Assessing the impact of occlusal plane rotation on facial aesthetics in orthodontic treatment: a machine learning approach.

BACKGROUND: Adequate occlusal plane (OP) rotation through orthodontic therapy enables satisfying profile improvements for patients who are disturbed by their maxillomandibular imbalance but reluctant to surgery. The study aims to quantify profile improvements that OP rotation could produce in orthodontic treatment and whether the efficacy differs among skeletal types via machine learning. MATERIALS AND METHODS: Cephalometric radiographs of 903 patients were marked and analyzed by trained orthodontists with assistance of Uceph, a commercial software which use artificial intelligence to perform the cephalometrics analysis. Back-propagation artificial neural network (BP-ANN) models were then trained based on collected samples to fit the relationship among maxillomandibular structural indicators, SN-OP and P-A Face Height ratio (FHR), Facial Angle (FA). After corroborating the precision and reliability of the models by T-test and Bland-Altman analysis, simulation strategy and matrix computation were combined to predict the consequent changes of FHR, FA to OP rotation. Linear regression and statistical approaches were then applied for coefficient calculation and differences comparison. RESULTS: The regression scores calculating the similarity between predicted and true values reached 0.916 and 0.908 in FHR, FA models respectively, and almost all pairs were in 95% CI of Bland-Altman analysis, confirming the effectiveness of our models. Matrix simulation was used to ascertain the efficacy of OP control in aesthetic improvements. Intriguingly, though FHR change rate appeared to be constant across groups, in FA models, hypodivergent group displayed more sensitive changes to SN-OP than normodivergent, hypodivergent group, and Class III group significantly showed larger changes than Class I and II. CONCLUSIONS: Rotation of OP could yield differently to facial aesthetic improvements as more efficient in hypodivergent groups vertically and Class III groups sagittally.

Seco-polyprenylated acylphloroglucinols from Hypericum elodeoides induced cell cycle arrest and apoptosis in MCF-7 cells via oxidative DNA damage.

Four undescribed seco-polyprenylated acylphloroglucinols (seco-PAPs), elodeoidesones A-D (1-4), were characterized from Hypericum elodeoides. Compound 1 represents the 1,6-seco-PAPs with fascinating 5/5 fused ring, while 2-4 possess a 1,2-seco-PAPs skeleton with a five-membered lactone core. Their structures including absolute configurations were established by spectroscopic analyses and quantum chemical computations. A possible biosynthetic pathway of 1-4 from normal PAPs was proposed. All the isolates were investigated for their cytotoxicity against tumor cells. Notably, 1 inhibited the proliferation of MCF-7 cells with the IC50 value of 7.34 µM. Mechanism investigation indicated that 1 induced MCF-7 cells apoptosis by blocking cell cycle at S phase via inducing oxidative DNA damage.

The vital role of Gli1+ mesenchymal stem cells in tissue development and homeostasis.

The hedgehog (Hh) signaling pathway plays an essential role in both tissue development and homeostasis. Glioma-associated oncogene homolog 1 (Gli1) is one of the vital transcriptional factors as well as the direct target gene in the Hh signaling pathway. The cells expressing the Gli1 gene (Gli1+ cells) have been identified as mesenchymal stem cells (MSCs) that are responsible for various tissue developments, homeostasis, and injury repair. This review outlines some recent discoveries on the crucial roles of Gli1+ MSCs in the development and homeostasis of varieties of hard and soft tissues.

NO2 exposure increases eczema outpatient visits in Guangzhou, China: an indication for hospital management.

BACKGROUND: Ambient nitrogen dioxide (NO2) is a common air pollutant in developing countries and causes skin conditions, but its effect on eczema in subtropical areas is not clear in China. OBJECT: To measure the effect of short-term exposure of NO2 on the incidence of eczema and the change of outpatient visits. METHODS: Data of daily temperature, air pollutants, and outpatient visits from 2013 to 2018 were collected in a row. The generalized additive model (GAM) and Poisson distribution were used to assess the association between short-term exposure of NO2 and the outpatient visits of patients with eczema. The cumulative exposure effect of lag 0-3 days and the displacement effect of NO2 and other pollutants were considered as well. A single pollutant model was used to examine the independent association, and a two-pollutant model was adopted to control the confounding effect. RESULTS: The daily outpatient visits of eczema increased from 75.26 to 190.85 from 2013 to 2018 (P < 0.001). The combined influence of NO2 and the related pollutant exerted a stronger influence on the incidence of eczema. The maximum effect of NO2 appeared on the exposed day. (lag 0) and disappeared on day 4 (lag 3). The children and seniors were more vulnerable to NO2 exposure. CONCLUSION: Exposure to NO2 is tightly associated with eczema incidence and outpatient visits. The hospitals should react to the visit fluctuations and adjust physician duty shifts to improve outpatient service efficiency.

The Effect of ß-Aminopropionitrile on Skeletal Micromorphology and Osteogenesis.

Collagen cross-linking, as a form of collagen post-translational modification, plays a crucial role in maintaining bone mechanical properties as well as in regulating cell biological functions. Shifts in cross-links profile are found apparently correlated to kinds of skeletal pathology and diseases, whereas little is known about the relationship between collagen cross-links and osteogenesis. Here, we hypothesized that the inhibition of collagen cross-links could impair skeletal microstructure and inhibit osteogenesis. A mouse model of collagen cross-linking defects has been established using subcutaneous injection of 350 mg/kg ß-aminopropionitrile (BAPN) daily for 4 weeks, and same dose of phosphate buffered saline (PBS) served as control group. The analysis of bone microstructural parameters revealed a significant decrease of bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), and increase of bone surface ratio (BS/BV), structure model index (SMI) as well as trabecular separation (Tb.Sp) in the experimental group (p < 0.05), whereas there was no difference observed in bone mineral density (BMD). Histological staining displayed that the BAPN treatment caused thinner trabeculae and decrease of collagen content in proximal tibiae. The analysis of osteogenesis PCR (Polymerase Chain Reaction) array reflected that BAPN remarkably influenced the expression of Alpl, Bglap, Bgn, Bmp5, Col10a1, Col1a1, Col1a2, Col5a1, Itga2b, and Serpinh1. The results of immunohistochemistry displayed a significant reduction in the mean optical densities of OCN and COL1 at the presence of BAPN. The overall results of this study suggested that BAPN alters bone microstructure and hinders the expression of osteogenic genes without affecting mineralization processes, indicating the influences of collagen cross-links on osteogenesis may be a potential pathological mechanism in skeletal diseases.

Effect of lysophosphatidylglycerol on intracellular free Ca2+ concentration in A10 vascular smooth muscle cells.

Although plasma levels of lysophosphatidylglycerol (LPG) are increased in hypertension, its role in the pathogenesis of vascular defects is not clear. In view of the importance of Ca2+ overload in causing vascular smooth muscle (VSM) dysfunction, the action of LPG on [Ca2+]i in cultured A10 VSM cell line was examined by using Fura 2-AM acetoxymethyl ester technique. LPG was found to induce a concentration-dependent increase in [Ca2+]i in VSM cells. This change was dependent both on the extracellular and intracellular Ca2+ sources, as it was reduced by 30% by EGTA, an extracellular Ca2+ chelator, and 70% by thapsigargin, a sarcoplasmic reticulum (SR) Ca2+-pump inhibitor. However the increase in [Ca2+]i due to LPG was not altered by caffeine or ryanodine, which affect Ca2+-release through the ryanodine receptors in the SR. On the other hand, LPG-induced change in [Ca2+]i was suppressed by 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate, a phospholipase C (PLC) inhibitor, as well as by xestospongin and 2-aminoethoxydiphenyl borate, two inositol trisphosphate (IP3) receptor inhibitors in the SR. These observations support the view that LPG-induced increase in [Ca2+]i in VSM cells is mainly a result of Ca2+ release from Ca2+ pool in the SR through PLC/IP3-sensitive signal transduction mechanism. Furthermore, it is suggested that the elevated level of LPG may induce intracellular Ca2+ overload and thus play a critical role in the development of vascular abnormalities.

The effectiveness of vibrational stimulus to accelerate orthodontic tooth movement: a systematic review.

BACKGROUND: In recent years, it has been a hot research topic to accelerate orthodontic tooth movement (OTM) through vibration. This review was therefore aimed to systematically evaluate the available evidences on the efficacy of vibrational stimulus to accelerate OTM. METHODS: Randomized controlled trials and controlled clinical trials that evaluated the efficacy of vibration on OTM acceleration were searched through electronic and manual search. Two review authors independently conducted the study inclusion, quality assessment and data extraction. The quality of synthesized evidence was assessed according to GRADE system. RESULTS: Eight clinical trials were included in this systematic review. Four studies found that vibration did not enhance the rate of OTM during alignment phase. Two studies revealed that the use of vibratory stimulation accelerated canine retraction. No deleterious effects including pain perceptions and root resorptions were reported. CONCLUSIONS: Within the limitations of this review, weak evidence indicates that vibrational stimulus is effective for accelerating canine retraction but not for alignment. The effects of vibration on pain intensity and root resorption during orthodontic treatment are inconclusive. Future high-quality clinical trials are needed before warranting recommendations to clinical application.

Role of Hippo signaling in cancer stem cells.

Cancer stem cells (CSCs) have been proposed and evidenced as the initiator of tumor formation and the seeds of metastases. Thereby, the molecular mechanisms regarding modulation of CSCs have been widely explored, aimed to improve treatment for cancer patients. Recent progress has highlighted the effects of Hippo signaling in tumorigenesis and cancer development, including its crucial role in CSC regulation. Although the kernel Hippo signaling cascade has been well studied, its upstream inputs and downstream transcriptional regulation still remain elusive. In this review, we summarize the current understanding of the mechanism and regulatory function of Hippo signaling in CSCs, with emphasis on its possible roles in regulation of CSC self-renewal, differentiation and tumorigenesis.

Mapping of individual sensory nerve axons from digits to spinal cord with the transparent embedding solvent system.

Achieving uniform optical resolution for a large tissue sample is a major challenge for deep imaging. For conventional tissue clearing methods, loss of resolution and quality in deep regions is inevitable due to limited transparency. Here we describe the Transparent Embedding Solvent System (TESOS) method, which combines tissue clearing, transparent embedding, sectioning and block-face imaging. We used TESOS to acquire volumetric images of uniform resolution for an adult mouse whole-body sample. The TESOS method is highly versatile and can be combined with different microscopy systems to achieve uniformly high resolution. With a light sheet microscope, we imaged the whole body of an adult mouse, including skin, at a uniform 0.8 × 0.8 × 3.5 µm3 voxel resolution within 120 h. With a confocal microscope and a 40×/1.3 numerical aperture objective, we achieved a uniform sub-micron resolution in the whole sample to reveal a complete projection of individual nerve axons within the central or peripheral nervous system. Furthermore, TESOS allowed the first mesoscale connectome mapping of individual sensory neuron axons spanning 5 cm from adult mouse digits to the spinal cord at a uniform sub-micron resolution.

A 3-D Visualization Technique for Bone Remodeling in a Suture Expansion Mouse Model.

Craniofacial sutures play a crucial role beyond being fibrous joints connecting craniofacial bones; they also serve as the primary niche for calvarial and facial bone growth, housing mesenchymal stem cells and osteoprogenitors. As most craniofacial bones develop through intramembranous ossification, the sutures' marginal regions act as initiation points. Due to this significance, these sutures have become intriguing targets in orthopedic therapies like spring-assisted cranial vault expansion, rapid maxillary expansion, and maxillary protraction. Under orthopedic tracing force, suture stem cells are rapidly activated, becoming a dynamic source for bone remodeling during expansion. Despite their importance, the physiological changes during bone remodeling periods remain poorly understood. Traditional sectioning methods, primarily in the sagittal direction, do not capture the comprehensive changes occurring throughout the entire suture. This study established a standard mouse model for sagittal suture expansion. To fully visualize bone remodeling changes post-suture expansion, the PEGASOS tissue clearing method was combined with whole-mount EdU staining and calcium chelating double labeling. This allowed the visualization of highly proliferating cells and new bone formation across the entire calvarial bones following expansion. This protocol offers a standardized suture expansion mouse model and a 3-D visualization method, shedding light on the mechanobiological changes in sutures and bone remodeling under tensile force loading.

Revealing the representative facial traits of different sagittal skeletal types: decipher what artificial intelligence can see by Grad-CAM.

OBJECTIVES: Aesthetic improvement is a significant concern in dental therapy. While orthodontic treatment primarily targets hard tissue, the impact on soft tissue and the extent of these changes remains empirical. This study aims to unveil the intricate relationship between facial soft tissue and skeletal types using artificial intelligence (AI) analysis. METHODS: First, we collected a dataset of 1044 3-side-photographs and categorized them based on cephalometric measurements. After pre-processing and data augmentation, samples were fed to two independent models (Sfa, Res model) for training and testing. After validating that the Sfa model could accurately recognize the skeletal types based merely on photographs, Grad-CAM algorithm was utilized for model decipherment. Verification of the vital traits were carried out by facial adjustment simulation. RESULTS: The Sfa model demonstrated superior accuracy (0.9293) in identifying skeletal types based solely on soft tissue, compared to the Res model (0.8395) and even trained orthodontists (0.764), testifying our hypothesis that AI could be more capable of processing imperceptible cues compared to mankind. Intriguingly, Grad-CAM revealed that cheek volume, forehead, chin and nasolabial traits could be representative features of each type, exceeding the traditional knowledge which merely concerns mandible and chin. CONCLUSION: By constructing a deep learning model as a classifier and then decipher it with Grad-CAM, we revealed the subtle and unnoticed cues associating skeletal and soft tissue, as well as provided a novel approach that could aid practitioners in devising tailored treatment plans for enhanced esthetic outcomes. CLINICAL SIGNIFICANCE: The proposed AI methods offer valuable assistance to practitioners in identifying uncoordinated facial traits that may detract from a patient's attractiveness. By incorporating these insights into customized treatment plans, dental therapy can maximize esthetic benefits for individual patient.

The effect of AKT in extracellular matrix stiffness induced osteogenic differentiation of hBMSCs.

Extracellular matrix (ECM) stiffness is an important biophysical factor in human bone marrow mesenchymal stem cells (hBMSCs) differentiation. Although there is evidence that Yes-associated protein (YAP) plays an important role in ECM elasticity induced osteogenesis, but the regulatory mechanism and signaling pathways have not been distinctly uncovered. In this study, hBMSCs were cultured on collagen-coated polydimethylsiloxane hydrogels with stiffness corresponding to Young's moduli of 0.5 kPa and 32 kPa, and gene chip analyses revealed the phosphoinositide 3-kinase (PI3K)-AKT pathway was highly correlated with ECM stiffness. Following western blots indicated that AKT phosphorylation was evidently affected in 5th-7th days after ECM stiffness stimulation, while PI3K showed little difference. The AKT activator SC79 and inhibitor MK2206 were utilized to modulate AKT phosphorylation. SC79 and MK2206 caused alteration in the mRNA expression and protein level of alkaline phosphatase (ALP), collagen type I alpha 1 (COL1A1) and runt related transcription factor 2 (RUNX2). On 32 kPa substrates, YAP enrichment in nucleus were significantly promoted by SC79 and remarkably decreased by MK2206. Besides, the ratio of YAP/p-YAP is upregulated by SC79 on both 32 kPa and 0.5 kPa substrates. In conclusion, these findings suggest that AKT is involved in the modulation of ECM stiffness induced osteogenesis, and AKT phosphorylation also influences the subcellular localization and activation of YAP.

Type II collagen-positive progenitors are important stem cells in controlling skeletal development and vascular formation.

Type II collagen-positive (Col2+) cells have been reported as skeletal stem cells (SSCs), but the contribution of Col2+ progenitors to skeletal development both prenatally and postnatally during aging remains unclear. To address this question, we generated new mouse models with ablation of Col2+ cells at either the embryonic or postnatal stages. The embryonic ablation of Col2+ progenitors resulted in the death of newborn mice due to a decrease in skeletal blood vessels, loss of all vertebral bones and absence of most other bones except part of the craniofacial bone, the clavicle bone and a small piece of the long bone and ribs, which suggested that intramembranous ossification is involved in long bone development but does not participate in spine development. The postnatal ablation of Col2+ cells resulted in mouse growth retardation and a collagenopathy phenotype. Lineage tracing experiments with embryonic or postnatal mice revealed that Col2+ progenitors occurred predominantly in the growth plate (GP) and articular cartilage, but a limited number of Col2+ cells were detected in the bone marrow. Moreover, the number and differentiation ability of Col2+ progenitors in the long bone and knee joints decreased with increasing age. The fate-mapping study further revealed Col2+ lineage cells contributed to, in addition to osteoblasts and chondrocytes, CD31+ blood vessels in both the calvarial bone and long bone. Specifically, almost all blood vessels in calvarial bone and 25.4% of blood vessels in long bone were Col2+ lineage cells. However, during fracture healing, 95.5% of CD31+ blood vessels in long bone were Col2+ lineage cells. In vitro studies further confirmed that Col2+ progenitors from calvarial bone and GP could form CD31+ vascular lumens. Thus, this study provides the first demonstration that intramembranous ossification is involved in long bone and rib development but not spine development. Col2+ progenitors contribute to CD31+ skeletal blood vessel formation, but the percentage differs between long bone and skull bone. The number and differentiation ability of Col2+ progenitors decreases with increasing age.

The effect of platelet-rich concentrates on orthodontic tooth movement: A review of randomized controlled trials.

Objectives: Platelet-rich concentrates, namely platelet-rich plasma (PRP) and platelet-rich fibrin (PRF), have recently shown potential roles in accelerating orthodontic tooth movement (OTM) and reducing treatment duration. Our study aims to systematically evaluate the effect of platelet-rich concentrates on OTM. Materials and methods: An electronic search of 11 databases, followed by a hand search of reference lists of eligible studies and related reviews, was conducted up to January 2022. Randomized controlled trials investigating OTM of patients with platelet-rich concentrates were included. Risk of bias was assessed by version 2 of Cochrane tool (RoB 2) for assessing risk of bias in randomized trials. Results: Among 715 records initially identified, 9 studies were included, of which 3 used PRP and the other 6 applied PRF. 7 studies supported a positive relationship between platelet-rich concentrates and OTM, but the other 2 studies reported a null and a negative effect of PRF, respectively. The overall qualities of evidence were moderate to high. Conclusions: Platelet-rich concentrates as PRP and PRF seem to be effective in accelerating OTM at early stages, while their long-term efficacy remains controversial. Repeated application of platelet concentrates may increase the accelerated stability of OTM.

Short-term exposure of PM2.5 and PM10 increases the number of outpatients with eczema in Guangzhou: A time-series study.

Background: The worldwide prevalence of eczema has continued to rise over the past decades. This has led to the emphasis on the association between air pollution and eczema. This study investigated the relationship between daily exposure to air pollution and the number of eczema outpatient visits in Guangzhou with the overarching goal of providing novel insights on the interventions for eczema aggravation and prevention. Methods: Daily air pollution data, meteorological data, and the number of eczema outpatients were obtained from 18 January 2013 to 31 December 2018 in Guangzhou. A generalized additive model with Poisson distribution was used to assess the association between the number of eczema outpatient visits and short-term exposure to PM2.5 and PM10. In addition, the association of PM2.5 and PM10 by age (<65 years, ≥65 years) and gender was evaluated. Results: A total of 293,343 eczema outpatient visits were recorded. The obtained results indicated that a 10 µg/m3 increase of the same day/lag 1 day/lag 2 days PM2.5 was associated with increments of 2.33%, 1.81%, and 0.95% in eczema outpatient risk, respectively. On the other hand, a 10 µg/m3 increase of PM10 was associated with eczema outpatients risk increments of 1.97%, 1.65%, and 0.98% respectively. Furthermore, the associations of PM on the increment of eczema were similar in the male and female groups. Results obtained after age stratified analyses indicated that the strongest positive association between PM2.5 exposure and eczema was observed at lag 0 day with the percent changes being 4.72% and 3.34% in <12 years old, ≥12 and <65 years old, and ≥65 years old groups, respectively. Conclusion: Short-term exposure to PM2.5 and PM10 increases the number of eczema outpatients, especially among children and the elderly. The relationship between air quality trends and hospital resource arrangement should be paid attention to by hospital managers which may aid in disease prevention and lower the health burden.

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).

Tissue Clearing and 3-D Visualization of Vasculature with the PEGASOS Method.

Tissue clearing techniques turn tissue transparent through a series of chemical and physical treatments. They have provided a useful tool for three-dimensional (3-D) imaging to study tissue spatial organization and interactions. Many tissue clearing methods have been developed in recent years. Each method has its own application range depending on the purposes of the study. Three criteria for selecting an appropriate clearing method include clearing transparency, fluorescence preservation, and broad tissue applicability. PEG-associated solvent system (PEGASOS) emerged recently as a solvent-based tissue clearing method capable of rendering diverse tissues highly transparent while preserving fluorescence. Combined with vascular labeling techniques, PEGASOS method enables 3-D visualization of vasculature in whole tissues at subcellular resolution. Here, we describe the standard PEGASOS passive immersion protocol and several compatible vascular labeling techniques. Methods of 3-D imaging, data processing, and annotations are also briefly introduced.

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.

Non-Coding RNAs Steering the Senescence-Related Progress, Properties, and Application of Mesenchymal Stem Cells.

The thirst to postpone and even reverse aging progress has never been quenched after all these decades. Unequivocally, mesenchymal stem cells (MSCs), with extraordinary abilities such as self-renewal and multi-directional differentiation, deserve the limelight in this topic. Though having several affable clinical traits, MSCs going through senescence would, on one hand, contribute to age-related diseases and, on the other hand, lead to compromised or even counterproductive therapeutical outcomes. Notably, increasing evidence suggests that non-coding RNAs (ncRNAs) could invigorate various regulatory processes. With even a slight dip or an uptick of expression, ncRNAs would make a dent in or even overturn cellular fate. Thereby, a systematic illustration of ncRNAs identified so far to steer MSCs during senescence is axiomatically an urgent need. In this review, we introduce the general properties and mechanisms of senescence and its relationship with MSCs and illustrate the ncRNAs playing a role in the cellular senescence of MSCs. It is then followed by the elucidation of ncRNAs embodied in extracellular vesicles connecting senescent MSCs with other cells and diversified processes in and beyond the skeletal system. Last, we provide a glimpse into the clinical methodologies of ncRNA-based therapies in MSC-related fields. Hopefully, the intricate relationship between senescence and MSCs will be revealed one day and our work could be a crucial stepping-stone toward that future.