inflammasome components than WT MGFs under lipopolysaccharide (LPS) stimulation. The expression and activation of these molecules were inhibited in lincRNA‐EPS overexpressed MGFs. Mechanistically, lincRNA‐EPS directly bound to transactive response DNA‐binding protein 43 (TDP43) in the nucleus of MGFs, and TDP43 knockdown exerted a similar inhibitory effect on NF‐κB activation and the inflammasomes as lincRNA‐EPS overexpression. Locally injecting lincRNA‐EPS‐expressing lentivirus weakened the periodontal damage. LincRNA‐EPS inhibits the LPS‐induced production and activation of caspase‐11 and NLRP3 inflammasomes by suppressing the activation of the NF‐κB signalling pathway via interacting with TDP43, thereby alleviating periodontitis.