Reactive oxygen species (ROS) are generated and consumed in living organism for normal metabolism. Paradoxically, the overproduction and/or mismanagement of ROS have been involved in pathogenesis and ...progression of various human diseases. Here, we reported a two-dimensional (2D) vanadium carbide (V
C) MXene nanoenzyme (MXenzyme) that can mimic up to six naturally-occurring enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase (GPx), thiol peroxidase (TPx) and haloperoxidase (HPO). Based on these enzyme-mimicking properties, the constructed 2D V
C MXenzyme not only possesses high biocompatibility but also exhibits robust in vitro cytoprotection against oxidative stress. Importantly, 2D V
C MXenzyme rebuilds the redox homeostasis without perturbing the endogenous antioxidant status and relieves ROS-induced damage with benign in vivo therapeutic effects, as demonstrated in both inflammation and neurodegeneration animal models. These findings open an avenue to enable the use of MXenzyme as a remedial nanoplatform to treat ROS-mediated inflammatory and neurodegenerative diseases.
Osteosarcoma has a poor prognosis, and the poor understanding of the genetic drivers of osteosarcoma hinders further improvement in therapeutic approaches. Transcription factor forkhead box P1 ...(FOXP1) is a crucial modulator in skeletal development and aging. Here, we determined the role and regulatory mechanisms of FOXP1 in osteosarcoma. Higher FOXP1 expression correlated with malignancy in both osteosarcoma cell lines and clinical biopsies. FOXP1 overexpression and knockdown in osteosarcoma cell lines revealed that FOXP1 promoted proliferation, tumor sphere formation, migration and invasion, and inhibited anoikis. Mechanistically, FOXP1 acted as a repressor of P21 and RB (retinoblastoma protein) transcription, and directly interacted with the tumor suppressor p53 to inhibit its activity. Extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/JNK) signaling and c-JUN/c-FOS transcription factors were found to be upstream activators of FOXP1. Moreover, FOXP1 silencing via lentivirus or adeno-associated virus (AAV)-mediated delivery of shRNA suppressed osteosarcoma development and progression in cell-derived and patient-derived xenograft animal models. Taken together, we demonstrate that FOXP1, which is transactivated by ERK/JNK-c-JUN/c-FOS, drives osteosarcoma development by regulating the p53-P21/RB signaling cascade, suggesting that FOXP1 is a potential target for osteosarcoma therapy.
The objective was to investigate the effect of kinsenoside (Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis (OA) progression. ...RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium (CM) and IL-1
β
were administered to chondrocytes. Micro-CT scanning and histological observations were conducted
in vivo
on anterior cruciate ligament transection (ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of I
κ
B
α
, which further reduced the downstream phosphorylation of P65 in nuclear factor-
κ
B (NF-
κ
B) signaling. Moreover, Kin inhibited mitogen-activated protein kinases (MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1
β
-induced chondrocyte damage.
In vivo
, Kin reduced the infiltration of M1 macrophages, promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.
Kinsenoside (Kin) repolarizes M1 macrophages to the M2 phenotype by inhibiting the phosphorylation of I
κ
B
α
and further reducing downstream phosphorylation of P65. Moreover, Kin inhibits p-JNK, p-Erk and p-p38 in MAPK signaling pathway, and promotes p-STATA6, which is an important transcription factor for M2 macrophages polarization.
fx1
We have explored the applicability of printed scaffold by comparing osteogenic ability and biodegradation property of three resorbable biomaterials. A polylactic acid/hydroxyapatite (PLA/HA) ...composite with a pore size of 500 μm and 60% porosity was fabricated by three-dimensional printing. Three-dimensional printed PLA/HA, β-tricalcium phosphate (β-TCP) and partially demineralized bone matrix (DBM) seeded with bone marrow stromal cells (BMSCs) were evaluated by cell adhesion, proliferation, alkaline phosphatase activity and osteogenic gene expression of osteopontin (OPN) and collagen type I (COL-1). Moreover, the biocompatibility, bone repairing capacity and degradation in three different bone substitute materials were estimated using a critical-size rat calvarial defect model in vivo. The defects were evaluated by micro-computed tomography and histological analysis at four and eight weeks after surgery, respectively. The results showed that each of the studied scaffolds had its own specific merits and drawbacks. Three-dimensional printed PLA/HA scaffolds possessed good biocompatibility and stimulated BMSC cell proliferation and differentiation to osteogenic cells. The outcomes in vivo revealed that 3D printed PLA/HA scaffolds had good osteogenic capability and biodegradation activity with no difference in inflammation reaction. Therefore, 3D printed PLA/HA scaffolds have potential applications in bone tissue engineering and may be used as graft substitutes in reconstructive surgery.
A novel poly(lactic-
-glycolic acid) (PLGA)-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) composite nanofiber wound dressing was prepared through electrospinning and the entrapment-graft ...technique as an antibacterial dressing for cutaneous wound healing. HACC with 30% degrees of substitution (DS) was immobilized onto the surface of PLGA membranes via the reaction between carboxyl groups in PLGA after alkali treatment and the reactive groups (⁻NH₂) in HACC molecules. The naked PLGA and chitosan graft PLGA (PLGA-CS) membranes served as controls. The surface immobilization was characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and energy dispersive X-ray spectrometry (EDX). The morphology studies showed that the membranes remain uniform after the immobilization process. The effects of the surface modification by HACC and CS on the biological properties of the membranes were also investigated. Compared with PLGA and PLGA-CS, PLGA-HACC exhibited more effective antibacterial activity towards both Gram-positive (
) and Gram-negative (
) bacteria. The newly developed fibrous membranes were evaluated in vitro for their cytotoxicity using human dermal fibroblasts (HDFs) and human keratinocytes (HaCaTs) and in vivo using a wound healing mice model. It was revealed that PLGA-HACC fibrous membranes exhibited favorable cytocompatibility and significantly stimulated adhesion, spreading and proliferation of HDFs and HaCaTs. PLGA-HACC exhibited excellent wound healing efficacy, which was confirmed using a full thickness excision wound model in
-infected mice. The experimental results in this work suggest that PLGA-HACC is a strong candidate for use as a therapeutic biomaterial in the treatment of infected wounds.
It is important to reorient the acetabular fragment into an optimal position and version to ensure a good long-term outcome after Bernese periacetabular osteotomy (PAO). Unfortunately, the ...intraoperative balance between overcorrection and undercorrection remains challenging for the surgeon. The purpose of this study was to answer two questions: (1) Does the femoral head coverage measured on intraoperative fluoroscopy agree with that measured on postoperative radiography? (2) What is the reliability of intraoperative fluoroscopy in identifying hip center correction in PAO?
A total of 173 patients (173 hips) who underwent PAO for developmental dysplasia of the hip (DDH) at our center from July 01, 2020, to December 31, 2020, were retrospectively reviewed. Imaging data from 111 patients (female/male, 98/13; right/left, 72/39; mean age, 28.93 years) were included in this study. The analysis included measurement of the lateral center-edge angle (LCEA), acetabular index (AI), anterior wall index (AWI), posterior wall index (PWI), extrusion index (EI), and medial offset distance (MO). These measurements were acquired from intraoperative fluoroscopic images and postoperative radiographs and compared by paired t test using SPSS (version 24.0). Significance was determined at a p value of < 0.05. Bland-Altman analysis, conducted using GraphPad Software (version 9), was used to quantify the agreement between intraoperative fluoroscopic images and postoperative radiographs.
The means (standard deviations, SDs) of the LCEA, AI, AWI, PWI, EI, and MO obtained on intraoperative fluoroscopy were 32.86° (5.73°), 0.66° (5.55), 0.29 (0.10), 0.75 (0.17), 11.15% (6.50%), and 8.49 mm (3.68 mm), respectively. On postoperative radiography, the corresponding values were 32.91° (6.31°), 1.63° (5.22°), 0.29 (0.15), 0.85 (0.14), 11.27% (7.36%), and 9.60 mm (3.79 mm). The differences in the LCEA, AWI, and EI acquired from intraoperative fluoroscopic images and postoperative radiographs were not significant (p = 0.90, 0.95, and 0.83, respectively), but those in the AI, PWI, and MO were significant (p < 0.05). The mean biases (95% limits of agreement) of the LCEA, AI, AWI, PWI, EI, and MO were - 0.04 (- 6.85), - 0.97 (- 7.78), 0 (- 0.30), - 0.11 (- 0.36), - 0.12 (- 11.92), and - 1.11 (- 5.51), respectively.
The LCEA, EI, and AWI can be used to reliably predict postoperative femoral head coverage at the level of 2D graphics. Acetabular inclination can be cautiously assessed using AI on intraoperative fluoroscopy. In the absence of intraoperative 3D image evaluation, the AWI and PWI demonstrate acceptable agreement between fluoroscopy and radiography in assessing the acetabular version. Although the MO shows slight bias, it can be helpful in properly positioning the acetabulum during PAO.
We sought to correlate various spinopelvic and lower limb alignments, and to examine the current spinopelvic theories on a Chinese cohort.
We retrospectively reviewed 166 patients undergoing THA. ...Among them, 138 patients with unilateral THA met the inclusion criteria. Sagittal alignments and cup orientations were measured on standing and sitting lateral EOS images. Patients were categorized into two groups with a scoring system for lumbar spine degeneration. Patients' demographics including age, sex, lumbar spine degeneration and radiographic measurements were studied.
PT, SS, LL and TK differed significantly between standing and sitting within each group except for TK in degenerative group (32.8 ± 13.9 vs. 32.9 ± 14.2, p = 0.905). Compared with degenerative spine group, non-degenerative spine patients have great pelvic mobility (ΔPT, -24.4 ± 12.5° vs. -17.6 ± 10.7, p = 0.0008), greater lumbar mobility (ΔLL, -34.8 ± 15.2 vs. -21.7 ± 12.2, p = < 0.0001) and compensatory cup orientation changes (ΔRA, -15.5 ± 11.1 vs. -12.0 ± 8.4, p = 0.00920; ΔRI, -10.8 ± 11.5 vs. -5.6 ± 7.5, p = 0.0055). Standing PT and ankle dorsiflexion angle correlated positively (R
= 0.236, p = 0.005).
THA patients in this cohort showed a spinopelvic motion paradigm similar to that from previous studies on Caucasians. Ankle dorsiflexion indicate greater posterior pelvic tilt on standing. Surgeons should beware of risks of instability in patients with lower limb compensations.
This study provides new insights into the clinical relevance of lower limb alignments to spinopelvic motion after THA in a relatively young Chinese population.
Cordycepin is a component of the extract obtained from Cordyceps militaris and has many biological activities, including anti-cancer, anti-metastatic and anti-inflammatory effects. Intervertebral ...disc degeneration (IDD) is a degenerative disease that is closely related to the inflammation of nucleus pulposus (NP) cells. The effect of cordycepin on NP cells in relation to inflammation and degeneration has not yet been studied. In our study, we used a rat NP cell culture and an intervertebral disc (IVD) organ culture model to examine the inhibitory effects of cordycepin on lipopolysaccharide (LPS)-induced gene expression and the production of matrix degradation enzymes (MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5) and oxidative stress-associated factors (nitric oxide and PGE2). We found a protective effect of cordycepin on NP cells and IVDs against LPS-induced matrix degradation and macrophage infiltration. In addition, western blot and luciferase assay results demonstrated that pretreatment with cordycepin significantly suppressed the LPS-induced activation of the NF-κB pathway. Taken together, the results of our research suggest that cordycepin could exert anti-inflammatory and anti-degenerative effects on NP cells and IVDs by inhibiting the activation of the NF-κB pathway. Therefore, cordycepin may be a potential treatment for IDD in the future.
Abstract
Background
Osteosarcoma has the highest incidence among bone malignant tumors and mainly occurs in adolescents and the elderly, but the pathological mechanism is still unclear, which makes ...early diagnosis and treatment very difficult. Bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the sources of osteosarcoma cells. Therefore, a full understanding of the gene expression differences between BMSCs and osteosarcoma cells is very important to explore the pathogenesis of osteosarcoma and facilitate the early diagnosis and treatment of osteosarcoma. Small noncoding RNAs (sncRNAs) are a class of RNAs that do not encode proteins but directly play biological functions at the RNA level. SncRNAs mainly include Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), repeat RNAs and microRNAs (miRNAs).
Methods
In this study, we compared the expression of sncRNAs in BMSCs and osteosarcoma cells by high-throughput sequencing and qPCR and looked for differentially expressed sncRNAs. CCK-8, clone formation and transwell assay were used to detect the effect of sncRNA in MG63 cells.
Results
We found that 66 piRNAs were significantly upregulated and 70 piRNAs were significantly downregulated in MG63 cells. As for snoRNAs, 71 snoRNAs were significantly upregulated and 117 snoRNAs were significantly downregulated in MG63 cells. As for snRNAs, 35 snRNAs were significantly upregulated and 17 snRNAs were significantly downregulated in MG63 cells. As for repeat RNAs, 6 repeat RNAs were significantly upregulated and 7 repeat RNAs were significantly downregulated in MG63 cells. As for miRNAs, 326 miRNAs were significantly upregulated and 281 miRNAs were significantly downregulated in MG63 cells. Overexpression of piRNA DQ596225, snoRNA ENST00000364830.2, snRNA ENST00000410533.1 and miRNA hsa-miR-369-5p inhibited the proliferation and migration of MG63 cells.
Conclusions
Our results provide a theoretical basis for the pathogenesis, early diagnosis and treatment of osteosarcoma.
Post-operative infections in orthopaedic implants are severe complications that require urgent solutions. Although conventional antibiotics limit bacterial biofilm formation, they ignore the bone ...loss caused by osteoclast formation during post-operative orthopaedic implant-related infections. Fortunately, enoxacin exerts both antibacterial and osteoclast inhibitory effects, playing a role in limiting infection and preventing bone loss. However, enoxacin lacks specificity in bone tissue and low bioavailability-related adverse effects, which hinders translational practice. Here, we developed a nanosystem (Eno@MSN-D) based on enoxacin (Eno)-loaded mesoporous silica nanoparticles (MSN), decorated with the eight repeating sequences of aspartate (D-Asp8), and coated with polyethylene glycol The release results suggested that Eno@MSN-D exhibits a high sensitivity to acidic environment. Moreover, this Eno@MSN-D delivery nanosystem exhibited both antibacterial and anti-osteoclast properties
in vitro
. The cytotoxicity assay revealed no cytotoxicity at the low concentration (20 μg/ml) and Eno@MSN-D inhibited RANKL-induced osteoclast differentiation. Importantly, Eno@MSN-D allowed the targeted release of enoxacin in infected bone tissue. Bone morphometric analysis and histopathology assays demonstrated that Eno@MSN-D has antibacterial and antiosteoclastic effects
in vivo
, thereby preventing implant-related infections and bone loss. Overall, our study highlights the significance of novel biomaterials that offer new alternatives to treat and prevent orthopaedic Staphylococcus aureus-related implantation infections and bone loss.
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