International Journal of Oral Science最新文献

Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.

Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A_2A receptor (A_2AR) on trigeminal ganglia. Antagonism of trigeminal A_2AR with a selective A_2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A_2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A_2AR. Therefore, we established trigeminal A_2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

The overall health condition of patients significantly affects the diagnosis, treatment, and prognosis of endodontic diseases. A systemic consideration of the patient’s overall health along with oral conditions holds the utmost importance in determining the necessity and feasibility of endodontic therapy, as well as selecting appropriate therapeutic approaches. This expert consensus is a collaborative effort by specialists from endodontics and clinical physicians across the nation based on the current clinical evidence, aiming to provide general guidance on clinical procedures, improve patient safety and enhance clinical outcomes of endodontic therapy in patients with compromised overall health.

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8⁺ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases, yet its association with progressive periodontitis remains unexplored. To investigate the involvement and significance of ferroptosis in periodontitis progression, we assessed sixteen periodontitis-diagnosed patients. Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid (GCF) collection was performed for further analyses. Clinical metrics, proteomic data, in silico methods, and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis. Subsequent western blot analyses validated key findings. Finally, a single-cell RNA sequencing (scRNA-seq) dataset (GSE164241) for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression. Periodontitis progression was identified as occurring at a faster rate than traditionally thought. GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles. In addition, specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins, including SNCA, CA1, HBB, SLC4A1, and ANK1 was strongly associated with the clinical progression status of periodontitis. Moreover, we found specific proteins - drivers or suppressors - associated with ferroptosis (SNCA, FTH1, HSPB1, CD44, and GCLC), revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis. Additionally, the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis. Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients, which offer new insights into the molecular mechanisms of progressive periodontal disease. These findings may lead to novel diagnostic and therapeutic strategies.

Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

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.

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

The aim of this study was to explore the impact of chronic apical periodontitis (CAP) on atherosclerosis in apoE^−/− mice fed high-fat diet (HFD). This investigation focused on the gut microbiota, metabolites, and intestinal barrier function to uncover potential links between oral health and cardiovascular disease (CVD). In this study, CAP was shown to exacerbate atherosclerosis in HFD-fed apoE^−/− mice, as evidenced by the increase in plaque size and volume in the aortic walls observed via Oil Red O staining. 16S rRNA sequencing revealed significant alterations in the gut microbiota, with harmful bacterial species thriving while beneficial species declining. Metabolomic profiling indicated disruptions in lipid metabolism and primary bile acid synthesis, leading to elevated levels of taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), and tauroursodeoxycholic acid (TDCA). These metabolic shifts may contribute to atherosclerosis development. Furthermore, impaired intestinal barrier function, characterized by reduced mucin expression and disrupted tight junction proteins, was observed. The increased intestinal permeability observed was positively correlated with the severity of atherosclerotic lesions, highlighting the importance of the intestinal barrier in cardiovascular health. In conclusion, this research underscores the intricate interplay among oral health, gut microbiota composition, metabolite profiles, and CVD incidence. These findings emphasize the importance of maintaining good oral hygiene as a potential preventive measure against cardiovascular issues, as well as the need for further investigations into the intricate mechanisms linking oral health, gut microbiota, and metabolic pathways in CVD development.

Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival biofilm. The therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative stress. Sinensetin (Sin) is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant activities. Our study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular mechanisms. We found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells (PDLCs) under inflammatory conditions. Administered Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in vivo. By molecular docking, we identified Bach1 as a strong binding target of Sin, and this binding was further verified by cellular thermal displacement assay and immunofluorescence assays. Chromatin immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter, subsequently upregulating the expression of the key antioxidant factor HO-1. Further functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant effects. Additionally, we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1, thereby inducing HO-1 expression and inhibiting oxidative stress. Overall, Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.