Journal of dental research最新文献

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.

Odontoblasts are terminally differentiated cells that exhibit mechanosensitivity and mineralization capacity. Mechanosensitive ion channels such as Piezo1 are present in odontoblasts and are associated with their physiological functions via Ca²⁺ signaling. Both Ca²⁺ signals via Ca²⁺ influx from mechanosensitive ion channels and Ca²⁺ release from Ca²⁺ stores function as secondary messenger systems for various biological phenomena. The endoplasmic reticulum (ER) serves as an intracellular Ca²⁺ store that mobilizes intracellular Ca²⁺. Changes in Ca²⁺ concentration inside the ER are among the factors that cause ER stress. Perivascular cells are located around odontoblasts in the dental pulp. Although such formation indicates that perivascular cells interact with odontoblasts, their detailed profiles under developmental and pathological conditions remain unclear. In this study, we revealed that pericyte marker, neural/glial antigen 2 (NG2)-positive cells, in cell-rich zones (CZs) can differentiate into Piezo1-positive odontoblasts following genetic odontoblast depletion in mice, and modeled as odontoblast death after severe dentin injury and as reparative dentin formation. NG2-positive pericytes differentiated into odontoblasts faster than glial cells. To determine how NG2-positive cells differentiate into Piezo1-positive odontoblasts, we focused on the ER-stress sensor protein, activating transcription factor 6a (ATF6a). After genetic odontoblast depletion, NG2-positive cells regenerated in the odontoblast layer and were capable of acting as functional odontoblasts. In the presence of extracellular Ca²⁺, the application of a sarco/ER Ca²⁺-ATPase (SERCA) inhibitor, thapsigargin, known as an ER-stress inducer, increased the intracellular Ca²⁺ concentration in the odontoblast lineage cells (OLCs). The increase was significantly inhibited by the application of a pharmacologic Piezo1 inhibitor, indicating that ER stress by SERCA inhibition augmented Piezo1-induced responses in odontoblast progenitor cells. However, the physiological activation of G_q-coupled receptors by adenosine diphosphate did not induce Piezo1 activation. Gene silencing of ATF6a and/or NG2 impaired the mineralization of OLCs. Overall, ATF6a orchestrates the differentiation of NG2-positive pericytes into functional odontoblasts that act as sensory receptor cells and dentin-forming cells.

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.

It has been questioned whether Streptococcus mutans can still be considered the major etiological agent for caries. The main argument is that most evidence has been based on single-species identification. The composition of the oral microbiome was not analyzed. This systemic review aims to assess the prevalence and abundance of S. mutans in caries-active (CA) and caries-free (CF) subjects based on clinical studies in which the microbiome was investigated. Three databases (PubMed, Cochrane, Embase) were searched until May 22, 2023, for eligible publications that included CA and CF subjects and reported the detection of both S. mutans and the oral microbial community, using DNA-based methods. The clinical and microbial outcomes were summarized and further analyzed using a random-effects model. Of 22 eligible studies, 3 were excluded due to the high risk of bias. In the remaining 19 studies, 16 reported the prevalence of S. mutans, 11 reported its relative abundance, and 8 reported both parameters. The prevalence of S. mutans in CA was either similar to (n = 4) or higher than (n = 12) the CF group. The reported relative abundance in CA was higher than CF in all 11 studies, although the values varied from 0.001% to 5%. Meta-analysis confirmed the significance of these findings. The summary of microbial community data did not reveal other caries-associated bacterial genera/species than S. mutans. In conclusion, the collected evidence based on microbiome studies suggests a strong association between the prevalence and abundance of S. mutans and caries experience. While the cariogenic role of S. mutans in the oral ecosystem should be recognized, its actual function warrants further exploration.

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.

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.

Cisplatin-based chemotherapy is a cornerstone treatment for advanced recurrent head and neck squamous cell carcinoma (HNSCC). However, the effectiveness of the treatment is often hindered by intrinsic and acquired resistance and associated toxicity, highlighting a pressing unmet clinical need. Here, our compound screening identified Aurora kinase inhibitors, particularly those targeting Aurora A kinase, as potential agents to sensitize resistant HNSCC cells to cisplatin. While Aurora kinases are well-established regulators of mitosis, their precise role in cisplatin resistance is largely unknown, given that cisplatin confers toxicity primarily in cells undergoing DNA replication. We confirmed that depletion of Aurora A or its activators enhanced cisplatin response in resistant HNSCC cells. Analyses of a comprehensive database and locally treated HNSCC patient samples revealed compelling associations between Aurora A overexpression/activation and cisplatin resistance, tumor recurrence, and poor patient survival. Pharmacologic inhibition of Aurora A effectively synergized with cisplatin treatment in cellular assays and a syngeneic mouse tumor model of HNSCC. Mechanistically, Aurora A inhibition enhanced apoptosis induction after cisplatin treatment, particularly in S-phase cells; induced replication stress; and suppressed the repair of cisplatin-induced DNA crosslinking. Taken together, our findings shed light on important functions of Aurora A kinase beyond mitotic regulation. The multifaceted roles of Aurora A suggest its potential as a prime anticancer drug target. Given the ongoing investigations into numerous Aurora inhibitors for cancer therapy, exploring their clinical applications in HNSCC, especially in combination with platinum drugs, may hold significant promise.

Due to the complex anatomical structures of the root canal, thorough intracanal disinfection has always been challenging in endodontic treatment. Existing intracanal medicaments exhibit limitations such as low permeability and suboptimal antibacterial performance. Thus, an intracanal medicament that combines excellent operating performance with potent antibacterial properties is required. Therefore, we designed an injectable hydrogel loaded with modified triple antibiotic drugs (mTAD) through a Schiff base reaction of carboxymethyl chitosan (CMCS) and polyethylene glycol aldehyde (OHC-PEG-CHO), mTAD/CMCS/OHC-PEG-CHO (mTCP). We subsequently evaluated the characteristics of mTCP. Moreover, the antibacterial capacity of the hydrogels was assessed in vitro. The effects of mTCP on the cell biocompatibility and odonto-/osteogenic differentiation of stem cells from the apical papilla (SCAPs) were also examined. Furthermore, we established a periapical inflammation model in the young permanent teeth of a Beagle dog and explored the effects of mTCP on root canal disinfection and root development. Our findings revealed that mTCP exhibited excellent operability, fluidity, and ease of removal from the root canal. mTCP presented outstanding antibacterial efficacy both in vitro and in vivo, attributed to its exceptional permeability and sustained release of mTAD. The odonto-/osteogenic differentiation of SCAPs was augmented by adding mTCP. Moreover, mTCP facilitated root elongation, dentinal wall thickening, and apical closure in the Beagle dog model. mTCP exhibited a pronounced effect on promoting periapical tissue healing and root development. In conclusion, mTCP hydrogel has promising potential for root canal disinfection in endodontic therapy.