Injectable, oxygen-releasing, thermosensitive hydrogel promotes vascularized bone formation with prolonged oxygen delivery and improved osteoinductivity.

The failure or delay in healing of critical bone defects is primarily due to early local anoxic conditions and reduced osteogenic activity. In this research, we integrated calcium peroxide (CPO) embedded polycaprolactone (PCL) microspheres and osteoinductive nanoparticles (Hydroxyapatite/Laponite) into a thermosensitive hydrogel (Pluronic F127), thereby formulating an injectable oxygen-releasing osteogenic thermosensitive hydrogel. Notably, the oxygen-releasing microspheres (ORMs) within the composite hydrogel provide stable oxygen release for up to 21 days, ensuring the survival, migration, and bioactivity of both mesenchymal stem cells and endothelial cells under anoxic conditions. Additionally, the composite hydrogel significantly augments the osteogenic potential of bone marrow mesenchymal stem cells by providing a biomimetic microenvironment with the incorporation of nano-hydroxyapatite/laponite. Ultimately, the injectable composite hydrogel successfully stimulated bone regeneration within a cranial defect in a rat model after 8 weeks, with enhanced vascularization and bone quality. The engineered hydrogel provides a minimally invasive approach to stimulate bone regeneration with a sustained oxygen supply and osteogenic microenvironment provision, underlining its potential for treating critical bone defects.

Novel injectable adhesive hydrogel loaded with exosomes for holistic repair of hemophilic articular cartilage defect.

Hemophilic articular cartilage damage presents a significant challenge for surgeons, characterized by recurrent intraarticular bleeding, a severe inflammatory microenvironment, and limited self-repair capability of cartilage tissue. Currently, there is a lack of tissue engineering-based integrated therapies that address both early hemostasis, anti-inflammation, and long-lasting chondrogenesis for hemophilic articular cartilage defects. Herein, we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin, loaded with exosomes derived from bone marrow stem cells (BMSCs) (Hydrogel-Exos). This hydrogel demonstrated favorable injectability, self-healing, biocompatibility, biodegradability, swelling, frictional and mechanical properties, providing a comprehensive approach to treating hemophilic articular cartilage defects. The adhesive hydrogel, featuring dynamic Schiff base bonds and hydrogen bonds, exhibited excellent wet tissue adhesiveness and hemostatic properties. In a pig model, the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions. Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway. This immunoregulatory effect, coupled with the extracellular matrix components provided by the adhesive hydrogel, enhanced chondrogenesis, promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects. In conclusion, our results highlight the significant application potential of Hydrogel-Exos for early hemostasis, immunoregulation, and long-term chondrogenesis in hemophilic patients with cartilage injuries. This innovative approach is well-suited for application during arthroscopic procedures, offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.

Interactive effect of hemodynamics in transverse sigmoid sinus and bone morphology on venous pulsatile tinnitus: a four-dimensional (4D) flow magnetic resonance imaging (MRI) study.

Background: The hemodynamic pathogenesis of venous pulsatile tinnitus (VPT) is still unclear. This study aimed to explore the mechanism of bone morphology and hemodynamic changes in transverse sigmoid sinus (TSS) on VPT patients. Methods: 49 patients with unilateral VPT, 26 patients with subjective tinnitus and 36 healthy controls were included in this retrospective clinical trial. Four-dimensional (4D) flow magnetic resonance imaging (MRI) was used to evaluate the hemodynamics of the TSS. High-resolution computed tomography was used to assess the perivenous bone structures. All images were independently assessed for each participant by two trained neuroradiologists. Kolmogorov-Smirnov test was used to determine the normal distribution of the data. Chi-square test and nonparametric test were used to compare classified or continuous variables. Stepwise linear regression and mediation effect analysis was used to explore the relationship between bone dehiscence (BD), hemodynamic factors and VPT symptoms. Results: Peak velocity (P=0.001) and maximum energy loss (P=0.041) in VPT group were risk factors for the severity of tinnitus. Energy loss [indirect effect =0.692, P<0.005, 95% confidence interval (CI): 0.201-1.377] and peak velocity (indirect effect =0.899, P<0.005, 95% CI: 0.406-1.582) demonstrated the complete mediation effect between the BD and VPT. BD showed a complete mediation effect between the wall shear stress (WSS) and VPT (indirect effect =15.181, P<0.005, 95% CI: 3.448-35.493). Conclusions: Cross-talk between the hemodynamic changes of TSS and BD can regulate the VPT symptoms. This type of analysis might be helpful in establishing the possible occurrence and development mechanism of the hemodynamics and bone morphology of the VPT.

Impaired T1 mapping and Tmax during the first 7 days after ischemic stroke. A retrospective observational study.

OBJECTIVE: To measure the relative T1 (rT1) value in different hypo-perfused regions after ischemic stroke using T1 mapping derived by Strategically Acquired Gradient Echo (STAGE) and assess its relationship with onset time and severity of ischemia. MATERIALS AND METHODS: Sixty-three patients with acute anterior circulation ischemic stroke from 2017 to 2022 who underwent STAGE, diffusion weighted imaging (DWI) and dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI) within 7 days were retrospectively enrolled. The areas with reduced diffusion and hypo-perfusion were segmented based on apparent diffusion coefficient (ADC) value < 0.62 × 10-3mm2/s and time-to-maximum (Tmax) thresholds (4, 6, 8, and 10 seconds). We measured the T1 value in the diffusion reduced and every 2 s Tmax strata regions and calculated rT1 (T1ipsi/T1contra) to explore the relationship between rT1 value, Tmax, and onset time. RESULTS: rT1 value was increased in diffusion reduced (1.42) and hypo-perfused regions (1.02, 1.06, 1.12, 1.27, Tmax 4-6 s, 6-8 s, 8-10 s, > 10 s, respectively; all different from 1, P < 0.001). rT1 value was positively correlated with Tmax (rs = 0.61, P < 0.001) and onset time in area with reduced diffusion (rs = 0.39, P = 0.014). CONCLUSIONS: Increased rT1 value in different hypo-perfused brain regions using T1 mapping derived by STAGE may reflect the edema; it was associated with the severity of Tmax and showed a weak correlation with the onset time in diffusion reduced areas.

Reactive Oxygen Species Scavenging Hydrogel Regulates Stem Cell Behavior and Promotes Bone Healing in Osteoporosis.

BACKGROUND: Implantation of bone marrow mesenchymal stem cells (BMSCs) is a potential alternative for promoting bone defects healing or osseointegration in osteoporosis. However, the reactive oxygen species (ROS) accumulated and excessive inflammation in the osteoporotic microenvironment could weaken the self-replication and multi-directional differentiation of transplanted BMSCs. METHODS: In this study, to improve the hostile microenvironment in osteoporosis, Poloxamer 407 and hyaluronic acid (HA) was crosslinked to synthetize a thermos-responsive and injectable hydrogel to load MnO2 nanoparticles as a protective carrier (MnO2@Pol/HA hydrogel) for delivering BMSCs. RESULTS: The resulting MnO2@Pol/HA hydrogel processed excellent biocompatibility and durable retention time, and can eliminate accumulated ROS effectively, thereby protecting BMSCs from ROS-mediated inhibition of cell viability, including survival, proliferation, and osteogenic differentiation. In osteoporotic bone defects, implanting of this BMSCs incorporated MnO2@Pol/HA hydrogel significantly eliminated ROS level in bone marrow and bone tissue, induced macrophages polarization from M1 to M2 phenotype, decreased the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1ß, and IL-6) and osteogenic related factors (e.g., TGF-ß and PDGF). CONCLUSION: This hydrogel-based BMSCs protected delivery strategy indicated better bone repair effect than BMSCs delivering or MnO2@Pol/HA hydrogel implantation singly, which providing a potential alternative strategy for enhancing osteoporotic bone defects healing.

A nomogram model based on the combination of the systemic immune-inflammation index, body mass index, and neutrophil/lymphocyte ratio to predict the risk of preoperative deep venous thrombosis in elderly patients with intertrochanteric femoral fracture: a retrospective cohort study.

OBJECTIVES: Deep vein thrombosis (DVT) has been considered as a frequent and serious consequence of intertrochanteric femoral fractures in the elderly. Several negative repercussions of DVT can be considerably mitigated by its timely recognition and treatment. The current work was aimed at exploring the factors independently predicting DVT among cases suffering from intertrochanteric femoral fractures and validate their predictive usefulness in diagnosing DVT. METHODS: Between April 2017 and July 2022, clinical information from 209 cases showing preoperative DVT for femoral intertrochanteric fractures were retrospectively evaluated. In patients with femoral intertrochanteric fractures, logistic regression analysis with a backward stepwise method was adopted for detecting independent predictors for the diagnosis of preoperative DVT. Using multivariate logistic regression, a nomogram prediction model was developed and verified with the testing group. RESULTS: According to multivariate logistic regression model, body mass index (BMI) (OR 0.79, 95% CI 0.63-0.99, P = 0.042), neutrophil/lymphocyte ratio (NLR) (OR 7.29, 95% CI 1.53, 34.64, P = 0.0012), and systemic immune-inflammation index (SII) (OR 6.61, 95% CI 2.35, 18.59, P = 0.001) were independent predictors for DVT before surgery among cases developing intertrochanteric femoral fracture. AUC values were 0.862 and 0.767 for training and testing groups, separately, while their mean errors in the calibration curve were 0.027 and 0.038 separately. Decision curve analysis (DCA) curve revealed a high value of clinical application for both groups. CONCLUSION: Upon admission, BMI, NLR, and SII are independent predictors of DVT before surgery among cases developing intertrochanteric femoral fractures. Additionally, the nomogram based on the BMI, NLR, and SII can assist clinicians in determining if preventive and symptomatic therapies are required to improve DVT prognosis and reduce its associated mortality.

[Retracted] Isopsoralen­mediated suppression of bone marrow adiposity and attenuation of the adipogenic commitment of bone marrow­derived mesenchymal stem cells.

Following the publication of the above article, an interested reader drew to the authors' attention that Figs. 1C and 2 in the paper appeared to contain instances of duplicated data. The authors were able to consult their original data files, and realized that these figures had indeed been assembled incorrectly. Moreover, they identified further errors with a number of the other figures in their published formats (specifically, Figs. 3, 4, 6 and 7), and requested that a corrigendum be published to take account of all the errors that were made during the compilation of these figures. The Editor of International Journal of Molecular Medicine has considered the authors' request to publish a corrigendum, but has declined this request on account of the large number of errors that have been identified, and subsequently determined that this article should be retracted from the Journal on the basis of an overall lack of confidence in the presented data. Upon receiving this decision from the Editor, the authors were in agreement that the article should be retracted. The Editor apologizes to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 39: 527­538, 2017; DOI: 10.3892/ijmm.2017.2880].

Using a degradable three-layer sandwich-type coating to prevent titanium implant infection with the combined efficient bactericidal ability and fast immune remodeling property.

Titanium (Ti) implant-associated infections are a challenge in orthopedic surgery, for which a series of antibacterial coatings have been designed and fabricated to reduce the risk of bacterial contamination. Herein, we created a degradable three-layer sandwich-type coating to achieve long-term antibacterial effects while simultaneously reconstructing the local immune microenvironment. The vancomycin (Van)-loaded vaterite coating constitutes the outer and inner layers, whereas Interleukin-12 (IL-12)-containing liposomes embedded in sodium alginate constitutes the middle layer. Van, released from the vaterite, demonstrated a favorable and rapid bactericidal ability against the representative methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains. The released IL-12 exhibited the desired immune reconstitution abilities, actively facilitating defenses against subsequent bacterial invasions. Furthermore, the biocompatibility and cell-binding feature of the multifunctional coating was beneficial for achieving solid interface intergradation. Overall, the benefits of the three-layer sandwich-type coating, including the convenient fabrication process, efficient antimicrobial activity, fast immune remodeling property, fine cell-binding feature, and biodegradability, highlight its promising translational potential in preventing implant infection. STATEMENT OF SIGNIFICANCE: To prevent titanium implant infections, researchers have designed various antibacterial coatings. However, most of these coatings focused only on killing the invading bacteria over a limited postoperative period. However, the local immune microenvironment is compromised during surgery. Local immune deflection impedes the ability of the local immune defenses to clear bacteria and limits immune memory building from active defense against long-term subsequent bacterial invasions. Furthermore, these coatings are usually nondegradable and differ substantially from bone components, thereby impairing the integration of the coating and bone interface and generating concerns about implant stability and bacterial contamination. In this work, we synthesized a degradable coating that provides sustained antibacterial activity, promotes immune reconstitution, and simultaneously achieves solid bone integration.

Simple and free-labeled voltammetry determination of glioma cell.

Glioma is one of the most frequent brain tumors with substantial mortality and morbidity, thus designing a simple sensor for achieving highly efficient determination of glioma cell is of great importance. In this work, by preparing 3,4,9,10-perylene tetracarboxylic acid (PTCA) non-covalently functionalized carbon black (CB) nanohybrids (CB-PTCA) as matrix and using angiopep-2 peptide (Ang-2) as receptor to recognize selectively glioma cell, a simple and free-labeled voltammetry sensor was developed for the first time to detect glioma cell by using Ang-2 and CB-PTCA modified glassy carbon electrode (Ang-2/CB/GCE): via introducing typical [Fe(CN)6]4-/3- as the signal probe, its electrochemical signal would be suppressed when glioma cells were recognized by Ang-2, and the values of peak current difference varied along with the concentrations of glioma cells. After optimizing the related testing conditions (the amounts of CB-PTCA, concentration of Ang-2 and recognition time of Ang-2 towards glioma cells), a wide linearity from 102 to 106 cells mL-1 and a low analytic limitation of 30 cells mL-1 were achieved for glioma cell. Furthermore, the application of the proposed immunosensor in human serum was also studied, revealing that the results are reliable and the designed proposal offers a significant clinical application for glioma detection.

Engineering Multifunctional Hydrogel With Osteogenic Capacity for Critical-Size Segmental Bone Defect Repair.

Treating critical-size segmental bone defects is an arduous challenge in clinical work. Preparation of bone graft substitutes with notable osteoinductive properties is a feasible strategy for critical-size bone defects. Herein, a biocompatible hydrogel was designed by dynamic supramolecular assembly of polyvinyl alcohol (PVA), sodium tetraborate (Na2B4O7), and tetraethyl orthosilicate (TEOS). The characteristics of the supramolecular hydrogel were evaluated by rheological analysis, swelling ratio, degradation experiments, and scanning electron microscopy (SEM). In in vitro experiments, this TEOS-hydrogel had self-healing property, low swelling rate, degradability, good biocompatibility, and induced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by upregulating the expression of Runx-2, Col-1, OCN, and osteopontin (OPN). In segmental bone defect rabbit models, the TEOS-containing hydrogel accelerated bone regeneration, thus restoring the continuity of bone and recanalization of the medullary cavity. The abovementioned results demonstrated that this TEOS-hydrogel has the potential to realize bone healing in critical-size segmental bone defects.

Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists.

TGR5 is emerging as an important and promising target for the treatment of non-alcoholic steatohepatitis, type 2 diabetes mellitus (T2DM), and obesity. A series of novel 3-phenoxypyrazine-2-carboxamide derivatives were designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 18g and 18k exhibited excellent hTGR5 agonist activity, which was superior to those of the reference drug INT-777. In addition, compound 18k could significantly reduce blood glucose levels in C57 BL/6 mice and stimulate GLP-1 secretion in NCI-H716 cells and C57 BL/6 mice.

Decreased serum CXCL12/SDF-1 concentrations may reflect disease severity of non-traumatic osteonecrosis of femoral head.

OBJECTIVE: The current study was performed to investigate the potential association of serum CXCL12 with disease severity in non-traumatic ONFH. METHODS: This study enrolled 182 patients with non-traumatic ONFH and 182 age- and gender-matched healthy controls. The CXCL12 levels in serum were measured by enzyme-linked immunosorbent assay. Meanwhile, serum levels of procollagen type I (PINP) and Interleukin-33(IL-33) were also detected. The radiographic severity was determined by FICAT grade. Clinical severity was evaluated by visual analogue scale (VAS), Harris Hip Score (HHS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Among the non-traumatic ONFH, 90 patients ONFH received total hip arthroplasty, the localization and expression of the CXCL12 protein and mRNA were detected by immunohistochemistry, Western blot analysis, RT-PCR and in necrotic area and adjacent non-necrotic area from lesioned femoral neck from ONFH patients and healthy femoral head from femoral neck fracture patients. Receiver operating characteristic (ROC) curve analysis was carried out to confirm the diagnostic value serum CXCL12, PINP and IL-33 with regard to the FICAT grade. RESULTS: Serum CXCL12 levels were significantly lower in non-traumatic ONFH patients compared with healthy controls. CXCL12 mRNA and protein expressions were both significantly decreased in necrotic area in comparison with non-necrotic area and healthy femoral head. Serum CXCL12 concentrations were drastically reduced in patients with FICAT stage 4 compared with stage 3, and CXCL12 concentrations in patients with stage 3 were markedly lower than stage 2. Serum CXCL12 levels were negatively related to FICAT grading. In addition, Serum CXCL12 concentrations were also negatively related to VAS, WOMAC scores and positively correlated with HHS scores. Meanwhile, serum CXCL12 levels were positively correlated with serum PINP and negatively correlated with IL-33 levels. ROC curve analysis implicated that decrease CXCL12 in serum may act as a favorable marker for FICAT grade. CONCLUSIONS: Decreased serum CXCL12 concentrations may reflect disease severity of non-traumatic ONFH.

C/EBP ß Mediates the Aberrant Inflammatory Response and Cell Cycle Arrest in Lps-stimulated Human Renal Tubular Epithelial Cells by Regulating NF-κB Pathway.

BACKGROUND AND AIMS: The main cause of sepsis-induced Acute kidney injury (AKI) is acute infection after surgery and subsequent progression. However, the mechanism by which AKI is caused and developed from sepsis are not completely known. Herein, we determined the role of CCAAT/enhancer-binding protein ß (C/EBP ß) in sepsis-induced AKI METHODS: C/EBP ß expression was up or down-regulated in LPS-stimulated human renal tubular epithelial cells in vitro by recombinant adenoviruses or siRNA. Subsequent analyses included the test of TNF-α and IL-6 levels by ELISA, cell cycle assay by flow cytometry. RESULTS: C/EBP ß was aberrantly expressed in renal tubular epithelial HK-2 cells exposed to LPS. C/EBP ß overexpression significantly enhanced, but C/EBP ß silencing obviously decreased the production and secretion of inflammatory cytokines TNF-α and IL-6 induced by LPS stimulus in HK-2 cells. And the cell cycle arrest of HK-2 cells induced by LPS was also enhanced after C/EBP ß overexpression while attenuated after C/EBP ß silencing. Consistent pattern of changes in Cyclin D1 and p21 expression were observed in LPS-stimulated HK-2 cells after C/EBP ß silencing and C/EBP ß overexpression. Additionally, the increased p-NF-κB levels induced by LPS were found to be obviously decreased after C/EBP ß silencing in HK-2 cells. And the enhanced TNF-α and IL-6 secretion as well as cell cycle arrest by C/EBP ß overexpression were blocked by BAY11-7082 inhibitor of NF-κB pathway. CONCLUSIONS: C/EBP ß could mediate the LPS-induced aberrant inflammatory response and cell cycle arrest in tubular epithelial cells by NF-κB pathway.

Diagnostic Value of Magnetic Resonance (MR) Combined with Computed Tomography (CT) in Patients with Stress Injury of Femoral Neck.

BACKGROUND The purpose of this research was to study and analyze the diagnostic value of magnetic resonance (MR) combined with computed tomography (CT) in patients with stress injury of the femoral neck. MATERIAL AND METHODS The 58 patients with stress injury of the femoral neck who were treated in our hospital from July 2017 until July 2019 were selected as subjects on the basis of clinical pathology and surgery, MR and CT examination, and related imaging data retrospectively analyzed. We observed all patients using different diagnostic methods to determine the value of diagnosis and treatment of disease. RESULTS The patients selected for this study were confirmed by clinicopathology and surgery; the positive rate of CT diagnosis was 65.5%, the positive rate of MR diagnosis was 74.1%, and the positive rate of combined diagnosis was 91.4%. Through statistical analysis, CT and MR showed no significant difference in the detection of stress lesions in different femoral necks, indicating no statistical significance (P>0.05). However, the amount of stress lesions detected in the combined diagnosis was higher than that in the two separate detection methods, with statistically significant difference (P<0.05). The grading of stress lesions in all patients examined through MR showed that there was no proportion of grade 0, whereas grades 3-4 were the highest, accounting for 20.7% and 32.8% respectively. In CT scanning of all patients, fracture lines were observed in 35 patients, of which 25 were transparent lines and 10 were strip dense shadows; Periosteal reaction was observed in 34 patients, of whom umbilical concave was observed in 18 patients. Osteoporosis was observed in 30 patients, and the lesion showed a zone of reduced density in the cortical bone, with a stripelike shape and unclear boundary. The density tended to increase in the cavum medullare of 32 patients, with porosis being visible. Compared with CT diagnosis, the accuracy, sensitivity, and specificity of MR detection were not significantly different (P>0.05). The accuracy, sensitivity, and specificity of the combined detection were higher than that of CT and MR detection alone, with statistically significant differences between groups (P<0.05). CONCLUSIONS The application of MR combined with CT in early clinical diagnosis and treatment of femoral neck stress injury will improve the diagnosis rate; the imaging signal is obvious, which is helpful to further evaluate the severity of disease.

Risk factors for osteoporosis in liver cirrhosis patients measured by transient elastography.

Osteoporosis or osteopenia is a common complication in patients with cirrhosis, but little is known about the risk factors for the occurrence of osteoporosis.Patients with liver cirrhosis due to chronic virus infection and alcoholic abuse were enrolled. Bone mineral density (BMD) was determined using dual-energy x-ray absorptiometry (DXA). Osteoporosis was diagnosed according to WHO criteria. The severity of liver stiffness was measured by Fibroscan. Demographic data, such as age, gender, weight, height, and body mass index (BMI), were collected. Logistic regression analysis was used to recognize the risk factors of osteoporosis in patients with cirrhosis.A total of 446 patients were included in this study: 217 had liver cirrhosis (male, 74.2%; mean age, 57.2 ±â€Š10.27) and 229 were matched controls (male, 69%, mean age, 56.69 ±â€Š9.37). Osteoporosis was found in 44 patients (44/217, 20.3%). The spine and hip BMD in cirrhotic patients were significantly lower than that in controls. When the cirrhotic and control subjects were stratified by age, gender, and BMI, the significant difference was also observed in women patients, patients older than 60, and patients with BMI < 18. Multivariate analysis showed that the older age [odds ratio (OR) = 1.78, P = .046], lower BMI (OR = 0.63, P = .049), greater fibroscan score (OR = 1.15, P = .009), and liver cirrhosis induced by alcohol liver disease (OR = 3.42, P < .001) were independently associated with osteoporosis in cirrhotic patients.Osteoporosis occurred in about one-fifth of patients with liver cirrhosis, which was associated with age, BMI, Fibroscan score, and alcohol liver disease related liver cirrhosis.

Leptocarpin Suppresses Proliferation, Migration, and Invasion of Human Osteosarcoma by Targeting Type-1 Insulin-Like Growth Factor Receptor (IGF-1R).

BACKGROUND Leptocarpin (LTC) has drawn much attention for suppressing tumor growth or reducing inflammation. However, the effect of LTC on osteosarcoma has rarely been reported. Our object was to determine whether LTC suppresses MG63 cell proliferation, migration, and invasion, and whether type-1 insulin-like growth factor receptor (IGF-1R) is one of the targets in LTC suppressing osteosarcoma. MATERIAL AND METHODS Cytotoxicity of LTC was performed by use of a cell-counting kit-8 (CCK-8). RNA interference (RNAi) or pEABE-bleo IGF-1R plasmid were used for silencing or overexpressing IGF-1R, Western blot (WB) analysis was used for IGF-1R expression, CCK-8 for proliferation, and transwell assay for migration and invasion. RESULTS LTC (23.533 µM) treatment for 48 h was taken as the 50% inhibiting concentration (IC50), which significantly (P<0.05) suppressed MG63 cells proliferation, migration, and invasion. LTC (IC50) obviously inhibited IGF-1R expression in MG63 cells, with similar effect to small interfering RNA (siRNA), while pEABE-bleo IGF-1R transfection overexpressed IGF-1R. siRNA silencing IGF-1R suppressed MG63 cells proliferation, migration, and invasion, while pEABE-bleo IGF-1R transfection was significantly (P<0.05) promoted. With or without siRNA or pEABE-bleo IGF-1R transfection, LTC (IC50) suppressed MG63 cells proliferation, migration, and invasion. The effect of LTC (IC50) combined with siRNA on suppressing MG63 cells proliferation, migration, and invasion was more obvious, while the effect of LTC (IC50) combined with pEABE-bleo IGF-1R transfection was less significant (P<0.05). CONCLUSIONS LTC suppressed osteosarcoma proliferation, migration, and invasion by inhibiting IGF-1R expression. IGF-1R is one of the targets in LTC suppressing osteosarcoma.

Isopsoralen-mediated suppression of bone marrow adiposity and attenuation of the adipogenic commitment of bone marrow-derived mesenchymal stem cells.

Osteoporosis (OP) increases the risk of bone fractures and other complications, and is thus a major clinical problem. In this study, we examined the effect of isopsoralen on the differentiation of bone-derived marrow mesenchymal stem cells (BMSCs) into osteoblasts and adipocytes, as well as bone formation under osteoporotic conditions. Primary femoral BMSCs isolated from C57BL/6 mice were used to evaluate the isopsoralen-mediated regulation of the expression of alkaline phosphatase (ALP), osteocalcin (OCN) and runt-related transcription factor 2 (RUNX2) during osteogenesis 2 weeks. We also examined the expression of peroxisome proliferator-activated receptor Î³ (PPARγ) and CCAAT/enhancer binding protein ß (C/EBPß) under adipogenic conditions for 1 and 2 weeks. In addition, ovariectomized (OVX) mice were used to examine the effects of isopsoralen on bone formation for 2 months. Finally, mammalian target of rapamycin complex 1 (mTORC1) signaling was examined under osteogenic and adipogenic conditions. We found that following treatment with isopsoralen, the expression levels of ALP, OCN and RUNX2 were upregulated, whereas those of PPARγ and C/EBPß were downregulated. mTORC1 signaling was also inhibited in vitro and in vivo. In the OVX mice that were intragastrically administered isopsoralen, bone parameters (trabecular thickness, bone volume/total volume and trabecular number) in the distal femoral metaphysis were significantly increased and the adipocyte number was decreased. On the whole, our findings demonstrate that isopsoralen promoted BMSC differentiation into osteoblasts and suppressed differentiation into adipocytes.

Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma.

Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%-75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma.

Differential diagnosis of osteoblastic metastases from bone islands in patients with lung cancer by single-source dual-energy CT: advantages of spectral CT imaging.

OBJECTIVES: To evaluate the diagnostic efficacy of spectral CT for the differentiation of osteoblastic metastases (OBMs) from bone islands (BIs) in patients with lung cancer. METHODS: In 94 patients with lung cancer who underwent spectral CT, focal hyperdense lesions in vertebral bodies were diagnosed as OBMs or BIs. Regions of interest were placed within each lesion to measure the mean CT value and its standard deviation (SD) on polychromatic single-energy CT (SECT) at 140 kVp and dual-energy virtual monochromatic spectral (VMS) images. The mean bone (Dbone(wa)) and water densities (Dwa(bone)) of each lesion were also measured. The slope (k) of the spectral curve was calculated. Independent-sample t-test was used to compare those values between OBMs and BIs. Receiver operator characteristic analysis was performed to compare the area under curve (AUC) for the differentiation of OBMs from BIs. RESULTS: A total of 79 OBMs and 43 BIs were confirmed. The CT and SD values on SECT at 140 kVp and VMS images at 50-130 keV, k value, and Dbone(wa) for OBMs were significantly lower than for BIs; Dwa(bone) was significantly higher for OBMs than for BIs (p<0.05 for all). The AUC for the SD value at 110 keV was the highest among those parameters. The optimal cut-off value for this differentiation was 68.6 HU for the SD value on VMS images at 110 keV with sensitivity of 93.0% and specificity of 93.3%. CONCLUSION: Spectral CT is helpful for the differentiation of OBMs from BIs in patients with lung cancer, particularly using SD of the CT value on high-energy VMS images.