Journal of dental research最新文献

Multiple sensory afferents, including mechanosensitive and nociceptive nerves, are projected to the periodontium. Peptidergic afferents expressing transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin, mediate pain caused by orthodontic forces. However, their role in orthodontic force-induced alveolar bone remodeling is poorly understood as is the contribution of mechanosensitive ion channels such as Piezo2 in nociceptive nerves. To investigate this role, we studied orthodontic tooth movement and alveolar bone remodeling using neural manipulations and genetic mouse models. Chemical ablation of TRPV1-expressing afferents localized to the trigeminal ganglia decreased orthodontic force-induced tooth movement and the number of osteoclasts in alveolar bone on the compression side. The extent of the force-induced increase in the ratio of receptor activator of nuclear factor kappa-B ligand/osteoprotegerin in the periodontium was modestly decreased in the chemical ablation group. Furthermore, chemogenetic silencing of TRPV1-lineage afferents reduced orthodontic tooth movement and the number of osteoclasts. Piezo2 was expressed in most periodontal afferents, and chemogenetic inhibition of Piezo2-expressing neurons decreased orthodontic tooth movement and the number of osteoclasts. In addition, the conditional knockout of Piezo2 in TRPV1-lineage afferents decreased orthodontic tooth movement and the number of osteoclasts. Overall, these results suggest that nociceptor neurons play critical roles in orthodontic force-induced alveolar bone remodeling and that the mechanical activation of neuronal Piezo2 in nociceptive nerves facilitates orthodontic tooth movement and associated alveolar bone remodeling.

Dental caries, as one of the prevalent oral infectious diseases worldwide, constitutes a considerable disease burden. Fluoride has been widely used to prevent dental caries for decades. However, fluoride alone may not always be sufficient. The major cariogenic bacterial species, Streptococcus mutans, has not been effectively controlled by daily fluoride exposure, possibly because it has a detoxification mechanism. Studies have shown that most microorganisms have fluoride exporters dedicated to exporting fluoride ions (F^-). S. mutans possesses 2 homologous genes, eriC^F1 and eriC^F2, which encode fluoride exporters, but their function has not been fully clarified. In this work, we constructed the markerless gene deletion mutants, overexpression, and complemented strains of S. mutans UA159. Assessing fluoride sensitivity, intracellular F^- levels, and cell membrane permeability revealed that EriC^F1 was the major functional unit of the fluoride exporter in S. mutans. To further enhance the antibacterial efficiency of fluoride, we identified 3 diphenylurea derivatives that might target EriC^F1 by molecular docking, which significantly enhanced the antibacterial effect of sodium fluoride (NaF) by synergistically impeding fluoride efflux, as demonstrated by chequerboard broth microdilution assays. Moreover, these compounds combined with 1 mM NaF impaired the cariogenicity of S. mutans significantly in vivo and with good biocompatibility, especially compounds 9 and 15. Collectively, these findings suggest that fluoride exporters in S. mutans could serve as a potential target for caries prevention, and the diphenylurea derivatives identified for targeting EriC^F1 could be a valuable therapeutic approach when combined with fluoride, providing promising measures for dental caries prevention.

The stability of messenger RNA (mRNA) is controlled by proteins that bind to adenosine-uridine-rich sequences (AREs) in their 3' untranslated regions (3'UTR), known as AU-binding proteins. One of these proteins is tristetraprolin (TTP; encoded by Zfp36), which promotes degradation of mRNAs with AREs in their 3'UTR. TTP accelerates the decay of its target transcripts, many of which encode proinflammatory mediators that promote tumorigenesis. TTP underexpression has been reported in multiple cancer types. Oral squamous cell carcinoma is an aggressive disease characterized by high morbidity and few therapeutic options. The role of TTP has not been studied in oral epithelium homeostasis nor in its carcinogenesis. Herein, using tissue-specific TTP knockout mice (TTP-KO), we show that TTP expression is relevant for oral epithelium homeostasis. TTP-KO mice developed dysplastic lesions in the tongue along with inflammatory infiltrates in the connective tissue. Analysis of the inflammatory infiltrate revealed the presence of mast cells (MCs), CD45+ cells, and CD11b+ cells, with the MCs being the most abundant cell type and associated with cyclooxygenase-2 expression. Recruitment of MCs was dependent on tumor necrosis factor-α (TNFα) upon TTP ablation in the tongue. Although the infiltration of MCs was dependent on TNFα activity, this did not affect the development of tongue dysplasia. We analyzed the status of the NF-κB pathway, finding its activation. In addition, we demonstrate that K-ras activation combined with Zfp36 deletion leads to the rapid onset of the oral tongue phenotype and significantly reduces mouse survival. Our results support the notion that TTP expression protects against oral carcinogenesis, regulates the inflammatory infiltrate, and maintains the epithelial microenvironment, potentially serving as a barrier to tumorigenesis.

Historically, broad-spectrum antibiotics have represented a major component of the therapeutic armamentarium used to treat common oral diseases associated with a bacterial etiology. The fact that these diseases are due to the accumulation of multispecies biofilms composed of ever-increasing numbers of resistant organisms has dramatically affected the efficacy of many of these drugs. Furthermore, it is now appreciated that repeated use of broad-spectrum antibiotics also affects the composition of the host commensal microbiota, which can have both local and systemic implications. In recognition of the limitations of classical antibiotics, alternative chemical, physical, and mechanical strategies are either in use or development. These include novel narrow-spectrum antimicrobials such as antitoxins, bacteriophages, and antibody-conjugated drugs that can target specific microbes while minimizing the emergence of resistant organisms and preserving eubiotic microbes. Other approaches, such as new broad-spectrum non-antibiotic strategies and probiotics, are aimed at disrupting or altering the composition of oral biofilms and their extracellular matrices to facilitate the elimination of overt pathogens by the host response and/or adjunctive antimicrobials. This critical review describes the use and limitations of broad- and narrow-spectrum strategies currently being used to treat common bacterially induced oral diseases as well as alternative methods in development.

Understanding how dental attendance evolves throughout life can inform targeted preventive health care policies by identifying key moments when people are more or less likely to seek dental care. Trajectory modeling of age and time trajectories takes a life course approach to understanding dental attendance, offering insights into both developmental perspectives (e.g., life stages) and structural perspectives (e.g., social position and health care systems) throughout the life course. This study used group-based trajectory modeling to identify (1) the age trajectories of dental attendance among Australian adults from young adulthood to retirement age and (2) the distinct time trajectories of dental attendance among Australian working-age adults. Data from the Household, Income and Labour Dynamics in Australia (HILDA) study was used to fit 2 trajectory models (age and time based). Age trajectories were fitted for individuals aged 15 to 64 y using dental attendance data from 3 time points: 2009, 2013, and 2017. Time trajectories were fitted for working-age adults (24-54 y) using data from 2009 to 2017 and descriptively analyzed by social characteristics. Dental attendance was classified as frequent (less than 2 y since the last visit) or infrequent (2 y or longer). Two distinct age trajectories emerged among participants (N = 11,189): the mostly frequent (75.1%) and declining-infrequent group (24.9%). A sharp decline in the probability of being frequent attendees was observed between 15 and 20 y in a quarter of the population with no subsequent change. Four time trajectories were identified (n = 7,033): consistently frequent (37.8%), consistently infrequent (8.9%), increasing attendance (22.2%), and declining attendance (31%). Descriptive analysis showed that age and social inequalities were evident in the trajectories. The findings emphasize the need for preventive health care policies that account for life-stage dynamics and their impact on attendance behaviors, in addition to improving structural factors.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck; however, the efficacy of existing treatment is limited and new effective strategies need to be explored. Our previous work demonstrates that isoguanosine (isoG) is a promising nucleoside molecule with superior self-assembly capability and significant anti-OSCC potential. However, the antitumor mechanism of isoG remains unclear. In this study, we reveal that the antiproliferative effect of isoG is mediated by its cellular metabolite, isoguanosine 5'-monophosphate (isoGMP), which induces excessive endoplasmic reticulum (ER) stress and cell death through adenosine monophosphate-activated protein kinase (AMPK) activation. IsoG activates AMPK and induces ER stress at low concentrations, with minimal impact on cell viability at these concentrations. To further explore the therapeutic potential of isoG, we investigated its role in modulating chemosensitivity. Our findings show that AMPK activation enhances the sensitivity of OSCC cells to 5-fluorouracil (5-FU), and the combination of isoG and 5-FU exhibits a synergistic anticancer effect. Building on the self-assembly characteristics of isoG, we developed an innovative treatment platform by introducing dynamic borate ester bonds to form an isoguanosine-phenylenediboronic acid-isoguanosine (isoGPBisoG) structure. When combined with 5-FU, this platform achieved remarkable therapeutic efficacy in 2 OSCC cell-derived xenograft models, with tumor inhibition rates of 71.0% and 56.6%, respectively, compared with control. These findings establish isoG as a potent enhancer of chemotherapeutic efficacy in OSCC via AMPK activation. More importantly, the isoGPBisoG and 5-FU combination represents a significant paradigm of a synergistic therapy platform. This novel approach offers a promising direction for the development of more effective OSCC treatments.

Head and neck squamous cell carcinoma (HNSCC) is one of the deadliest human cancers, with the overall 5-year survival rate stagnating in recent decades due to the lack of innovative treatment approaches. Apart from the recently Food and Drug Administration-approved epidermal growth factor receptor inhibitor and immune checkpoint inhibitor, alternative therapeutic strategies that target epigenetic abnormalities, an emerging cancer hallmark, remain to be fully explored. A pathological epigenetic landscape, characterized by widespread reprogramming of chromatin modifications such as DNA methylation and histone modifications, which drives transcription deregulation and genome reorganization, has been extensively documented in numerous cancers, including HNSCC. Growing evidence indicates that these frequent epigenomic alterations play pivotal roles in regulating malignant transformation, promoting metastasis and invasion, and reshaping the tumor microenvironment. Furthermore, these epigenetic changes also present unique vulnerabilities that open new avenues for identifying novel prognostic biomarkers and developing targeted antitumor therapies. In this review, we summarize recent discoveries of epigenetic dysregulations in HNSCC, with a focus on deregulated chromatin modifications, which include aberrant DNA methylation, oncohistone H3 lysine 36 to methionine (H3K36M) mutation, as well as recurrent mutations or altered expression of chromatin-modifying enzymes such as NSD1, EZH2, and KMT2C/D. Importantly, we discuss the various molecular mechanisms underlying the contributions of these epigenetic alterations to HNSCC development, particularly their involvement in deregulated cell proliferation and cell death, metabolic reprogramming, tumor immune evasion, and phenotypic plasticity. Finally, we conclude by highlighting the translational and clinical implications of targeting the epigenetic machinery, which offers promising prospects for overcoming resistance to conventional radiotherapy/chemotherapy and enhancing the response to immunotherapy in HNSCC.

It is important to maintain confidence in the risk and benefit balance of major caries-preventive programs using fluoride. The ongoing debate about potential effects of early-life exposures to fluoride on cognitive neurodevelopment requires high-quality scientific evidence. This study aimed to investigate the potential effects of fluoride exposure on cognitive neurodevelopment assessed with the Wechsler Adult Intelligence Scale 4th edition (WAIS-IV) in an Australian population-based sample. The sample was selected from the National Child Oral Health Study (NCOHS) 2012-2014. NCOHS collected data on socioeconomic factors, oral health behaviors, and residential history to estimate percentage lifetime exposure to fluoridated water during the first 5 y of life (%LEFW). NCOHS children were also examined by trained and calibrated examiners to assess dental fluorosis (a reliable and valid individual biomarker of total fluoride intake during early childhood). The sample was followed up in 2022-2023 to collect data on cognitive neurodevelopment (intelligence quotient [IQ]) using the WAIS-IV, which was administered by trained and calibrated qualified psychologists. Multivariable regression models were generated to investigate associations between the 2 exposure measurements (%LEFW and dental fluorosis) with full-scale IQ (FSIQ) scores, controlling for important confounding effects. Hypotheses of noninferiority were also tested, contrasting different levels of exposure to fluoride. Some 357 participants aged 16 to 26 y completed the WAIS-IV, with a mean FSIQ score of 109.2 (95% confidence interval [CI]: 107.8-110.5). The estimates of the multivariable regression models demonstrated slightly higher FSIQ scores among the exposed than the nonexposed. The adjusted β of 100%LEFW versus 0%LEFW was 1.07 (95% CI: -2.86, 5.01) and of having dental fluorosis versus no fluorosis was 0.28 (95% CI: -3.00, 3.57). The hypothesis of noninferiority tests found that FSIQ scores of those exposed and nonexposed to fluoride were equivalent. The study provided consistent evidence that early childhood exposure to fluoride does not have effects on cognitive neurodevelopment.

The long-term success of dental implants depends on the ability of soft tissues to form a protective barrier, limiting pathogen infiltration into peri-implant tissues. Here, we investigated the impact of an anodized surface modification on mucosal integration. Scanning electron microscopy and surface chemistry characterization were carried out on miniaturized implants. Following placement in fresh extraction sockets of mice, peri-implant tissues were examined at 4 time points. Histology along with quantitative immunohistochemistry for Keratin14, Vimentin, Laminin5, and CD68 were carried out on postimplant day (PID) 3 to assess early events in soft-tissue repair; on PID7, when peri-implant epithelialization was complete; at PID14, when osseointegration was complete; and at PID28, when soft-tissue maturation was nearing completion. In all cases, an intact junctional epithelium served as a reference. These analyses supported 3 conclusions: first, maturation of the peri-implant epithelium (PIE) is a protracted process, consistent with clinical observations. Second, maturation of the soft tissue-implant interface is slower than maturation of the bone-implant interface. Third, there is a benefit, albeit transient, to soft-tissue maturation around an anodized implant surface. Given its prolonged time course, strategies to improve and/or accelerate PIE maturation are likely to have significant clinical benefit.

Early childhood caries (ECC) is the most common noncommunicable childhood disease-an important health problem with known environmental and social/behavioral influences lacking consensus genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multiancestry population of U.S. preschool-age children (N = 6,103) ages 3 to 5 y participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used International Caries Detection and Assessment System criteria to measure ECC; the primary trait was the number of primary tooth surfaces with caries experience (i.e., dmfs index). We estimated heritability and concordance rates and conducted genome-wide association analyses to estimate overall genetic effects as well as stratified by sex, household water fluoride, and dietary sugar and leveraged combined gene/gene-environment effects using 2-degree-of-freedom joint tests. Common genetic variants explained 24% of ECC phenotypic variance among unrelated individuals, while concordance rates were 0.64 (95% confidence interval [CI] = 0.42-0.79) among monozygotic twins and 0.44 (95% CI = 0.34-0.53) among first-degree relatives. Across all analyses, we identified 21 novel nonoverlapping genome-wide significant loci (P < 5 × 10^-8) and 1 genome-wide significant gene (TAAR6) associated with ECC. The taste receptor activity gene set, with known roles in chemosensing, bacterial recognition, and innate immunity in the oral cavity, was strongly associated with ECC. While no locus remained significant after studywise multiple-testing correction, 3 loci were nominally significant (P < 0.05) and directionally consistent in external cohorts of 285,248 adults (rs1442369, DLGAP1 and rs74606067, RP11-856F16.2) and 18,994 children (rs71327750, SLC41A3). Meanwhile, the strongest marker known to be associated with adult caries (rs1122171, tagging the long noncoding RNA PITX1-AS1) was nominally significant (P = 0.01) and directionally consistent with ECC in our study. Taken together, the results of this study add to the genomics knowledge base for early childhood caries, offer several plausible candidates for future mechanistic studies, and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations.