Expert consensus on pediatric orthodontic therapies of malocclusions in children.

Malocclusion, identified by the World Health Organization (WHO) as one of three major oral diseases, profoundly impacts the dental-maxillofacial functions, facial esthetics, and long-term development of ~260 million children in China. Beyond its physical manifestations, malocclusion also significantly influences the psycho-social well-being of these children. Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition, by mitigating the negative impact of abnormal environmental influences on the growth. Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development, ranging from fetal stages to the early permanent dentition phase. From an economic and societal standpoint, the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated, underlining its profound practical and social importance. This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children, emphasizing critical need for early treatment. It elaborates on corresponding core principles and fundamental approaches in early orthodontics, proposing comprehensive guidance for preventive and interceptive orthodontic treatment, serving as a reference for clinicians engaged in early orthodontic treatment.

Efficacy of a Virtual 3D Simulation-Based Digital Training Module for Building Dental Technology Students' Long-Term Competency in Removable Partial Denture Design: Prospective Cohort Study.

Background: Removable partial denture (RPD) design is crucial to long-term success in dental treatment, but shortcomings in RPD design training and competency acquisition among dental students have persisted for decades. Digital production is increasing in prevalence in stomatology, and a digital RPD (D-RPD) module, under the framework of the certified Objective Manipulative Skill Examination of Dental Technicians (OMEDT) system reported in our previous work, may improve on existing RPD training models for students. Objective: We aimed to determine the efficacy of a virtual 3D simulation-based progressive digital training module for RPD design compared to traditional training. Methods: We developed a prospective cohort study including dental technology students at the Stomatology College of Chongqing Medical University. Cohort 1 received traditional RPD design training (7 wk). Cohort 2 received D-RPD module training based on text and 2D sketches (7 wk). Cohort 3 received D-RPD module pilot training based on text and 2D sketches (4 wk) and continued to receive training based on 3D virtual casts of real patients (3 wk). RPD design tests based on virtual casts were conducted at 1 month and 1 year after training. We collected RPD design scores and the time spent to perform each assessment. Results: We collected the RPD design scores and the time spent to perform each assessment at 1 month and 1 year after training. The study recruited 109 students, including 58 (53.2%) female and 51 male (56.8%) students. Cohort 1 scored the lowest and cohort 3 scored the highest in both tests (cohorts 1-3 at 1 mo: mean score 65.8, SD 21.5; mean score 81.9, SD 6.88; and mean score 85.3, SD 8.55, respectively; P<.001; cohorts 1-3 at 1 y: mean score 60.3, SD 16.7; mean score 75.5, SD 3.90; and mean score 90.9, SD 4.3, respectively; P<.001). The difference between cohorts in the time spent was not statistically significant at 1 month (cohorts 1-3: mean 2407.8, SD 1370.3 s; mean 1835.0, SD 1329.2 s; and mean 1790.3, SD 1195.5 s, respectively; P=.06) but was statistically significant at 1 year (cohorts 1-3: mean 2049.16, SD 1099.0 s; mean 1857.33, SD 587.39 s; and mean 2524.3, SD 566.37 s, respectively; P<.001). Intracohort comparisons indicated that the differences in scores at 1 month and 1 year were not statistically significant for cohort 1 (95% CI -2.1 to 13.0; P=.16), while cohort 3 obtained significantly higher scores 1 year later (95% CI 2.5-8.7; P=.001), and cohort 2 obtained significantly lower scores 1 year later (95% CI -8.8 to -3.9; P<.001). Conclusions: Cohort 3 obtained the highest score at both time points with retention of competency at 1 year, indicating that progressive D-RPD training including virtual 3D simulation facilitated improved competency in RPD design. The adoption of D-RPD training may benefit learning outcomes.

IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress.

OBJECTIVES: The aim of this study was to investigate the effect of 4µ8c, an inhibitor targeting the endoplasmic reticulum stress-associated factor IRE1α, on macrophage polarization in an experimental model of diabetic periodontitis through ex vivo experiments. MATERIALS AND METHODS: Local alveolar bone parameters were evaluated using Micro-CT following intraperitoneal administration of 4µ8c in mice with experimental diabetic periodontitis. Surface markers indicating macrophage polarization were identified using immunofluorescence. In vitro experiments were performed employing bone marrow-derived macrophages and gingival fibroblasts. Macrophage polarization was determined using flow cytometry. Principal impacted signaling pathways were identified through Western blot analysis. RESULTS: Results from both in vitro and in vivo experiments demonstrated that 4µ8c mitigated alveolar bone resorption and inflammation in mice with diabetic periodontitis. Furthermore, it modulated macrophage polarization towards the M2 phenotype and augmented M2 macrophage polarization through the MAPK signaling pathway. CONCLUSIONS: These findings suggest that inhibiting IRE1α can modulate macrophage polarization and alleviate ligature-induced diabetic periodontitis via the MAPK signaling pathway. This unveils a novel mechanism, offering a scientific foundation for the treatment of experimental diabetic periodontitis.

A Nature-Derived, Hetero-Structured, Pro-Healing Bioadhesive Patch for High-Performance Sealing of Wet Tissues.

Tissue adhesives are promising alternatives to sutures and staples to achieve wound closure and hemostasis. However, they often do not work well on tissues that are soaked in blood or other biological fluids, and organs that are typically exposed to a variety of harsh environments such as different pH values, nonhomogeneous distortions, continuous expansions and contractions, or high pressures. In this study, a nature-derived multilayered hetero-bioadhesive patch (skin secretion of Andrias davidianus (SSAD)-Patch) based on hydrophilic/hydrophobic pro-healing bioadhesives derived from the SSAD is developed, which is designed to form pressure-triggered strong adhesion with wet tissues. The SSAD-Patch is successfully applied for the sealing and healing of tissue defects within 10 s in diverse extreme injury scenarios in vivo including rat stomach perforation, small intestine perforation, fetal membrane defect, porcine carotid artery incision, and lung lobe laceration. The findings reveal a promising new type of self-adhesive regenerative SSAD-Patch, which is potentially adaptable to broad applications (under different pH values and air or liquid pressures) in sutureless wound sealing and healing.

An ultrasound-triggered injectable sodium alginate scaffold loaded with electrospun microspheres for on-demand drug delivery to accelerate bone defect regeneration.

Biological processes, such as bone defects healing are precisely controlled in both time and space. This spatiotemporal characteristic inspires novel therapeutic strategies. The sustained-release systems including hydrogels are commonly utilized in the treatment of bone defect; however, traditional hydrogels often release drugs at a consistent rate, lacking temporal precision. In this study, a hybrid hydrogel has been developed by using sodium alginate, sucrose acetate isobutyrate, and electrospray microspheres as the base materials, and designed with ultrasound response, and on-demand release properties. Sucrose acetate isobutyrate was added to the hybrid hydrogel to prevent burst release. The network structure of the hybrid hydrogel is formed by the interconnection of Ca2+ with the carboxyl groups of sodium alginate. Notably, when the hybrid hydrogel is exposed to ultrasound, the ionic bond can be broken to promote drug release; when ultrasound is turned off, the release returned to a low-release state. This hybrid hydrogel reveals not only injectability, degradability, and good mechanical properties but also shows multiple responses to ultrasound. And it has good biocompatibility and promotes osteogenesis efficiency in vivo. Thus, this hybrid hydrogel provides a promising therapeutic strategy for the treatment of bone defects.

Integrated analyses revealed the potential role and immune link of mitochondrial dysfunction between periodontitis and type 2 diabetes mellitus.

There is a reciprocal comorbid relationship between periodontitis and type 2 diabetes mellitus (T2DM). Recent studies have suggested that mitochondrial dysfunction (MD) could be the key driver underlying this comorbidity. The aim of this study is to provide novel understandings into the potential molecular mechanisms between MD and the comorbidity, and identify potential therapeutic targets for personalized clinical management. MD-related differentially expressed genes (MDDEGs) were identified. Enrichment analyses and PPI network analysis were then conducted. Six algorithms were used to explore the hub MDDEGs, and these were validated by ROC analysis and qRT-PCR. Co-expression and potential drug targeting analyses were then performed. Potential biomarkers were identified using LASSO regression. The immunocyte infiltration levels in periodontitis and T2DM were evaluated via CIBERSORTx and validated in mouse models. Subsequently, MD-related immune-related genes (MDIRGs) were screened by WGCNA. The in vitro experiment verified that MD was closely associated with this comorbidity. GO and KEGG analyses demonstrated that the connection between periodontitis and T2DM was mainly enriched in immuno-inflammatory pathways. In total, 116 MDDEGs, eight hub MDDEGs, and two biomarkers were identified. qRT-PCR revealed a distinct hub MDDEG expression pattern in the comorbidity group. Altered immunocytes in disease samples were identified, and their correlations were explored. The in vivo examination revealed higher infiltration levels of inflammatory immunocytes. The findings of this study provide insight into the mechanism underlying the gene-mitochondria-immunocyte network and provide a novel reference for future research into the function of mitochondria in periodontitis and T2DM.

Craniocervical posture in patients with skeletal malocclusion and its correlation with craniofacial morphology during different growth periods.

The association between craniocervical posture and craniofacial structures in the various sagittal skeletal malocclusion during different growth stages has been the focus of intense interest in fields of orthodontics, but it has not been conclusively demonstrated. Thus, this study aimed to investigate the association between craniofacial morphology and craniocervical posture in patients with sagittal skeletal malocclusion during different growth periods. A total of 150 from a large pool of cephalograms qualified for the inclusion and exclusion were evaluated and classified into three groups according to the Cervical Vertebral Maturation (CVM) by examining the morphological modifications of the second through fourth cervical vertebrae, each group consisted of 50 cephalograms. In each growth period, for the comparison of head and cervical posture differences among various skeletal classes, the radiographs were further subdivided into skeletal Class I (0° < ANB < 5°, n = 16), skeletal Class II (ANB ≥ 5°, n = 18), and skeletal Class III (0° ≤ ANB, n = 16) on the basis of their ANB angle. There was no significant difference in gender (P > 0.05). Some variables were found to be significant during pubertal growth and later in patients with sagittal skeletal malocclusion (P < 0.05). Most indicators describing craniocervical posture were largest in skeletal Class II and smallest in skeletal Class III during the peak growth periods and later. Cervical inclination variables were greater in skeletal Class III than in skeletal Class II. Variables of craniofacial morphology and craniocervical posture are more correlated during the pubertal growth period and later in patients with sagittal skeletal malocclusion. A tendency is an indication of the close interrelationship that a more extended head was in skeletal Class II while a flexed head was in skeletal Class III. Nevertheless, with the considerations of some limitations involved in this study, further longitudinal studies with large samples are required to elucidate the relationship clearly.

Lipotoxicity: The missing link between diabetes and periodontitis?

Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis.

Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

An Automatic Grading System for Orthodontically Induced External Root Resorption Based on Deep Convolutional Neural Network.

Orthodontically induced external root resorption (OIERR) is a common complication of orthodontic treatments. Accurate OIERR grading is crucial for clinical intervention. This study aimed to evaluate six deep convolutional neural networks (CNNs) for performing OIERR grading on tooth slices to construct an automatic grading system for OIERR. A total of 2146 tooth slices of different OIERR grades were collected and preprocessed. Six pre-trained CNNs (EfficientNet-B1, EfficientNet-B2, EfficientNet-B3, EfficientNet-B4, EfficientNet-B5, and MobileNet-V3) were trained and validated on the pre-processed images based on four different cross-validation methods. The performances of the CNNs on a test set were evaluated and compared with those of orthodontists. The gradient-weighted class activation mapping (Grad-CAM) technique was used to explore the area of maximum impact on the model decisions in the tooth slices. The six CNN models performed remarkably well in OIERR grading, with a mean accuracy of 0.92, surpassing that of the orthodontists (mean accuracy of 0.82). EfficientNet-B4 trained with fivefold cross-validation emerged as the final OIERR grading system, with a high accuracy of 0.94. Grad-CAM revealed that the apical region had the greatest effect on the OIERR grading system. The six CNNs demonstrated excellent OIERR grading and outperformed orthodontists. The proposed OIERR grading system holds potential as a reliable diagnostic support for orthodontists in clinical practice.

The effect of enhanced structure in the posterior segment of clear aligners during anterior retraction: a three-dimensional finite element and experimental model analysis.

BACKGROUND: Mesial tipping of posterior teeth occurs frequently during space closure with clear aligners (CAs). In this study, we proposed a new modification of CA by localized thickening of the aligner to form the enhanced structure and investigate its biomechanical effect during anterior retraction. METHODS: Two methods were employed in this study. First, a finite element (FE) model was constructed, which included alveolar bone, the first premolars extracted maxillary dentition, periodontal ligaments (PDL), attachments and aligners. The second method involved an experimental model-a measuring device using multi-axis transducers and vacuum thermoforming aligners. Two groups were formed: (1) The control group used common CAs and (2) the enhanced structure group used partially thickened CAs. RESULTS: FE model revealed that the enhanced structure improved the biomechanics during anterior retraction. Specifically, the second premolar, which had a smaller PDL area, experienced a smaller protraction force and moment, making it less likely to tip mesially. In the same vein, the molars could resist movement due to their larger PDL area even though they were applied larger forces. The resultant force of the posterior tooth was closer to the center of resistance, reducing the tipping moment. The canine was applied a larger retraction force and moment, resulting in sufficient retraction of anterior teeth. The experimental model demonstrated a similar trend in force variation as the FE model. CONCLUSIONS: Enhanced structure allowed force distribution more in accordance with optimal principles of biomechanics during the extraction space closure while permitting less mesial tipping and anchorage loss of posterior teeth and better retraction of anterior teeth. Thus, enhanced structure alleviated the roller coaster effect associated with extraction cases and offered a new possibility for anchorage reinforcement in clear aligner therapy.

Comparative assessment of orthodontic clear aligner versus fixed appliance for anterior retraction: a finite element study.

BACKGROUND: The aim of this study is to conduct a comparative evaluation of different designs of clear aligners and examine the disparities between clear aligners and fixed appliances. METHODS: 3D digital models were created, consisting of a maxillary dentition without first premolars, maxilla, periodontal ligaments, attachments, micro-implant, 3D printed lingual retractor, brackets, archwire and clear aligner. The study involved the creation of five design models for clear aligner maxillary anterior internal retraction and one design model for fixed appliance maxillary anterior internal retraction, which were subsequently subjected to finite element analysis. These design models included: (1) Model C0 Control, (2) Model C1 Posterior Micro-implant, (3) Model C2 Anterior Micro-implant, (4) Model C3 Palatal Plate, (5) Model C4 Lingual Retractor, and (6) Model F0 Fixed Appliance. RESULTS: In the clear aligner models, a consistent pattern of tooth movement was observed. Notably, among all tested models, the modified clear aligner Model C3 exhibited the smallest differences in sagittal displacement of the crown-root of the central incisor, vertical displacement of the central incisor, sagittal displacement of the second premolar and second molar, as well as vertical displacement of posterior teeth. However, distinct variations in tooth movement trends were observed between the clear aligner models and the fixed appliance model. Furthermore, compared to the fixed appliance model, significant increases in tooth displacement were achieved with the use of clear aligner models. CONCLUSIONS: In the clear aligner models, the movement trend of the teeth remained consistent, but there were variations in the amount of tooth displacement. Overall, the Model C3 exhibited better torque control and provided greater protection for posterior anchorage teeth compared to the other four clear aligner models. On the other hand, the fixed appliance model provides superior anterior torque control and better protection of the posterior anchorage teeth compared to clear aligner models. The clear aligner approach and the fixed appliance approach still exhibit a disparity; nevertheless, this study offers a developmental direction and establishes a theoretical foundation for future non-invasive, aesthetically pleasing, comfortable, and efficient modalities of clear aligner treatment.

Virtual and Interprofessional Objective Structured Clinical Examination in Dentistry and Dental Technology: Development and User Evaluations.

BACKGROUND: Interprofessional education (IPE) facilitates interprofessional collaborative practice (IPCP) to encourage teamwork among dental care professionals and is increasingly becoming a part of training programs for dental and dental technology students. However, the focus of previous IPE and IPCP studies has largely been on subjective student and instructor perceptions without including objective assessments of collaborative practice as an outcome measure. OBJECTIVE: The purposes of this study were to develop the framework for a novel virtual and interprofessional objective structured clinical examination (viOSCE) applicable to dental and dental technology students, to assess the effectiveness of the framework as a tool for measuring the outcomes of IPE, and to promote IPCP among dental and dental technology students. METHODS: The framework of the proposed novel viOSCE was developed using the modified Delphi method and then piloted. The lead researcher and a group of experts determined the content and scoring system. Subjective data were collected using the Readiness for Interprofessional Learning Scale and a self-made scale, and objective data were collected using examiner ratings. Data were analyzed using nonparametric tests. RESULTS: We successfully developed a viOSCE framework applicable to dental and dental technology students. Of 50 students, 32 (64%) participated in the pilot study and completed the questionnaires. On the basis of the Readiness for Interprofessional Learning Scale, the subjective evaluation indicated that teamwork skills were improved, and the only statistically significant difference in participant motivation between the 2 professional groups was in the mutual evaluation scale (P=.004). For the viOSCE evaluation scale, the difference between the professional groups in removable prosthodontics was statistically significant, and a trend for negative correlation between subjective and objective scores was noted, but it was not statistically significant. CONCLUSIONS: The results confirm that viOSCE can be used as an objective evaluation tool to assess the outcomes of IPE and IPCP. This study also revealed an interesting relationship between mutual evaluation and IPCP results, further demonstrating that the IPE and IPCP results urgently need to be supplemented with objective evaluation tools. Therefore, the implementation of viOSCE as part of a large and more complete objective structured clinical examination to test the ability of students to meet undergraduate graduation requirements will be the focus of our future studies.

Developmental endothelial locus-1 promotes osteogenic differentiation and alveolar bone regeneration in experimental periodontitis with type 2 diabetes mellitus.

OBJECTIVES: This study sought to explore the role of developmental endothelial locus-1 (DEL-1) in osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and investigate the therapeutic effect of DEL-1 in ligature-induced experimental periodontitis with type 2 diabetes mellitus (T2DM). BACKGROUND: T2DM is a significant risk factor for periodontitis. Treatment modalities for periodontitis with T2DM are being explored. DEL-1 is a versatile protein that can modulate the different stages of inflammatory diseases including periodontitis. The direct effect of DEL-1 on osteogenic differentiation of PDLSCs in periodontitis with T2DM is poorly understood. METHODS: Primary hPDLSCs were isolated from periodontal ligament tissue and identified by flow cytometry. In osteogenesis experiments, alkaline phosphatase (ALP), Alizarin Red staining and western blot were used to assess the osteogenic effect of DEL-1 on hPDLSCs in high glucose and inflammation environments. The mouse model of ligature-induced experimental periodontitis was established. H&E and Masson's trichrome staining were used to assess the change of periodontal tissue after local periodontal injection of DEL-1. Immunohistochemical staining was used to evaluate osteogenic-related protein expression. RESULTS: hPDLSCs expressed mesenchymal stem cell (MSC)-specific surface markers and were negative for hematopoietic cell surface markers. hPDLSCs had the potential for multidirectional differentiation. DEL-1 could enhance the osteogenic differentiation of hPDLSCs in high glucose and inflammation environments, although it did not return to the control level. Histological staining showed that DEL-1 contributed to alveolar bone regeneration and osteogenic-related protein expression, but the degree of improvement in T2DM mice was lower than in non-T2DM mice. CONCLUSIONS: In summary, we demonstrated that DEL-1 could promote osteogenic differentiation of hPDLSCs in high glucose and inflammation environment and rescue alveolar bone loss in experimental periodontitis with T2DM, which could provide a novel therapeutic target for periodontitis with T2DM.

Adaptive Nanoparticle-Mediated Modulation of Mitochondrial Homeostasis and Inflammation to Enhance Infected Bone Defect Healing.

Infected bone defects (IBDs) exhibit impaired healing due to excessive inflammation triggered by pathogen-associated molecular patterns (PAMPs) from bacteria. As a vital factor in orchestrating immune responses, mitochondrial homeostasis maintenance is central to inflammation blockade. This research developed a chameleon-like nanoplatform by covering hydroxyapatite nanoparticles with a cerium ion coordinated tannic acid supramolecular network (HA@Ce-TA), which adaptively functions to regulate mitochondrial homeostasis based on intra- and extracellular environments. Extracellularly, acidic conditions activate HA@Ce-TA's peroxidase/oxidase-mimicking activity to produce reactive oxygen species (ROS), and external near-infrared (NIR) irradiation excites nanoscale Ce-TA to produce hyperthermia, which is found and explained by chemical computation. ROS production with photothermal therapy can eliminate bacteria effectively and reduce mitochondrial stress. Intracellularly, HA@Ce-TA remodels mitochondrial dynamics by upregulating mitochondrial fusion genes and eliminates excessive ROS by mimicking superoxidase/catalase. Consequently, this comprehensive modulation of mitochondrial homeostasis inhibits inflammasome overactivation. In vitro and in vivo studies showed HA@Ce-TA can modulate the mitochondria-centered inflammatory cascade to enhance IBD treatment, highlighting the potential of engineering nanotherapeutics to recalibrate mitochondrial homeostasis as an infected disease-modifying intervention.

Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin.

BACKGROUND: Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N6-methyladenosine (m6A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m6A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m6A modification mechanism in diabetes-associated periodontitis. METHODS: Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M6A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining. RESULTS: Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m6A level in total RNA. FTO knockdown increased the m6A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m6A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling. CONCLUSIONS: AGEs impaired BMSCs osteogenesis by regulating SOST in an m6A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.

Validation of a physiological type 2 diabetes model in human periodontal ligament stem cells.

OBJECTIVES: Type 2 diabetes (T2DM), a recognized risk factor for periodontitis, is characterized by insulin resistance. However, the molecular mechanisms concerning the role of insulin resistance in linking T2DM and periodontitis remain poorly elucidated due to the absence of an appropriate T2DM cell model. We aimed to explore an appropriate model of T2DM in human periodontal ligament stem cells (hPDLSCs) and uncover the involved mechanisms. MATERIALS AND METHODS: hPDLSCs were incubated with common reagents for recapitulating insulin resistance state including high glucose (HG) (15, 25, 35, 45 mM), glucosamine (0.8, 8, 18, 28, 38 mM), or palmitic acid (PA; 100, 200, 400, 800 µM), combined with LPS for 48 h. The insulin signaling pathway, inflammation, and pyroptosis were detected by western blots and quantitative real-time polymerase chain reaction (RT-qPCR). The effects on osteogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, RT-qPCR, and western blots. RESULTS: HG failed to recapitulate insulin resistance. Glucosamine was sufficient to induce insulin resistance but failed to trigger inflammation. In total, 100 and 200 µM PA exhibited the most proinflammatory, insulin resistance, and pyroptosis induced role, and inhibited the osteogenic differentiation of hPDLSCs. CONCLUSION: Palmitic acid is a promising candidate for developing T2DM model in hPDLSCs.

Mechanical loading and autophagy: A study on the BoNT-A injection-induced condylar cartilage degeneration.

Botulinum toxin A (BoNT-A) has emerged as a treatment option for temporomandibular disorder (TMD). By injecting BoNT-A into the masseter muscle, it is possible to reduce mechanical loading on the temporomandibular joint (TMJ). However, numerous prior studies have indicated excessive reduction in mechanical loading can have detrimental effects on TMJ cartilage. This study proposes that autophagy, a process influenced by mechanical loading, could play a role in BoNT-A-induced mandibular condyle cartilage degeneration. To explore this hypothesis, we employed both BoNT-A injection and an excessive biting model to induce variations in mechanical loading on the condyle cartilage of C57BL/6 mice, thereby simulating an increase and decrease in mechanical loading, respectively. Results showed a significant reduction in cartilage thickness and downregulation of Runt-related transcription factor 2 (Runx2) expression in chondrocytes following BoNT-A injection. In vitro experiments demonstrated that the reduction of Runx2 expression in chondrocytes is associated with autophagy, possibly dependent on decreased YAP expression induced by low mechanical loading. This study reveals the potential involvement of the YAP/LC3/Runx2 signaling pathway in BoNT-A mediated mandibular condylar cartilage degeneration.

Regulation of Near-Field Radiative Heat Transfer between Multilayer BP/hBN Heterostructures.

As an allotrope of phosphorus and a promising 2D semiconductor, black phosphorus (BP) exhibits in-plane anisotropy along its armchair and zigzag crystal directions, allowing for efficient regulation of near-field radiative heat transfer (NFRHT). In this work, we investigate the NFRHT between two multilayer BP/hBN heterostructures and theoretically demonstrate that thermal regulation can be realized by tuning the electron density and rotation angle of BP. Results show that a larger electron density leads to the coupling of anisotropic surface plasmon polaritons (SPPs) of BP with hyperbolic modes of hBN, and rotation of BP changes the anisotropic characteristic of coupled SPPs on both sides, whereby a regulation ratio of 5.8 can be obtained. We also analyze the effects of period number, hBN layer thickness, and topmost-layer material on the NFRHT. This work may be beneficial for efficient nanoscale thermal management and physical understanding of radiative heat transfer based on anisotropic SPPs.

Comparative Efficacy of Venetoclax-Based Combination Therapies and Other Therapies in Treatment-Naive Patients With Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: A Network Meta-Analysis.

OBJECTIVES: This network meta-analysis (NMA) assessed the efficacy of venetoclax (VEN) + azacitidine (AZA) and VEN + low-dose cytarabine (LDAC) compared with AZA, LDAC, and decitabine monotherapies and best supportive care (BSC) in adults with untreated acute myeloid leukemia ineligible for intensive chemotherapy. METHODS: A systematic literature review and feasibility assessment was conducted to select phase III randomized controlled trials for inclusion in the NMA. Complete remission + complete remission with incomplete blood count recovery and overall survival (OS) were compared using a Bayesian fixed-effects NMA. Treatments were ranked using surface under the cumulative ranking curves (SUCRAs) with higher values indicating a higher likelihood of being effective. RESULTS: A total of 1140 patients across 5 trials were included. VEN + LDAC (SUCRA 91.4%) and VEN + AZA (87.5%) were the highest ranked treatments for complete remission + complete remission with incomplete blood count recovery. VEN + LDAC was associated significantly higher response rates versus AZA (odds ratio 5.64), LDAC (6.39), and BSC (23.28). VEN + AZA was also associated significantly higher response rates than AZA (5.06), LDAC (5.74), and BSC (20.68). In terms of OS, VEN + AZA (SUCRA: 95.2%) and VEN + LDAC (75.9%) were the highest ranked treatments. VEN + AZA was associated with significant improvements in OS compared with AZA (hazard ratio 0.66), LDAC (0.57), and BSC (0.37), and VEN + LDAC was associated with significant improvements in OS compared with LDAC (0.70) and BSC (0.46). CONCLUSIONS: VEN + AZA and VEN + LDAC demonstrated improved efficacy compared with alternative therapies among treatment-naive patients with acute myeloid leukemia ineligible for intensive chemotherapy.