CircCOX6A1 suppresses osteogenic differentiation and aggravates osteoporosis via miR-512-3p/DYRK2 axis.

BACKGROUND: Osteoporosis (OP), characterized by compromised bone integrity and increased fracture risk, poses a significant health challenge. Circular RNAs (circRNAs) have emerged as crucial regulators in various pathophysiological processes, prompting investigation into their role in osteoporosis. This study aimed to elucidate the involvement of circCOX6A1 in OP progression and understand its underlying molecular mechanisms. The primary objective was to explore the impact of circCOX6A1 on bone marrow-derived mesenchymal stem cells (BMSCs) and its potential interactions with miR-512-3p and DYRK2. METHODS: GSE161361 microarray analysis was employed to assess circCOX6A1 expression in OP patients. We utilized in vitro and in vivo models, including BMSC cultures, osteogenic differentiation assays, and an OVX-induced mouse model of OP. Molecular techniques such as quantitative RT-PCR, western blotting, and functional assays like alizarin red staining (ARS) were employed to evaluate circCOX6A1 effects on BMSC proliferation, apoptosis, and osteogenic differentiation. The interaction between circCOX6A1, miR-512-3p, and DYRK2 was investigated through dual luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down assays. RESULTS: CircCOX6A1 was found to be upregulated in osteoporosis patients, and its expression inversely correlated with osteogenic differentiation of BMSCs. CircCOX6A1 knockdown enhanced osteogenic differentiation, as evidenced by increased mineralized nodule formation and upregulation of osteogenic markers. In vivo, circCOX6A1 knockdown ameliorated osteoporosis progression in OVX mice. Mechanistically, circCOX6A1 acted as a sponge for miR-512-3p, subsequently regulating DYRK2 expression. CONCLUSION: This study provides compelling evidence for the role of circCOX6A1 in osteoporosis pathogenesis. CircCOX6A1 negatively regulates BMSC osteogenic differentiation through the miR-512-3p/DYRK2 axis, suggesting its potential as a therapeutic target for mitigating OP progression.

Molecular characterization of Golgi apparatus-related genes indicates prognosis and immune infiltration in osteosarcoma.

BACKGROUND: The Golgi apparatus (GA) is crucial for protein synthesis and modification, and regulates various cellular processes. Dysregulation of GA can lead to pathological conditions like neoplastic growth. GA-related genes (GARGs) mutations are commonly found in cancer, contributing to tumor metastasis. However, the expression and prognostic significance of GARGs in osteosarcoma are yet to be understood. METHODS: Gene expression and clinical data of osteosarcoma patients were obtained from the TARGET and GEO databases. A consensus clustering analysis identified distinct molecular subtypes based on GARGs. Discrepancies in biological processes and immunological features among the subtypes were explored using GSVA, ssGSEA, and Metascape analysis. A GARGs signature was constructed using Cox regression. The prognostic value of the GARGs signature in osteosarcoma was evaluated using Kaplan-Meier curves and a nomogram. RESULTS: Two GARG subtypes were identified, with Cluster A showing better prognosis, immunogenicity, and immune cell infiltration than Cluster B. A novel risk model of 3 GARGs was established using the TARGET dataset and validated with independent datasets. High-risk patients had poorer overall survival, and the GARGs signature independently predicted osteosarcoma prognosis. Combining risk scores and clinical characteristics in a nomogram improved prediction performance. Additionally, we discovered Stanniocalcin-2 (STC2) as a significant prognostic gene highly expressed in osteosarcoma and potential disease biomarker. CONCLUSIONS: Our study revealed that patients with osteosarcoma can be divided into two GARGs subgroups. Furthermore, we have developed a GARGs prognostic signature that can accurately forecast the prognosis of osteosarcoma patients.

Fenton-like Reaction Inspired "·OH Catalyzed" Osteogenic Process for the Treatment of Osteoporosis.

Inspired by the Fenton-like reaction, this work combines copper peroxide (CP) nanoparticles with black phosphorus (BP) nanosheets to form a hydroxyl radical (·OH)-centered "catalytic" osteogenic system. CP-produced ·OH interacts with BP to rapidly produce a large amount of phosphate ions, thus accelerating self-mineralization and promoting bone formation. In turn, BP not only exerts anti-inflammatory effects, thereby providing a favorable microenvironment for bone formation, but also offsets the potential toxicity of CP induced by reactive oxygen species (ROS). Together with copper ions (Cu2+), phosphate ions are also released as a byproduct of this process, which can contribute to the comprehensive promotion of osteogenesis.

Role of LINC00240 on T-helper 9 differentiation in allergic rhinitis through influencing DNMT1-dependent methylation of PU.1.

BACKGROUND: Allergic rhinitis (AR) is a common allergic disease with increasing prevalence globally. However, the molecular mechanism underlying AR pathogenesis remains largely undefined. METHODS: Peripheral blood and nasal mucosa samples obtained from patients with AR (n = 22), and ovalbumin-induced AR mouse model (n = 8 per group) were prepared for subsequent detection. qRT-PCR and western blot were used to detect the expression of LINC00240, miR-155-5p, PU.1 and other key molecules. ELISA assay and flow cytometry were employed to evaluate the secretion of IL-9 and T-helper 9 (Th9) cell ratio, respectively. Bioinformatics analysis, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and luciferase reporter assays were employed to further elucidate the regulatory network of LINC00240/miR-155-5p/DNMT1. The methylation of PU.1 promoter was assessed by methylation-specific PCR (MSP). This signaling axis was further validated in the mouse model of AR. RESULTS: LINC00240 was downregulated, while miR-155-5p and PU.1 were upregulated in the peripheral blood and nasal mucosa of AR patients, as well as in AR mice. This was accompanied with the increased ratio of Th9 cells and elevated IL-9 secretion. Mechanistically, LINC00240 served as a miR-155-5p sponge, and DNMT1 was a target of miR-155-5p. In addition, DNMT1 mediated the methylation of PU.1 promoter. In vivo studies verified that LINC00240 mitigated AR progression, possibly via miR-155-5p/DNMT1/PU.1-dependent Th9 differentiation. CONCLUSION: The involvement of LINC00240 in AR pathogenesis is closely associated with Th9 differentiation through modulating DNMT1-dependent methylation of PU.1 by sponging miR-155-5p.

Unilateral Biportal Endoscopic Discectomy versus Percutaneous Endoscopic Lumbar Discectomy for Lumbar Disc Herniation: A Systematic Review and Meta-analysis.

BACKGROUND: Unilateral biportal endoscopic discectomy (UBED) is a novel and minimally invasive surgery for lumbar disc herniation (LDH). However, efficacy and safety of UBED compared to the conventional percutaneous endoscopic lumbar discectomy (PELD) remains to be determined. A meta-analysis was performed in this study to compare between UBED and PELD for LDH. METHODS: Relevant cohort studies were found by searching Medline, Web of Science, Embase, Wanfang, and CNKI from database inception to October 13, 2022. Results were pooled using a random-effects model incorporating heterogeneity. RESULTS: In this meta-analysis, 12 studies involving 1175 patients with LDH were included. Pooled results showed that compared with PELD, UBED was associated with a longer surgery time (mean difference [MD] 17.62 min, P < 0.001) and hospital stay (MD 1.40 day, P = 0.04). However, UBED and PELD showed comparative efficacies in improving the Visual Analogue Scale of leg and back, and Oswestry Disability Index, scores. The incidence of perioperative complications was not significantly different between the 2 procedures (risk ratio [RR] 1.62, P = 0.25), while UBED was associated with a lower LDH recurrence during follow-up (RR 0.29, P = 0.03). CONCLUSIONS: Although UBED is associated with longer surgery time and hospital stay, it shows similar efficacy to PELD in relieving pain and improving functional ability in patients with LDH. In addition, limited evidence suggests that UBED may be associated with a lower LDH recurrence as compared to PELD, while the incidence of perioperative complications is not different. These findings support UBED as a treatment for patients with LDH.

Bimetallic Metal-Organic Framework for Mitigating Aseptic Osteolysis.

The disability rate of joint diseases can be reduced by the use of artificial joints, but joint loosening at a late state limits the lifespan and surgical efficacy of the joints. Wear particles can be recognized by macrophages and induce cells to produce reactive oxygen species (ROS) and inflammatory factors, causing persistent inflammation and decreased osteogenic activity, which ultimately leads to loosening of joint prostheses. Here, the platinum (Pt) nanozymes with excellent ROS scavenging and anti-inflammatory capabilities were encapsulated in zinc imidazolium zeolite framework-8 (ZIF-8), and then the osteogenic active element lanthanum (La) was introduced through ion exchange to finally construct a bimetallic metal-organic framework (Pt@ZIF-8@La). In vitro and in vivo experiments demonstrated that this multifunctional nanoplatform possessed the functions of efficient scavenging of ROS, immune regulation, and promotion of osteogenic differentiation. Meanwhile, the mechanism is explored that Pt@ZIF-8@La can also promote osteogenic mineralization by upregulating the ratio of the osteoprotegerin (OPG)/receptor activator of the NF-κB ligand (RANKL), which can achieve a synergistic therapeutic effect of immunomodulation and osteogenesis, thereby realizing the purpose of relieving aseptic osteolysis.

Identification of pyroptosis-related genes and long non-coding RNAs signatures in osteosarcoma.

Osteosarcoma is a highly malignant tumor, with very high disability and fatality rates. However, the overall prognosis is not optimistic. Pyroptosis is a newly discovered cell death modality accompanied by inflammation, which is closely related to varieties of cancers. In this study, the RNA-seq data were downloaded from public databases, the differences in the expression of the pyroptosis-related genes (PRGs) were identified, and the six PRGs signature was established through the univariate and LASSO Cox analysis. The patients were grouped according to the PRGs signature, and the prognosis between the two groups was further compared. In addition, a ten pyroptosis-related lncRNAs (PRLs) prognostic signature was also constructed. Through functional analysis of the differentially expressed genes (DEGs), the immune-related pathways were found to be enriched. The Pearson correlation analysis showed a strong correlation between the pyroptosis-related biomarkers. Finally, we identified a promising biomarker, CHMP4C, which is highly expressed in osteosarcoma. Overexpression of CHMP4C promoted the proliferation, migration and invasion of the osteosarcoma cell. Our results thus provide new evidence for exploring prognostic biomarkers and therapeutic targets of osteosarcoma.

High special surface area and "warm light" responsive ZnO: Synthesis mechanism, application and optimization.

In this study, a new series of zinc oxide (ZnO) with high specific surface area and narrow energy band gap are prepared using a facile microwave-induced method. The corresponding formation mechanism is also discussed for the first time. Due to the introduction of C, these ZnO can be excited by long wave temperature light without harmful short wave radiation, and play an efficient photocatalytic activity. This valuable property fundamentally improves the biological safety of its photocatalytic application. Herein, taking teeth whitening as an example, the photocatalytic performance of ZnO is evaluated. The "pure" yellow light-emitting diode (PYLED) with high biological safety is used as the excitation source. It is found that this method could effectively remove pigment on the tooth surface through physical adsorption. In addition, these ZnO could generate active oxygen to degrade the pigment on the tooth surface under the irradiation of yellow light. Some further optimization of these "warm light" responsive ZnO is also discussed in this systematical study, which could open up new opportunities in biomedical field.

IRF4 transcriptionally activate HOTAIRM1, which in turn regulates IRF4 expression, thereby affecting Th9 cell differentiation and involved in allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is an inflammatory reaction caused by irritation of nasal mucosa by external allergens, which seriously affects the life of patients. Here, we aimed to investigate the effect and mechanism of long non-coding RNA HOX antisense intergenic RNA myeloid 1 (lncRNA HOTAIRM1) on AR development. METHODS: The nasal mucosa samples were collected from AR patients and AR model mice (induced by ovalbumin). T helper type 9 (Th9) cells were examined by flow cytometry. Fluorescence in situ hybridization was conducted to examine the localization of HOTAIRM1 in CD4+ T cells. Dual-luciferase reporter assay or RNA immunoprecipitation was conducted to examine the bond between HOTAIRM1 and miR-148a-3p, miR-148a-3p, and interferon regulatory factor 4 (IRF4). Chromatin Immunoprecipitation assay was conducted to detect the interaction between IRF4 and HOTAIRM1 promoter. RESULTS: HOTAIRM1, interleukin-9 (IL-9), and IRF4 were highly expressed in the AR model. The ratio of Th9 cells was increased in AR mice and overexpressing HOTAIRM1 further promoted Th9 cell differentiation, while the effect was reversed after overexpression of miR-148a-3p. Besides, in vivo experiments showed that interfering with HOTAIRM1 reduced the number of sneezing and rubbing movements, reduced immunoglobulin E (IgE) and IL-9 levels, as well as Th9 cells. HOTAIRM1 was expressed in the cytoplasm and the interactions between HOTAIRM1 and miR-148a-3p, miR-148a-3p and IRF4, were confirmed. Furthermore, IRF4 bound to the HOTAIRM1 promoter and promoted its transcriptional activation. CONCLUSION: HOTAIRM1 was highly expressed in the AR model. Besides, IRF4 activated HOTAIRM1 transcription, and HOTAIRM1, in turn, up-regulated IRF4 expression through competitively binding to miR-148a-3p with IRF4, thereby affecting Th9 cell differentiation and participating in the occurrence and development of AR. Our results suggested that interference with HOTAIRM1 might become a treatment for AR.

Circ_0067835 regulates allergic inflammatory response in type-2 innate lymphoid cells in allergic rhinitis (AR) via miR-155/GATA3.

Allergic rhinitis (AR) is a familiar respiratory allergic inflammatory disease with higher incidence. The pathogenesis of AR is particularly complex. Therefore, a lot of work is acquired to excavate deep mechanisms, thereby providing effective strategies for AR diagnose and treatment. AR mice model was induced by recombinant murine IL-33 (0.05 µg/µl) on days 1, 3, and 5. The lentiviral vectors carrying si-circ_0067835, miR-155 mimic, si-NC or miR-NC were injected into AR mice. Thus, mice were divided into control, AR, AR + si-NC, AR + si-circ_0067835, AR + si-circ_0067835 + miR-NC, and AR + si-circ_0067835 + miR-155 mimic groups. qRT-PCR experiment was used to measure the expression of circ_0067835 and miR-155. Behavioral test result was quantified to assess AR mice model. Hematoxylin and eosin (HE) staining was performed to analyze histopathological changes. Helper T cell 2 (Th2) cytokines (IL-4, IL-5, IL-9 and IL-13) and percentage of type-2 innate lymphoid cells (ILC2s) in nasal mucosa tissues in AR mice model were evaluated needing western blot, ELISA, and flow cytometry. Besides, the targeting relationship between circ_0067835 and miR-155, or between miR-155 and GATA3, was investigated via luciferase report assay. Circ_0067835 expression levels were raised in the nasal mucosa tissues of AR mice. Inhibiting circ_0067835 could reduce Type2 cytokines and ILC2s levels in AR mice model. Furthermore, circ_0067835 targeted and positively regulated miR-155 expression, and GATA3 was a downstream target of miR-155 and adjusted by circ_0067835/miR-155 axis. In addition, silencing circ_0067835 inhibited cytokines and ILC2s levels by down-regulating miR-155. Circ_0067835 effectively inhibited AR response in ILC2s through participation of miR-155/GATA3 axis.

Percutaneous Endoscopic Interlaminar Discectomy via Laminoplasty Technique for L5 -S1 Lumbar Disc Herniation with a Narrow Interlaminar Window.

OBJECTIVE: To improve the treatment effect of patients with L5 S1 lumber disc herniation (LDH) with a narrow interlaminar window, we proposed an alternative approach to percutaneous endoscopic interlaminar discectomy (PEID) via the laminoplasty technique. METHODS: Fifteen L5 S1 LDH patients (7 men and 8 women; age range, 22 to 56 years; median age, 34 years; 9 left, 6 right) were enrolled in the present study retrospectively. The interlaminar windows of all patients were narrow (the transverse diameter of the L5 S1 interlaminar window is equal to or less than that of L4-5 ). Percutaneous laminoplasty and endoscopic interlaminar discectomy surgery were undergone by all patients from July 2018 to July 2019. All operations were completed under local anesthesia. The target laminoplasty area was the safety zone, use of which avoids both transverse and exit nerve roots. Under fluoroscopic guidance or clear endoscopic visualization, the trephines were used to enlarge the interlaminar window, which allowed the working cannula to enter the spinal canal but avoid nerve roots and the dural sac. The preoperative/postoperative visual analogue scale (VAS) scores and Oswestry disability index (ODI) were statistically analyzed. The modified MacNab criterion was used to assess the clinical effects. The radiological outcomes were evaluated by MRI and CT. SPSS 19.0 software was used for the statistical evaluation. RESULTS: The operative time ranged from 70 to 120 min, with a median time of 92 min, and the fluoroscopy times ranged from 8 to 12, with a median of 9.7 times. The body mass index (BMI) of patients ranged from 18.10 to 26.06, with a median of 22.04. All patients were followed up in the outpatient department for at least 12 months after surgery. At the last follow up, the average VAS-Back score of the study patients was reduced from 5.33 ± 2.09 to 2.00 ± 1.20 (P < 0.001) and the average VAS-Leg score was reduced from 7.53 ± 1.69 to 1.47 ± 0.92 (P < 0.001). The average ODI scores improved from 47.87 ± 11.41 to 12.93 ± 3.24 (P < 0.01). According to the modified MacNab criteria, 11 cases achieved excellent results and 4 cases achieved good results. All of the operations were successful. There wertr no nerve root injuries, dural tears, or other complications. CONCLUSION: The laminoplasty approach for PEID provides a safe and useful alternative for the treatment of L5-S1 LDH patients with a narrow interlaminar window.

A magnetically modified black phosphorus nanosheet-based heparin delivery platform for preventing DVT accurately.

A new heparin targeting delivery platform was developed based on iron oxide (Fe3O4) nanoparticles and polyethyleneimine (PEI) functionalized black phosphorus nanosheets (BP NSs). Both in and ex vivo studies suggested that this drug delivery platform (PEI/Fe3O4@BP NSs) possessed high heparin loading capacity (≈450%), accurate magnetic enrichment capacity, and good biocompatibility. With the aid of near-infrared (NIR) laser irradiation, this BP NS based delivery platform could further enhance the photothermal thrombolysis effect. Most importantly, the experiments in vivo confirmed that the proposed PEI/Fe3O4@BP NSs could considerably prolong the effective drug concentration duration of heparin. By which means, accurate, long-acting, and effective thromboprophylaxis could be accomplished with limited drug dosage, which could radically reduce the perniciousness of drug overdose.

3D printed zirconia ceramic hip joint with precise structure and broad-spectrum antibacterial properties.

Background: Nowadays, zirconia ceramic implants are widely used as a kind of hip prosthesis material because of their excellent biocompatibility and long-term wear resistance. However, the hip joint is one of the major joints with complex 3D morphological structure and greatly individual differences, which usually causes great material waste during the process of surgical selection of prosthesis. Methods: In this paper, by combining ceramic 3D printing technology with antibacterial nano-modification, zirconia ceramic implant material was obtained with precise 3D structure and effective antibacterial properties. Among which, two technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. Through in vivo and in vitro experiments, it was confirmed that the as prepared hip prosthesis could precisely matched the corresponding parts, which also exhibited good biocompatibility and impressive antibacterial activities. Results: 1) Two inherent technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. 2) It could be seen that the surface of the ZrO2 material was covered with a layer of ZnO nano-particles. A universal testing machine was used to measure the tensile, bending and compression experiments of ceramic samples. It could be found that the proposed ZnO modification had no significant effect on the mechanical properties of ZrO2 ceramics. 3) According to the plate counting results, ceramics modified with ZnO exhibited significantly higher antibacterial efficiency than pure ZrO2 ceramics, the ZrO2-ZnO ceramics had a significant killing effect 8 hours. 4) The removed implants and the tissue surrounding the implant were subjected to HE staining. For ZrO2-ZnO ceramics, inflammation was slight, while for pure ZrO2 ceramics, the inflammatory response could be seen that the antibacterial rate of the ZrO2-ZnO ceramics was significantly better than that of the pure ZrO2 ceramics group. 5) It could be seen that the cytotoxicity did not increase proportionally with the increase of concentration, all of viability were still above 80%. This suggested that our materials were safe and could be applied as a type of potential biomaterial in the future. 6) Further animal studies demonstrated that the implant was in good position without dislocation. This resulted implied that the proposed method can achieve accurate 3D printing preparation of ceramic joints. In addition, the femurs and surrounding muscles around the implant were then sectioned and HE stained. Results of muscle tissue sections further showed no significant tissue abnormalities, and the growth of new bone tissue was observed in the sections of bone tissue. Conclusion: 1) The ceramic 3D printing technology combined with antibacterial nano-modification can quickly customize the ideal implant material with precise structure, wear-resistant and effective antibacterial properties. 2) Two inherent technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. 3) ZnO nano-materials were modified on the ceramic surface, which could effectively killing pathogenic bacteria.

Cicada and catkin inspired dual biomimetic antibacterial structure for the surface modification of implant material.

Implant infections frequently occur in various kinds of surgery. Apart from antibiotics, the surface modification of implant material is a promising avenue to resolve this global problem. An ideal implant interface is expected to possess good biocompatibility, as well as broad-spectrum and long-term bacterial inhibition capabilities. Here, a delicate cicada and catkin inspired dual biomimetic structure was proposed, for the first time, to improve the antibacterial properties of implant material. By using poly(ether-ether-ketone) (PEEK) as a model implant, the relative in vitro and in vivo evaluations demonstrated that this dual biomimetic structure could simultaneously provide less bacterial adhesion, wider antimicrobial range and longer antibacterial durability. Meanwhile, the modified implant also retained ideal biocompatibility. Most importantly, the relative dual biomimetic structure engineering process could be accomplished through a simple, economic and fast hydrothermal chemical reaction, which might have an impact on the development of future biomedical materials.

ZnO and Hydroxyapatite-Modified Magnesium Implant with a Broad Spectrum of Antibacterial Properties and a Unique Minimally Invasive Defined Degrading Capability.

ZnO and hydroxyapatite-based membranes have been proposed to improve the antibacterial properties and anticorrosion capabilities of the magnesium implant, simultaneously. More importantly, the concept of minimally invasive surgery has been introduced to define the degradation timing of the as-modified magnesium implant. With the aid of a Kirschner wire, the as-prepared membrane could immediately change from the "protective layer" to the "degradation accelerator" of the implant material. The subsequent studies have implied that this membrane could be a promising avenue to create a biocompatible and lightweight implant material with a valuable personal customized degradable timing capability.

Microstructural Orientation and Precise Regeneration: A Proof-of-Concept Study on the Sugar-Cane-Derived Implants with Bone-Mimetic Hierarchical Structure.

It is of great importance to develop a 3D scaffold that matches the bone in aspects of element and structure. In order to achieve this aim, the sugarcane aerogel derived borate glasses scaffolds were developed through in situ bioglass modification. Sol-gel-derived borate glasses of the 30-5B (Si/B ratio) have been prepared to produce 3D borate scaffolds with sugarcane morphologies. As a result, not only the elemental distribution but also the multilevel structure of this Gramineae plant derived implants were remarkably matched with natural bone. The subsequent animal implantation experiment found that the microstructural orientation of the implant had an important impact on the result of bone repair. The relative mechanisms were also discussed for the first time.