A structured biomimetic nanoparticle as inflammatory factor sponge and autophagy-regulatory agent against intervertebral disc degeneration and discogenic pain.

Lower back pain (LBP) is a common condition closely associated with intervertebral disc degeneration (IDD), causing a significant socioeconomic burden. Inflammatory activation in degenerated discs involves pro-inflammatory cytokines, dysregulated regulatory cytokines, and increased levels of nerve growth factor (NGF), leading to further intervertebral disc destruction and pain sensitization. Macrophage polarization is closely related to autophagy. Based on these pathological features, a structured biomimetic nanoparticle coated with TrkA-overexpressing macrophage membranes (TMNP@SR) with a rapamycin-loaded mesoporous silica core is developed. TMNP@SR acted like sponges to adsorbe inflammatory cytokines and NGF and delivers the autophagy regulator rapamycin (RAPA) into macrophages through homologous targeting effects of the outer engineered cell membrane. By regulating autophagy activation, TMNP@SR promoted the M1-to-M2 switch of macrophages to avoid continuous activation of inflammation within the degenerated disc, which prevented the apoptosis of nucleus pulposus cells. In addition, TMNP@SR relieved mechanical and thermal hyperalgesia, reduced calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat IDD model. In summary, TMNP@SR spontaneously inhibits the aggravation of disc inflammation to alleviate disc degeneration and reduce the ingress of sensory nerves, presenting a promising treatment strategy for LBP induced by disc degeneration.

Identification of key genes involved in collagen hydrogel-induced chondrogenic differentiation of mesenchymal stem cells through transcriptome analysis: the role of m6A modification.

Collagen hydrogel has been shown promise as an inducer for chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), contributing to the repair of cartilage defects. However, the precise molecular mechanism underlying this phenomenon remains poorly elucidated. Here, we induced chondrogenic differentiation of BMSCs using collagen hydrogel and identified 4451 differentially expressed genes (DEGs) through transcriptomic sequencing. Our analysis revealed that DEGs were enriched in the focal adhesion pathway, with a notable decrease in expression levels in the collagen hydrogel group compared to the control group. Protein-protein interaction network analysis suggested that actinin alpha 1 (ACTN1) and actinin alpha 4 (ACTN4), two proteins also involved in cytoskeletal recombination, may be crucial in collagen hydrogel-induced chondrogenic differentiation of BMSCs. Additionally, we found that N6-methyladenosine RNA methylation (m6A) modification was involved in collagen hydrogel-mediated chondrogenic differentiation, with fat mass and obesity-associated protein (FTO) implicated in regulating the expression of ACTN1 and ACTN4. These findings suggest that collagen hydrogel might regulate focal adhesion and actin cytoskeletal signaling pathways through down-regulation of ACTN1 and ACTN4 mRNA via FTO-mediated m6A modification, ultimately driving chondrogenic differentiation of BMSCs. In conclusion, our study provides valuable insights into the molecular mechanisms of collagen hydrogel-induced chondrogenic differentiation of BMSCs, which may aid in developing more effective strategies for cartilage regeneration.

Efficient and Durable Oxidation Removal of Formaldehyde over Layered Double Hydroxide Catalysts at Room Temperature.

Room temperature catalytic oxidation (RTCO) using non-noble metals has emerged as a highly promising technique for removal of formaldehyde (HCHO) under ambient conditions; however, non-noble catalysts still face the challenges related to poor water resistance and low stability under harsh conditions. In this study, we synthesized a series of layered double hydroxides (LDHs) incorporating various dual metals (MgAl, ZnAl, NiAl, NiFe, and NiTi) for formaldehyde oxidation at ambient temperature. Among the synthesized catalysts, the NiTi-LDH catalyst showed an HCHO removal efficiency and CO2 yield close to 100.0%, and exceptional water resistance and chemical stability on running 1300 min. The abundant hydroxyl groups in LDHs directly bonded with HCHO, leading to the production of CO2 and H2O, thus inhibiting the formation of CO, even in the absence of O2 and H2O. The coexistence of O2 effectively reduced the reaction barrier for H2O molecule dissociation, facilitating the formation of hydroxyl groups and their subsequent backfill on the catalyst surface. The mechanisms underlying the involvement and regeneration of hydroxyl groups in room temperature oxidation of formaldehyde were elucidated with the combined in situ DRIFTS, HCHO-TPD-MS, and DFT calculations. This work not only demonstrates the potential of LDH catalysts in environmental applications but also advances the understanding of the fundamental processes involved in room temperature oxidation of formaldehyde.

An Engineered Bionic Nanoparticle Sponge as a Cytokine Trap and Reactive Oxygen Species Scavenger to Relieve Disc Degeneration and Discogenic Pain.

The progressive worsening of disc degeneration and related nonspecific back pain are prominent clinical issues that cause a tremendous economic burden. Activation of reactive oxygen species (ROS) related inflammation is a primary pathophysiologic change in degenerative disc lesions. This pathological state is associated with M1 macrophages, apoptosis of nucleus pulposus cells (NPC), and the ingrowth of pain-related sensory nerves. To address the pathological issues of disc degeneration and discogenic pain, we developed MnO2@TMNP, a nanomaterial that encapsulated MnO2 nanoparticles with a TrkA-overexpressed macrophage cell membrane (TMNP). Consequently, this engineered nanomaterial showed high efficiency in binding various inflammatory factors and nerve growth factors, which inhibited inflammation-induced NPC apoptosis, matrix degradation, and nerve ingrowth. Furthermore, the macrophage cell membrane provided specific targeting to macrophages for the delivery of MnO2 nanoparticles. MnO2 nanoparticles in macrophages effectively scavenged intracellular ROS and prevented M1 polarization. Supportively, we found that MnO2@TMNP prevented disc inflammation and promoted matrix regeneration, leading to downregulated disc degenerative grades in the rat injured disc model. Both mechanical and thermal hyperalgesia were alleviated by MnO2@TMNP, which was attributed to the reduced calcitonin gene-related peptide (CGRP) and substance P expression in the dorsal root ganglion and the downregulated Glial Fibrillary Acidic Protein (GFAP) and Fos Proto-Oncogene (c-FOS) signaling in the spinal cord. We confirmed that the MnO2@TMNP nanomaterial alleviated the inflammatory immune microenvironment of intervertebral discs and the progression of disc degeneration, resulting in relieved discogenic pain.

Hsa_circ_0007031 promotes the proliferation and migration of osteosarcoma cells by sponging miR-196a-5p to regulate the HOXB6.

Circular RNAs (circRNAs), a subclass of noncoding RNAs, have been demonstrated to play an essential role in osteosarcoma (OS) development. However, there is still a significant gap in investigating its biological functions and underlying molecular mechanisms, and novel targets of circRNAs have yet to be fully explored. Herein, we found that hsa_circ_0007031 is noticeably raised in OS clinical tissues and cell lines. Hsa_circ_0007031 accelerates OS cell proliferation and migration in vitro and tumor growth and metastasis in vivo and is strongly linked with the stemness of cancer stem cells in OS. Mechanistically, hsa_circ_0007031 shares miRNA response elements with Homeobox B6 (HOXB6), which is identified as a novel pro-tumorigenic gene of OS. Hsa_circ_0007031 competitively binds to miR-196a-5p to prevent miR-196a-5p from lowering the level of HOXB6, which modulates chemokines of cytokine-cytokine receptor interaction signaling pathway and finally promotes OS malignant behavior. In summary, our data unveiled that hsa_circ_0007031/miR-196a-5p/HOXB6 axis-mediated cytokine-cytokine receptor interaction facilitates the progression of OS and maintains the properties of tumor stem cells, which could be a promising therapeutic target for OS.

Extracellular Vesicle-Conjugated Functional Matrix Hydrogels Prevent Senescence by Exosomal miR-3594-5p-Targeted HIPK2/p53 Pathway for Disc Regeneration.

Nucleus pulposus stem cells (NPSCs) senescence plays a critical role in the progression of intervertebral disc degeneration (IDD). Stem cell-derived extracellular vesicles (EV) alleviate cellular senescence. Whereas, the underlying mechanism remains unclear. Low stability largely limited the administration of EV in vivo. RGD, an arginine-glycine-aspartic acid tripeptide, strongly binds integrins expressed on the EV membranes, allowing RGD to anchor EV and prolong their bioavailability. An RGD-complexed nucleus pulposus matrix hydrogel (RGD-DNP) is developed to enhance the therapeutic effects of small EV (sEV). RGD-DNP prolonged sEV retention in vitro and ex vivo. sEV-RGD-DNP promoted NPSCs migration, decreased the number of SA-ß-gal-positive cells, alleviated cell cycle arrest, and reduced p16, p21, and p53 activation. Small RNA-seq showed that miR-3594-5p is enriched in sEV, and targets the homeodomain-interacting protein kinase 2 (HIPK2)/p53 pathway. The HIPK2 knockdown rescues the impaired therapeutic effects of sEV with downregulated miR-3594-5p. RGD-DNP conjugate with lower amounts of sEV achieved similar disc regeneration with free sEV of higher concentrations in DNP. In conclusion, sEV-RGD-DNP increases sEV bioavailability and relieves NPSCs senescence by targeting the HIPK2/p53 pathway, thereby alleviating IDD. This work achieves better regenerative effects with fewer sEV and consolidates the theoretical basis for sEV application for IDD treatment.

Animal models of cancer metastasis to the bone.

Cancer metastasis is a major cause of mortality from several tumors, including those of the breast, prostate, and the thyroid gland. Since bone tissue is one of the most common sites of metastasis, the treatment of bone metastases is crucial for the cure of cancer. Hence, disease models must be developed to understand the process of bone metastasis in order to devise therapies for it. Several translational models of different bone metastatic tumors have been developed, including animal models, cell line injection models, bone implant models, and patient-derived xenograft models. However, a compendium on different bone metastatic cancers is currently not available. Here, we have compiled several animal models derived from current experiments on bone metastasis, mostly involving breast and prostate cancer, to improve the development of preclinical models and promote the treatment of bone metastasis.

Identification of Candidate MicroRNA-mRNA Subnetwork for Predicting the Osteosarcoma Progression by Bioinformatics Analysis.

Osteosarcoma (OS) is the pretty common primary cancer of the bone among the malignancies in adolescents. A single molecular component or a limited number of molecules is insufficient as a predictive biomarker of OS progression. Hence, it is necessary to find novel network biomarkers to improve the prediction and therapeutic effect for OS. Here, we identified 230 DE-miRNAs and 821 DE-mRNAs through two miRNA expression-profiling datasets and three mRNA expression-profiling datasets. We found that hsa-miR-494 is closely linked with the survival of OS patients. In addition, we analyzed GO and KEGG enrichment for targets of hsa-miR-494-5p and hsa-miR-494-3p through R programming. And five mRNAs were predicted as common targets of hsa-miR-494-5p and hsa-miR-494-3p. We further revealed that upregulated TRPS1 was strongly correlated with poor outcomes in OS patients through the survival analysis based on the TARGET database. The qRT-PCR study verified that the expression of hsa-miR-494-5p and hsa-miR-494-3p was declined considerably, while TRPS1 was notably raised in OS cells when compared to the osteoblasts. Thus, we generated a new regulatory subnetwork of key miRNAs and target mRNAs using Cytoscape software. These results indicate that the novel miRNA-mRNA subnetwork composed of hsa-miR-494-5p, hsa-miR-494-3p, and TRPS1 might be a characteristic molecule for assessing the prognostic value of OS patients.

Metal-organic framework derived carbon-supported bimetallic copper-nickel alloy electrocatalysts for highly selective nitrate reduction to ammonia.

Developing electrocatalysts for efficient reduction of nitrate contaminant to value-added ammonia as energy carrier is a pivotal part for restoring the nitrogen cycle. However, the selectivity of ammonia is far from satisfaction, often suffering from accumulation of toxic nitrite byproduct. Herein, a series of CuNi alloy nanoparticles embedded in nitrogen-doped carbon matrix (CuNi/NC) with hierarchical pores were fabricated by pyrolysis of bimetallic metal-organic frameworks (MOFs). The catalysts exhibited excellent selectivity (94.4%) and faradaic efficiency (79.6%) for nitrate reduction to ammonia, greatly outperforming the performance of monometallic Cu/NC (selectivity of 60.8% and faradaic efficiency of 60.6%). Impressively, the introduction of nickel distinctly suppressed the production of toxic byproduct of nitrite. Online differential electrochemical mass spectrometry (DEMS) and in situ surface-enhanced infrared absorption spectroscopy (SEIRAS) tests were utilized to reveal the key intermediates and the reaction pathway. Density functional theory (DFT) calculations demonstrated that the introducing of nickel into copper lattice modified both the electronic and geometric structures of the catalysts. The copper and nickel sites in the CuNi alloy catalysts operate synergistically to facilitate the hydrogenation of NO2* to HNO2* and suppress the hydrogen evolution reaction, boosting the selective formation of ammonia. This work could provide a new synthetic route for bimetallic catalysts and mechanistic understanding for nitrate to ammonia reaction.

Analysis and identification of m6A RNA methylation regulators in metastatic osteosarcoma.

Osteosarcoma (OS) is characterized by rapid growth and early metastasis. However, its mechanism remains unclear. N6-methyladenosine (m6A) modification and its regulatory factors play essential roles in most cancers, including OS. In this study, we screened out 21 m6A modifiers using the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, followed by the identification of the critical m6A methylation modifiers. The results revealed that the expression levels of three m6A methylation regulators, namely RBM15, METTL3, and LRPPRC, were associated with the low survival rate of patients with OS. We further studied the independent prognostic factors by performing univariate and multivariate Cox analyses and found that metastasis was an independent prognostic factor for patients with OS. Furthermore, we found for the first time that RBM15 was specific for metastatic OS rather than non-metastatic OS. Moreover, the significant overexpression of RBM15 was validated in metastatic OS cell lines and in actual human clinical specimens. We also revealed that RBM15 promoted the invasion, migration, and metastasis of OS cells through loss-functional and gain-functional experiments and an animal metastatic model. In conclusion, RBM15 has a high correlation with OS metastasis formation and the decreased survival rate of patients with OS, and this may serve as a useful biomarker for predicting metastasis and prognosis of patients with OS.

Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages.

Osteoarthritis (OA) is a degenerative illness that greatly impacts the life quality of patients. Currently, the therapeutic approaches for OA are very limited in clinical. The extracellular vesicles (EVs) derived from different mesenchymal stem cells displayed a prominent therapeutic effect on OA. But most EVs have limited resources and the risks of host rejection, immunological response, and etc. Human umbilical cord mesenchymal stem cells (hUCMSCs) hold the advantages of easy availability, minimal immune rejection, and excellent immunomodulatory effects, although hUCMSCs-EVs have seldom been applied in OA. Herein, we investigated the potential immunomodulatory and anti-inflammatory effects of hUCMSCs-EVs on the treatment of OA. In our results, the treatment of hUCMSCs-EVs promoted the polarization of M2-type macrophages and the expression of anti-inflammation-related cytokines (IL-10). Notably, the supernate of M2 macrophages induced by hUCMSCs-EVs inhibited the level of inflammation-associated factors in OA chondrocytes caused by IL-1ß. Further, injection of hUCMSCs-EVs in the articular lumen ameliorated progression of OA and exerted chondroprotective potential based on the OA joint model created by the surgical transection of the anterior cruciate ligament (ACLT). In addition, we found five highly enriched miRNAs in hUCMSCs-EVs, including has-miR-122-5p, has-miR-148a-3p, has-miR-486-5p, has-miR-let-7a-5p, and has-miR-100-5p by High-throughput sequencing of miRNAs, with targeted genes mainly enriched in the PI3K-Akt signaling pathway. Furthermore, we also detected the protein abundance of hUCMSCs-EVs using liquidation chromatography with tandem quadrupole mass spectrometry (LC-MS/MS) analysis. Thus, our study indicates that hUCMSCs-EVs can alleviate cartilage degradation during the OA progression, mechanically may through delivering key proteins and modulating the PI3K-Akt signaling pathway mediated by miRNAs to promote polarization of M2 macrophage, exhibiting potent immunomodulatory potential. The current findings suggest that hUCMSCs-EVs might serve as a new reagent for the therapy of OA.

Identification of deactivation-resistant origin of In(OH)3 for efficient and durable photodegradation of benzene, toluene and their mixtures.

Aromatic hydrocarbon is a representative type of VOCs, which causes adverse effects to human health. The degradation stability of aromatic hydrocarbon is of vital importance to commercializing a photocatalyst for its practical application. The most commonly used titanium dioxide photocatalyst (P25) was deactivated rapidly in the photocatalytic VOCs degradation process. In this work, the indium hydroxide (In(OH)3) photocatalyst was developed, which exhibited not only higher efficient activity but also ultra-stable stability for degradation of benzene, toluene and their mixtures. The origin of the activity difference between two catalysts was investigated by combined experimental and theoretical ways. Based on in situ DRIFTS and GC-MS, it was revealed that benzoic acid and carbonaceous byproducts were specifically formed and accumulated on P25, which were responsible for deactivation of photocatalyst. In contrast, as revealed by both DFT calculations and experimental results, the reaction pathway with byproducts blocking the active sites can be thermodynamically avoided on In(OH)3. This rendered high durability to In(OH)3 photocatalyst in degradations of aromatic pollutants. The elucidation of deactivation-resistant effect and reaction mechanism as an ideal photocatalyst for practical usage were provided.

Prognostic Implications of the Complement Protein C1Q and Its Correlation with Immune Infiltrates in Osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most widespread bone tumour among childhood cancers, and distant metastasis is the dominant factor in poor prognosis for patients with OS. Therefore, it is necessary to identify new prognostic biomarkers for identifying patients with aggressive disease. METHODS: Two OS datasets (GSE21257 and GSE33383) were downloaded from the Gene Expression Omnibus (GEO) and subsequently subjected to weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (DGE) to screen candidate genes. A prognostic model was constructed using OS data derived from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program to further screen key genes and perform gene ontology (GO) analysis. The prognostic values of key genes were assessed using the Kaplan-Meier (KM) plotter. The GEO dataset was used for immune infiltration analysis and association analysis of key genes. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the expression levels of potentially crucial genes in OS cell lines. RESULTS: In the present study, we found 114 genes with a highly significant correlation in the module and 44 downregulated genes; 25 candidate genes overlapped in the two parts of the genes. Among these, three key genes, C1QA, C1QB, and C1QC, were the most significant hub genes, which had the highest node degrees, were clustered into one group, and implicated in most significant biological processes (regulation of immune effector process). Moreover, these three key genes were negatively associated with the prognosis of OS and positively associated with three immune cells (follicular helper T cells, memory B cells, and CD8 T cells). Additionally, compared to non-metastatic OS cell lines, the expression of three key genes was significantly downregulated in metastatic OS cell lines. CONCLUSION: Our results revealed that three key genes (C1QA, C1QB, and C1QC) were implicated in tumour immune infiltration and may be promising biomarkers for predicting metastasis and prognosis of patients with OS.