Global trends in publications regarding macrophages-related diabetic foot ulcers in the last two decades.

BACKGROUND: Diabetic foot ulcers (DFUs) are one of the most severe and popular complications of diabetes. The persistent non-healing of DFUs is the leading cause of ampu-tation, which causes significant mental and financial stress to patients and their families. Macrophages are critical cells in wound healing and perform essential roles in all phases of wound healing. However, no studies have been carried out to systematically illustrate this area from a scientometric point of view. Although there have been some bibliometric studies on diabetes, reports focusing on the investigation of macrophages in DFUs are lacking. AIM: To perform a bibliometric analysis to systematically assess the current state of research on macrophage-related DFUs. METHODS: The publications of macrophage-related DFUs from January 1, 2004, to December 31, 2023, were retrieved from the Web of Science Core Collection on January 9, 2024. Four different analytical tools: VOSviewer (v1.6.19), CiteSpace (v6.2.R4), HistCite (v12.03.07), and Excel 2021 were used for the scientometric research. RESULTS: A total of 330 articles on macrophage-related DFUs were retrieved. The most published countries, institutions, journals, and authors in this field were China, Shanghai Jiao Tong University of China, Wound Repair and Regeneration, and Aristidis Veves. Through the analysis of keyword co-occurrence networks, historical direct citation networks, thematic maps, and trend topics maps, we synthesized the prevailing research hotspots and emerging trends in this field. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of macrophage-related DFUs research and insights into promising upcoming research.

Analysis of PANoptosis-related ceRNA network reveals lncRNA MIR17HG involved in osteogenic differentiation inhibition impaired by tumor necrosis factor-α.

BACKGROUND: Inflammatory cytokines such as Interleukin 1ß(IL1ß), IL6,Tumor Necrosis Factor-α (TNF-α) can inhibit osteoblast differentiation and induce osteoblast apoptosis. PANoptosis, a newly identified type of programmed cell death (PCD), may be influenced by long noncoding RNA (lncRNAs) which play important roles in regulating inflammation. However, the potential role of lncRNAs in inflammation and PANoptosis during osteogenic differentiation remains unclear. This study aimed to investigate the regulatory functions of lncRNAs in inflammation and apoptosis during osteogenic differentiation. METHODS AND RESULTS: High-throughput sequencing was used to identify differentially expressed genes involved in osteoblast differentiation under inflammatory conditions. Two lncRNAs associated with inflammation and PANoptosis during osteogenic differentiation were identified from sequencing data and Gene Expression Omnibus (GEO) databases. Their functionalities were analyzed using diverse bioinformatics methodologies, resulting in the construction of the lncRNA-miRNA-mRNA network. Among these, lncRNA (MIR17HG) showed a high correlation with PANoptosis. Bibliometric methods were employed to collect literature data on PANoptosis, and its components were inferred. PCR and Western Blotting experiments confirmed that lncRNA MIR17HG is related to PANoptosis in osteoblasts during inflammation. CONCLUSIONS: Our data suggest that TNF-α-induced inhibition of osteogenic differentiation and PANoptosis in MC3T3-E1 osteoblasts is associated with MIR17HG. These findings highlight the critical role of MIR17HG in the interplay between inflammation, PANoptosis, and osteogenic differentiation, suggesting potential therapeutic targets for conditions involving impaired bone formation and inflammatory responses.

Microbiological profile of diabetic foot infections in China and worldwide: a 20-year systematic review.

Introduction: Pathogens causing diabetic foot infections (DFIs) vary by region globally; however, knowledge of the causative organism is essential for effective empirical treatment. We aimed to determine the incidence and antibiotic susceptibility of DFI pathogens worldwide, focusing on Asia and China. Methods: Through a comprehensive literature search, we identified published studies on organisms isolated from DFI wounds from January 2000 to December 2020. Results: Based on our inclusion criteria, we analyzed 245 studies that cumulatively reported 38,744 patients and 41,427 isolated microorganisms. DFI pathogens varied according to time and region. Over time, the incidence of Gram-positive and Gram-negative aerobic bacteria have decreased and increased, respectively. America and Asia have the highest (62.74%) and lowest (44.82%) incidence of Gram-negative bacteria, respectively. Africa has the highest incidence (26.90%) of methicillin-resistant Staphylococcus aureus. Asia has the highest incidence (49.36%) of Gram-negative aerobic bacteria with species infection rates as follows: Escherichia coli, 10.77%; Enterobacter spp., 3.95%; and Pseudomonas aeruginosa, 11.08%, with higher local rates in China and Southeast Asia. Linezolid, vancomycin, and teicoplanin were the most active agents against Gram-positive aerobes, while imipenem and cefoperazone-sulbactam were the most active agents against Gram-negative aerobes. Discussion: This systematic review showed that over 20 years, the pathogens causing DFIs varied considerably over time and region. This data may inform local clinical guidelines on empirical antibiotic therapy for DFI in China and globally. Regular large-scale epidemiological studies are necessary to identify trends in DFI pathogenic bacteria. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023447645.

Diabetes and osteoporosis: a two-sample mendelian randomization study.

BACKGROUND: The effects on bone mineral density (BMD)/fracture between type 1 (T1D) and type 2 (T2D) diabetes are unknown. Therefore, we aimed to investigate the causal relationship between the two types of diabetes and BMD/fracture using a Mendelian randomization (MR) design. METHODS: A two-sample MR study was conducted to examine the causal relationship between diabetes and BMD/fracture, with three phenotypes (T1D, T2D, and glycosylated hemoglobin [HbA1c]) of diabetes as exposures and five phenotypes (femoral neck BMD [FN-BMD], lumbar spine BMD [LS-BMD], heel-BMD, total body BMD [TB-BMD], and fracture) as outcomes, combining MR-Egger, weighted median, simple mode, and inverse variance weighted (IVW) sensitivity assessments. Additionally, horizontal pleiotropy was evaluated and corrected using the residual sum and outlier approaches. RESULTS: The IVW method showed that genetically predicted T1D was negatively associated with TB-BMD (ß = -0.018, 95% CI: -0.030, -0.006), while T2D was positively associated with FN-BMD (ß = 0.033, 95% CI: 0.003, 0.062), heel-BMD (ß = 0.018, 95% CI: 0.006, 0.031), and TB-BMD (ß = 0.050, 95% CI: 0.022, 0.079). Further, HbA1c was not associated with the five outcomes (ß ranged from - 0.012 to 0.075). CONCLUSIONS: Our results showed that T1D and T2D have different effects on BMD at the genetic level. BMD decreased in patients with T1D and increased in those with T2D. These findings highlight the complex interplay between diabetes and bone health, suggesting potential age-specific effects and genetic influences. To better understand the mechanisms of bone metabolism in patients with diabetes, further longitudinal studies are required to explain BMD changes in different types of diabetes.

Chronic osteomyelitis risk is associated with NLRP3 gene rs10754558 polymorphism in a Chinese Han Population.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the nucleotide-binding domain leucine-rich repeat protein-3 (NLRP3) gene are reported to be linked to many inflammatory disorders. However, uncertainty persists over the associations between these SNPs and susceptibilities to chronic osteomyelitis (COM). This study aimed to investigate potential relationships between NLRP3 gene SNPs and the risks of developing COM in a Chinese Han cohort. METHODS: The four tag SNPs of the NLRP3 gene were genotyped in a total of 428 COM patients and 368 healthy controlsusing the SNapShot technique. The genotype distribution, mutant allele frequency, and the four genetic models (dominant, recessive, homozygous, and heterozygous) of the four SNPs were compared between the two groups. RESULTS: A significant association was found between rs10754558 polymorphism and the probability of COM occurence by the heterozygous model (P = 0.037, odds ratio [OR] = 1.541, 95% confidence interval [CI] = 1.025-2.319), indicating that rs10754558 may be associated with a higher risk of developing COM.In addition, possible relationship was found between rs7525979 polymorphism and the risk of COM development by the outcomes of homozygous (P = 0.073, OR = 0.453, 95% CI = 0.187-1.097) and recessive (P = 0.093, OR = 0.478, 95% CI = 0.198-1.151) models, though no statistical differences were obtained. CONCLUSIONS: Outcomes of the present study showed, for the first time, that rs10754558 polymorphism of the NLRP3 gene may increase the risk of COM development in this Chinese Han population, with genotype CG as a risk factor. Nonetheless, this conclusion requires verification from further studies with a larger sample size.

MicroRNA-18a regulates the Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) of osteoblasts induced by tumor necrosis factor-α via hypoxia-inducible factor-1α.

BACKGROUND: Tumor necrosis factor-α (TNF-α) is involved in inflammatory responses and promotes cell death and the inhibition of osteogenic differentiation. MicroRNA (miRNA) plays a crucial role in the infected bone diseases, however, the biological role of miRNAs in inflammation-induced impaired osteogenic differentiation remains unclear. This study aimed to explore the role of miRNA-18a-5p (miR-18a) in regulating PANoptosis and osteogenic differentiation in an inflammatory environment via hypoxia-inducible factor-1α (HIF1-α). METHODS: The expression of miR-18a in MC3T3-E1 cells was analyzed using quantitative reverse transcription-polymerase chain reaction in an inflammatory environment induced by TNF-α. The expression of HIF1-α and NLRP3 in LV-miR-18a or sh-miR-18a cells was analyzed using western blotting. Fluorescence imaging for cell death, flow cytometry, and alkaline phosphatase activity analysis were used to analyze the role of miR-18a in TNF-α-induced PANoptosis and the inhibition of osteogenic differentiation. An animal model of infectious bone defect was established to validate the regulatory role of miR-18a in an inflammatory environment. RESULTS: The expression of miRNA-18a in the MC3T3-E1 cell line was significantly lower under TNF-α stimulation than in the normal environment. miR-18a significantly inhibited the expression of HIF1-α and NLRP3, and inhibition of HIF1-α expression further inhibited NLRP3 expression. Furthermore, inhibition of miR-18a expression promoted the TNF-α-induced PANoptosis and inhibition of osteogenic differentiation, whereas miR-18a overexpression and the inhibition of both HIF1-α and NLRP3 reduced the effects of TNF-α. These findings are consistent with those of the animal experiments. CONCLUSION: miRNA-18a negatively affects HIF1-α/NLRP3 expression, inhibits inflammation-induced PANoptosis, and impairs osteogenic differentiation. Thus, it is a potential therapeutic candidate for developing anti-inflammatory strategies for infected bone diseases.

Effects of mitochondrial dysfunction on bone metabolism and related diseases: a scientometric study from 2003 to 2022.

BACKGROUND: In recent years, mitochondrial dysfunction has been extensively studied and published, but research on the effects of mitochondrial dysfunction on bone metabolism and related diseases is only just beginning. Furthermore, no studies have been carried out to systematically illustrate this area from a scientometric point of view. The goal of this research is to review existing knowledge and identify new trends and possible hotspots in this area. METHODS: All publications related to the relationship between mitochondrial dysfunction and bone metabolism and related diseases from 2003 to 2022 were searched at the Web of Science Core Collection (WoSCC) on May 7, 2022. Four different analytical tools: VOSviewer 1.6.18, CiteSpace V 6.1, HistorCite (12.03.07), and Excel 2021 were used for the scientometric research. RESULTS: The final analysis included 555 valid records in total. Journal of Biological Chemistry (Co-citations = 916) is the most famous journal in this field. China (Percentage = 37%), the United States (Percentage = 24%), and Korea (Percentage = 12%) are the most productive countries. Blanco FJ and Choi EM are the main researchers with significant academic influence. Current research hotspots are basic research on mitochondrial dysfunction and the prevention or treatment of bone metabolism-related diseases. CONCLUSION: The study of the consequences of mitochondrial dysfunction on bone metabolism and associated diseases is advancing rapidly. Several prominent researchers have published extensive literature and are widely cited. Future research in this area will focus on oxidative stress, aging, gene expression, and the pathogenesis of bone metabolism-related diseases.

Prophylactic Effects of NFκB Essential Modulator-Binding Domain Peptides on Bone Infection: An Experimental Study in a Rabbit Model.

Introduction: Osteomyelitis is characterized by intensive inflammatory bone disease and remains a clinical challenge in orthopedic surgery, despite the advances made in medical and surgical therapies. Staphylococcus aureusis a major causative agent of osteomyelitis, causing the progressive inflammatory destruction of bone. Prophylaxis of osteomyelitis during orthopedic surgery is necessary. NFκB essential modulator-binding domain (NBD) peptides are cell-permeable peptide inhibitors of the IκB-kinase complex. The prophylactic effect of NBD peptides in relieving inflammation and inhibiting bone defects in osteomyelitis is still under investigation. Our purpose was to determine the preventive effect of NBD peptides in S. aureus infection-induced bone defects in osteomyelitis. Methods: An S. aureus osteomyelitis rabbit model was used in this study. The rabbits were divided into four groups: NBD, cefazolin, control, and PBS. Clinical and laboratory indicators of erythrocyte-sedimentation rate, CRP, and TNFα levels were assessed to monitor systemic reactions. The efficacy of NBD peptides in S. aureus-induced osteomyelitis was evaluated by radiological, histological, and microbiological examinations, immunohistochemistry, immunofluorescence, and micro-CT scans. Results: In general, NBD peptides effectively reduced clinical signs in rabbits when compared with the control group. Radiography indicated that there was more severe osteomyelitis in the bacterium-infection control group. There was no significance between cefazolin- and NBD-group average scores. The histological results of the lesion slices further confirmed different severity among the groups. Additionally, significant pathological differences were found between the cefazolin and NBD groups, and the PBS group showed no obvious pathological changes. Conclusion: Prophylactic administration of NBD peptides to bone-defect areas inhibited bacterial spread and promoted bone regeneration, making NBD peptides a possible treatment option for prophylaxis in bone infections.

Novel Elongator Protein 2 Inhibitors Mitigating Tumor Necrosis Factor-α Induced Osteogenic Differentiation Inhibition.

Tumor necrosis factor-α is a common cytokine that increases in inflammatory processes, slows the differentiation of bone formation, and induces osteodystrophy in the long-term inflammatory microenvironment. Our previous study confirmed that the Elongation protein 2 (ELP2) plays a significant role in osteogenesis and osteogenic differentiation, which is considered a drug discovery target in diseases related to bone formation and differentiation. In this study, we applied an in silico virtual screening method to select molecules that bind to the ELP2 protein from a chemical drug molecule library and obtained 95 candidates. Then, we included 11 candidates by observing the docking patterns and the noncovalent bonds. The binding affinity of the ELP2 protein with the candidate compounds was examined by SPR analysis, and 5 out of 11 compounds performed good binding affinity to the mouse ELP2 protein. After in vitro cell differentiation assay, candidates 2# and 5# were shown to reduce differentiation inhibition after tumor necrosis factor-α stimulation, allowing further optimization and development for potential clinical treatment of inflammation-mediated orthopedic diseases.

Green Synthesized Gold Nanoparticles Using Viola betonicifolia Leaves Extract: Characterization, Antimicrobial, Antioxidant, and Cytobiocompatible Activities.

INTRODUCTION: Viola betonicifolia is a rich source of numerous secondary metabolites, such as alkaloids, flavonoids, tannins, phenolic compounds, saponins, triterpenoids, and so on, that are biologically active towards different potential biomedical applications. To broaden the potential use of Viola betonicifolia in the realm of bionanotechnology, we investigated the plant's ability to synthesize gold nanoparticles (Au NPs) in a green and efficient manner for the very first time. METHODS: The gold nanoparticles (VB-Au NPs) were synthesized using the leaves extract of Viola betonicifolia, in which plant's secondary metabolites function as both reducing and capping agents. The VB-Au NPs were successfully characterized with spectroscopic techniques. The antimicrobial properties of the VB-Au NPs were further explored against bacterial and mycological species. Additionally, their antioxidant, cytotoxic, and cytobiocompatibility properties were examined in vitro against linoleic acid peroxidation, MCF-7 cancer cells, and human mesenchymal stem cells (hMSCs), respectively. RESULTS: Results demonstrated that VB-Au NPs presented excellent antibacterial, antifungal, and biofilm inhibition performance against all the tested microbial species compared to plant leaves extract and commercially purchased chemically synthesized gold NPs (CH-Au NPs). Moreover, they also exhibited significant antioxidant potential, comparable to the external standard. The VB-Au NPs displayed good cytobiocompatibility with hMSCs and demonstrated excellent cytotoxic potential against MCF-7 cancer cells compared to CH-Au NPs. The current work presents a green method for synthesizing VB-Au NPs with enhanced antioxidant, antimicrobial, cytotoxic and biofilm inhibition efficacy compared to CH-Au NPs might be attributed to the synergistic effect of the nanoparticle's physical properties and the adsorbed biologically active phytomolecules from the plant leaves extract on their surface. CONCLUSION: Thus, our study establishes a novel ecologically acceptable route for nanomaterials' fabrication with increased and/or extra medicinal functions derived from their herbal origins.

[Short term effect of double channel decompression and bone grafting via greater trochanter combined with allograft fibula propping in the treatment of femoral head necrosis].

OBJECTIVE: To investigate the short-term clinical effect of double channel decompression and bone grafting through the greater trochanter combined with allograft fibula propping in the treatment of osteonecrosis of femoral head (ONFH). METHODS: Twenty two patients (23 hips) with osteonecrosis of the femoral head were included from November 2017 to February 2019. According to Association Research Cirulation Osseous(ARCO) staging, there were 13 hips at stageⅡgroup, aged from 20 to 48 years old with an average of(32.5±8.5)years old;10 hips at stageⅢgroup, aged from 18 to 45 years old with an average of(32.7±8.6) years old. A single approach through the greater trochanterwas used for decompression, bone grafting and fibula support. Harris scoring system was used to evaluate the function of hip joint before and after implantation, and the anteroposterior and lateral X-ray films of hip joint were taken at 3, 6, 12 and 18 months after implantation to observe and analyze the progress of femoral head necrosis and regeneration. RESULTS: All patients were followed up, and the duration ranged from 12 to 18 months with an average of (14.6±2.1) months. Harris score of stageⅡand stageⅢpatients increased from 73.2± 5.5 and 66.5±3.4 to 87.6±8.7(P<0.001) and 77.2±14.0 (P<0.05) respectively. After 12 months, the X-ray film of all patients showed that 12 hips were improved at stageⅡgroup and 7 hips were improved at stageⅢgroup. CONCLUSION: The effect of double trochanteric decompression and bone grafting combined with fibular allograft propping in the treatment of early and middle stage avascular necrosis of the femoral head is good, especially suitable for young and middle aged patients with ARCOⅡstage avascular necrosis of the femoral head.

A Novel Mechanical-Based Injective Hydrogel for Treatment with Aromatase Inhibitors Caused Joint Inflammation via the NF-κB Pathway.

Synovium has widely participated in induced inflammation, suggesting that it is a potential target to reduce aromatase inhibitors (AIs) causing joint inflammation or pain. Exercise and mechanical stimulation are important strategies for precaution and treatment of bone inflammation. In this work, we developed a novel thermo-sensitive hydrogel, which could be injected intra-articularly. The aim of this research was to investigate the role of various mechanical strength hydrogels in reducing synovium inflammation. The effect of different mechanical strength hydrogels on regulating synovium inflammation was used to stimulate human fibroblast-like synoviocytes (FLS) under a cyclic mechanical compression environment in vitro. Cytokine and metalloprotease expression in FLS was analyzed by the western blot and q-PCR method, in which FLS were cultured with the different mechanical strength hydrogels. The results showed that a moderate-intensity hydrogel mechanical stimulation might be suitable in reducing AI-induced FLS inflammation via the NK-κB pathway. In addition, we built an AI-treated rat model and injected the different mechanical strength hydrogels. Similarly, the moderate-strength mechanical hydrogel could reduce the inflammatory factor and metalloproteinase expression in synovial tissues and intra-articular synovia.

Halloysites modified polyethylene glycol diacrylate/thiolated chitosan double network hydrogel combined with BMP-2 for rat skull regeneration.

Hydrogel serve as bone tissue engineering have lately received great attention for their good biocompatibility and structures similar to natural extracellular matrices. However, a single component polymer hydrogel is generally detrimental to cell adhesion due to the weaker mechanical properties, which limits their application considerably. In an effort to overcome this disadvantage, we adopt an unconventional dual network hydrogels consisting of the polyethylene glycol diacrylate (PEGDA) covalent network, a thiolated chitosan (TCS) ion crosslinking network and thiolated halloysites (T-HNTs) as reinforcing filler. In addition, bone morphogenetic protein-2 (BMP-2) was loaded into the prepared dual network (DN) hydrogel to improve the bone regeneration function of the DN hydrogel. The resulting PEGDA/TCS/T-HNTs hydrogels showed favourable mechanical property, higher crosslinking density, the lower swelling degree, excellent biocompatibility and cell adhesion ability. The histomorphometric and immunohistochemical analyses revealed the excellent bone regeneration ability for composite hydrogel after implant into rat skull defect. Thus, our results indicated that composite scaffold can be applied as a new bone regeneration biomaterial to be applied as a local drug delivery system with good bone induction performance.

Efficacy of NEMO-binding domain peptide used to treat experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus: an in-vivo study.

Purpose: Treatment of chronic osteomyelitis (bone infection) remains a clinical challenge. Our previous study had demonstrated that NEMO-binding domain (NBD) peptide effectively ameliorates the inhibition of osteoblast differentiation by TNF-α in vitro. In this work, NBD peptide was evaluated in vivo for treating chronic osteomyelitis induced by methicillin-resistant Staphylococcus aureus (MRSA) in a rabbit model. Methods: Tibial osteomyelitis was induced in 50 New Zealand white rabbits by tibial canal inoculation of MRSA strain. After 3 weeks, 45 rabbits with osteomyelitis were randomly divided into four groups that correspondingly received the following interventions: 1) Control group (9 rabbits, no treatment); 2) Van group (12 rabbits, debridement and parenteral treatment with vancomycin); 3) NBD + Van group (12 rabbits, debridement and local NBD peptide injection, plus parenteral treatment with vancomycin); 4) NBD group (12 rabbits, debridement and local NBD peptide injection). Blood samples were collected weekly for the measurement of leucocyte count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. The rabbits in all four groups were sacrificed 6 weeks after debridement; the anti-infective efficacy was evaluated by radiological, histological, and microbiological examination, and promotion of bone remodeling was quantified by micro-CT using the newly formed bone. Results: Except two rabbits in the Control group and one in the NBD group that died from severe infection before the end point, the remaining 42 animals (7, 12, 12, 11 in the Control, Van, NBD + Van, and NBD group respectively) were sacrificed 6 weeks after debridement. In general, there was no significant difference in the leucocyte count, and ESR and CRP levels, although there were fluctuations throughout the follow-up period after debridement. MRSA was still detectable in bone tissue samples of all animals. Interestingly, treatment with NBD peptide plus vancomycin significantly reduced radiological and histological severity scores compared to that in other groups. The best therapeutic efficacy in bone defect repair was observed in the NBD peptide + Van group. Conclusions: In a model of osteomyelitis induced by MRSA, despite the failure in demonstrating antibacterial effectiveness of NBD peptide in vivo, the results suggest antibiotics in conjunction with NBD peptide to possibly have promising therapeutic potential in osteomyelitis.

ELP2 negatively regulates osteoblastic differentiation impaired by tumor necrosis factor α in MC3T3-E1 cells through STAT3 activation.

Tumor necrosis factor-α (TNF-α) is a pluripotent signaling molecule. The biological effect of TNF-α includes slowing down osteogenic differentiation, which can lead to bone dysplasia in long-term inflammatory microenvironments. Signal transducer and activator of transcription 3 (STAT3)-interacting protein 1 (StIP1, also known as elongator complex protein 2, ELP2) play a role in inhibiting TNF-α-induced osteoblast differentiation. In the present study, we investigated whether and how ELP2 activation mediates the effects of TNF-α on osteoblastic differentiation. Using in vitro cell cultures of preosteoblastic MC3T3-E1 cells, we found that TNF-α inhibited osteoblastic differentiation accompanied by an increase in ELP2 expression and STAT3 activation. Forced ELP2 expression inhibited osteogenic differentiation of MC3T3-E1 cells, with a decrease in the expression of osteoblast marker genes, alkaline phosphatase activity, and matrix mineralization capacity. In contrast, ELP2 silencing ameliorated osteogenic differentiation in MC3T3-E1 cells, even after TNF-α stimulation. The TNF-α-induced inhibitory effect on osteoblastic differentiation was therefore mediated by ELP2, which was associated with Janus kinase 2 (JAK2)/STAT3 activation. These results suggest that ELP2 is upregulated at the differentiation of MC3T3-E1 cells into osteoblasts and inhibits osteogenic differentiation in response to TNF-α through STAT3 activation.

Discovery of novel elongator protein 2 inhibitors by compound library screening using surface plasmon resonance.

Tumour necrosis factor-α (TNF-α) is a pleiotropic cytokine that becomes elevated in chronic inflammatory states, including slowing down osteogenic differentiation, which leads to bone dysplasia in long-term inflammatory microenvironments. The elongator complex plays a role in gene regulation and association with various cellular activities, including the downstream signal transduction of TNF-α in osteogenic cells. To find an inhibitor of Elongator Protein 2 (Elp2), we performed a compound library screen and verified the pharmaceutical effects of candidate compounds on the mouse myoblast cell (C2C12) and mouse osteoblastic cells (MC3T3-E1). The commercial FDA-approved drug (FD) library and the bioactive compound (BC) library were used as candidate libraries. After a label-free, high-throughput affinity measurement with surface plasmon resonance (SPRi), seven kinds of compounds showed binding affinity with mouse Elp2 protein. The seven candidates were then used to perform an inhibition test with TNF-α-induced C2C12 and MC3T3-E1 cell lines. One candidate compound reduced the differentiation suppression caused by TNF-α with resuscitated alkaline phosphatase (ALP) activity, mineralization intensity and expression of osteogenic differentiation marker genes. The results of our study provide a competitive candidate to mitigate the TNF-α-induced osteogenic differentia.

The effect of cupping therapy for low back pain: A meta-analysis based on existing randomized controlled trials.

BACKGROUND: LBP is one of the most common symptoms with high prevalence throughout the world. Conflicting conclusions exist in RCTs on cupping for LBP. OBJECTIVE: To assess the effects and safety of cupping for the patients with LBP. METHODS: Pubmed, Cochrane Library databases, and Embase database were electronically researched. RCTs reporting the cupping for the patients with LBP were included. The meta-analysis was conducted using Review Manager software (version 5.3, Nordic Cochrane Centre). The primary outcome was VAS scores. The secondary outcomes included ODI scores, MPPI scores and complications. RESULTS: Six RCTs were included in this synthesized analysis. The results showed that cupping therapy was superior to the control management with respect to VAS scores (SMD: -0.73, [95% CI: -1.42 to -0.04]; P= 0.04), and ODI scores (SMD: -3.64, [95% CI: -5.85 to -1.42]; P= 0.001). There was no statistical significant difference as regard to MPPI scores. No serious adverse event was reported in the included studies. CONCLUSIONS: Cupping therapy can significantly decrease the VAS scores and ODI scores for patients with LBP compared to the control management. High heterogeneity and risk of bias existing in studies limit the authenticity of the findings.

[Preparation and biocompatibility of a novel strontium-containing calcium sulfate].

OBJECTIVE: To prepare a novel strontium-containing calcium sulfate and assess its and biocompatibility. METHODS: A novel strontium-containing α-calcium sulfate hemihydrate (Sr-caS) bone substitute as prepared with hydrothermal reaction and examined for X-ray diffraction (XRD), Fourier transform infrared (FTIR) and thermogravimetric differential scanning calorimetric (TG-DSC) patterns. The biocompatibility of the material was evaluated by in vitro cytotoxicity test in L-929 cells, hemolysis test of blood, and in vivo implantation test in SD rats. RESULTS: The XRD spectra of the prepared Sr-CaS powder highlighted 3 strong characteristic peaks of α-CaSO4 at 14.63°, 25.72° and 29.80° with a strontium-specific peak at 24.78°. The FTIR patterns of Sr-CaS resembled those of CaS. TG-DSC results showed that the material contained a non-evaporable water content of 6.03%. In vitro cytotoxicity test in L-929 cells suggested that the material had a class 1 cytotoxicity, and the hemolysis rate of its aqueous extract was 4.3%. The material implanted in the muscular tissues of SD rats maintained a steady state in the surrounding tissues. CONCLUSION: This strontium-containing calcium sulfate material we prepared shows an excellent biocompatibility for potential use as a novel artificial bone material.

Quantitative proteomics reveals ELP2 as a regulator to the inhibitory effect of TNF-α on osteoblast differentiation.

TNF-α, one of the most potent pro-inflammatory cytokines, plays a critical role in inhibition of osteoblast differentiation and bone regeneration in persistent inflammatory microenvironment. To explore the mechanism, quantitative proteomics based on iTRAQ and MRM was employed. The results showed 6 proteins involved in BMP-2 induced osteoblast differentiation inhibition by TNF-α: Periostin, Protein S100-A4, ATPase inhibitor, Cytochrome b5, SERCA3, and ELP2. The altered proteins were involved in molecular transport, tissue development, energy metabolism, and inflammation. One specific protein, ELP2 (STAT3-interacting protein 1, StIP1) up-regulated in the inhibition of osteoblast differentiation by TNF-α was verified to play a critical role in STAT3 pathway. Overexpression or knockdown of ELP2 in C2C12 and MC3T3-E1 cells affected osteoblast differentiation inhibition induced by TNF-α. These results highlight the function of ELP2 in inflammatory microenvironment, ELP2 up-regulation and STAT3 pathway activation may down-regulate BMPR2, then BMP-2 was blocked and osteoblast differentiation inhibited. The protein-expression profile revealed here should offer at least partly new clues to understand the mechanism of osteoblast differentiation inhibition by inflammation. BIOLOGICAL SIGNIFICANCE: Persistent inflammation is always associated with osteogenesis and affects this balance to reduce bone mass including traumatic open bone fracture, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but the cellular mechanisms are not fully elucidated. Tumor necrosis factor-α (TNF-α) is one of the most potent pro-inflammatory cytokines and is known to be a catabolic factor in these inflammatory reaction of diseases. We show for the first time using proteomics methods that in inflammatory microenvironment, osteoblast differentiation will be inhibited by TNF-α induced ELP2 up-regulation and STAT3 pathway activation. Our results are significant since they point to targeting ELP2 activity as a novel therapeutic option to limit the inhibition of osteoblast differentiation by inflammatory microenvironment.

A novel resorbable strontium-containing α-calcium sulfate hemihydrate bone substitute: a preparation and preliminary study.

Distraction osteogenesis after aggrieved bone segment resections is promising in the treatment of bone tumors and osteomyelitis. However, there is ambiguity with regard to the optimal choice of bone substitute, with biodegradability and excellent bone repair performance constituting key requirements. The purpose of this study was to develop a novel resorbable strontium-containing α-calcium sulfate hemihydrate (Sr-CaS) bone substitute to provide an alternative option for surgeons that better meets these requirements. The Sr-CaS was prepared using co-precipitation and hydrothermal methods and analyzed using x-ray diffraction (XRD), Fourier transform infrared (FTIR) scanning and thermogravimetric differential scanning calorimeter (TG-DSC) patterns. Cytotoxicity by tetrazolium bromide (MTT), sub-acute toxicity and hemolysis tests were performed to assess the initial biocompatibility of the new bone substitute. Radiographic analysis, micro-CT measurements and histological observation were used to evaluate the bone repair ability in rat tibia bone defects. The XRD and FTIR patterns of Sr-CaS were both very similar to CaS and the product had comparable characteristics similar to α-CaS as demonstrated by TG-DSC. Cytotoxicity of the substitute was class 1 (no cytotoxicity) and hemolysis was 4.3% (no hemolysis). Sub-acute toxicity was not seen after a 14 day evaluation. The substitute was radio-opaque. The empty group exhibited the lowest levels of both bone mineral densities (BMD) and bone volume/total volume (BV/TV) of the defects when compared to all other groups. The two Sr-CaS groups resulted in significantly greater BMDs and BV/TV of the defect compared to the CaS only group. However, there was no significant difference between the 5% and 10% Sr-CaS groups. The Sr-CaS was resorbable with satisfactory biocompatibility. The doped strontium ions enhanced the bone repair performance of CaS in a rat model and the new substitute demonstrated promising results for clinical use.