Magnesium–zinc–calcium alloy has emerged as a key focus in the field of medical degradable materials due to its excellent biodegradability and osteoconductive properties.Grain size is crucial for the physicochemical...Magnesium–zinc–calcium alloy has emerged as a key focus in the field of medical degradable materials due to its excellent biodegradability and osteoconductive properties.Grain size is crucial for the physicochemical and biological properties of Mg–Zn–Ca alloy,but it has not been clearly elucidated yet.In this research,Mg-1Zn-0.2Ca-1.0MgO with different grain sizes were prepared to investigate the effect of grain size on the physicochemical properties,corrosion resistance,and osteogenesis.The results indicate that grain refinement improves the mechanical properties and enhances the corrosion resistance of the alloy.The bone surface area to bone volume ratio,bone surface area to tissue volume ratio,and bone volume fraction of the 0.6–0.8μm group show significantly better performance compared to the 2–3μm group and 5–6μm group,indicating that grain refinement can promote the osseointegration between alloy and natural bone.This may be achieved by enhancing the metabolic intensity of alanine,aspartate,glutamate,serine,and glycine around the implant.This work illustrates the effect of grain size on the osseointegration of bone implants and provides a reference for optimizing the properties of bone implant alloys.展开更多
Cases of widespread bone hydatid infection are relatively rare in clinical practice.In this study,we reported for the first time a validated integrated repair therapy for multiple bone tissues,including the hip,femur,...Cases of widespread bone hydatid infection are relatively rare in clinical practice.In this study,we reported for the first time a validated integrated repair therapy for multiple bone tissues,including the hip,femur,and knee,caused by echinococ cosis.Artificial intelligence(AI)was used to develop a targeted surgical plan and to design a personalized prosthesis.Finite element analysis(FEA)was used to optimize the mechanical effectiveness of a customized integrated replacement prosthesis and to model stress distribution in the surrounding bone.Three-dimensional(3 D)printing was used to fabricate a customized prosthesis.With the assistance of AI,FEA,and 3 D printing technology,a personalized surgical plan and customized prosthesis were successfully constructed based on the patient’s disease.This approach achieved a successful therapeutic effect,demonstrating that AI-assisted personalized medicine holds great promise for the future.展开更多
To investigate the clinical characteristics of chondroblastoma with an emphasis on lesions located in the long bone diaphysis,we reviewed the clinical data of 7 patients with histologically proven chondroblastoma trea...To investigate the clinical characteristics of chondroblastoma with an emphasis on lesions located in the long bone diaphysis,we reviewed the clinical data of 7 patients with histologically proven chondroblastoma treated in Tianjin Medical University Cancer Hospital and Fudan University Cancer Hospital between January 1995 and May 2009.There were two rare cases of chondroblastoma in the long bone diaphysis.One patient with a lesion in the tibial diaphysis underwent intralesional curettage and bone grafting,and the postoperative bone function was measured as excellent according to the Enneking scoring system.The patient was still alive upon follow-up at 60 months.The other patient with a lesion in the humeral diaphysis underwent resection,and the postoperative bone function was excellent at 48 months,at which there was no evidence of recurrence or metastasis.Thus,except for the distinctive site of the long bone diaphysis,which made diagnosis difficult,the patients' ages,symptoms,X-ray and CT images,treatment,and prognosis were in accordance with typical lesions in the epiphysis and metaphysis.The diagnosis of chondroblastoma in the long bone diaphysis significantly depends on histopathologic characteristics.展开更多
Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingl...Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic （n---70） and diabetes （n = 51） groups. Tibial plateaus were also collected from cadaver donors （n = 20） and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase （TRAP）, osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International （OARSI） scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP~ osteoclasts and lower number of Osterix~ osteoprogenitors and Osteocalcin~ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA.展开更多
Objective： To demonstrate the validity and reliability of volumetric quantitative computed tomography （vQCT） with multi-slice computed tomography （MSCT） and dual energy X-ray absorptiometry （DXA） for hip bone m...Objective： To demonstrate the validity and reliability of volumetric quantitative computed tomography （vQCT） with multi-slice computed tomography （MSCT） and dual energy X-ray absorptiometry （DXA） for hip bone mineral density （BMD） measurements, and to compare the differences between the two techniques in discriminating postmenopausal women with osteoporosis-related vertebral fractures from those without. Methods： Ninety subjects were enrolled and divided into three groups based on the BMD values of the lumbar spine and/or the femoral neck by DXA. Groups 1 and 2 consisted of postmenopausal women with BMD changes 〈-2SD, with and without radiographically confirmed vertebral fracture （n= 11 and 33, respectively）. Group 3 comprised normal controls with BMD changes 〉-ISD （n-46）. Post-MSCT （GE, LightSpeed16） scan reconstructed images of the abdominal-pelvic region, 1.25 mm thick per slice, were processed by OsteoCAD software to calculate the following parameters： volumetric BMD values of trabecular bone （TRAB）, cortical bone （CORT）, and integral bone （INTGL） of the left femoral neck, femoral neck axis length （NAL）, and minimum cross-section area （mCSA）. DXA BMD measurements of the lumbar spine （AP-SPINE） and the left femoral neck （NECK） also were performed for each subject. Results： The values of all seven parameters were significantly lower in subjects of Groups 1 and 2 than in normal postmenopausal women （P〈0.05, respectively）. Comparing Groups 1 and 2, 3D-TRAB and 3D-INTGL were significantly lower in postmenopausal women with vertebral fracture（s） [（109.8±9.61） and （243.3±33.0） mg/cm^3, respectively] than in those without [（148.9±7.47） and （285.4±17.8） mg/cm^3, respectively] （P〈0.05, respectively）, but no significant differences were evident in AP-SPINE or NECK BMD. Conclusion： the femoral neck-derived volumetric BMD parameters using vQCT appeared better than the DXA-derived ones in discriminating osteoporotic postmenopausal women with vertebral fractures from those without, vQCT might be useful to evaluate the effect of osteoporotic vertebral fracture status on changes in bone mass in the femoral neck.展开更多
Antimicrobial drugs of several classes play an important role in the treatment of bone and joint infections. In addition to fighting pathogenic microorganisms, the effects of drugs on local tissues and cells are also ...Antimicrobial drugs of several classes play an important role in the treatment of bone and joint infections. In addition to fighting pathogenic microorganisms, the effects of drugs on local tissues and cells are also related to the course and prognosis of bone and joint infections. The multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells (MSCs) is essential for tissue repair after local injury, which is directly related to the recovery of bone, cartilage, and medullary adipose tissue. Our previous studies and the literature indicate that certain antimicrobial agents can regulate the differentiation potential of bone marrow-derived MSCs. Here, in order to systematically analyze the effects of various antimicrobial drugs on local tissue regeneration, we comprehensively review the studies on the effects of these drugs on MSC differentiation, and classify them according to the three differentiation directions (osteogenesis, chondrogenesis, and adipogenesis). Our review demonstrates the specific effects of different antimicrobial agents on bone marrow-derived MSCs and the range of concentrations at which they work, and provides a basis for drug selection at different sites of infection.展开更多
OBJECTIVE: To investigate the effects of Ermiao Fang(EM) with medical guide Xixin(Herba Asari Mandshurici)(HAM) on bone marrow stem cell migration to a focal zone in osteoarthritis(OA) rats.METHODS: OA rats were induc...OBJECTIVE: To investigate the effects of Ermiao Fang(EM) with medical guide Xixin(Herba Asari Mandshurici)(HAM) on bone marrow stem cell migration to a focal zone in osteoarthritis(OA) rats.METHODS: OA rats were induced by arthrectomy and assigned to sham-operated, model, EM, or EM plus HAM groups.All rats were injected with recombinant human granulocyte colony-stimulating factor 30μg·kg-1·d-1for7 days and treated with EMor EM plus HAM at 1.6 or 1.9 g·kg-1·d-1 for 3 or 6 weeks, respectively. Chondrocyte apoptosis and cartilage matrix components were tested by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay and special staining. Levels of interleukin-1 beta(IL-1β) tumor necrosis factor alpha(TNF-α) nitric oxide(NO), and inducible nitric oxide synthase(iNOS) in serum were detected by enzyme-linked immunosorbent assay or radioimmunoassay. Matrix metalloproteinases(MMPs)-13,tissue inhibitors of metalloproteinases(TIMPs)-1,Bromodeoxyuridine(BrdU), cluster of differentiation 34(CD34), and stromal cell-derived factor 1(SDF-1) were measured by immunohistochemical assay.RESULTS:The EM and EM plus HAM groups had significantly less cartilage damage and synovium inflammation the model group. Moreover, the EM and EM plus HAM groups had less chondrocyte apoptosis and more proteoglycan and collagen content than the model group.The EM and EMplus HAM groups had obviously higher MMPs-13 and TIMPs-1 expression in the cartilage than the model group. Moreover, the two formula groups had less release of IL-1β, TNF-α, NO, and iNOS than model group. Importantly, the expressions of BrdU, CD34,and SDF-1 in cartilage were significantly higher in the EM and EM plus HAM-Medtreated rats than model group. Notably, the EM plus HAM treatment seemed to have the greatest effects.CONCLUSION: HAM improves the therapeutic effects of EM on OA rats by enhancing BMSC directional homing to the focal zone.展开更多
Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,includ...Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.展开更多
Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recent...Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.展开更多
Riverside Scene at Qingming Festival records some lively medical scenes in the Song Dynasty,including the pediatrics clinic,the bone orthopedics clinic,and the exchanges of genuine regional drugs of traditional Chines...Riverside Scene at Qingming Festival records some lively medical scenes in the Song Dynasty,including the pediatrics clinic,the bone orthopedics clinic,and the exchanges of genuine regional drugs of traditional Chinese medicine(TCM).All these scenes together reveal that TCM is highly developed and the medical specialties are becoming increasingly precise and detailed.展开更多
Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed t...Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.展开更多
Introduction:Dexamethasone(Dex)caused impaired osteoblast differentiation and oxidative stress(OS)in bone marrow mesenchymal stem cells(BMSCs).This work sought to elucidate the precise molecular pathway through which ...Introduction:Dexamethasone(Dex)caused impaired osteoblast differentiation and oxidative stress(OS)in bone marrow mesenchymal stem cells(BMSCs).This work sought to elucidate the precise molecular pathway through which Dex influences osteogenic differentiation(OD)and OS in BMSCs.Methods:The expression of Runt-related transcription factor 1(RUNX1)and alpha-2 macroglobulin(A2M)was assessed in Dex-treated BMSCs using qRTPCR and Western Blot.Following the functional rescue experiments,cell proliferation was determined by MTT assay,reactive oxygen species(ROS)expression by DCFH-DA fluorescent probe,lactate dehydrogenase(LDH),superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(Gpx)expression by kits,OD by alkaline phosphatase(ALP)staining and activity quantification,and the expression of OD-related proteins RUNX2,collagen type 1 alpha 1(COL1A1),and osteocalcin(OCN)by qRT-PCR and Western Blot.The binding of RUNX1 to A2M was initially analyzed through Jaspar website and subsequently verified by dual-luciferase reporter and ChIP assays.Results:Dextreated BMSCs had low RUNX1 and A2M expression.Dex treatment apparently elevated ROS and LDH levels,diminished cell proliferation rate and SOD,CAT,and Gpx expression,lightened intensity of ALP staining,and declined calcified nodules,ALP activity,and RUNX2,COL1A1,and OCN expression in BMSCs,which was counterweighed by RUNX1 or A2M overexpression.RUNX1 positively targeted A2M.A2M knockdown effectively nullified the ameliorative effects of RUNX1 overexpression on impaired OD and OS injury in Dex-induced BMSCs.Conclusions:Overexpression of RUNX1 attenuated Dex-induced impaired OD and OS injury in BMSCs by promoting A2M transcription.展开更多
Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma ...Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.展开更多
In this editorial,we comment on the article by Jiang et al.Non-alcoholic fatty liver disease(NAFLD)is a chronic liver disease characterized by the accumulation of fat in the liver without evidence of significant alcoh...In this editorial,we comment on the article by Jiang et al.Non-alcoholic fatty liver disease(NAFLD)is a chronic liver disease characterized by the accumulation of fat in the liver without evidence of significant alcohol consumption.NAFLD can progress to more serious conditions such as non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.This disease is considered an emerging public health problem in several countries as it has increased in recent decades,currently affecting around 30%of the world’s population.The fatty diet and the current lifestyle of the Western population are identified as the main culprits of the disease.Drug treatment aims to reduce the weight of patients and treat metabolic alterations and diseases,including type 2 diabetes mellitus and other comorbidities that coexist with NAFLD.In this scenario,cell therapy with mesenchymal stem/stromal cells(MSCs)has been proposed as a perspective treatment of numerous diseases that do not have definitive curative treatment,such as Crohn’s disease and coronavirus disease 2019.This is due to the versatile,immunomodulatory and regenerative properties of MSCs.The possibility of MSCs being used in patients with severe liver disease progressing to non-alcoholic steatohepatitis or cirrhosis is summarized,because of the therapeutic benefits in reducing fibrosis of affected livers.It remains to be seen when MSC transplantation should be indicated for NAFLD,that is,at what stage of the disease and which phenotype,as well as deciding on the best source of MSCs,the dose,and the administration route.We conclude that well-designed clinical trials are essential in order to obtain robust results for the implementation of this modality in the medical practice.展开更多
Objective The aim of this study was to explore the influence of working length(determined by the screw position)on the stiffness and interfragmentary strain(IFS)of femoral locking compression plate(LCP)external fixato...Objective The aim of this study was to explore the influence of working length(determined by the screw position)on the stiffness and interfragmentary strain(IFS)of femoral locking compression plate(LCP)external fixators for lower tibial fractures under full weight-bearing conditions,with the goal of providing a reference basis for clinical applications.Methods Finite element analysis software was used to construct a model of a lower tibial fracture with external femoral LCP fixation.The models were divided into four groups according to the different working lengths(external femoral locking plate fixation 1[EF1],EF2,EF3,and EF4).Stress distribution clouds,fracture end displacements,stiffness and IFS were tested for each model group at different loads.Results Compared with those in the EF1 group,the stiffnesses in the EF2,EF3,and EF4 groups decreased by 28%,31%,and 37%,respectively,under axial compression loading.Compared with those in the EF1 group,the stiffnesses in the EF2,EF3,and EF4 groups decreased by 19%,33%,and 35%,respectively,under axial torsion loading.Compared with those in the EF1 group,the stiffnesses in the EF2,EF3,and EF4 groups decreased by 32%,33%,and 35%,respectively,under a three-point bending load.The IFS of the four finite element models increased with the working length of the plate,with EF1(76%)<EF2(107%)<EF3(110%)<EF4(122%).Finite element analysis revealed that under full weight-bearing conditions,the structural stiffness of the femoral LCP external fixator decreased with increasing working length,leading to an increase in the IFS,which resulted in an IFS that exceeded the ideal range required for secondary healing.Conclusion For unstable lower tibial fractures,screws in the femoral LCP external fixator should be placed as close to the fracture end as possible to increase stability and promote fracture healing.展开更多
Background:Human adipose-derived stem cells(hADSCs)are seed cells with application prospects in cartilage repair.However,the mechanism of hADSC chondrogenic differentiation is still unclear.This study identifies a nov...Background:Human adipose-derived stem cells(hADSCs)are seed cells with application prospects in cartilage repair.However,the mechanism of hADSC chondrogenic differentiation is still unclear.This study identifies a novel circRNA,circNR3C2,which is significantly upregulated during the chondrogenic differentiation of hADSCs.Methods:To analyze their role in hADSC chondrogenic differentiation,hADSCs were separated and identified by flow cytometry.Thereafter,we conducted Alcian Blue staining to assess chondrogenic differentiation levels.Additionally,RT-qPCR was carried out to detect levels of the cartilage-related genes COL2,Aggrecan and SOX9.Moreover,overlapping target SOX9 and circNR3C2 miRNAs were detected by bioinformatics and luciferase analyses.Finally,the role of circNR3C2 was confirmed in vivo using animal models.Results:We confirmed that the cell surface receptors CD44,CD90 and CD105 were positively expressed on hADSCs,and their cartilage differentiation levels dramatically increased after 2 weeks.Expression of the cartilage-related genes COL2 and Aggrecan and circNR3C2 also markedly increased.CircNR3C2 overexpression enhanced cartilage differentiation of hADSCs,while up-regulating COL2,SOX9 and Aggrecan.Bioinformatics analysis identified hsa-miR-647 as the target miRNA of circ-NR3C2 and SOX9.Hsa-miR-647 overexpression in hADSCs can antagonize the effect of circNR3C2 on chondrogenic differentiation,and reverse its effect on regulating the expression of COL2,Aggrecan,and SOX9.We also showed that hADSCs overexpressing circNR3C2 promote cartilage repair in vivo.Conclusions:We show that circNR3C2 modulates SOX9 expression to promote hsamiR-647-mediated hADSC chondrogenic differentiation;targeting circNR3C2 may help to develop new treatments to manage cartilage-related disorders.展开更多
Background: Tumor angiogenesis is related to solid tumor occurrence. Ubiquitin-specific peptidase 13 (USP13) is a deubiquitinating enzyme with a pivotal effect on tumor proliferation, metastasis, and tumorigenesis. No...Background: Tumor angiogenesis is related to solid tumor occurrence. Ubiquitin-specific peptidase 13 (USP13) is a deubiquitinating enzyme with a pivotal effect on tumor proliferation, metastasis, and tumorigenesis. Nonetheless, its effect on colorectal cancer (CRC) angiogenesis remains poorly understood. Methods: Human umbilical vein endothelial cells (HUVECs) and CRC cells were cultivated, followed by USP13 knockdown/overexpression using shRNA lentiviral vectors or plasmids. Conditioned media (CM) from treated CRC cells were collected to assess HUVEC migration, invasion, and tube formation. Phosphatase and tensin homolog (PTEN) overexpression and recombinant vascular endothelial growth factor A (VEGFA) rescue experiments were performed. Molecular mechanisms were analyzed via Western blot (PTEN, p-AKT, VEGFA), co-immunoprecipitation (PTEN ubiquitination), and in vivo nude mice study to detect the role of USP13 in tumor angiogenesis. Results: USP13 expression in CRC cells is downregulated and negatively related to platelet endothelial cell adhesion molecule-1 (CD31) expression. Furthermore, the conditioned medium from CRC cells with USP13 knockdown significantly promoted HUVEC migration, invasion, and tube formation, while USP13 overexpression exerted the opposite effect. Additionally, USP13 overexpression significantly increased PTEN expression while decreasing protein kinase B (AKT) phosphorylation levels. Concurrently, USP13 overexpression significantly reduced PTEN ubiquitination, whereas USP13 knockdown remarkably increased this modification. Overexpression of PTEN in sh-USP13 CRC cells decreased the expression levels of VEGFA and p-AKT. USP13 also inhibited tumor angiogenesis through downregulating VEGFA, and recombinant VEGFA blocked the inhibition of the conditioned medium from USP13-overexpressing CRC cells against HUVEC angiogenesis in vivo. Conclusions: USP13 downregulated VEGFA and inhibited tumor angiogenesis via the PTEN-AKT pathway.展开更多
PRUNE2 plays an important role in regulating tumor cell differentiation,proliferation,and invasiveness in neuroblastoma.Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately d...PRUNE2 plays an important role in regulating tumor cell differentiation,proliferation,and invasiveness in neuroblastoma.Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately differentiated leiomyosarcoma from gastrointestinal stromal tumor.However,the association between PRUNE2 expression and prognosis in leiomyosarcoma is poorly understood.In this study,we evaluated the prognostic role of PRUNE2 in leiomyosarcoma.PRUNE2 expression was detected using immunohistochemistry in 30 formalin-fixed,paraffin-embedded leiomyosarcoma tissues from MD Anderson Cancer Center,and high expression was detected in 36.7%(11/30)of the samples.To validate these results,immunohistochemistry was performed on another cohort of 45 formalin-fixed,paraffinembedded leiomyosarcoma tissues from Tianjin Medical University Cancer Institute&Hospital,and high PRUNE2 protein expression was detected in 37.8%(17/45)of the samples.Moreover,elevated PRUNE2expression was significantly associated with tumor size(P=0.03)and hemorrhage/cyst(P=0.014),and was an independent favorable prognostic factor for overall survival in leiomyosarcoma patients from Tianjin Medical University Cancer Institute&Hospital(P<0.05).These data suggest that increased PRUNE2protein expression may serve as a favorable prognostic marker in human leiomyosarcoma.展开更多
Objective:To study the effect of low intensity pulsed ultrasound(LIPUS) on the expression of tissue inhibitor of metalloproteinase-2(TIMP-2) in the serum and expression of matrix metallopeptidase 13(MMP-13) in the art...Objective:To study the effect of low intensity pulsed ultrasound(LIPUS) on the expression of tissue inhibitor of metalloproteinase-2(TIMP-2) in the serum and expression of matrix metallopeptidase 13(MMP-13) in the articular cartilage cells of rabbits with knee osteoarthritis(OA).Methods:Inner patellar ligament defect method was used to establish the model of knee OA.Four weeks after the modeling,the arterial blood was drawn from the ear of each rabbit,while ELISA was employed to detect the expression of TIMP-2 in the serum.The chondrocytes were separated from animals in each group and then cultured in vitro.All rabbits were divided into control group,OA model group and OA + LIPUS group.Cells in the control and OA groups were not treated,while cells in the OA+ LIPUS group were treated with LIPUS(40 mW/cnr.1 time/day).Cells were collected 7 d later and the RNA and total protein were extracted respectively.Real-time PCR and Western blotting were employed to analyze the expression of MMP-13 in chondrocytes at the mRNA and protein level,respectively.Results:The success rate of establishment of OA model was 83%.The results of ELISA showed that the content of TIMP-2 in the serum of animals with OA was 22.3%,lower than the one in the control group(P<0.05).Compared with the normal control group,the expression of TIMP-2in the OA model group was significantly increased,while the expression of MMP-13 was significantly increased(P<0.05).After the stimulation of LIPUS,the expression of TIMP-2 and MMP-13 was close to the one in the normal control group.Conclusions:The inner patellar ligament defect method is a mature method to establish the rabbit OA model,with high success rate.The expression of serum TIMP-2 in the OA model group is significantly decreased.LIPUS can up-regulate TIMP-2 and down-regulate MMP-13.展开更多
During the pathogensis of rheumatoid arthritis(RA),activated RA fibroblast-like synoviocytes(RA-FLSs)combines similar proliferative features as tumor and inflammatory features as osteoarthritis,which eventually leads ...During the pathogensis of rheumatoid arthritis(RA),activated RA fibroblast-like synoviocytes(RA-FLSs)combines similar proliferative features as tumor and inflammatory features as osteoarthritis,which eventually leads to joint erosion.Therefore,it is imperative to research and develop new compounds,which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression.Neohesperidin(Neo)is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties.In this study,the anti-inflammation,anti-migration,anti-invasion,anti-oxidant and apoptosis-induced effects of Neo on RAFLSs were explored to investigate the underlying mechanism.The results suggested that Neo decreased the levels of interleukin IL-1β,IL-6,IL-8,TNF-α,MMP-3,MMP-9 and MMP-13 in FLSs.Moreover,Neo blocked the activation of the MAPK signaling pathway.Furthermore,treatment with Neo induced the apoptosis of FLSs,and inhibited the migration of FLSs.It was also found that Neo reduced the accumulation of reactive oxygen species(ROS)induced by TNF-α.Taken together,our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA.展开更多
基金financially supported by the Foundation of Tianjin city of China(Nos.21JCYBJC00490 and 21JCQNJC01040)Science and Technology Project of Tianjin Municipal Health Commission(Nos.TJWJ2023MS023 and TJWJ2022MS027)+3 种基金the project of Tianjin Municipal Health Commission(No.2023168)the crosswise tasks of Tianjin Hospital of Integrated Chinese and Western Medicine(No.HXKY2020-0825)Cooperation Project for Basic Research of Beijing-Tianjin-Hebei(No.22JCZXJC00130)Science and technology project of Tianjin Municipal Health Commission(Nos.ZC20112 and KJ20131)。
文摘Magnesium–zinc–calcium alloy has emerged as a key focus in the field of medical degradable materials due to its excellent biodegradability and osteoconductive properties.Grain size is crucial for the physicochemical and biological properties of Mg–Zn–Ca alloy,but it has not been clearly elucidated yet.In this research,Mg-1Zn-0.2Ca-1.0MgO with different grain sizes were prepared to investigate the effect of grain size on the physicochemical properties,corrosion resistance,and osteogenesis.The results indicate that grain refinement improves the mechanical properties and enhances the corrosion resistance of the alloy.The bone surface area to bone volume ratio,bone surface area to tissue volume ratio,and bone volume fraction of the 0.6–0.8μm group show significantly better performance compared to the 2–3μm group and 5–6μm group,indicating that grain refinement can promote the osseointegration between alloy and natural bone.This may be achieved by enhancing the metabolic intensity of alanine,aspartate,glutamate,serine,and glycine around the implant.This work illustrates the effect of grain size on the osseointegration of bone implants and provides a reference for optimizing the properties of bone implant alloys.
基金partially supported by the National Natural Science Foundation of China(Nos.32471474 and 82102574)the Precision Medicine Project of People’s Hospital of Xinjiang Uygur Autonomous Region(No.20220305)+4 种基金Chengdu Advanced Metal Materials Industry Technology Research Institute Co.,Ltd.Support Project(No.24H0802)Sichuan Science and Technology Program(Nos.2025YFHZ0086,2023YFS0053,2024YFHZ0125,and 2025ZNSFSC0381)Project of Tianfu Jincheng Laboratory(No.2025ZH009)Guangdong Basic and Applied Basic Research Foundation(No.2023A1515220102)Xinjiang Autonomous Region Science and Technology Support Project Plan(Directive)Project(No.2024E02049)。
文摘Cases of widespread bone hydatid infection are relatively rare in clinical practice.In this study,we reported for the first time a validated integrated repair therapy for multiple bone tissues,including the hip,femur,and knee,caused by echinococ cosis.Artificial intelligence(AI)was used to develop a targeted surgical plan and to design a personalized prosthesis.Finite element analysis(FEA)was used to optimize the mechanical effectiveness of a customized integrated replacement prosthesis and to model stress distribution in the surrounding bone.Three-dimensional(3 D)printing was used to fabricate a customized prosthesis.With the assistance of AI,FEA,and 3 D printing technology,a personalized surgical plan and customized prosthesis were successfully constructed based on the patient’s disease.This approach achieved a successful therapeutic effect,demonstrating that AI-assisted personalized medicine holds great promise for the future.
文摘To investigate the clinical characteristics of chondroblastoma with an emphasis on lesions located in the long bone diaphysis,we reviewed the clinical data of 7 patients with histologically proven chondroblastoma treated in Tianjin Medical University Cancer Hospital and Fudan University Cancer Hospital between January 1995 and May 2009.There were two rare cases of chondroblastoma in the long bone diaphysis.One patient with a lesion in the tibial diaphysis underwent intralesional curettage and bone grafting,and the postoperative bone function was measured as excellent according to the Enneking scoring system.The patient was still alive upon follow-up at 60 months.The other patient with a lesion in the humeral diaphysis underwent resection,and the postoperative bone function was excellent at 48 months,at which there was no evidence of recurrence or metastasis.Thus,except for the distinctive site of the long bone diaphysis,which made diagnosis difficult,the patients' ages,symptoms,X-ray and CT images,treatment,and prognosis were in accordance with typical lesions in the epiphysis and metaphysis.The diagnosis of chondroblastoma in the long bone diaphysis significantly depends on histopathologic characteristics.
基金supported by National Natural Science Foundation of China(NSFC Nos.81601930 and U1613224)Natural Science Foundation of Guangxi(2016JJB140050)+1 种基金Research Grant Council of Hong Kong(HKU715213 and 17206916)Shenzhen Peacock Project
文摘Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic （n---70） and diabetes （n = 51） groups. Tibial plateaus were also collected from cadaver donors （n = 20） and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase （TRAP）, osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International （OARSI） scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP~ osteoclasts and lower number of Osterix~ osteoprogenitors and Osteocalcin~ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA.
文摘Objective： To demonstrate the validity and reliability of volumetric quantitative computed tomography （vQCT） with multi-slice computed tomography （MSCT） and dual energy X-ray absorptiometry （DXA） for hip bone mineral density （BMD） measurements, and to compare the differences between the two techniques in discriminating postmenopausal women with osteoporosis-related vertebral fractures from those without. Methods： Ninety subjects were enrolled and divided into three groups based on the BMD values of the lumbar spine and/or the femoral neck by DXA. Groups 1 and 2 consisted of postmenopausal women with BMD changes 〈-2SD, with and without radiographically confirmed vertebral fracture （n= 11 and 33, respectively）. Group 3 comprised normal controls with BMD changes 〉-ISD （n-46）. Post-MSCT （GE, LightSpeed16） scan reconstructed images of the abdominal-pelvic region, 1.25 mm thick per slice, were processed by OsteoCAD software to calculate the following parameters： volumetric BMD values of trabecular bone （TRAB）, cortical bone （CORT）, and integral bone （INTGL） of the left femoral neck, femoral neck axis length （NAL）, and minimum cross-section area （mCSA）. DXA BMD measurements of the lumbar spine （AP-SPINE） and the left femoral neck （NECK） also were performed for each subject. Results： The values of all seven parameters were significantly lower in subjects of Groups 1 and 2 than in normal postmenopausal women （P〈0.05, respectively）. Comparing Groups 1 and 2, 3D-TRAB and 3D-INTGL were significantly lower in postmenopausal women with vertebral fracture（s） [（109.8±9.61） and （243.3±33.0） mg/cm^3, respectively] than in those without [（148.9±7.47） and （285.4±17.8） mg/cm^3, respectively] （P〈0.05, respectively）, but no significant differences were evident in AP-SPINE or NECK BMD. Conclusion： the femoral neck-derived volumetric BMD parameters using vQCT appeared better than the DXA-derived ones in discriminating osteoporotic postmenopausal women with vertebral fractures from those without, vQCT might be useful to evaluate the effect of osteoporotic vertebral fracture status on changes in bone mass in the femoral neck.
基金National Natural Science Foundation of China,Nos.81472119 and 81672196Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support,No.20161423
文摘Antimicrobial drugs of several classes play an important role in the treatment of bone and joint infections. In addition to fighting pathogenic microorganisms, the effects of drugs on local tissues and cells are also related to the course and prognosis of bone and joint infections. The multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells (MSCs) is essential for tissue repair after local injury, which is directly related to the recovery of bone, cartilage, and medullary adipose tissue. Our previous studies and the literature indicate that certain antimicrobial agents can regulate the differentiation potential of bone marrow-derived MSCs. Here, in order to systematically analyze the effects of various antimicrobial drugs on local tissue regeneration, we comprehensively review the studies on the effects of these drugs on MSC differentiation, and classify them according to the three differentiation directions (osteogenesis, chondrogenesis, and adipogenesis). Our review demonstrates the specific effects of different antimicrobial agents on bone marrow-derived MSCs and the range of concentrations at which they work, and provides a basis for drug selection at different sites of infection.
基金Supported by Grants from the National Natural Science Foundation of China Project of Guiding Traditional Chinese Medicine Induced Bone Marrow Stem Cell Directional Homing to a Focal Zone for the Treatment of Osteoarthritis(No.81072900)
文摘OBJECTIVE: To investigate the effects of Ermiao Fang(EM) with medical guide Xixin(Herba Asari Mandshurici)(HAM) on bone marrow stem cell migration to a focal zone in osteoarthritis(OA) rats.METHODS: OA rats were induced by arthrectomy and assigned to sham-operated, model, EM, or EM plus HAM groups.All rats were injected with recombinant human granulocyte colony-stimulating factor 30μg·kg-1·d-1for7 days and treated with EMor EM plus HAM at 1.6 or 1.9 g·kg-1·d-1 for 3 or 6 weeks, respectively. Chondrocyte apoptosis and cartilage matrix components were tested by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay and special staining. Levels of interleukin-1 beta(IL-1β) tumor necrosis factor alpha(TNF-α) nitric oxide(NO), and inducible nitric oxide synthase(iNOS) in serum were detected by enzyme-linked immunosorbent assay or radioimmunoassay. Matrix metalloproteinases(MMPs)-13,tissue inhibitors of metalloproteinases(TIMPs)-1,Bromodeoxyuridine(BrdU), cluster of differentiation 34(CD34), and stromal cell-derived factor 1(SDF-1) were measured by immunohistochemical assay.RESULTS:The EM and EM plus HAM groups had significantly less cartilage damage and synovium inflammation the model group. Moreover, the EM and EM plus HAM groups had less chondrocyte apoptosis and more proteoglycan and collagen content than the model group.The EM and EMplus HAM groups had obviously higher MMPs-13 and TIMPs-1 expression in the cartilage than the model group. Moreover, the two formula groups had less release of IL-1β, TNF-α, NO, and iNOS than model group. Importantly, the expressions of BrdU, CD34,and SDF-1 in cartilage were significantly higher in the EM and EM plus HAM-Medtreated rats than model group. Notably, the EM plus HAM treatment seemed to have the greatest effects.CONCLUSION: HAM improves the therapeutic effects of EM on OA rats by enhancing BMSC directional homing to the focal zone.
文摘Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.
基金supported by the Natural Science Foundation with grants from the National Key R&D Program of China(2018YFC2002500)National Natural Science Foundation of China(81602360,82072470,82350003,92049201)+6 种基金Key Laboratory Construction Project of Guangzhou Science and Technology Bureau(202102100007)supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(No.JNU1AF-CFTP-2022-a01221)Natural Science Foundation of Guangdong Province(2021A1515012154,2019A1515011082,2017A030313665,2018A030313544,2020B1515120038)Science and Technology Projects in Guangzhou(201707010493,202102010069)Macao Foundation for Development of Science and Technology(0029/2019/A)Youth Talent Support Project of Guangzhou Association for Science&Technology(X20200301018)pilot project of clinical collaboration from National Administration of Traditional Chinese Medicine and National Health Commission of the People’s Republic of China and Logistics Support Department of the Central Military Commission。
文摘Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.
文摘Riverside Scene at Qingming Festival records some lively medical scenes in the Song Dynasty,including the pediatrics clinic,the bone orthopedics clinic,and the exchanges of genuine regional drugs of traditional Chinese medicine(TCM).All these scenes together reveal that TCM is highly developed and the medical specialties are becoming increasingly precise and detailed.
基金the support of the National Natural Science Foundation of China (Grant No.82272503)Natural Science Foundation of Zhejiang Province (Grant No. LQN25H060006)
文摘Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.
基金the Natural Science Foundation of Fujian Province(No.2023J011558)the Innovation of Science and Technology of Fujian Province(No.2021Y9098)Fujian Provincial Finance Project(No.BPB-2022FSH).
文摘Introduction:Dexamethasone(Dex)caused impaired osteoblast differentiation and oxidative stress(OS)in bone marrow mesenchymal stem cells(BMSCs).This work sought to elucidate the precise molecular pathway through which Dex influences osteogenic differentiation(OD)and OS in BMSCs.Methods:The expression of Runt-related transcription factor 1(RUNX1)and alpha-2 macroglobulin(A2M)was assessed in Dex-treated BMSCs using qRTPCR and Western Blot.Following the functional rescue experiments,cell proliferation was determined by MTT assay,reactive oxygen species(ROS)expression by DCFH-DA fluorescent probe,lactate dehydrogenase(LDH),superoxide dismutase(SOD),catalase(CAT),and glutathione peroxidase(Gpx)expression by kits,OD by alkaline phosphatase(ALP)staining and activity quantification,and the expression of OD-related proteins RUNX2,collagen type 1 alpha 1(COL1A1),and osteocalcin(OCN)by qRT-PCR and Western Blot.The binding of RUNX1 to A2M was initially analyzed through Jaspar website and subsequently verified by dual-luciferase reporter and ChIP assays.Results:Dextreated BMSCs had low RUNX1 and A2M expression.Dex treatment apparently elevated ROS and LDH levels,diminished cell proliferation rate and SOD,CAT,and Gpx expression,lightened intensity of ALP staining,and declined calcified nodules,ALP activity,and RUNX2,COL1A1,and OCN expression in BMSCs,which was counterweighed by RUNX1 or A2M overexpression.RUNX1 positively targeted A2M.A2M knockdown effectively nullified the ameliorative effects of RUNX1 overexpression on impaired OD and OS injury in Dex-induced BMSCs.Conclusions:Overexpression of RUNX1 attenuated Dex-induced impaired OD and OS injury in BMSCs by promoting A2M transcription.
基金Natural Science Foundation of Xinjiang Uygur Autonomous Region(2022D01C803).
文摘Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.
文摘In this editorial,we comment on the article by Jiang et al.Non-alcoholic fatty liver disease(NAFLD)is a chronic liver disease characterized by the accumulation of fat in the liver without evidence of significant alcohol consumption.NAFLD can progress to more serious conditions such as non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.This disease is considered an emerging public health problem in several countries as it has increased in recent decades,currently affecting around 30%of the world’s population.The fatty diet and the current lifestyle of the Western population are identified as the main culprits of the disease.Drug treatment aims to reduce the weight of patients and treat metabolic alterations and diseases,including type 2 diabetes mellitus and other comorbidities that coexist with NAFLD.In this scenario,cell therapy with mesenchymal stem/stromal cells(MSCs)has been proposed as a perspective treatment of numerous diseases that do not have definitive curative treatment,such as Crohn’s disease and coronavirus disease 2019.This is due to the versatile,immunomodulatory and regenerative properties of MSCs.The possibility of MSCs being used in patients with severe liver disease progressing to non-alcoholic steatohepatitis or cirrhosis is summarized,because of the therapeutic benefits in reducing fibrosis of affected livers.It remains to be seen when MSC transplantation should be indicated for NAFLD,that is,at what stage of the disease and which phenotype,as well as deciding on the best source of MSCs,the dose,and the administration route.We conclude that well-designed clinical trials are essential in order to obtain robust results for the implementation of this modality in the medical practice.
基金supported by the Health Commission of Guizhou Province(No.gzwkj2024-400)the“Open Competition Project”of Bijie Science and Technology Bureau(BST Major Project No.1,2022).
文摘Objective The aim of this study was to explore the influence of working length(determined by the screw position)on the stiffness and interfragmentary strain(IFS)of femoral locking compression plate(LCP)external fixators for lower tibial fractures under full weight-bearing conditions,with the goal of providing a reference basis for clinical applications.Methods Finite element analysis software was used to construct a model of a lower tibial fracture with external femoral LCP fixation.The models were divided into four groups according to the different working lengths(external femoral locking plate fixation 1[EF1],EF2,EF3,and EF4).Stress distribution clouds,fracture end displacements,stiffness and IFS were tested for each model group at different loads.Results Compared with those in the EF1 group,the stiffnesses in the EF2,EF3,and EF4 groups decreased by 28%,31%,and 37%,respectively,under axial compression loading.Compared with those in the EF1 group,the stiffnesses in the EF2,EF3,and EF4 groups decreased by 19%,33%,and 35%,respectively,under axial torsion loading.Compared with those in the EF1 group,the stiffnesses in the EF2,EF3,and EF4 groups decreased by 32%,33%,and 35%,respectively,under a three-point bending load.The IFS of the four finite element models increased with the working length of the plate,with EF1(76%)<EF2(107%)<EF3(110%)<EF4(122%).Finite element analysis revealed that under full weight-bearing conditions,the structural stiffness of the femoral LCP external fixator decreased with increasing working length,leading to an increase in the IFS,which resulted in an IFS that exceeded the ideal range required for secondary healing.Conclusion For unstable lower tibial fractures,screws in the femoral LCP external fixator should be placed as close to the fracture end as possible to increase stability and promote fracture healing.
基金supported by the Science and Technology Projects in Guangzhou(202201020566)Medical Joint Fund of Jinan University(YXJC2022005)+1 种基金Fundamental Research Funds for the Central Universities(21623319)Huadu District Basic and Applied Basic Research District and Hospital Joint Funding Program(23HDQYLH20).
文摘Background:Human adipose-derived stem cells(hADSCs)are seed cells with application prospects in cartilage repair.However,the mechanism of hADSC chondrogenic differentiation is still unclear.This study identifies a novel circRNA,circNR3C2,which is significantly upregulated during the chondrogenic differentiation of hADSCs.Methods:To analyze their role in hADSC chondrogenic differentiation,hADSCs were separated and identified by flow cytometry.Thereafter,we conducted Alcian Blue staining to assess chondrogenic differentiation levels.Additionally,RT-qPCR was carried out to detect levels of the cartilage-related genes COL2,Aggrecan and SOX9.Moreover,overlapping target SOX9 and circNR3C2 miRNAs were detected by bioinformatics and luciferase analyses.Finally,the role of circNR3C2 was confirmed in vivo using animal models.Results:We confirmed that the cell surface receptors CD44,CD90 and CD105 were positively expressed on hADSCs,and their cartilage differentiation levels dramatically increased after 2 weeks.Expression of the cartilage-related genes COL2 and Aggrecan and circNR3C2 also markedly increased.CircNR3C2 overexpression enhanced cartilage differentiation of hADSCs,while up-regulating COL2,SOX9 and Aggrecan.Bioinformatics analysis identified hsa-miR-647 as the target miRNA of circ-NR3C2 and SOX9.Hsa-miR-647 overexpression in hADSCs can antagonize the effect of circNR3C2 on chondrogenic differentiation,and reverse its effect on regulating the expression of COL2,Aggrecan,and SOX9.We also showed that hADSCs overexpressing circNR3C2 promote cartilage repair in vivo.Conclusions:We show that circNR3C2 modulates SOX9 expression to promote hsamiR-647-mediated hADSC chondrogenic differentiation;targeting circNR3C2 may help to develop new treatments to manage cartilage-related disorders.
基金supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(No.JNU1AF-CFTP-2022-a01223)Guangzhou Science and Technology Plan City-School Joint Funding Project(2024A03J0825)+2 种基金Science and Technology Projects in Guangzhou(202201020566)Medical Joint Fund of Jinan University(YXJC2022005)the Fundamental Research Funds for the Central Universities(21623319).
文摘Background: Tumor angiogenesis is related to solid tumor occurrence. Ubiquitin-specific peptidase 13 (USP13) is a deubiquitinating enzyme with a pivotal effect on tumor proliferation, metastasis, and tumorigenesis. Nonetheless, its effect on colorectal cancer (CRC) angiogenesis remains poorly understood. Methods: Human umbilical vein endothelial cells (HUVECs) and CRC cells were cultivated, followed by USP13 knockdown/overexpression using shRNA lentiviral vectors or plasmids. Conditioned media (CM) from treated CRC cells were collected to assess HUVEC migration, invasion, and tube formation. Phosphatase and tensin homolog (PTEN) overexpression and recombinant vascular endothelial growth factor A (VEGFA) rescue experiments were performed. Molecular mechanisms were analyzed via Western blot (PTEN, p-AKT, VEGFA), co-immunoprecipitation (PTEN ubiquitination), and in vivo nude mice study to detect the role of USP13 in tumor angiogenesis. Results: USP13 expression in CRC cells is downregulated and negatively related to platelet endothelial cell adhesion molecule-1 (CD31) expression. Furthermore, the conditioned medium from CRC cells with USP13 knockdown significantly promoted HUVEC migration, invasion, and tube formation, while USP13 overexpression exerted the opposite effect. Additionally, USP13 overexpression significantly increased PTEN expression while decreasing protein kinase B (AKT) phosphorylation levels. Concurrently, USP13 overexpression significantly reduced PTEN ubiquitination, whereas USP13 knockdown remarkably increased this modification. Overexpression of PTEN in sh-USP13 CRC cells decreased the expression levels of VEGFA and p-AKT. USP13 also inhibited tumor angiogenesis through downregulating VEGFA, and recombinant VEGFA blocked the inhibition of the conditioned medium from USP13-overexpressing CRC cells against HUVEC angiogenesis in vivo. Conclusions: USP13 downregulated VEGFA and inhibited tumor angiogenesis via the PTEN-AKT pathway.
基金partly supported by grants from the National Nature Science Foundation of China (No.81372872 to J.Yang and No.81320108022 to K.Chen)the University Cancer Foundation via the Sister Institution Network Fund (SINF) at the Tianjin Medical University Cancer Institute & Hospital (TMUCIH)+3 种基金Fudan University Shanghai Cancer Center (FUSCC)University of Texas MD Anderson Cancer Center (UTMDACC)Changjiang Scholars and Innovative Research Team in University (PCSIRT) in China (No.IRT1076)National Key Scientific and Technological Project (No.2011ZX09037-001-04) (K.Chen)
文摘PRUNE2 plays an important role in regulating tumor cell differentiation,proliferation,and invasiveness in neuroblastoma.Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately differentiated leiomyosarcoma from gastrointestinal stromal tumor.However,the association between PRUNE2 expression and prognosis in leiomyosarcoma is poorly understood.In this study,we evaluated the prognostic role of PRUNE2 in leiomyosarcoma.PRUNE2 expression was detected using immunohistochemistry in 30 formalin-fixed,paraffin-embedded leiomyosarcoma tissues from MD Anderson Cancer Center,and high expression was detected in 36.7%(11/30)of the samples.To validate these results,immunohistochemistry was performed on another cohort of 45 formalin-fixed,paraffinembedded leiomyosarcoma tissues from Tianjin Medical University Cancer Institute&Hospital,and high PRUNE2 protein expression was detected in 37.8%(17/45)of the samples.Moreover,elevated PRUNE2expression was significantly associated with tumor size(P=0.03)and hemorrhage/cyst(P=0.014),and was an independent favorable prognostic factor for overall survival in leiomyosarcoma patients from Tianjin Medical University Cancer Institute&Hospital(P<0.05).These data suggest that increased PRUNE2protein expression may serve as a favorable prognostic marker in human leiomyosarcoma.
基金supported by Shandong Key Scientific and Technological Project Fund(No.:2012GSF11845)
文摘Objective:To study the effect of low intensity pulsed ultrasound(LIPUS) on the expression of tissue inhibitor of metalloproteinase-2(TIMP-2) in the serum and expression of matrix metallopeptidase 13(MMP-13) in the articular cartilage cells of rabbits with knee osteoarthritis(OA).Methods:Inner patellar ligament defect method was used to establish the model of knee OA.Four weeks after the modeling,the arterial blood was drawn from the ear of each rabbit,while ELISA was employed to detect the expression of TIMP-2 in the serum.The chondrocytes were separated from animals in each group and then cultured in vitro.All rabbits were divided into control group,OA model group and OA + LIPUS group.Cells in the control and OA groups were not treated,while cells in the OA+ LIPUS group were treated with LIPUS(40 mW/cnr.1 time/day).Cells were collected 7 d later and the RNA and total protein were extracted respectively.Real-time PCR and Western blotting were employed to analyze the expression of MMP-13 in chondrocytes at the mRNA and protein level,respectively.Results:The success rate of establishment of OA model was 83%.The results of ELISA showed that the content of TIMP-2 in the serum of animals with OA was 22.3%,lower than the one in the control group(P<0.05).Compared with the normal control group,the expression of TIMP-2in the OA model group was significantly increased,while the expression of MMP-13 was significantly increased(P<0.05).After the stimulation of LIPUS,the expression of TIMP-2 and MMP-13 was close to the one in the normal control group.Conclusions:The inner patellar ligament defect method is a mature method to establish the rabbit OA model,with high success rate.The expression of serum TIMP-2 in the OA model group is significantly decreased.LIPUS can up-regulate TIMP-2 and down-regulate MMP-13.
基金supported by the National Natural Science Foundation of China(No.81672161).
文摘During the pathogensis of rheumatoid arthritis(RA),activated RA fibroblast-like synoviocytes(RA-FLSs)combines similar proliferative features as tumor and inflammatory features as osteoarthritis,which eventually leads to joint erosion.Therefore,it is imperative to research and develop new compounds,which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression.Neohesperidin(Neo)is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties.In this study,the anti-inflammation,anti-migration,anti-invasion,anti-oxidant and apoptosis-induced effects of Neo on RAFLSs were explored to investigate the underlying mechanism.The results suggested that Neo decreased the levels of interleukin IL-1β,IL-6,IL-8,TNF-α,MMP-3,MMP-9 and MMP-13 in FLSs.Moreover,Neo blocked the activation of the MAPK signaling pathway.Furthermore,treatment with Neo induced the apoptosis of FLSs,and inhibited the migration of FLSs.It was also found that Neo reduced the accumulation of reactive oxygen species(ROS)induced by TNF-α.Taken together,our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA.
