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Abstract Accumulating evidence has demonstrated that apoptotic vesicles (apoVs) derived from mesenchymal stem cells (MSCs; MSC-apoVs) are vital for bone regeneration, and possess superior capabilities compared to MSCs and other extracellular vesicles derived from MSCs (such as exosomes). The osteoinductive effect of MSC-apoVs is attributed to their diverse contents, especially enriched proteins or microRNAs (miRNAs). To optimize their osteoinduction activity, it is necessary to determine the unique cargo profiles of MSC-apoVs. We previously established the protein landscape and identified proteins specific to MSC-apoVs. However, the features and functions of miRNAs enriched in MSC-apoVs are unclear. In this study, we compared MSCs, MSC-apoVs, and MSC-exosomes from two types of MSC. We generated a map of miRNAs specific to MSC-apoVs and identified seven miRNAs specifically enriched in MSC-apoVs compared to MSCs and MSC-exosomes, which we classified as apoV-specific miRNAs. Among these seven specific miRNAs, hsa-miR-4485-3p was the most abundant and stable. Next, we explored its function in apoV-mediated osteoinduction. Unexpectedly, hsa-miR-4485-3p enriched in MSC-apoVs inhibited osteogenesis and promoted adipogenesis by targeting the AKT pathway. Tailored apoVs with downregulated hsa-miR-4485-3p exhibited a greater effect on bone regeneration than control apoVs. Like releasing the brake, we acquired more powerful osteoinductive apoVs. In summary, we identified the miRNA cargos, including miRNAs specific to MSC-apoVs, and generated tailored apoVs with high osteoinduction activity, which is promising in apoV-based therapies for bone regeneration.

Abstract Background Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus, contributing to end-stage renal disease with limited treatment options. The development of DKD is attributed to podocyte injury resulting from abnormal podocyte autophagy. Consequently, the restoration of podocyte autophagy is deemed a practicable approach in the treatment of DKD. Methods Diabetic mice were induced by streptozotocin and high-fat diet feeding. Following 8 weeks of “QN” agarwood treatment, metrics such as albuminuria, serum creatinine (Scr), and blood urea nitrogen (BUN) were evaluated. Renal histological lesions were evaluated by H&E, PAS, Masson, and Sirius red staining. Evaluation of the effects of “QN” agarwood on renal inflammation and fibrosis in DKD mice through WB, q-PCR, and IHC staining analysis. Cytoscape 3.7.1 was used to construct a PPI network. With the DAVID server, the gene ontology (GO) functional annotation and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the target enrichment were performed. Molecular docking and binding affinity calculations were conducted using AutoDock, while PyMOL software was employed for visualizing the docking results of active compounds and protein targets. Results The results of this study show that “QN” agarwood reduced albuminuria, Scr, and BUN in DKD mice, and improved the renal pathological process. Additionally, “QN” agarwood was observed to downregulate the mRNA and protein expression levels of pro-inflammatory and pro-fibrotic factors in the kidneys of DKD mice. Network pharmacology predicts that “QN” agarwood modulates the epidermal growth factor receptor (EGFR) signaling pathway. “QN” agarwood can increase the expression of LC3B and Nphs1 in DKD mice while reducing the expression of EGFR. Conclusion The present study demonstrated that “QN” agarwood ameliorated renal injury in DKD by targeting EGFR and restoring podocyte autophagy. Graphical Abstract

Abstract Background Tooth brushing with fluoridated toothpaste has become the most important way to provide the anti-caries effect of fluoride around the world. China has promoted the use of fluoridated toothpaste since 1989. However, there are few studies on the national profile of use of fluoridated toothpaste and related factors in Chinese adolescents. We carried out this study to investigate oral hygiene behaviours, especially the status of tooth brushing with fluoridated toothpaste and its correlates among adolescents, based on data from the latest Nation Oral Health Survey in mainland China. Methods This cross-sectional study recruited 118,601 participants aged 12–15 years using multistage stratified sampling. Questionnaires were completed by students at school. Data employed in analyses were extracted from the questionnaire, including information on tooth brushing, fluoridated toothpaste, dental floss, sociodemographic factors, fluoride knowledge and attitude towards regular dental check-ups. A binary logistic regression was performed to compute the odds ratios (OR). Tooth brushing twice daily with fluoridated toothpaste was the dependent variable. Sociodemographic factors, fluoride knowledge, attitude towards regular dental check-ups, dental visit experience and perceived oral health were the independent variables. P

Abstract Background Periodontitis has become an increasingly important public health issue, coupled with a high economic burden for prevention and treatment. Exposure to essential trace heavy metals has been associated with various diseases; however, the relationships between essential trace heavy metals and periodontitis remain inconclusive. Objectives To investigate the association between essential trace heavy metals in tap water and periodontitis in a nationally representative sample in China. Methods We conducted a nationwide study including 1348 participants from the Fourth National Oral Health Survey in the 2015–2016 period. The trace heavy metals concentration was measured in the local pipeline terminal tap water. Periodontitis was diagnosed according to the classification scheme proposed at the 2018 world workshop on the classification of periodontal and peri-implant diseases and conditions. We used weighted multivariable logistic regression to estimate the association between essential trace heavy metals and the risk of periodontitis. We additionally used spline analysis to explore the possible nonlinear dose-response associations. Results Periodontitis patients were exposed to higher concentrations of essential trace heavy metals. In adjusted models, for 1 SD increase in the concentration of iron, manganese, and copper in tap water, the risk of periodontitis increased by 30% (OR: 1.30, 95%CI: 1.12–1.50), 20% (OR: 1.20, 95%CI: 1.03–1.41), and 20% (OR: 1.20, 95%CI: 1.04–1.39), respectively. Stratified analyses demonstrated that the associations between essential trace heavy metals and periodontitis were higher in females, elders, and rural residents. Spline analysis revealed nonlinear exposure-response relationships between periodontitis and exposure to iron, manganese, and copper in tap water. Conclusions Exposures to essential trace heavy metals in drinking water were associated with greater odds of periodontitis. Given the growing burden of periodontitis, our study sheds light on tailored public health policies for improving drinking water standards to alleviate periodontitis impairment.

Abstract Objective This cross-sectional study aimed to investigate socioeconomic inequalities in dental caries among adults (35 years and older) in China and explore the contributions of various factors to these inequalities. Methods This study included 10,983 adults (3,674 aged 35–44 years, 3,769 aged 55–64 years and 3,540 aged 65–74 years) who participated in the 4th National Oral Health Survey (2015–2016) in China. Dental caries status was evaluated by the decayed, missing and filled teeth (DMFT) index. Concentration indices (CIs) were applied to quantify the different degrees of socioeconomic-related inequality in DMFT, decayed teeth with crown or root caries (DT), missing teeth due to caries or other reasons (MT), and filled teeth without any primary or secondary caries (FT) among adults of different age groups. Decomposition analyses were conducted to identify the determinants and their associations with inequalities in DMFT. Results The significant negative CI indicated that DMFT for the total sample were concentrated among socioeconomically disadvantaged adults (CI = − 0.06; 95% confidence interval [CI], − 0.073 to − 0.047). The CIs for DMFT for adults aged 55–64 and 65–74 years were − 0.038 (95% CI, − 0.057 to − 0.018) and − 0.039 (95% CI, − 0.056 to − 0.023), respectively, while the CI for DMFT for adults aged 35–44 years was not statistically significant (CI = − 0.002; 95% CI, − 0.022 to 0.018). The concentration indices of DT were negative and concentrated in disadvantaged populations, while FT showed pro-rich inequalities in all age groups. Decomposition analyses showed that age, education level, toothbrushing frequency, income and type of insurance contributed substantially to socioeconomic inequalities, accounting for 47.9%, 29.9%, 24.5%,19.1%, and 15.3%, respectively. Conclusion Dental caries was disproportionately concentrated among socioeconomically disadvantaged adults in China. The results of these decomposition analyses are informative for policy-makers attempting to develop targeted health policy recommendations to reduce dental caries inequalities in China.

Abstract Background Astronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term space flight. A risk-free and antiresorptive drug is urgently needed to prevent bone loss during space missions. D-mannose is a natural C-2 epimer of D-glucose and is abundant in cranberries. This study aimed to investigate the protective effects and potential mechanisms of D-mannose against bone loss under weightlessness. Methods The hind legs of tail-suspended (TS) rats were used to mimic weightlessness on Earth. Rats were administered D-mannose intragastrically. The osteoclastogenic and osteogenic capacity of D-mannose in vitro and in vivo was analyzed by micro-computed tomography, biomechanical assessment, bone histology, serum markers of bone metabolism, cell proliferation assay, quantitative polymerase chain reaction, and western blotting. RNA-seq transcriptomic analysis was performed to detect the underlying mechanisms of D-mannose in bone protection. Results The TS rats showed lower bone mineral density (BMD) and poorer bone morphological indices. D-mannose could improve BMD in TS rats. D-mannose inhibited osteoclast proliferation and fusion in vitro, without apparent effects on osteoblasts. RNA-seq transcriptomic analysis showed that D-mannose administration significantly inhibited the cell fusion molecule dendritic cell-specific transmembrane protein (DC-STAMP) and two indispensable transcription factors for osteoclast fusion (c-Fos and nuclear factor of activated T cells 1 [NFATc1]). Finally, TS rats tended to experience dysuria-related urinary tract infections (UTIs), which were suppressed by treatment with D-mannose. Conclusion D-mannose protected against bone loss and UTIs in rats under weightlessness. The bone protective effects of D-mannose were mediated by inhibiting osteoclast cell fusion. Our findings provide a potential strategy to protect against bone loss and UTIs during space missions.

Understanding mechanisms underlying the heterogeneity of multipotent stem cells offers invaluable insights into biogenesis and tissue development. Extracellular matrix (ECM) stiffness has been acknowledged as a crucial factor regulating stem cell fate. However, how cells sense stiffness cues and adapt their metabolism activity is still unknown. Here we report the novel role of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) in enhancing osteogenesis in 3D ECM via glycolysis. We experimentally mimicked the physical characteristics of 3D trabeculae network of normal and osteoporotic bone with different microstructure and stiffness, observing that PCK2 promotes osteogenesis in 3D ECM with tunable stiffness in vitro and in vivo. Mechanistically, PCK2 enhances the rate-limiting metabolic enzyme pallet isoform phosphofructokinase (PFKP) in 3D ECM, and further activates AKT/extracellular signal-regulated kinase 1/2 (ERK1/2) cascades, which directly regulates osteogenic differentiation of MSCs. Collectively, our findings implicate an intricate crosstalk between cell mechanics and metabolism, and provide new perspectives for strategies of osteoporosis.

Abstract Background In tissue engineering, mesenchymal stem cells (MSCs) are common seed cells because of abundant sources, strong proliferation ability and immunomodulatory function. Numerous researches have demonstrated that MSC-macrophage crosstalk played a key role in the tissue engineering. Macrophages could regulate the differentiation of MSCs via different molecular mechanisms, including extracellular vesicles. Apoptotic macrophages could generate large amounts of apoptotic vesicles (apoVs). ApoVs are rich in proteins, RNA (microRNAs, mRNAs, ncRNAs, etc.) and lipids, and are a key intercellular communication mediator that can exert different regulatory effects on recipient cells. MiRNAs account for about half of the total RNAs of extracellular vesicles, and play important roles in biological processes such as cell proliferation and differentiation, whereas the functions of macrophage-derived apoVs remain largely unknown. There was no research to clarify the role of macrophage-derived apoVs in MSC fate choices. In this study, we aimed to characterize macrophage-derived apoVs, and investigate the roles of macrophage-derived apoVs in the fate commitment of MSCs. Methods We characterized macrophage-derived apoVs, and investigated their role in MSC osteogenesis and adipogenesis in vitro and in vivo. Furthermore, we performed microRNA loss- and gain-of-function experiments and western blot to determine the molecular mechanism. Results Macrophages could produce a large number of apoVs after apoptosis. MSCs could uptake apoVs. Then, we found that macrophage-derived apoVs inhibited osteogenesis and promoted adipogenesis of MSCs in vitro and in vivo. In mechanism, apoVs were enriched for microRNA155 (miR155), and apoVs regulated osteogenesis and adipogenesis of MSCs by delivering miR155. Besides, miR155 regulated osteogenesis and adipogenesis of MSCs cultured with macrophage-derived apoVs via the SMAD2 signaling pathway. Conclusions Macrophage-derived apoVs could regulate the osteogenesis and adipogenesis of MSCs through delivering miR155, which provided novel insights for MSC-mediated tissue engineering.

Guided bone regeneration membranes have been effectively applied in oral implantology to repair bone defects. However, typical resorbable membranes composed of collagen (Col) have insufficient mechanical properties and high degradation rate, while non-resorbable membranes need secondary surgery. Herein, we designed a photocrosslinkable collagen/polycaprolactone methacryloyl/magnesium (Col/PCLMA/Mg) composite membrane that provided spatiotemporal support effect after photocrosslinking. Magnesium particles were added to the PCLMA solution and Col/PCLMA and Col/PCLMA/Mg membranes were developed; Col membranes and PCL membranes were used as controls. After photocrosslinking, an interpenetrating polymer network was observed by scanning electron microscopy (SEM) in Col/PCL and Col/PCL/Mg membranes. The elastic modulus, swelling behavior, cytotoxicity, cell attachment, and cell proliferation of the membranes were evaluated. Degradation behavior in vivo and in vitro was monitored according to mass change and by SEM. The membranes were implanted into calvarial bone defects of rats for 8 weeks. The Col/PCL and Col/PCL/Mg membranes displayed much higher elastic modulus (p 0.05). The Col/PCL and Col/PCL/Mg membranes had lower degradation rates than the Col membranes, both in vivo and in vitro (p

Abstract Background The aim of this study was to assess the income-related inequality of edentulism among the aged in China and identify the contributing factors. Methods A secondary analysis of data from the 4th National Oral Health Epidemiology Survey in China was conducted, and 65–74 years old were selected for the analysis of income-related inequality of edentulism. The concentration curve, Concentration index (CI) and Erreygers-corrected concentration index (EI) were used to represent inequality and its degree qualitatively and quantitatively, respectively. A decomposition method based on probit model was employed to determine the contributors of inequality, including demographic factors, income status, oral health-related knowledge, attitude and practices and self-perceived general health status. Results In China, aged people with edentulism were concentrated in the poor. The CI was − 0.2337 (95% CIs: − 0.3503, − 0.1170). The EI was − 0.0413 (95% CIs: − 0.0619, − 0.0207). The decomposition results showed that income (75.02%) and oral health-related knowledge, attitude and practices (15.52%) were the main contributors to the inequality. Conclusion This study showed that pro-poor inequality among the elderly with edentulism existed in China. Corresponding policies against the contributors could be considered to promote the health equality of the elders.

Objectives To evaluate the association between periodontitis severity and hypertension based on Chinese epidemiological data.Design This cross-sectional survey enrolled adults from the Fourth National Oral Health Survey of China (2015–2016).Setting The data were obtained from the Fourth National Oral Health Survey of China (2015–2016).Participants The study included individuals aged 35–44 years (n=4409), 55–64 years (n=4568) and 65–74 years (n=4218).Primary and secondary outcome measures Periodontal status, defined on the basis of the 2017 classification scheme, and periodontal parameters (eg, bleeding on probing (BOP)) were compared between individuals with hypertension and individuals with normotension. Smoothed scatterplots were constructed to demonstrate the associations of periodontal parameters and periodontal status with hypertension.Results Severe periodontitis (stages III and IV) was present in 41.4% of individuals with hypertension and 28.0% of individuals with normotension, respectively (p

Abstract Background To investigate the related risk factors of periodontal health status among Chinese middle school students. Methods This study is a part of the Fourth National Oral Health Epidemiological Survey, which is by far the largest oral epidemiological survey in China, including all provinces, municipalities and autonomous regions in mainland China. A multi-stage stratified sampling method was used to select middle school students aged 12–15 from the sampled middle school for investigation. The survey consisted of two parts: oral examination and questionnaire survey. The oral examination included gingival bleeding and calculus. The questionnaire included sociodemographic information, oral health knowledge, attitudes and behaviors. Logistic regression and generalized linear mixed model were used to investigate the risk factors of gingival bleeding and calculus. Results A total of 118,514 middle-school students has been examined. Less gingival bleeding (OR = 0.746, CI 0.718–0.774) and calculus (OR = 0.550, CI 0.529–0.527) were found in 12-year-old group compared to 15-year-old group. The periodontal health status of males was worse than that of females (gingival bleeding OR = 1.102, CI 1.074–1.132, calculus OR = 1.258, CI 1.223–1.295). Besides age and gender, region, living place, ethnic groups, family structure, parent’s education level, oral health knowledge and behavior were also related to gingival bleeding and calculus. Conclusions Gingival bleeding and calculus occurred most of 12–15 years old adolescents in China. Several related factors, such as gender, age, ethnicity, father’s education level, oral health knowledge and behavior, were found in multi-factorial models. The impact of province should arouse people’s attention.

Abstract Background As a promising way to repair bone defect, bone tissue engineering has attracted a lot of attentions from researchers in recent years. Searching for new molecular target to modify the seed cells and enhance their osteogenesis capacity is one of the hot topics in this field. As a member of aldo-keto reductase family, aldo-keto reductase family 1 member C1 (AKR1C1) is reported to associate with various tumors. However, whether AKR1C1 takes part in regulating differentiation of adipose-derived mesenchymal stromal/stem cells (ASCs) and its relationship with progesterone receptor (PGR) remain unclear. Methods Lost-and-gain-of-function experiments were performed using knockdown and overexpression of AKR1C1 to identify its role in regulating osteogenic and adipogenic differentiation of hASCs in vitro. Heterotypic bone and adipose tissue formation assay in nude mice were used to conduct the in vivo experiment. Plasmid and siRNA of PGR, as well as western blot, were used to clarify the mechanism AKR1C1 regulating osteogenesis. Results Our results demonstrated that AKR1C1 acted as a negative regulator of osteogenesis and a positive regulator of adipogenesis of hASCs via its enzyme activity both in vitro and in vivo. Mechanistically, PGR mediated the regulation of AKR1C1 on osteogenesis. Conclusions Collectively, our study suggested that AKR1C1 could serve as a regulator of osteogenic differentiation via targeting PGR and be used as a new molecular target for ASCs modification in bone tissue engineering.

Primary bone mesenchymal stem cells (BMSCs) gradually lose stemness during in vitro expansion, which significantly affects the cell therapeutic effects. Here, we chose murine PαS (SCA-1+PDGFRα+CD45−TER119−) cells as representative of BMSCs and aimed to explore the premium culture conditions for PαS cells. Freshly isolated (fresh) PαS cells were obtained from the limbs of C57/6N mice by fluorescence-activated cell sorting (FACS). We investigated the differences in the stemness of PαS cells by proliferation, differentiation, and stemness markers in vitro and by ectopic osteogenesis and chondrogenesis ability in vivo, as well as the changes in the stemness of PαS cells during expansion in vitro. Gain- and loss-of-function experiments were applied to investigate the critical role and underlying mechanism of the basic helix–loop–helix family member E40 (BHLHE40) in maintaining the stemness of PαS cells. The stemness of fresh PαS cells representative in vivo was superior to that of passage 0 (P0) PαS cells in vitro. The stemness of PαS cells in vitro decreased gradually from P0 to passage 4 (P4). Moreover, BHLHE40 plays a critical role in regulating the stemness of PαS cells during in vitro expansion. Mechanically, BHLHE40 regulates the stemness of PαS cells by targeting Zbp1 through the Wnt/β-catenin signaling pathway. This work confirms that BHLHE40 is a critical factor for regulating the stemness of PαS cells during expansion in vitro and may provide significant indications in the exploration of premium culture conditions for PαS cells.

Abstract Background Bone defects are a common clinical condition that has gained an increasing amount of attention in recent years. Causes of bone defect include tumors, inflammation, and fractures. Bone tissue engineering is a novel treatment of bone defect, and human mesenchymal stem cells (hMSCs) are the ideal seed cells for bone tissue engineering due to their multi-lineage differentiation potential and immunogenicity. The laminin α2 (LAMA2) gene encodes the α2 subunit of laminins. Mutations in this gene have been reported to cause muscular dystrophy, but thus far no studies have elucidated the role of LAMA2 in the fate choices of MSCs. Here, we aimed to investigate the critical role of LAMA2 in the osteogenesis and adipogenesis of mesenchymal stem cells (MSCs). Methods We investigated LAMA2 function in osteogenic and adipogenic differentiation of MSCs in vitro and in vivo through loss- and gain-of-function experiments. In addition, molecular mechanism was clarified by Western blot and siRNA. Results Our results demonstrated that LAMA2 was a critical regulator for fate commitment of MSCs. Both in vitro and in vivo studies indicate that LAMA2 inhibits osteogenesis and promotes adipogenesis. Mechanistically, we found that LAMA2 regulated osteogenesis and adipogenesis of MSCs by modulating the hedgehog signaling pathway. Conclusions The present work confirms that LAMA2 is a new molecular target for MSC-based bone regeneration.

Abstract Background This study sought to evaluate dental utilization among 3-,4-, and 5-year-old children in China and to use Andersen’s behavioural model to explore influencing factors, thereby providing a reference for future policy making. Methods This study is a cross-sectional study. Data of 40,305 children aged 3–5 years were extracted from the Fourth National Oral Health Survey, which was performed from August 2015 to December 2016. Patient data were collected using a questionnaire, which was answered by the child’s parents, and clinical data were collected during a clinical examination. Stratification and survey weighting were incorporated into the complex survey design. Descriptive statistics, bivariate correlations and hierarchical logistic regression results were then analysed to find the factors associated with oral health service utilization. Results The oral health service utilization prevalence during the prior 12 months were 9.5% (95%CI: 8.1–11.1%) among 3-year-old children, 12.1% (95%CI: 10.8–13.5%) among 4-year-old children, and 17.5% (95%CI: 15.6–19.4%) among 5-year-old children. “No dental diseases” (71.3%) and “dental disease was not severe” (12.4%) were the principal reasons why children had not attended a dental visit in the past 12 months. The children whose parents had a bachelor’s degree or higher (OR: 2.29, 95%CI: 1.97–2.67, p

Abstract Background As the representative of fenamic acids, an important group of NSAIDs, flufenamic acid (FFA) has been used for anti-inflammation and analgesia in the clinic. Recently, researches have focused on the role of some members of NSAIDs in promoting osteogenesis. However, little attention has been paid to the subgroup of fenamic acids, and it remains unclear whether FFA and other fenamic acids could regulate mesenchymal stem cells’ (MSCs) lineage commitment and bone regeneration. Methods Here we treated two kinds of human MSCs with FFA at different concentrations in vitro and examined the effect of FFA on osteogenic differentiation of human MSCs. This was followed by heterotopic bone formation assay in nude mice. In addition, ovariectomized and aged mice were used as osteoporotic models to test the effect of FFA on osteoporosis. Besides, activators and inhibitor of nuclear factor-κB (NF-κB) signaling pathway and western blot were used to clarify the mechanism of the promoting effect of low concentration FFA on osteogenesis. Results Our results indicated that low concentrations of FFA could significantly enhance osteogenic differentiation of human MSCs in vitro, as well as in vivo. In addition, FFA treatment suppressed bone loss in ovariectomized and aged mice. Mechanistically, FFA at low concentrations promoted osteogenesis differentiation of human MSCs by inhibition of the NF-κB signaling pathway. Conclusions Collectively, our study suggested that low concentration FFA could be used in bone tissue engineering or osteoporosis by promoting osteogenic differentiation of human MSCs.

Objective: To understand the oral health status of urban and rural residents in China, the Fourth National Oral Health Epidemiological Survey (FNOHES) was conducted in 2015. Materials and methods: Based on the principles of multi-stage, stratified, equal capacity, and random sampling, the subjects included five groups of residents aged 3–5, 12–15, 35–44, 55–64, and 65–74 years in all 31 provinces, cities, and autonomous regions except Hong Kong, Macao, and Taiwan. The total sample size was 172,425. The survey covered two areas, namely oral health status and knowledge, attitude and oral health behavior. Results: Residents in China had serious caries and poor periodontal condition. The prevalence of caries was above 50% in all age groups, subjects without periodontal disease accounted for

Bone defects and fractures heal slowly compared with injuries to other tissues, creating a heavy burden for patients, their families, and society. Alongside conventional treatment methods for fractures and bone defects, adjuvant therapies play an important but underappreciated role. In a previous study, we found that systemic administration of flufenamic acid promoted osteogenesis in vivo, but its side effects limited the application of our findings. In the present study, we assess the effects of external butyl flufenamate ointment on the healing of cranial defects in mice. We found that application of butyl flufenamate ointment on the surface of the skin accelerated the healing of cranial defects in mice by promoting BMP2 secretion from mouse-skin mesenchymal stem-cells. These findings indicate that butyl flufenamate ointment has potential therapeutic value for treating superficial fractures or bone defects while avoiding the toxicity and side effects of systemic medication, representing a safe and convenient adjuvant therapy to promote healing of superficial bone defects and fractures.

Background: D-mannose exhibits strong anti-inflammatory properties, but whether it has beneficial effects on preventing and treating osteoporosis remains unknown. Methods: Female, 12-month-old senile C57BL6/J mice (s-Man group) and 8-week-old ovariectomized C57BL6/J mice (OVX-Man group) were treated with D-mannose in drinking water for 2 months (six mice/group). Microcomputed tomography analysis and hematoxylin and eosin staining were performed to investigate the effect of D-mannose on attenuation of bone loss. Tartrate-resistant acid phosphatase staining of tissue sections, flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and gut microbiome biodiversity tests were used to explore the underlying mechanisms. Results: D-mannose-induced marked increases in cortical bone volume and trabecular bone microarchitecture in the s-Man and OVX-Man group compared with that in the s-CTRL (senile control) and OVX group, respectively. Moreover, D-mannose downregulated osteoclastogenesis-related cytokines in the bone marrow and expanded regulatory T cells in the spleen of mice. Furthermore, D-mannose reconstructed the gut microbiota and changed the metabolite composition. Conclusion: D-mannose attenuated bone loss induced by senility and estrogen deficiency in mice, and this effect may be mediated by D-mannose-induced proliferation of regulatory T cells and gut microbiota-dependent anti-inflammatory effects.

Abstract Background An appropriate level of human resources for oral health [HROH] is required to meet the oral health needs of population, and enable maximum improvement in health outcomes. The aim of this study was to estimate the required HROH to meet the oral health needs of the World Health Organization [WHO] reference group of 12-year-olds in China and consider the implications for education, practice, policy and HROH nationally. Methods We estimated the need of HROH to meet the needs of 12-year-olds based on secondary analysis of the epidemiological and questionnaire data from the 3rd Chinese National Oral Health Survey, including caries experience and periodontal factors (calculus), dentally-related behaviour (frequency of toothbrushing and sugar intake), and social factors (parental education). Children’s risk for dental caries was classified in four levels from low (level 1) to high (level 4). We built maximum and minimum intervention models of dental care for each risk level, informed by contemporary evidence-based practice. The needs-led HROH model we used in the present study incorporated need for treatment and risk-based prevention using timings verified by experts in China. These findings were used to estimate HROH for the survey sample, extrapolated to 12-year-olds nationally and the total population, taking account of urban and rural coverage, based on different levels of clinical commitment (60-90%). Results We found that between 40,139 and 51,906 dental professionals were required to deliver care for 12-year-olds nationally based on 80% clinical commitment. We demonstrated that the majority of need for HROH was in the rural population (72.5%). Over 93% of HROH time was dedicated to prevention within the model. Extrapolating the results to the total population, the estimate for HROH nationally was 3.16–4.09 million to achieve national coverage; however, current HROH are only able to serve an estimated 5% of the population with minimum intervention based on a HROH spending 90% of their time in providing clinical care. Conclusions The findings highlight the gap between dental workforce needs and workforce capacity in China. Significant implications for health policy and human resources for oral health in this country with a developing health system are discussed including the need for public health action.

Objectives. Flufenamic acid (FFA) is a representative of the fenamic acids, an important group of NSAIDs. In the present study, we study the effects of FFA on adipogenesis of human mesenchymal stem cells (MSCs) and we explore the potential mechanism. Methods. To investigate the effects of FFA on adipogenic differentiation of hMSCs, human adipose-derived stem cells (hASCs) and human bone marrow mesenchymal stem cells (hBMMSCs), representative of hMSCs, were treated with FFA during adipogenic differentiation in vitro. The effects of FFA in vivo were evaluated using a heterotopic adipose formation assay in nude mice as well as ovariectomized (OVX) and aged mice. To explore the mechanism of FFA, Western blot was used to determine activation of the PI3K/AKT signaling pathway. Results. Our results demonstrate that, at certain concentrations, FFA inhibited adipogenesis of human MSCs both in vitro and in vivo. Mechanistically, FFA inhibited adipogenesis of human MSCs by inhibiting the PI3K/AKT pathway. Conclusions. The present study indicated that FFA could be used to inhibit adipogenesis of human MSCs in tissue engineering and diseases related to excessive adipogenic differentiation of MSCs.

ObjectivesDental caries occur through a multifactorial process that may influence all tooth surfaces throughout an individual's life. The application of decision analytical modeling (DAM) has gained an increasing level of attention in long-term outcome assessment and economic evaluation of interventions on caries in recent years. The objective of this study was to systematically review the application of DAM and assess their methodological quality in the context of dental caries.MethodsA systematic review of the literature published to 31st December 2018 was conducted in Medline, EMBASE, NHSEED, and Web of Science electronic databases. The main information and model characteristics of studies was extracted with the methodological quality of included studies reviewed and assessed using the Philips' checklist.ResultsTwenty five studies from different settings were included. Modeling techniques mainly comprised main type of modeling including Markov models (n = 12), Markov/microsimulation mixed model (n = 7), systematic dynamic models (n = 3), microsimulation models (n = 2) and decision tree (n = 1). The mean number of criteria fulfilled was 25.1 out of 60 items, which varied between year of study and research groups. The percentage of criteria fulfilled for data dimension was lower than for the structure and consistency dimension. Critical issues were data quality, incorporation of utility values, and uncertainty analysis in modeling.ConclusionThe current review revealed that the methodological quality of DAM in dental caries economic evaluations is unsatisfied. Future modeling studies should adhere more closely to good practice guidelines, especially with respect to data quality evaluation, utility values incorporation, and uncertainty analysis in DAM based studies.

This study explored catastrophic health expenditure in China, due to out-of-pocket payments for dental care, and its associated individual- and contextual-level factors. We pooled data from 31,566 adults who participated in the third National Oral Health Survey with province-level data from different sources. We defined catastrophic dental health expenditure (CDHE) as payments for dental services and/or medication for dental problems during the last year that exceeded the 10% and 20% of the household income. The association of individual and contextual factors with catastrophic dental health expenditure was evaluated using two-level logistic regression models with individuals nested within provinces. Socioeconomic position (education and household income), household size and dental status (pain in teeth or mouth and number of teeth) were the individual-level factors associated with CDHE among the full sample of participants; and, also, among those who used dental services in the past year. Greater gross domestic product per capita was the only contextual factor associated with CDHE, and only at the lower income threshold. This study shows that out-of-pocket expenses for dental services may put a considerable, and unnecessary, burden on households' finances. Our findings also help characterise those households more likely to face catastrophic expenditure on health if they have to pay for dental services.