mTOR Signaling Pathway in Bone Diseases Associated with Hyperglycemia.

The interplay between bone and glucose metabolism has highlighted hyperglycemia as a potential risk factor for bone diseases. With the increasing prevalence of diabetes mellitus worldwide and its subsequent socioeconomic burden, there is a pressing need to develop a better understanding of the molecular mechanisms involved in hyperglycemia-mediated bone metabolism. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that senses extracellular and intracellular signals to regulate numerous biological processes, including cell growth, proliferation, and differentiation. As mounting evidence suggests the involvement of mTOR in diabetic bone disease, we provide a comprehensive review of its effects on bone diseases associated with hyperglycemia. This review summarizes key findings from basic and clinical studies regarding mTOR's roles in regulating bone formation, bone resorption, inflammatory responses, and bone vascularity in hyperglycemia. It also provides valuable insights into future research directions aimed at developing mTOR-targeted therapies for combating diabetic bone diseases.

Hyperglycemia modulates M1/M2 macrophage polarization via reactive oxygen species overproduction in ligature-induced periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis in diabetic patients is characterized by enhanced inflammation and aggravated tissue damage in comparison with that in non-diabetic counterparts. The progression of periodontal damage under diabetic condition can be partly ascribed to hyperglycemia-induced disturbance between immune activation and inflammation resolution, where macrophages are capable of participating given their plasticity in response to different stimuli. Herein, we aimed to investigate the changes of macrophage polarization in periodontitis under diabetic condition and the underlying mechanism. MATERIALS AND METHODS: Type-1 diabetes was induced by the injection of streptozotocin (STZ, 60 mg/kg) in Sprague-Dawley rats. Rats in N-acetyl cysteine (NAC)-treated groups received NAC dissolved in drinking water (200 mg/kg/day). Experimental periodontitis was induced by ligating 3-0 silk around left maxillary second molars for 4 weeks. Alveolar bone destruction was tested by micro-computed tomography and tartrate-resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization in periodontal tissue was detected by immunohistochemistry staining. RAW264.7 were cultured in normal glucose (5.5 mM) or high glucose environment (25 mM) with or without NAC (8 mmol/L). LPS (100 ng/ml) and IL-4 (20 ng/ml) were used to induce M1 macrophages and M2 macrophages, respectively. M1/M2 macrophage polarization was detected by qRT-PCR, immunofluorescent staining, and flow cytometry. Reactive oxygen species (ROS) accumulation was detected by fluorogenic probes. RANKL (100 ng/ml) were applied to induce osteoclastogenic differentiation of RAW264.7, and osteoclast formation was examined by TRAP staining. RESULTS: Rats with diabetes displayed enhanced macrophages infiltration and M1 macrophage polarization in periodontal lesions compared with vehicle-treated rats. Under LPS or IL-4 stimulation, high glucose culture of RAW264.7 elevated ROS level and increased the expression of M1 macrophage markers (iNOS, TNF-α, and IL-6) whereas decreased the expression of M2 macrophage markers (Arg-1 and CD206). Supernatants of high glucose-treated M1/M2 macrophages enhanced osteoclast formation compared to normal glucose-cultured cells. Decreasing ROS level via NAC partially reversed the effect of high glucose on M1/M2 macrophage polarization. Meanwhile, daily intake of NAC in rodent models inhibited M1 macrophage polarization, which subsequently ameliorated alveolar bone loss and decreased osteoclast numbers in periodontitis in diabetic rats. CONCLUSION: These findings demonstrated that hyperglycemia could polarize macrophage toward M1 macrophages via overproducing ROS under inflammatory condition, which might take responsibility for aggravated periodontal damage in periodontitis under diabetic condition. Inhibiting M1 macrophages and restoring M2 macrophages by ROS scavenger is hopefully a potential adjunct treatment strategy for diabetic periodontitis.

PTH/PTHrP in controlled release hydrogel enhances orthodontic tooth movement by regulating periodontal bone remodaling.

OBJECTIVE: This study aimed to evaluate the effects of local application of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) on osteogenesis and osteoclastogenesis during orthodontic tooth movement (OTM). BACKGROUND: Periodontal bone remodeling is the crucial biological process in the OTM that involves both bone resorption and formation, with the former more important as the initiator. PTH or PTHrP both play dual roles in bone remodeling regulation, and the balance may shift to the bone resorption side when they are given continuously, suggesting them as potential candidate medicine for OTM acceleration. METHODS: A total of 40 rats underwent orthodontic mesialization of the maxillary first molars and received no micro-perforation (MOP), or MOP followed by injection of temperature-sensitive hydrogel containing PTH, PTHrP, or normal saline. The rats were sacrificed after 2-week OTM, except for the relapse groups, which had one more week of observation after removal of the force appliances. The amount of tooth movement, rate of relapse after OTM, and effects on the bone remodeling were assessed through micro-computed tomography (µCT) analysis, alkaline phosphatase (ALP) assay, alizarin red staining, tartrate-resistant acid phosphatase (TRAP) staining, immunohistochemistry (IHC) analysis, Western blot (WB), and quantitative real-time polymerase chain reaction (qRT-PCR). The effects of PTHrP on the osteogenic differentiation of human periodontal ligament cells (hPDLCs) were explored in vitro. RESULTS: The cumulative release of PTH or PTHrP from PECE hydrogels was beyond 75% at 14 days in a sustained manner. After the intervention in vivo, the distance of OTM in the PTH (0.78 ± 0.06 mm) or PTHrP (0.81 ± 0.04 mm) group was significantly larger than that of the MOP only (0.51 ± 0.04 mm) or the no MOP (0.46 ± 0.05 mm) group. Moreover, PTH injection significantly reduced the rate of relapse after OTM (25.7 ± 4.3%) compared to the control (69.6 ± 6.1%). µCT analysis showed decreased BV/TV, BS/BV, and Tb.N, while increased Tb.Sp of alveolar bone in the PTH or PTHrP group. There were also more TRAP-positive osteoclasts in the PTH or PTHrP group with a significantly enhanced ratio of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG). The protein expressions of PTH/PTHrP type 1 receptor (PTHR1), alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), and ß-catenin were significantly increased in the PTH or PTHrP group, as well as the gene expressions of Pth1r, Bglap, and Alpl. There was no significant difference between the effects of PTH and PTHrP. Nevertheless, inhibition of PTHrP on the osteogenic differentiation of hPDLCs was detected in vitro with decreased expression of OCN, RUNX2, COL-1, and ALP. CONCLUSION: Local injection of either PTH or PTHrP carried by controlled release PECE hydrogel similarly enhances OTM in rats through regulating periodontal bone remodeling, which deserves further study for potential clinical application.

Biocompatible orthodontic cement with antibacterial capability and protein repellency.

BACKGROUND: White spot lesions (WSLs) often occur in orthodontic treatments. The objectives of this study were to develop a novel orthodontic cement using particles of nano silver (NAg), N-acetylcysteine (NAC) and 2-methacryloyloxyethyl phosphorylcholine (MPC), and to investigate the effects on bonding strength, biofilms and biocompatibility. METHODS: A commercial resin-modified glass ionomer cement (RMGIC) was modified by adding NAg, NAC and MPC. The unmodified RMGIC served as the control. Enamel bond strength and cytotoxicity of the cements were investigated. The protein repellent behavior of cements was also evaluated. The metabolic assay, lactic acid production assay and colony-forming unit assay of biofilms were used to determine the antibacterial capability of cements. RESULTS: The new bioactive cement with NAg, NAC and MPC had clinically acceptable bond strength and biocompatibility. Compared to commercial control, the new cement suppressed metabolic activity and lactic acid production of biofilms by 59.03% and 70.02% respectively (p < 0.05), reduced biofilm CFU by 2 logs (p < 0.05) and reduced protein adsorption by 76.87% (p < 0.05). CONCLUSIONS: The new cement with NAg, NAC and MPC had strong antibacterial capability, protein-repellent ability and acceptable biocompatibility. The new cement is promising to protect enamel from demineralization during orthodontic treatments.

Effect of conventional combined orthodontic-surgical treatment on oral health-related quality of life: A systematic review and meta-analysis.

INTRODUCTION: Although conventional combined orthodontic-surgical treatment is frequently applied in orthodontic clinic practice, its actual effect on oral health-related quality of life (OHRQoL) remains inconclusive. We aimed to appraise trials investigating the effect of conventional combined orthodontic-surgical treatment on OHRQoL in patients with dentofacial deformities. METHODS: Electronic searches of 6 databases and manual searches were conducted up to January 2019. Randomized controlled trials, controlled clinical trials, and prospective cohort studies that investigated the impact of combined orthodontic-surgical treatment on OHRQoL using validated instruments were included. The risk of bias within individual studies was assessed with the use of the Cochrane tool or the Newcastle-Ottawa Scale according to study designs. Meta-analysis was conducted, and OHRQoL at different time points during conventional combined orthodontic-surgical treatment were statistically pooled and compared. RESULTS: Of the 893 records initially identified, 24 studies were included in this review. Relative to pretreatment, the condition-specific OHRQoL was significantly improved 6 months after surgery, particularly in the perceptions to social aspects (mean difference [MD] 4.88, 95% confidence interval [CI] 2.45 to 7.32), facial appearance (MD 5.48, 95% CI 4.18 to 6.79), and oral function (MD 4.49, 95% CI 3.27 to 5.72). In terms of changes during combined orthodontic-surgical treatment, the condition-specific OHRQoL worsened in the presurgical orthodontic treatment (MD -7.25, 95% CI -13.29 to -1.22) and improved postsurgically compared with pretreatment (MD 16.59, 95% CI 10.41 to 22.77). Similar patterns were observed in the general OHRQoL changes. CONCLUSIONS: For patients undergoing combined orthodontic-surgical treatment, the OHRQoL seems to decrease temporarily in presurgical orthodontic treatment compared with pretreatment and to increase to a level better than it was before treatment during postsurgical orthodontic treatment. Based on the present review, combined orthodontic-surgical treatment could be an effective choice to improve OHRQoL for patients affected with severe dentofacial deformities.

Comparison of the success rate between self-drilling and self-tapping miniscrews: a systematic review and meta-analysis.

Background: Both the self-drilling and self-tapping miniscrews have been commonly used as anchorage reinforcement devices in orthodontic treatment. Objective: The aim of this study was to compare the success rates of self-drilling and self-tapping miniscrews in orthodontic practice. Search methods: Literature searches were performed by electronic search in database including PubMed, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure and SIGLE, and manual search of relevant journals and reference lists of included studies. Eligibility criteria: Randomized controlled trials, clinical controlled trials and cohort studies comparing the success rates of self-drilling and self-tapping miniscrews as orthodontic anchorage. Data collection and analysis: The data of success rates and root contact rates were extracted by two investigators independently. After evaluating the risk of bias, the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analysis was performed on the basis of study design, follow-ups, participant ages and immediate/delayed loading. Sensitivity analysis was performed to test the stability of the results in meta-analysis. Results: Six studies assessed as high quality were included in the meta-analysis. The meta-analysis results showed no difference between the two types of screws in the success rates. The root contact rates of the two screws were similar, while self-drilling miniscrews displayed higher risk of failure when contacting with a tooth root. Conclusions: Currently available clinical evidence suggests that the success rates of self-tapping and self-drilling miniscrews are similar. Determination of the position and direction of placement should be more precise when self-drilling miniscrews are used in sites with narrow root proximity. Registration: None. Conflict of interest: None.

Investigation of optimal orthodontic force at the cellular level through three-dimensionally cultured periodontal ligament cells.

OBJECTIVES: Optimal orthodontic force (OOF), important as it is, has generally been addressed at the level of tissue response. This study, for the first time, aimed to investigate its underlying mechanisms at the cellular level. METHODS: Human periodontal ligament tissue cells (PDLCs) were three-dimensionally (3D) cultured in a thin sheet of poly-lactic-co-glycolic acid (PLGA) scaffold. The 3D cultured PDLCs were treated with static compressive force of 0, 5, 15, and 25g/cm(2) for 6, 24, and 72 hours, respectively. After that, methylthiazolyl tetracolium assay was done to evaluate the cell proliferation. The target gene expression in PDLCs was investigated through real-time PCR analysis. The conditioned media was collected for enzyme-linked immunosorbent assay (ELISA) assay, and also used for the coculture of osteoblasts and osteoclast precursors. Tartrate-resistant acid phosphatase (TRAP) staining was employed to examine osteoclasts. RESULTS: Compressive force inhibited proliferation of PDLCs in a magnitude-dependent manner. Heavier force upregulated expression of the osteoclastogenesis inducers, including RANKL, COX-2, PTHrP, and IL-11, more rapidly; however in the long run, no significant difference was found among different force magnitudes, either in the expression of osteoclastogenesis inducers by PDLCs, or in the osteoclast formation detected by TRAP staining. LIMITATIONS: The results regarding specific force magnitude as OOF should be confined to the present specific model, but not be extrapolated, without caution, to different in vitro models, nor even to in vivo studies or clinical application. CONCLUSIONS: Compared with heavier force, lighter force has similar pro-osteoclastogenic whilst less anti-proliferative effects on PDLCs, which provides a novel interpretation for OOF.

Root resorption during orthodontic treatment with self-ligating or conventional brackets: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to compare the external apical root resorption (EARR) in patients receiving fixed orthodontic treatment with self-ligating or conventional brackets. METHODS: Studies comparing the EARR between orthodontic patients using self-ligating or conventional brackets were identified through electronic search in databases including CENTRAL, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and SIGLE, and manual search in relevant journals and reference lists of the included studies until Apr 2016. The extraction of data and risk of bias evaluation were conducted by two investigators independently. The original outcome underwent statistical pooling by using Review Manager 5. RESULTS: Seven studies were included in the systematic review, out of which, five studies were statistically pooled in meta-analysis. The value of EARR of maxillary central incisors in the self-ligating bracket group was significantly lower than that in the conventional bracket group (SMD -0.31; 95% CI: -0.60--0.01). No significant differences in other incisors were observed between self-ligating and conventional brackets. CONCLUSIONS: Current evidences suggest self-ligating brackets do not outperform conventional brackets in reducing the EARR in maxillary lateral incisors, mandible central incisors and mandible lateral incisors. However, self-ligating brackets appear to have an advantage in protecting maxillary central incisor from EARR, which still needs to be confirmed by more high-quality studies.

Biomaterials Designed to Modulate Reactive Oxygen Species for Enhanced Bone Regeneration in Diabetic Conditions.

Diabetes mellitus, characterized by enduring hyperglycemia, precipitates oxidative stress, engendering a spectrum of complications, notably increased bone vulnerability. The genesis of reactive oxygen species (ROS), a byproduct of oxygen metabolism, instigates oxidative detriment and impairs bone metabolism in diabetic conditions. This review delves into the mechanisms of ROS generation and its impact on bone homeostasis within the context of diabetes. Furthermore, the review summarizes the cutting-edge progress in the development of ROS-neutralizing biomaterials tailored for the amelioration of diabetic osteopathy. These biomaterials are engineered to modulate ROS dynamics, thereby mitigating inflammatory responses and facilitating bone repair. Additionally, the challenges and therapeutic prospects of ROS-targeted biomaterials in clinical application of diabetic bone disease treatment is addressed.

Osteogenesis of bone marrow mesenchymal stem cell in hyperglycemia.

Diabetes mellitus (DM) has been shown to be a clinical risk factor for bone diseases including osteoporosis and fragility. Bone metabolism is a complicated process that requires coordinated differentiation and proliferation of bone marrow mesenchymal stem cells (BMSCs). Owing to the regenerative properties, BMSCs have laid a robust foundation for their clinical application in various diseases. However, mounting evidence indicates that the osteogenic capability of BMSCs is impaired under high glucose conditions, which is responsible for diabetic bone diseases and greatly reduces the therapeutic efficiency of BMSCs. With the rapidly increasing incidence of DM, a better understanding of the impacts of hyperglycemia on BMSCs osteogenesis and the underlying mechanisms is needed. In this review, we aim to summarize the current knowledge of the osteogenesis of BMSCs in hyperglycemia, the underlying mechanisms, and the strategies to rescue the impaired BMSCs osteogenesis.

Ablation of transient receptor potential vanilloid subtype 1-expressing neurons in rat trigeminal ganglia aggravated bone resorption in periodontitis with diabetes.

OBJECTIVES: We aimed to investigate the contribution of neurons expressing transient receptor potential vanilloid subtype 1 (TRPV1) to alveolar bone homeostasis in periodontitis with diabetes. DESIGN: Diabetes was induced by streptozotocin injection in Sprague-Dawley rats. Resiniferatoxin was injected into left trigeminal ganglia to ablate TRPV1-expressing neurons. 3-0 silks were tied around left maxillary second molars to induce experimental periodontitis. Alveolar bone was assessed by micro-computed tomography and tartrate-resistant acid phosphatase staining. Macrophages were detected by immunohistochemistry staining. RESULTS: TRPV1 expression in trigeminal ganglia was increased in diabetic rats compared to non-diabetic counterparts. Local ablation of TRPV1 eliminated facial heat hyperalgesia but aggravated alveolar bone damage and osteoclastogenesis in experimental periodontitis in both diabetic and non-diabetic rats. Immunohistochemistry staining presented enhanced macrophage infiltration and M1 macrophage polarization in periodontal lesions in TRPV1-ablated groups. CONCLUSIONS: These findings demonstrated that TRPV1 expression in trigeminal ganglia could be enhanced in diabetic condition, and the integrity of TRPV1-expressing neurons in trigeminal ganglia exerted a neuroprotective effect against alveolar bone resorption and inflammation in diabetic periodontitis.

A Quartet Network Analysis Identifying Mechanically Responsive Long Noncoding RNAs in Bone Remodeling.

Mechanical force, being so ubiquitous that it is often taken for granted and overlooked, is now gaining the spotlight for reams of evidence corroborating their crucial roles in the living body. The bone, particularly, experiences manifold extraneous force like strain and compression, as well as intrinsic cues like fluid shear stress and physical properties of the microenvironment. Though sparkled in diversified background, long noncoding RNAs (lncRNAs) concerning the mechanotransduction process that bone undergoes are not yet detailed in a systematic way. Our principal goal in this research is to highlight the potential lncRNA-focused mechanical signaling systems which may be adapted by bone-related cells for biophysical environment response. Based on credible lists of force-sensitive mRNAs and miRNAs, we constructed a force-responsive competing endogenous RNA network for lncRNA identification. To elucidate the underlying mechanism, we then illustrated the possible crosstalk between lncRNAs and mRNAs as well as transcriptional factors and mapped lncRNAs to known signaling pathways involved in bone remodeling and mechanotransduction. Last, we developed combinative analysis between predicted and established lncRNAs, constructing a pathway-lncRNA network which suggests interactive relationships and new roles of known factors such as H19. In conclusion, our work provided a systematic quartet network analysis, uncovered candidate force-related lncRNAs, and highlighted both the upstream and downstream processes that are possibly involved. A new mode of bioinformatic analysis integrating sequencing data, literature retrieval, and computational algorithm was also introduced. Hopefully, our work would provide a moment of clarity against the multiplicity and complexity of the lncRNA world confronting mechanical input.

Response of Gli1+ Suture Stem Cells to Mechanical Force Upon Suture Expansion.

Normal development of craniofacial sutures is crucial for cranial and facial growth in all three dimensions. These sutures provide a unique niche for suture stem cells (SuSCs), which are indispensable for homeostasis, damage repair, as well as stress balance. Expansion appliances are now routinely used to treat underdevelopment of the skull and maxilla, stimulating the craniofacial sutures through distraction osteogenesis. However, various treatment challenges exist due to a lack of full understanding of the mechanism through which mechanical forces stimulate suture and bone remodeling. To address this issue, we first identified crucial steps in the cycle of suture and bone remodeling based on the established standard suture expansion model. Observed spatiotemporal morphological changes revealed that the remodeling cycle is approximately 3 to 4 weeks, with collagen restoration proceeding more rapidly. Next, we traced the fate of the Gli1+ SuSCs lineage upon application of tensile force in three dimensions. SuSCs were rapidly activated and greatly contributed to bone remodeling within 1 month. Furthermore, we confirmed the presence of Wnt activity within Gli1+ SuSCs based on the high co-expression ratio of Gli1+ cells and Axin2+ cells, which also indicated the homogeneity and heterogeneity of two cell groups. Because Wnt signaling in the sutures is highly upregulated upon tensile force loading, conditional knockout of ß-catenin largely restricted the activation of Gli1+ SuSCs and suppressed bone remodeling under physiological and expansion conditions. Thus, we concluded that Gli1+ SuSCs play essential roles in suture and bone remodeling stimulated by mechanical force and that Wnt signaling is crucial to this process. © 2022 American Society for Bone and Mineral Research (ASBMR).

Exploring the Epigenetic Regulatory Role of m6A-Associated SNPs in Type 2 Diabetes Pathogenesis.

PURPOSE: Genetic factors in type 2 diabetes (T2D) pathogenesis have been widely explored by the genome-wide association studies (GWAS), identifying a great amount of susceptibility loci. With the development of high-resolution sequencing, the N(6)-methyladenosine (m6A) RNA modification has been proved to be affected by genetic variation. In this study, we identified the T2D-associated m6A-SNPs from T2D GWAS data and explored the underlying mechanism of the pathogenesis of T2D. METHODS: We examined the association of m6A-SNPs with T2D among large-scale T2D GWAS summary statistics and further performed multi-omics integrated analysis to explore the potential role of the identified m6A-SNPs in T2D pathogenesis. RESULTS: Among the 15,124 T2D-associated m6A-SNPs, 71 of them reach the genome-wide significant threshold (5.0e-05). The leading SNP rs4993986 (C>G), which is located near the m6A modification site at the 3' end of the HLA-DQB1 transcript, is expected to participate in the pathogenesis of T2D by influencing m6A modification to regulate the HLA-DQB1 expression. CONCLUSION: The current study has suggested a potential correlation between m6A-SNPs and T2D pathogenesis and also provided new insights into the pathogenic mechanism of the T2D susceptibility loci identified by GWAS.

Biomechanical and biological responses of periodontium in orthodontic tooth movement: up-date in a new decade.

Nowadays, orthodontic treatment has become increasingly popular. However, the biological mechanisms of orthodontic tooth movement (OTM) have not been fully elucidated. We were aiming to summarize the evidences regarding the mechanisms of OTM. Firstly, we introduced the research models as a basis for further discussion of mechanisms. Secondly, we proposed a new hypothesis regarding the primary roles of periodontal ligament cells (PDLCs) and osteocytes involved in OTM mechanisms and summarized the biomechanical and biological responses of the periodontium in OTM through four steps, basically in OTM temporal sequences, as follows: (1) Extracellular mechanobiology of periodontium: biological, mechanical, and material changes of acellular components in periodontium under orthodontic forces were introduced. (2) Cell strain: the sensing, transduction, and regulation of mechanical stimuli in PDLCs and osteocytes. (3) Cell activation and differentiation: the activation and differentiation mechanisms of osteoblast and osteoclast, the force-induced sterile inflammation, and the communication networks consisting of sensors and effectors. (4) Tissue remodeling: the remodeling of bone and periodontal ligament (PDL) in the compression side and tension side responding to mechanical stimuli and root resorption. Lastly, we talked about the clinical implications of the updated OTM mechanisms, regarding optimal orthodontic force (OOF), acceleration of OTM, and prevention of root resorption.

PPARß/δ Agonist Alleviates Diabetic Osteoporosis via Regulating M1/M2 Macrophage Polarization.

Diabetic osteoporosis is a common complication in diabetic patients, leading to increased fracture risk and impaired bone healing. As a member of the peroxisome proliferator-activated receptor (PPAR) family, PPARß/δ agonist is suggested as a therapeutic target for the treatment of metabolic syndrome, and has been reported to positively regulate bone turnover by improving osteogenesis. However, its regulatory role in diabetic osteoporosis has not been reported yet. Here, we explored the therapeutic effects and potential mechanisms of PPARß/δ agonist to the osteoporotic phenotypes of diabetic mice. Our results indicated that the osteoporotic phenotypes could be significantly ameliorated in diabetic mice by the administration of PPARß/δ agonists. In vitro experiments suggested that PPARß/δ agonist treatment could alleviate the abnormal increase of osteoclast activity in diabetic mice by rectifying high glucose-mediated macrophage dysfunction instead of directly inhibiting osteoclast differentiation. Mechanistically, Angptl4 may act as a downstream target of PPARß/δ to regulate macrophage polarization. In conclusion, our study demonstrates the potential of PPARß/δ agonist as a therapeutic target for the treatment of osteoporosis and immune homeostasis disorder in diabetic patients.

PPARß/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy.

BACKGROUND: Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) ß/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARß/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. METHODS: We detected the effect of PPARß/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARß/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. RESULTS: Our results demonstrated that the activation of PPARß/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARß/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARß/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARß/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. CONCLUSION: In conclusion, our study demonstrates the potential role of PPARß/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

The effect of N-acetylcysteine on the antibacterial capability and biocompatibility of nano silver-containing orthodontic cement.

OBJECTIVES: To determine whether the incorporation of N-acetylcysteine (NAC) improves the antibacterial ability and biocompatibility of nano silver (NAg)-containing orthodontic cement. MATERIALS AND METHODS: NAg was synthesized using a sodium citrate reduction method. NAg particles were characterized using transmission electron microscopy and ultraviolet-visible absorption spectra. NAg and NAC were incorporated into a resin-modified glass ionomer cement. Enamel shear bond strength (SBS), antibacterial capability, and cytotoxicity were evaluated. RESULTS: Incorporating 0.15% NAg and 20% NAC had no adverse effect on the SBS of orthodontic cement (P > .1). Adding NAC into NAg-containing cement greatly reduced the biofilm metabolic activity and lactic acid production (P < .05) and lowered the colony unit-forming counts by approximately 1 log (P < .05). The cell viability against NAg-containing cement was improved by NAC (P < .05). CONCLUSIONS: The incorporation of NAC into NAg-containing cement achieved stronger antibacterial capability and better biocompatibility, without compromising the enamel SBS. The combined use of NAC and NAg is promising to combat caries in orthodontic practice.

Effects of nutrition and hormones on functional appliance treatment outcome in patients with skeletal Class II malocclusion.

BACKGROUND: Functional appliances has been used for treatment of skeletal Class II malocclusion for a long time; however, the real skeletal effects, mandibular growth particularly, remain insufficient. Several auxiliary approaches have been attempted with the hope of enhancing treatment effects. In this review, we summarize and discuss the use of additional nutrition and hormones to assist the functional appliance treatment on patients with skeletal Class II malocclusion. METHODS: Relevant articles were identified by electronic research in MEDLINE Ovid using keywords such as "nutrition," "hormone," "functional appliance," "orthodontics," "maxillofacial development," and "maxillofacial abnormalities." References of related articles were assessed for relevant studies to identify additional published references. RESULTS: The literature search yielded 239 studies. According to the current literature, use of additional nutrition and hormones, including growth hormones, sex hormones, insulin, and insulin-like growth factor I, seem to improve the effects of functional appliance treatment on patients with skeletal Class II malocclusion. CONCLUSIONS: The current evidence indicates that additional nutrition or hormones might improve the treatment effects on mandibular hypoplasia compared with the functional appliance alone, which is a promising approach and calls for further studies.

Risk of Bias and Its Impact on Intervention Effect Estimates of Randomized Controlled Trials in Endodontics.

INTRODUCTION: The aims of this study were to evaluate the methodological quality of randomized controlled trials (RCTs) recently published in endodontics and to investigate the influences of methodological characteristics on the magnitude of treatment effects. METHODS: PubMed was searched for RCTs published from October 2013 to October 2018 in 3 leading endodontic journals. The methodological quality of the included studies was determined by using the Cochrane Collaboration risk of bias (RoB) tool. The estimates of intervention effects were expressed or calculated as odds ratios and the standardized mean difference for binary and continuous outcomes, respectively. Meta-regression analyses and Monte Carlo permutation tests were performed to identify the association between RoB and intervention effect estimates. RESULTS: A total of 121 RCTs were identified as eligible for the current study. For both the studies with binary and continuous outcome measures, the domain of blinding of participants and personnel had the highest percentage of high RoB. For binary outcomes, methodological deficiencies in allocation concealment tended to produce exaggerated treatment effects. For continuous outcomes, risk regarding blinding of participants and personnel and incomplete outcome data were more likely to provide overestimated trial results. CONCLUSIONS: The methodological quality of RCTs within endodontics is suboptimal, and these methodological deficiencies could exaggerate intervention effect estimates in endodontic RCTs. Better trial methodology and more explicit reporting are needed to improve the reliability of evidence in endodontic RCTs.