搜索结果：Journal of oral biosciences

The Journal of Oral Biosciences is dedicated to advancing and disseminating fundamental knowledge across the full spectrum of oral biosciences. This editorial features recently published review articles spanning key domains, including "craniofacial biology"; "bone, tooth, and mineral biology"; "periodontal and pulp biology"; "microbiology and immunology"; "pharmacology"; "biomaterials"; "oncology"; "salivary research"; and "regenerative medicine." The featured review articles address a diverse range of topics, including buccal bifurcation cysts, mandibular prognathism, glucose metabolism, gingival overgrowth, dextrins, chemokine receptor 5, electrical stimulation, the tumor microenvironment, computer-aided diagnosis, adiponectin, myoepithelial cells, secretory granules, apoptosis, dental regenerative medicine, and three-dimensional in vitro models. The review articles featured in the Journal of Oral Biosciences provide comprehensive insights into contemporary research themes and emerging concepts in oral biosciences. This editorial discusses their key findings and underscores their significance in advancing the understanding of oral health and disease.

Oral squamous cell carcinoma (OSCC) is characterized by aggressive biological behavior and limited therapeutic responsiveness. In this study, the objectives were to investigate the effects of cinobufagin (CBG) on the progression of OSCC, and to elucidate the underlying molecular mechanisms. The effects of CBG on OSCC cells were evaluated using in vitro assays to assess cell proliferation, clonogenic growth, apoptosis, migration, and invasion. Nuclear factor-kappa B (NF-κB) signaling activity was determined by immunoblotting, luciferase reporter assay, and p65 subcellular localization. The antitumor activity of CBG was further assessed in a xenograft mouse model, and its potential toxicity was evaluated by histological examination of the major organs. CBG treatment suppressed proliferation and clonogenic capacity of OSCC cells, while promoting apoptotic cell death. In addition, CBG significantly reduced the migratory and invasive abilities of OSCC cells. Mechanistically, CBG attenuated NF-κB signaling by decreasing p65 phosphorylation and inhibiting its nuclear translocation, resulting in reduced NF-κB transcriptional activity. Pharmacological activation of NF-κB partially reversed the antitumor effects of CBG. Moreover, CBG markedly inhibited in vivo tumor growth, and no histological toxicity was observed. CBG suppressed the malignant progression of OSCC, in vitro and in vivo. Its antitumor effects are associated with inhibition of p65 nuclear translocation and attenuation of NF-κB signaling, suggesting that CBG may represent a potential therapeutic candidate for OSCC.

Dental caries are caused by organic acids produced by cariogenic bacteria through carbohydrate metabolism. Suppression of acid production without disrupting the oral microbiome is a promising preventive strategy against dental caries. Surfactin, a naturally derived biosurfactant, has several biological activities. However, its effects on acid production by cariogenic bacteria remain unclear. In this study, the effects of surfactin on lactate production, growth, biofilm formation, and metabolic activity of Streptococcus sobrinus, were investigated. In vitro assays were performed to distinguish surfactin-mediated suppression of acidogenic metabolism from its effects on bacterial growth or biofilm formation, combined with molecular and enzymatic analyses to explore the underlying regulatory mechanisms. Surfactin significantly reduced lactate production in planktonic and biofilm-associated S. sobrinus, and it delayed environmental pH reduction in the presence of sucrose. Notably, these effects were observed without inhibition of bacterial growth or biofilm formation. There were no significant changes in the expression of lactate production-related genes, and lactate dehydrogenase activity was not inhibited by surfactin. In contrast, in the MTT assay, there was a transient reduction in metabolic activity, accompanied by delayed initiation of growth. These findings indicate that surfactin selectively attenuates acidogenicity in S. sobrinus, without markedly affecting bacterial viability or biofilm architecture, which is consistent with an anti-virulence mode of action. Although further validation in more complex oral environments and comprehensive safety assessments are required, this study provides fundamental evidence supporting the potential of naturally derived biosurfactants as a basis for future preventive strategies for caries.

Dental plaque is a highly organized polymicrobial biofilm, in which extracellular DNA serves as a vital structural and functional component of the extracellular matrix. The human antimicrobial peptide LL-37 plays an important role in oral innate defense, exhibiting both antimicrobial and immunomodulatory activities. Our recent study indicated that LL-37 forms stable complexes with bacterial DNA in dental plaque. This review summarizes current knowledge of the molecular mechanisms and immunological consequences of LL-37-bacterial DNA interactions in dental plaque, highlighting their potential implications in biofilm structure, innate immunity, and periodontal pathogenesis. LL-37 binds to oral bacterial DNA forming stable, nuclease-resistant, high-molecular-weight complexes with an aggregated morphology. These complexes abrogate the intrinsic antimicrobial activity of LL-37 while enhancing the stability and cohesiveness of the biofilm matrix. Moreover, LL-37-bacterial DNA complexes act as immunostimulatory molecules by activating TLR9 and the NLRP3 inflammasome, thereby triggering proinflammatory cytokine production in host immune cells. Notably, this immunostimulatory capacity varies with the bacterial source of the DNA, suggesting species-specific modulation of host responses. LL-37-bacterial DNA complex formation represents a key event at the interface of innate defense and dysbiosis in dental plaque. This dual nature of LL-37, whereby it acts as an antimicrobial peptide when alone, yet promotes biofilm formation and inflammation when complexed with bacterial DNA, sheds new light on the mechanisms underlying biofilm persistence and chronic inflammation. Understanding this interaction may open new avenues for therapeutic strategies targeting biofilm-associated periodontal diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is one of the most prevalent liver diseases globally, contributing to both economic and health-related challenges. We aimed to evaluate the global, regional, and national burden of MASLD from 1990 to 2023, quantify the contribution of identified modifiable risk factors, and project future prevalence up to the year 2050. Estimates of MASLD prevalence and disability-adjusted life-years (DALYs) were produced by age, sex, region, Socio-demographic Index (SDI), and Healthcare Access and Quality (HAQ) index across 204 countries and territories from 1990 to 2023 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023. The MASLD burden attributable to three risk factors (smoking, high BMI, and high fasting plasma glucose) was assessed as part of the GBD comparative risk assessment. As a secondary analysis, we used these estimates to forecast MASLD prevalence up to 2050 using fasting plasma glucose and mean BMI as predictors. Furthermore, to examine the relative contributions of population ageing, population growth, and changes in MASLD prevalence rate to the forecasted changes in case counts from 2023 to 2050, we conducted a decomposition analysis. In 2023, approximately 1·3 billion (95% uncertainty interval [UI] 1·2 to 1·4) individuals were estimated to be living with MASLD (ie, 16·1% of the global population), with an age-standardised prevalence rate of 14 429·3 (95% UI 13 268·3 to 15 990·6) per 100 000 population, representing a percentage increase of 142·7% (95% UI 139·2 to 146·7) in crude numbers from 1990 (0·5 billion [0·5 to 0·6]) and of 28·6% (27·8 to 29·5) in the rate (11 217·2 [10 276·8 to 12 467·0] per 100 000 in 1990). An estimated 3·6 million (2·8 to 4·5) total DALYs were attributable to MASLD worldwide in 2023, corresponding to an age-standardised DALY rate of 39·6 (31·2 to 49·9) per 100 000 population. Despite a 116·3% (93·3 to 139·4) increase in crude DALYs (from 1·7 million [1·3 to 2·1] in 1990), its age-standardised estimate remained consistent (1·8% [-8·6 to 12·8]) from 1990 (38·9 [30·1 to 49·8] per 100 000) to 2023. There was substantial variation in age-standardised estimates across regions. North Africa and the Middle East had the highest prevalence rate (29 246·1 [26 848·3 to 32 048·7] per 100 000) and Andean Latin America showed the highest DALY rate (152·3 [114·1 to 194·7] per 100 000). By contrast, the high-income Asia Pacific region had the lowest prevalence rate (8653·5 [7923·7 to 9592·8] per 100 000) and east Asia had the lowest DALY rate (16·3 [13·5 to 19·9] per 100 000) among all GBD regions. North Africa and the Middle East showed disproportionately higher prevalence rates relative to other regions with similar SDIs. Lower SDIs and HAQs were associated with higher age-standardised DALY rates. The age-standardised prevalence rate was consistently higher in males (15 616·4 [14 349·2 to 17 263·3] per 100 000 people in 2023) than in females (13 245·2 [12 132·0 to 14 692·6] per 100 000 people), and peaked at age 80-84 years in both sexes. The number of MASLD prevalent cases was the highest in younger adults, peaking at age 35-39 years for males and age 55-59 years for females. Among the risk factors for MASLD, high fasting plasma glucose presented the largest contribution to the age-standardised DALY rate of total MASLD in 2023 (2·2 [95% UI 1·6 to 3·1] per 100 000 people), followed by high BMI (1·4 [0·6 to 2·4] per 100 000 people) and smoking (1·0 [0·3 to 1·8] per 100 000 people). Our forecasting model estimates that 1·8 billion (95% UI 1·6 to 2·0) individuals are likely to have MASLD by 2050, representing a 42·0% increase from 2023. The age-standardised prevalence rate is expected to increase to 15 774·9 (95% UI 14 613·9 to 17 336·2) per 100 000 people in 2050, representing an average annual percentage change of 0·3% (95% UI 0·3-0·3). According to our decomposition analysis, this change will be primarily due to population growth, particularly in sub-Saharan Africa and North Africa and Middle East, and less by population ageing or epidemiological change. With a global prevalence of 16·1% and approximately 1·3 billion people already living with MASLD in 2023, the condition has and will continue to have substantial health and economic impacts worldwide. An inverse association between the HAQ Index and age-standardised DALY rates suggests that countries with lower health-care access and quality might be less well positioned to manage the growing MASLD burden, underscoring the need for strengthened health-system capacity in these settings. Gates Foundation.

Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. Gates Foundation, St Jude Children's Research Hospital.

Oral squamous cell carcinoma (OSCC) arises from the mucosal epithelium and is the most common cancer of the oral cavity. There are few major oncogenic events that could be therapeutically targeted in OSCC; therefore, the identification of novel target factors based on the molecular mechanisms of the tumorigenesis of OSCC is required. The extracellular matrix (ECM), a component of the tumor microenvironment, surrounds tumor cells, and it provides a scaffold for tumors. The ECM promotes tumor progression, and mechanical cues from increased ECM stiffness are involved in tumorigenesis. Recently, mechanosensitive ion channels have been identified as receptors for the ECM. Mechanosensitive ion channels respond to mechanical cues, alter intracellular signaling and affect tumor cell behavior such as cell proliferation. This review explores the role of the ECM and its receptors, mechanosensitive ion channels, and particularly Ca2+ channels. Mechanosensitive Ca2+ channels, Piezo-type mechanosensitive ion channel component 1 and transient receptor potential vanilloid 4, promote tumorigenesis of OSCC. We demonstrated that Ca2+ channels may represent novel molecular targets in OSCC.

Circadian rhythms in peripheral organs undergo dynamic reorganization during postnatal development. However, the mechanisms underlying the maturation of circadian clocks in the salivary glands, particularly in relation to feeding behavior, remain poorly understood. In this study, we aimed to characterize the developmental maturation of circadian rhythms in the mouse submandibular gland (SMG). PERIOD2::LUCIFERASE bioluminescence rhythms were recorded from cultured suprachiasmatic nucleus (SCN) and SMG tissues isolated from mice at postnatal days 0, 1, 7, 14, 21, and 28, and 8 weeks. Maternal behavior and pup feeding activity were continuously monitored using infrared video recording. Peak phases and circadian periods were analyzed to evaluate developmental changes. Robust circadian oscillations were observed in the SCN tissue at all developmental stages, with stable periods and peak phases. In contrast, rhythms in the SMG were rapidly damped in culture, and exhibited a progressive phase shift from the light phase to the middle of the dark phase during postnatal development. Circadian periods in both tissues remained close to 24 h throughout development. Behavioral analyses revealed that developmental changes in maternal care and feeding activity were closely associated with the phase realignment of SMG rhythms. After weaning, SMG peak phases resembled those in adult mice. Postnatal maturation of circadian rhythms in the SMG is characterized by progressive phase realignment that parallels the transition from suckling to independent feeding. These findings suggest that developmental coordination between feeding behavior and peripheral clock machinery contributes to the establishment of circadian regulation of salivary function.

The junctional epithelium (JE) is a specialized barrier that maintains periodontal tissue homeostasis. Although age-related changes have been reported in other epithelial tissues, the mechanisms underlying age-associated dysfunction in the JE remain largely unknown. In this study, the aims were to determine whether there is cellular senescence in the JE during natural aging, and to elucidate the underlying molecular mechanisms. JE was harvested from the maxillae of young (eight-week-old) and aged (72-week-old) male mice, and tissue sections were prepared. To evaluate age-related changes, histological analyses, including hematoxylin-eosin (HE) staining, immunofluorescence staining, and TUNEL assays, as well as bulk RNA sequencing (RNA-seq) for gene expression profiling, were performed. Differentially expressed genes (DEGs) were identified from the RNA-seq data, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Histological examination revealed no overt morphological differences in the JE between young and aged mice. However, the JE from aged mice had significantly fewer Ki67-positive cells and more TUNEL-positive apoptotic cells. RNA-seq identified DEGs in the JE of aged mice. GO and KEGG analyses indicated significant enrichment of inflammation- and aging-related pathways. RT-qPCR confirmed the increased expression of p16, Lcn2, and Defb3 in the JE of aged mice. Immunostaining also revealed increased numbers of γ-H2AX, p-STAT3, 8-OHdG, and 4-HNE positive cells in the JE of aged mice. The JE of aged mice had molecular hallmarks of cellular senescence. These findings highlight the role of senescence in the aging of periodontal barrier tissue.

Sodium hypochlorite (NaClO) is widely used as a root canal irrigant because it is an effective antimicrobial agent; however, cytotoxicity to periapical tissues remains a clinical concern. Peracetic acid (PAA) is a well-established disinfectant, but its oral biocompatibility, particularly at low concentrations, and commercially formulated preparations have not been fully evaluated. The antimicrobial efficacy and biocompatibility of a low-concentration PAA-based commercial disinfectant (Actril) were tested against representative oral pathogenic bacteria. Minimum inhibitory, bactericidal, and biofilm inhibitory concentrations were determined, and cytotoxicity toward gingival epithelial cells and periodontal ligament fibroblasts was assessed. Bactericidal activity against Enterococcus faecalis biofilms were evaluated using live/dead staining. Irrigation efficacy was further examined in E. faecalis-infected extracted human teeth using scanning electron microscopy and quantitative polymerase chain reaction. Actril exhibited antimicrobial activity at PAA-equivalent concentrations markedly lower than those required for NaClO, with reduced cytotoxicity toward periodontal tissue-related cells. Live/dead staining demonstrated bactericidal effects within E. faecalis biofilms, although variability was observed at threshold concentrations. In extracted tooth models, Actril facilitated biofilm disruption and exposure of dentinal tubules within a clinically relevant irrigation time. Quantitative analyses confirmed significant reduction of bacteria compared with non-irrigated controls, comparable to the effects of NaClO. Although PAA itself is not a novel antimicrobial agent, a low-concentration, commercially formulated PAA-based disinfectant demonstrated a favorable balance between antimicrobial efficacy and biocompatibility in oral biofilm models. These findings support the potential application of PAA as a low-toxicity antimicrobial strategy in endodontic environments.

Tooth morphogenesis is controlled by various molecules, and the enamel knot plays a important role as a signaling center. Here, we aimed to analyze the role of AmeloD in the development of the enamel knot. The AmeloD-stably expressing dental epithelial cell line, SF2, was established and RNA sequencing analysis was performed. The cusp morphology of AmeloD-deficient mouse molars was analyzed by micro-computed tomography. AmeloD-binding molecules were screened using the yeast two-hybrid methods. AmeloD was expressed in the enamel knot during tooth development. Proliferation was suppressed in cells overexpressing AmeloD, which was consistent with the cessation of proliferation in the enamel knot. RNA sequencing analysis revealed that the expression of proliferation-related molecules, such as Mki67, Ccnd1, and Ccnd2, decreased in AmeloD-overexpressing cells. Shh was expressed in the enamel knot, and in AmeloD-overexpressing cells, Shh promoted the expression of ameloblastin and Sox21. Furthermore, AmeloD-deficient mice had reduced intercuspal distance, mesiodistal and buccolingual diameters, and enamel hypoplasia. Odam, Selenof, Kct2, and TCF4 were identified as AmeloD-binding molecules using the yeast two-hybrid methods. AmeloD and Odam were expressed in similar regions during the earlier stages of ameloblast differentiation. To clarify how Odam regulates AmeloD, the Odam gene was transfected into AmeloD-overexpressing cells. In Odam-expressing cells, the suppression of proliferation and migration by AmeloD was inhibited. AmeloD promotes cell cycle arrest and activation of Shh signaling in the enamel knot, and it binds to Odam in the early stages of ameloblast differentiation, inhibiting the proliferation activity of Odam through these interactions.

To investigate the dose-dependent effects of Bisphenol A-glycidyl methacrylate (Bis-GMA), a monomer released from dental resin composites, on the proteome of human gingival fibroblasts. Primary human gingival fibroblasts were exposed to different concentrations of Bis-GMA (0.002 mM, 0.02 mM, and 0.2 mM) for 72 h, and protein extracts were analyzed using two-dimensional electrophoresis coupled with liquid chromatography-tandem mass spectrometry. Differentially abundant proteins were identified and functionally classified using STRING and Gene Ontology enrichment analysis. A total of 45 proteins were differentially abundant across the three exposure conditions. At 0.002 mM, there were indicators of an adaptive response, with upregulation of proteins related to mitochondrial function and cytoskeletal integrity. At 0.02 mM, there were indicators of cellular stress, including alterations in nuclear transport, cytoskeletal disorganization, and energy metabolism. At 0.2 mM, there was a marked shift towards protein underabundance, which may indicate disruption of proteostasis, oxidative stress, and endoplasmic reticulum stress. The proteomic profiles reflect the progressive loss of homeostasis, culminating in a cellular state compatible with apoptosis or senescence. These findings raise concerns regarding low-level exposure to Bis-GMA, which is often encountered after dental restorations. These results support the necessity to adopt clinical procedures that minimize release of monomers and to develop safer monomers.

The Fat gene family, also known as atypical cadherins, contributes to the formation of planar cell polarity, which determines organ shape, size, and polarity. However, their roles in tooth morphogenesis remain unclear. In this study, the aim was to investigate the spatiotemporal expression patterns of Fat1-Fat4 during murine tooth development. Quantitative polymerase chain reaction was performed using total RNA from newborn C57BL/6J murine tissues to determine Fat1-Fat4 expression. In situ hybridization was performed to examine the localization of Fat family transcripts during tooth development from embryonic Day 12.5 to birth. The dental epithelial stem cell line, M3H1, was used as an in vitro differentiation model, and small-interfering-RNA-mediated knockdown of Fat2 was performed to assess its function. Public single-cell RNA-sequence (scRNA-seq) datasets were analyzed to confirm cell-type specificity. All Fat genes were expressed in the teeth, with Fat2 having the highest level among tissues examined. Fat1 was expressed in the epithelial and mesenchymal cells, and Fat2 expression was restricted to the outer enamel epithelium (OEE) and stratum intermedia (SI). Fat3 and Fat4 were expressed in the dental mesenchyme. In M3H1 cells, Fat1 and Fat2 had biphasic expression at undifferentiated and differentiated stages. Fat2 knockdown decreased Sox2 and nephronectin expression, and increased Foxj1 expression. scRNA-seq supported Fat2 specificity in the OEE and SI. Fat genes have cell-type-specific and developmentally regulated expression during tooth development. Among them, Fat2 emerges as a novel marker of OEE and SI, and it may contribute to epithelial identity and differentiation during odontogenesis.

Nanostructured 2D/2D heterojunctions are emerging as efficient biosensing materials, providing unique electrochemical properties. Therefore, an ultrathin titanium carbide MXene-graphitic carbon nitride (Ti3C2/g-C3N4 denoted as TCN) heterojunction-based electrochemical immunosensor was developed for ultrasensitive and picomolar level quantification of TNF-α, as the persistent and elevated levels of TNF-α in the saliva have been correlated to oral cancer and its aggressiveness. A simple and one-pot hydrothermal synthesis technique was used for the synthesis of Ti3C2 MXene/g-C3N4 2D/2D heterojunction in various concentrations, and among these, 100TCN was chosen due to its superior electrochemical response and deposited on SPE for further bioconjugation. The synthesized heterojunctions and modified platform were well-characterized using several analytical and electrochemical techniques. The superior coupling interface of the heterojunction provides enhanced surface area and electrochemical properties by which the immunosensor exhibited a linear detection range of 1- 200 pg mL-1 with a sensitivity of 0.85 μA (pg/mL)-1 cm-2, a LOD of 1.05 pg mL-1 and a LOQ of 4.54 pg mL-1. It also exhibited good specificity towards the detection of TNF-α in presence of different interferents along with remarkable reproducibility (%RSD = 2.32%) as well as repeatability (%RSD = 3.03%). Furthermore, in spiked artificial saliva samples, the immunosensor achieved excellent recovery (91.6% to 102%). By enabling early, sensitive, and non-invasive detection, this immunosensor paves the way for transforming oral cancer from a silent killer into a disease that can be timely diagnosed and effectively managed.

Leptin receptor (LepR)+ stromal cells are widely recognized as skeletal stem/progenitor cells (SSPCs) in the bone marrow that generate osteolineage cells, and contribute to skeletal homeostasis under steady-state conditions and tissue repair. By expressing representative niche factors, including stem cell factor and C-X-C motif chemokine ligand 12, LepR+ SSPCs function as key microenvironmental components of the hematopoietic stem cell (HSC) niche. Over the past decade, genetic cell-labeling studies have identified LepR+ SSPCs in craniofacial tissues, including in the periodontal ligament and alveolar bone marrow, where they differentiate into osteoblasts and cementoblasts. Emerging evidence indicates that periodontal LepR + cells contribute to orthodontic remodeling, periodontal repair, and extraction socket healing. Independent SSPC populations may coexist with LepR+ SSPCs in oral tissues and contribute in parallel to tissue homeostasis. Periodontal LepR+ cells also express HSC niche-associated factors, suggesting their possible role in the regulation of local immune and hematopoietic environments. Because oral tissues are continuously exposed to mechanical forces and the oral microbiome, LepR+ SSPCs in the oral environment may function through unique regulatory mechanisms that influence skeletal homeostasis and hematopoiesis. In this review, current knowledge regarding LepR+ SSPCs in periodontal tissues is summarized, and their emerging roles in skeletal maintenance, tissue repair, and hematopoietic regulation is discussed. Further elucidation of the regulatory mechanisms governing these cells will advance understanding of oral skeletal and hematopoietic biology, and may provide new insights into oral health and regenerative strategies.

Remimazolam, a novel ultra-short-acting benzodiazepine anesthetic, provides rapid recovery with minimal circulatory depression, making it a promising agent for procedural sedation. However, differences in regulatory approvals and safety requirements across countries limit its clinical use. Therefore, its pharmacological properties and safety should be clarified in further studies. In this study, jugular vein-cannulated model mice were administered intravenous anesthetic, and the sedative effects of remimazolam were compared with those of midazolam and propofol. Following jugular vein cannulation, each mouse was administered a single intravenous dose of remimazolam or midazolam, and changes in sedation levels were assessed using a sedation scale. In another test, continuous infusion of propofol or remimazolam was administered using a precise microflow pump and sedation scale scores, defensive reflexes, and vital signs were analyzed. The sedation scale score increased after a single administration of remimazolam or midazolam in a concentration-dependent manner, followed by gradual recovery, whereas continuous administration caused a gradual increase that stabilized over time. Continuous remimazolam administration (30 mg/kg/h) produced sedation comparable to that produced by propofol administration (120 mg/kg/h), although with much smaller decreases in heart and breathing rates. Defensive reflex reactivity in mice administered remimazolam exhibited a shorter time to reflex extinction than in those administered propofol, with repeated extinction and recovery cycles. Our findings suggest that the jugular vein-cannulated mouse model is useful for evaluating time-dependent sedative effects. Continuous remimazolam administrationmaintained stable sedation with minimal vital depression and faster defensive reflex suppression than propofol administration.

Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.

While commensal microbiota are known to play essential roles in functional maturation of the innate immune system, the mechanisms by which microbial signals shape pulmonary immunity remain unclear. We performed single-cell RNA sequencing of lung immune cells from germ-free (GF) and conventional (CV) mice under normal physiological and LPS-induced septic conditions. Lung immune cells were isolated from GF and CV mice exposed to normal or septic conditions. Single-cell RNA sequencing data were analyzed using standard pipelines with cell-type annotation and pathway profiling based on enrichment analyses. In GF mice, innate immune cell populations, including neutrophils, macrophages, and natural killer cells, exhibited an altered baseline transcriptional state characterized by reduced inflammatory readiness and a shift toward metabolic and stress-associated programs relative to these cell populations in CV mice. Neutrophils from GF mice exhibited a disrupted maturation trajectory with loss of transitional states and immature cell accumulation, suggesting that microbiota-derived cues are necessary to complete peripheral maturation and support a conserved systemic mechanism of microbiota-dependent innate immune differentiation. The lipopolysaccharide-responsive sub-cluster of macrophages exhibited high CCAAT enhancer-binding protein beta (Cebpb) expression in CV mice, which was linked to preferential engagement of inflammatory rather than homeostatic programs, whereas these macrophages in GF mice failed to induce Cebpb. During LPS-induced sepsis, lack of microbial priming results in blunted inflammatory responses and inadequate transcriptional network activation. Commensal microbiota influence transcriptional activity and maturation of pulmonary innate immune cells under experimental conditions, thereby influencing susceptibility to LPS-induced lung injury. Targeting microbiota-guided immune training pathways may allow modulation of pulmonary host defenses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral agent responsible for the COVID-19 pandemic and primarily invades the body through the oral cavity. Cetylpyridinium chloride (CPC), a widely used component of oral care products, has demonstrated antiviral effects against SARS-CoV-2; however, the clinical evidence remains limited. This study investigated the virucidal effects of oral CPC in patients with COVID-19 and its impact on reverse transcription polymerase chain reaction (RT-PCR) positivity. Thirty-four patients with COVID-19 were initially recruited after obtaining positive PCR test result. This study was conducted during a nationwide Delta-variant-driven epidemic characterized by high viral loads and enhanced transmissibility. Saliva was collected at seven predefined time points to assess the effects of CPC-containing tablets and mouthwash. Viral RNA levels and infectious viral titers were quantified using qRT-PCR and plaque assays. Sixteen patients with detectable SARS-CoV-2 RNA in baseline saliva samples who completed all scheduled samplings constituted the final analytical cohort. During the Delta-variant-predominant period, CPC-containing tablets reduced both SARS-CoV-2 RNA levels and viral infectivity in saliva. In contrast, CPC-containing mouthwashes did not significantly reduce viral RNA levels compared to baseline samples. The RT-PCR positivity rates after CPC use varied according to the applied cycle threshold (Ct) cutoff values. CPC-containing tablets transiently decrease the SARS-CoV-2 salivary viral load and infectivity and may help reduce the risk of transmission in public settings. When CPC formulations are used prior to saliva-based PCR testing, the Ct cut-off values may require adjustment. Despite challenges in conducting saliva-based clinical research in COVID-19 patients, this study provides clinical evidence supporting the antiviral efficacy of CPC formulations on salivary SARS-CoV-2 during the Delta-variant pandemic.