Journal of dental research最新文献

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.

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.

Porphyromonas gingivalis is one of the major pathogens of chronic periodontitis. P. gingivalis can cause systemic inflammation, amyloid β protein deposition, and hyperphosphorylation of tau protein, leading to Alzheimer's disease (AD)-like lesions. P. gingivalis oral infection causes gut microbiota alteration, gut barrier dysfunction, and intestinal immune response and inflammation. The microbiota-gut-brain axis has a potential role in the pathogenesis of AD. Whether P. gingivalis affects AD-like lesions via the gut-brain axis needs more study. In this study, orally administered P. gingivalis induced alveolar resorption, intestinal barrier impairment, and AD-like lesions. Oral infection with P. gingivalis induced oral and gut microflora dysbiosis, imbalance of the tryptophan metabolism pathway of gut microbiota, and elevated levels of 3-hydroxykynurenine in the sera and hippocampi. The key metabolite, 3-hydroxykynurenine, suppressed Bcl2 gene expression, leading to neuronal apoptosis and promoting AD-like lesions in vivo and in vitro. These findings suggest that P. gingivalis can induce AD pathogenesis through the gut-brain axis, providing new ideas for the prevention and treatment of AD.

Sjögren's disease (SjD), an autoimmune inflammatory disease, is associated with reduced androgen levels. Testosterone replacement therapy alleviates SjD progression, but the exact mode of action is unclear and adverse effects are reported. Our present study found that dihydrotestosterone (DHT) enhances the transcription and expression of aquaporin 5 (AQP5) in human salivary gland epithelial cells via androgen receptor (AR) signaling. The DHT/AR complex binds to the androgen response element of the AQP5 promoter, upregulating AQP5 expression. Using orchiectomized mice, we observed that reduced levels of DHT resulted in hyposalivation and SjD progression. By screening compounds with similar structures to DHT, we identified that DHT-like ginsenoside Rg3, a natural product, upregulates AQP5 expression in salivary gland epithelial cells via binding with AR. The Rg3/AR complex acts like DHT/AR and binds to the androgen response element of the AQP5 promoter to promote AQP5 transcription in salivary gland epithelial cells. Gavage of Rg3 restored saliva secretion and submandibular gland morphology in orchiectomized and nonobese diabetic mice. Transcriptome analysis revealed that Rg3 treatment upregulates saliva secretion-related signaling and downregulates inflammation and immune activation-related signaling in the submandibular glands of orchiectomized mice. In conclusion, our results indicated that Rg3 restores androgen deficiency-triggered xerostomia via AR-mediated AQP5 upregulation.

Genetic dental disorders (GDDs) can occur either isolated or as part of syndromes. Clinically, deviations in tooth shape, size, or structure, as well as the absence of multiple teeth, lead to severe dysfunction and a reduced quality of life, requiring lifelong preventive, conservative, and prosthodontic dental care. The dental management of prevalent dental diseases, such as caries or periodontitis, has been based on decades of research, whereas scientific data on the dental management of GDDs are scarce. This lack of data is challenging for dental practitioners, who must primarily rely on empirical knowledge only. Therefore, a systematic literature search and review were conducted on the dental management of common GDDs, such as ectodermal dysplasia, amelogenesis imperfecta, dentinogenesis imperfecta, periodontitis as a manifestation of rare systemic diseases, and X-linked hypophosphatemia and hypophosphatasia. The review revealed that 468 of the 9,115 retrieved publications met the inclusion criteria, with most being case reports or case series, highlighting a lack of robust clinical trials. This critical review provides a brief summary of the genetic background, key clinical signs, and treatment options for these conditions. The dominance of case reports emphasizes the need for improved reporting standards and long-term follow-up to support comprehensive data synthesis and meta-analyses. In addition, the uneven global distribution of publications suggests disparities in access to advanced dental care for GDDs. Efforts to standardize reporting and improve treatment documentation globally are crucial to addressing these challenges. In this way, information on GDD management can be improved, and statistical analyses of the data can be performed.