Inflammation is a key physiological process in the regeneration of bone tissue following injury. The acute inflammatory response, along with the timely resolution of inflammation, is essential for effective bone tissue repair. Exacerbation of either acute or chronic inflammation can lead to impaired bone regeneration, which is closely associated with interactions between immune cells and bone-related cells, as well as the regulatory roles of various inflammatory cytokines. In this review, we discuss the role of the immune microenvironment in bone regeneration and the negative impact of dysregulated inflammation on bone regeneration, and highlight on the need for timely elimination of inflammation. Additionally, the application of nanobiomaterials with immunomodulatory function in the treatment of inflammatory bone defects is discussed to clarify its current challenges and the future direction of its development.

The aging of mesenchymal stromal cells (MSCs) is characterized by impaired osteogenic differentiation and enhanced adipogenic differentiation. Studies have identified stanniocalcin‑1 (STC1) as a core component of the senescence‑associated secretory phenotype and a regulator of osteoblast maturation; however, its role in MSC biology remains poorly understood. In the present study, bone marrow‑derived MSCs were used and in vitro functional assays together with molecular and omics‑based analyses were performed to investigate the role of STC1. It was observed that STC1 expression was upregulated in aged MSCs and during both osteogenic and adipogenic differentiation. Small interfering RNA‑mediated depletion of STC1 reduced cellular senescence and notably impaired osteogenic differentiation, whereas adipogenic and chondrogenic differentiation were not significantly affected. RNA sequencing revealed that STC1 knockdown led to the downregulation of osteogenesis‑related genes and the concomitant upregulation of inflammatory factors. Genes associated with closing differentially accessible regions (DARs) were enriched in osteogenic pathways, whereas those associated with opening DARs were predominantly involved in inflammatory responses. Mechanistically, STC1 knockdown led to the activation of NF‑κB signaling. Pharmacological inhibition assays using NF‑κB inhibitors were performed to validate pathway involvement. Pharmacological inhibition of NF‑κB signaling significantly mitigated the impairment in osteogenic differentiation and attenuated the inflammatory response induced by STC1 depletion. Collectively, these findings suggest that STC1 is involved in the regulation of osteogenic differentiation and inflammatory signaling through the modulation of NF‑κB activity in MSCs. Furthermore, targeting STC1 while inhibiting NF‑κB signaling may represent a promising therapeutic strategy for alleviating MSC dysfunction and age‑related bone loss.

DAZAP1 promotes OSCC progression via phase separation.

AIM:To evaluate the clinical and radiographic outcomes of transcrestal sinus floor elevation (TSFE) with simultaneous implant placement in sites with residual bone height (RBH) of 3-5 mm. MATERIALS AND METHODS:This retrospective cohort study included patients who underwent TSFE with simultaneous implant placement between December 2017 and September 2023. According to the intraoperative bone grafting status, patients were divided into two groups: the non-grafting group and the grafting group (Bio-Oss Collagen). Patient medical histories were collected, and radiographic parameters were measured at the following timepoints: preoperative (T0), immediate postoperative (T1), healing phase (T2, 4-6 months postoperatively), and follow-up period (T3, 1-6 years postoperatively). Implant survival rate, complication-free survival rate, incidence of sinus membrane perforation (SMP), endo-sinus bone gain volume (ESBGV), endo-sinus bone gain height (ESBGH), marginal bone loss (MBL), apical bone height (ABH), and mean cost of treatment were evaluated. A linear mixed model (LMM) regression was employed to identify key determinants influencing endo-sinus bone augmentation following TSFE. RESULTS:Sixty-six dental implants placed in 57 patients were included (non-grafting group: 26 implants in 21 patients; grafting group: 40 implants in 36 patients). After the 1- to 6-year follow-up, the survival rate of implants was 100% in two groups (p > 0.05) and complication-free survival rate was 84.85% at implant level (non-grafting group: 80.77%, grafting group: 87.50%; p > 0.05) and 82.46% at patient level (non-grafting group: 76.19%, grafting group: 86.11%; p > 0.05). The incidence of SMP was 11.54% and 10.00% in non-grafting and grafting groups, respectively (p > 0.05). ESBGV, ESBGH, and ABH were significantly greater in the grafting group compared to the non-grafting group (p < 0.05). No significant differences in MBL were found (p > 0.05). The total treatment cost was significantly lower in the non-grafting group than in the grafting group (p < 0.05), whereas no significant difference was found in retreatment costs between the groups (p > 0.05). The LMM regression results showed that the core determinant of ESBGV was postoperative maxillary sinus augmentation volume (p < 0.05). CONCLUSION:Within the limitations of this study, TSFE with simultaneous implant placement demonstrated medium- to long-term stable clinical and radiographic outcomes in the posterior atrophic maxilla ridges with RBH ranging from 3 to 5 mm regardless of bone grafting. While the grafting strategy significantly enhanced endo-sinus bone augmentation, the non-grafted approach was associated with significantly lower overall treatment costs.

Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibition has shown significant therapeutic benefit in fibrous dysplasia. However, sustained RANKL inhibition is required to maintain its therapeutic effect. Moreover, disease rebound following discontinuation of denosumab, a human monoclonal RANKL antibody, poses a major clinical challenge to fibrous dysplasia treatment, thereby highlighting the need for strategies that preserve lesion-level efficacy while limiting systemic exposure. Matrix metalloproteinases (MMPs), which are essential for osteoclast function and bone remodeling, have emerged as a key pathogenic pathway in fibrous dysplasia. Lesion profiling revealed elevated expression of MMP-9, -13, and -14 in osteoclast-rich fibrous dysplasia lesions, with dynamic regulation in response to pharmacologic RANKL inhibition and withdrawal. We hypothesized that matrix metalloproteinases may serve as lesion-associated biological cues for localized drug delivery in fibrous dysplasia. We developed an injectable, sustained, and matrix metalloproteinase-responsive local drug delivery system by integrating triglycerol monostearate nanoparticles within a dynamically crosslinked hyaluronic acid-based hydrogel scaffold (HPD/TGMS). To validate this strategy, the small-molecule RANKL inhibitor AS2676293 was loaded into triglycerol monostearate to generate HPD/TGMS@A. Matrix metalloproteinase-mediated cleavage of the ester linkage in triglycerol monostearate enabled protease-responsive drug release, further regulated by hydrogel-constrained perilesional retention. HPD/TGMS@A demonstrated favorable injectability, self-healing behavior, cytocompatibility, and matrix metalloproteinase-dependent anti-osteoclastic activity in vitro. HPD/TGMS@A significantly attenuated fibrous dysplasia lesion progression and improved bone microarchitecture in a GNASR201C knock-in fibrous dysplasia mouse model through perilesional injection. Altogether, these findings establish HPD/TGMS as a localized, lesion-responsive drug delivery strategy in fibrous dysplasia.

Supramolecular hydrogels hold significant potential in drug delivery and tissue engineering, with standing out for their unique properties. Despite their promise, predicting nucleoside bioactivity remains challenging. This study aims to predict the biological activity of nucleosides to guide the rational synthesis of hydrogels. Specifically, nine predictive models and databases for various biological activities were built with feature-selected machine learning methods including decision trees, logistic regression, random forest, and extreme gradient boosting. Then, the Molecular Bioactivity Specificity Index (MBSI) was introduced to gauge the primary bioactivity of nucleoside derivatives, and the Composite Molecular Attribute Score (CMAS) was devised to measure the overall performance of nucleoside derivatives. Subsequently, screening strategies for bioactive nucleoside hydrogels were established, and two candidate hydrogels (GMP and dGMP) with high hydrogel-forming ability, biocompatibility, and antibacterial activity were identified. Finally, two hydrogels were validated for antibacterial treatment of periodontitis. This study highlights the feasibility of ML-based strategies and MBSI/CMAS in rationally designing bioactive nucleoside hydrogels for biomedical applications. The discovery of GMP and dGMP hydrogels and their successful validation in periodontitis models highlight the potential of this strategy for developing targeted therapies for oral diseases.

Oral submucous fibrosis (OSF) is a chronic, progressive, premalignant disorder with expanding epidemiology, rising annual incidence, and increasing malignant transformation rates. Therefore, elucidating its pathogenesis and establishing early intervention strategies remain urgent priorities. In this study, we evaluated the interplay between USP10 and IL-6 and its potential influence on the development of oral submucous fibrosis. Immunohistochemistry and immunofluorescence were used to examine the correlation among IL-6, USP10, and pathological angiogenesis in OSF clinical samples and mouse models, revealing high IL-6 expression in the inflammatory microvasculature alongside downregulated USP10. Functional experiments on human umbilical vein endothelial cells (HUVECs) in vitro, including administration of recombinant human IL-6, demonstrated that USP10 inhibited angiogenesis, cell migration, and cell proliferation, and that targeting USP10 reversed IL-6-mediated pathological angiogenesis. RNA sequencing further identified differentially expressed genes in HUVECs, while mass spectrometry, western blotting, and co-immunoprecipitation uncovered that USP10 interacts with vascular endothelial growth factor receptor 1 (VEGFR1) and inhibits its ubiquitination, thereby suppressing angiogenesis. Collectively, these findings indicate that IL-6 promotes pathological angiogenesis by suppressing USP10 and its interaction with VEGFR1, thus accelerating OSF progression, and suggest that targeting USP10 may represent a promising mechanism for further investigation in OSF therapy.

Supervised training for oral potentially malignant disorder (OPMD) image segmentation requires expensive annotated data, particularly scarce in remote regions with few medical specialists. This study aims to propose a self-guided pre-training method to automatically extract features from unlabeled images, enhancing the performance of OPMD lesion segmentation. This study utilized 3,417 OPMD photographs from ZJUSS as the internal dataset and two independent external datasets from WCHS and CS-SJTU for validation. The internal labeled dataset was evaluated using five independent patient-level train/validation/test splits to prevent patient-level data leakage. We proposed a multiscale separable attention masked image model, MS-SAMIM, and a self-guided mask generation method. To enhance robustness, we incorporated a teacher–student consistency constraint and a contrastive learning constraint. Our model achieved 84.35

TRIM21, a member of the TRIM family of E3 ubiquitin ligases, is increasingly recognized for its role in immune regulation and has been implicated in various malignancies. However, its function in oral squamous cell carcinoma (OSCC) remains undefined. Here, we show that TRIM21 is significantly upregulated in human OSCC tissues and serves as an independent adverse prognostic factor for overall survival. Consistently, systemic Trim21 deficiency significantly suppressed OSCC tumorigenesis in a 4-nitroquinoline 1-oxide-induced oral carcinogenesis model. In contrast, TRIM21 knockdown did not significantly affect OSCC cell proliferation or migration in vitro, suggesting that its tumor-promoting effects may not be primarily mediated by the tumor cell-intrinsic behaviors examined under these conditions. Supporting this notion, bioinformatic analyses revealed strong associations between TRIM21 expression, immune checkpoint-related pathways, and immune cell infiltration. To further assess the contribution of TRIM21 in the tumor microenvironment in vivo, we established an orthotopic tongue allograft model and found that microenvironmental Trim21 deficiency markedly suppressed tumor growth. CyTOF and mIHC analyses further showed that microenvironmental Trim21 deficiency reduced PD-L1 expression on conventional dendritic cells (cDCs) and enhanced the cytotoxic activity of tumor-infiltrating CD8+ T cells. Collectively, TRIM21 promotes OSCC progression predominantly through modulation of the tumor immune microenvironment. This role may involve supporting an immunosuppressive cDC phenotype and restraining CD8+ T-cell-mediated antitumor immunity. TRIM21 may therefore serve as an independent prognostic biomarker and a potential therapeutic target in OSCC, with possible relevance to combination strategies involving immune checkpoint blockade.

OBJECTIVES:To develop an automated system for generating standardized reports for oral potentially malignant disorders (OPMDs) from white-light images, aiming to reduce documentation workload, facilitate early intervention, and enable longitudinal lesion monitoring. METHODS:We proposed the SegORG model using 441 oral mucosa images and 1323 corresponding reports. It employed SegFormer for lesion segmentation; a visual encoder extracted global and local visual embeddings, which were projected into a pre-trained large language model (LLM feature) space via a lightweight visual mapper. The Qwen2.5-7B model then generated structured diagnostic reports, enhanced by text augmentation techniques to improve diversity and professionalism. RESULTS:SegORG achieved BLEU-4, ROUGE-L, and CIDEr scores of 0.291, 0.517, and 0.578, respectively. Additionally, the model obtained a clinical diagnostic F1-score of 0.695 and a median expert rating of 4 on the Likert scale (p < 0.001). It significantly outperformed conventional baseline models (R2Gen, METransformer, and SwinB+BERT9k) and contemporary general-purpose multimodal LLMs (GPT-4, Gemini 2.5 Pro, and Qwen2.5-VL), despite its lean architecture (90.4 M trainable parameters). CONCLUSIONS:By enhancing visual feature extraction and achieving efficient text alignment, SegORG offers an effective technical pathway for OPMDs reports automation. While single-center validation shows promise, multicenter trials are needed to assess generalizability.

Discoidin domain receptors (DDRs) are nonintegrin collagen receptors which could be activated by various collagens. Overexpressed in numerous cancers, DDRs participate in tumorigenesis, tumor growth, dissemination, and metastasis. Immune checkpoint inhibitors (ICIs) have demonstrated low response rates in tumors such as head and neck cancer and pancreatic cancer, possibly due to the insufficient presence of effector T cells and the abundant collagen fibers in the tumor microenvironment. Recently, several studies indicate that DDRs account for ICIs resistance. For instance, DDR1 can prevent the anti-tumor immune responses via mediating the rearrangement of collagen fibers, increasing the secretion of interleukin-18 (IL-18) as well as facilitating the formation of neutrophil extracellular traps (NETs). DDR2 may participate in the establishment of immunosuppressive tumor microenvironment by recruiting myeloid-derived suppressor cells (MDSCs) and promoting the M2 polarization of macrophages. Notably, the interaction between collagens and immune cells also acts as a pivotal role in mediating tumor immune escape. Targeting DDRs and upstream regulators including collagen has been reported to significantly restore the antitumor immunity or inhibit tumor development, such as utilizing DDR1 inhibitors via AI screening from FDA-approved therapeutics or natural products, and strategies for collagen synthesis inhibition or collagen degradation. However, the above approaches are largely limited to preclinical studies and still warrant further validation in clinical trials. Based on the current evidences, DDRs serve as promising targets for improving the efficacy of ICIs against cancers; more studies are anticipated to reveal unclarified mechanisms of DDRs in regulating anti-tumor immunity.

BACKGROUND:Periodontal health is increasingly recognized as an integral component of systemic homeostasis. However, whether its disruption contributes to the development of autoimmune diseases (ADs) remains unclear in prospective settings. OBJECTIVES:The aim of this study was to prospectively evaluate the association between periodontal symptoms and the risk of ADs, with particular attention to immunometabolic pathways and shared disease clusters. MATERIAL AND METHODS:A total of 465,454 participants from the UK Biobank were included. Cox proportional hazards models were employed to evaluate the association between periodontal symptoms and the incidence of 20 ADs. Sensitivity and subgroup analyses were conducted to assess the robustness of the results. Mediation analyses explored the potential mediating roles of 6 immunometabolic biomarkers. To address inter-disease correlations and reduce multicollinearity, factor analysis was applied to identify latent clusters of ADs. RESULTS:During a median follow-up of 13.3 years, 33,895 participants developed at least 1 AD. Periodontal symptoms were linked to a higher risk of several ADs, with significant associations observed for bullous disorders, lichen planus, primary biliary cholangitis (PBC), and psoriasis. Mediation analyses revealed modest but statistically significant contributions of immunometabolic markers, particularly C-reactive protein (CRP). Factor analysis identified 3 AD clusters - autoantibody-mediated, autoimmune inflammatory and autoimmune metabolic diseases - all of which were significantly associated with poor periodontal health. CONCLUSIONS:Periodontal symptoms were positively associated with multiple ADs and latent clusters, with these correlations being partly mediated by immunometabolic factors. The findings highlight the role of periodontal-systemic interactions in autoimmune pathogenesis.

Periodontitis represents a persistent inflammatory condition marked by gradual damage to the gingival connective tissues and alveolar bone. Programmed cell death (PCD) is essential for preserving immune balance and includes various forms such as apoptosis, pyroptosis, necroptosis, and ferroptosis. Nevertheless, the principal PCD pathway that contributes periodontal inflammation has not been clearly identified. In this work, we integrated multiple publicly available single-cell RNA sequencing datasets and applied diverse gene set scoring approaches to systematically characterize the dynamic expression of PCD-associated genes in periodontitis-affected tissues. Ferroptosis emerged as one of the important PCD pathways, mainly occurring in macrophages. Cell-cell communication and spatial analyses suggested that ferroptotic macrophages were located adjacent to fibroblast-enriched regions and may interact with fibroblasts through Galectin and OSM signaling pathways. Functionally, ferroptotic macrophages suppressed fibroblast proliferation and migration while amplifying their pro-inflammatory response, underscoring their pivotal role in sustaining chronic inflammation. Furthermore, machine-learning analyses identified LAPTM5 as one of the ferroptosis-associated hub genes in macrophages. Knockdown of LAPTM5 in macrophages suppressed ferroptosis and subsequently attenuated fibroblast inflammatory responses. Collectively, our study highlights ferroptosis as one of the key pathogenic mechanisms in periodontitis and identifies LAPTM5-driven macrophage ferroptosis as a key driver of fibroblast dysfunction and chronic inflammation, providing potential therapeutic insights for restoring periodontal immune balance.

Oxygen consumption rate (OCR) and Extracellular acidification rate (ECAR) analysis in DAZAP1-overexpression and -knockdown Cal27 and HN6 cell lines.

Objectives To investigate the proficiency of artificial intelligence (ChatGPT-4 and DeepSeek-v3) in responding to frequently asked questions (FAQs) related to oral lichen planus (OLP). Study Design Twenty-three OLP-related FAQs were adapted from reputable sources. Responses generated by ChatGPT-4 and DeepSeek-v3 were assessed by expert panels across five domains: accuracy, comprehensibility, logic, fairness, and simplicity. Results DeepSeek-v3 outperformed ChatGPT-4 in comprehensiveness (4.65 ± 0.37 vs. 4.04 ± 0.54; P < 0.001), logic (4.41 ± 0.32 vs. 4.03 ± 0.35; P < 0.001), and fairness (4.34 ± 0.33 vs. 4.03 ± 0.27; P < 0.001). ChatGPT-4 scored higher in simplicity (4.25 ± 0.31 vs. 4.04 ± 0.28; P = 0.034), while DeepSeek-v3 had a modest advantage in accuracy (4.49 ± 0.38 vs. 4.22 ± 0.34; P = 0.025). DeepSeek-v3 performed better in comprehensiveness and logic for “Causes” and “Symptoms,” and in accuracy for “Risk & Complications.” ChatGPT-4’s simplicity was most evident in “Causes” and “Symptoms.” In “Treatment & Management,” DeepSeek-v3 excelled in logic and comprehensiveness, while ChatGPT-4 showed greater simplicity and occasional accuracy. Conclusion ChatGPT-4 provides concise, accessible information, whereas DeepSeek-v3 offers broader, more detailed responses. Combining both models may improve patient understanding of OLP.

Oral submucous fibrosis (OSF) and oral leukoplakia (OLK) are both potentially malignant disorders. Patients with habits of betel quid chewing and smoking are frequently diagnosed with both conditions. Notably, the rate of malignant transformation is significantly higher in individuals with concurrent OSF and OLK than in those with either condition alone. Laser assisted photodynamic therapy (PDT) is a therapeutic modality that has been applied in the management of OLK, though its use in OSF remains unveiled. In this study, we report three patients with concurrent OSF and OLK who underwent laser-assisted PDT and demonstrated favorable outcomes and safety. These findings suggest that laser-assisted PDT may be a suitable therapeutic option for patients with OLK in the context of OSF.

Proliferative verrucous leukoplakia (PVL) is an uncommon but highly aggressive oral potentially malignant disorder, characterized by a high rate of malignant transformation and notable resistance to conventional treatments, including surgery, laser ablation, and systemic agents. Herein, we present a case of PVL in a 60‑year‑old female with no history of tobacco, alcohol, or betel nut consumption. The lesion, situated on the left buccal mucosa, was treated with laser‑assisted photodynamic therapy (PDT). Following two sessions, the lesion resolved completely, with no recurrence during a 20‑month follow‑up. This case report reinforces the limited evidence advocating PDT as a viable alternative for PVL, particularly when combined with laser pretreatment to circumvent the impediment posed by lesion hyperkeratosis.

Dynamic monitoring of cell-matrix interfacial remodeling remains challenging with conventional endpoint assays, particularly in degeneration-relevant microenvironments. The cartilage endplate (CEP), a key structure for load transmission and solute exchange in the intervertebral disc, provides a model in which early pathological changes involve abnormal cell-matrix adhesion and extracellular matrix remodeling. Here, we established a label-free, long-term monitoring platform based on metasurface-enhanced surface plasmon resonance microscopy (Meta-SPRM) to quantify CEP chondrocyte interfacial dynamics under mechanical, genetic, and inflammatory perturbations. Under perfusion-induced shear, CEP chondrocytes exhibited magnitude-dependent interfacial adaptation, with high shear causing a more sustained reduction in interfacial coupling and contact area. FGFBP1 knockdown further exacerbated this shear-associated loss, supporting a protective role for FGFBP1 in interfacial stability under mechanical stress. Under inflammatory stimulation with M1 macrophage-conditioned medium, interfacial signals increased despite a late decrease in cell spreading, consistent with enhanced interfacial adhesion and matrix remodeling. Axin2 expression increased under shear, was further increased by FGFBP1 knockdown in the shear model, and was also elevated under inflammatory stimulation, supporting its use as an endpoint readout of Wnt/β-catenin-associated transcription across the tested perturbations. Collectively, Meta-SPRM enables continuous live-cell monitoring of CEP chondrocyte interfacial dynamics and relates these changes to endpoint molecular readouts, providing a reproducible platform for comparative biointerface studies and in vitro screening of candidate interventions.

Cisplatin-based chemotherapy responses are highly heterogeneous across cancers, with the mechanisms governing drug sensitivity remaining incompletely understood. Using genome-wide CRISPR-Cas9 knockout screening, we systematically characterized regulators of cisplatin response and uncovered a counterintuitive finding: mTOR inhibition promotes cisplatin tolerance, contradicting the canonical view that PI3K-AKT-mTOR activation confers chemoresistance. Mechanistically, both mTOR suppression and cisplatin treatment converge to activate cytoprotective autophagy, which enhances cancer cell survival under therapeutic stress. The amino acid transporter SLC7A5 was identified and validated as a key integrator of the mTOR-autophagy axis that modulates cisplatin sensitivity. SLC7A5 expression positively correlates with cisplatin sensitivity across cancer cell lines, and its downregulation is associated with cisplatin resistance in multiple cancer types, supporting its potential as a mechanistically grounded predictive biomarker. Translationally, leucine supplementation sensitizes cancer cells to cisplatin in an SLC7A5-mTOR-autophagy-dependent manner. Collectively, our study defines a novel mTOR-autophagy adaptive loop governing cisplatin tolerance, positions SLC7A5 as a central regulatory node with both biomarker and therapeutic target value, and proposes leucine supplementation as a simple, translatable strategy to improve cisplatin efficacy in SLC7A5-expressing tumors.

Periodontitis is a chronic inflammatory disease driven by subgingival dysbiosis. Despite progress in characterizing microbial diversity, functional heterogeneity at the single-cell level remains poorly understood, mainly due to challenges from low microbial biomass and host contamination. Here, we present a single-cell RNA sequencing framework for profiling subgingival bacteria, enabling high-resolution analysis of these communities in health and periodontitis. Using 16 subgingival samples, we generated an atlas spanning 133,458 cells across 285 species, including 57 core active species grouped into eight functional clusters. Health-associated subpopulations specializing in adhesion and polysaccharide degradation decline in periodontitis, coinciding with hypoxia and elevated amino acid availability. The keystone pathogens T. denticola and P. gingivalis display species-specific tendencies in amino acid metabolism-related transcriptional profiles, while P. intermedia harbors a proteolytic subpopulation enriched in periodontitis. These insights deepen our understanding of periodontitis pathogenesis and inform precision diagnostics and therapeutic strategies.