Abstract Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)‐activated NF‐κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l ‐tetrahydropalmatine ( l ‐THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l ‐THP inhibited osteoclastic differentiation at the early stage, down‐regulated transcription level of osteoclastogenesis‐related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l ‐THP inhibited the phosphorylation of P50, P65, IκB, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF‐κB was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co‐immunoprecipitation indicated that l ‐THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l ‐THP significantly inhibited ovariectomy‐induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l ‐THP suppressed osteoclastogenesis by blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways. l ‐THP is a promising agent for treating osteoclastogenesis‐related diseases such as post‐menopausal osteoporosis.
Aim: To investigate the biological fate of cuprous oxide nanoparticles (Cu2O-NPs) and to evaluate their potential in uveal melanoma therapy. Materials & methods: The protein corona, cellular uptake mechanism and localization of Cu2O-NPs were investigated. Furthermore, the effect of Cu2O-NPs on uveal melanoma cell proliferation, migration and invasion, and possible mechanisms were studied in detail. Results: Cu2O-NPs are able to adsorb serum proteins in cell culture medium, which are then internalized by uveal melanoma cells mainly through lipid raft-mediated endocytosis. Furthermore, Cu2O-NPs selectively inhibit cancer cell growth and impair the ability of uveal melanoma cell migration, invasion and the cytoskeleton assembly. The mechanism may be that Cu2O-NPs located in and damage mitochondria, autophagolysosomes and lysosomes, leading to elevated reactive oxygen species level and over-stimulated apoptosis and autophagy. Conclusion: The data provide detailed information of Cu2O-NPs for further application and indicate that Cu2O-NPs could be a potential agent for uveal melanoma therapy.
Exosomes are nanosized extracellular vesicles which are emerging as novel therapeutic nanoparticles. This paper reports a novel concept of engineering exosomes using nanomaterial inside the vascular endothelial cells (ECs). Gold nanorods (GNRs) could inhibit EC division and internalized GNRs located in endosomes of binucleated ECs. The GNRs could alter the composition of bioactive molecules loaded in exosomes. The engineered EC‐derived exosomes could inhibit tumor cell proliferation, migration, and invasion in vitro and suppress tumor growth in vivo. miRNA sequencing showed that the engineered exosomes contained various miRNAs that could disrupt the TGF β pathway. Further data suggested that the engineered exosomes could suppress the expression of TGF β 1 and TGF β 2, thus inhibiting the activation of SMAD2 and SMAD3. These data highlighted the therapeutic potential of engineering exosomes using nanomaterials.
Less apoptosis and excessive growth of fibroblasts contribute to the progression of hypertrophic scar formation. Cuprous oxide nanoparticles (CONPs) could have not only inhibited tumor by inducing apoptosis and inhibiting proliferation of tumor cells, but also promoted wound healing. The objective of this study was to further explore the therapeutic effects of CONPs on hypertrophic scar formation in vivo and in vitro.In vivo, a rabbit ear scar model was established on New Zealand albino rabbits. Six full-thickness and circular wounds (10 mm diameter) were made to each ear. Following complete re-epithelization observed on postoperative day 14, an intralesional injection of CONPs or 5% glucose solution was conducted to the wounds. The photo and ultrasonography of each wound were taken every week and scars were harvested on day 35 for further histomorphometric analysis. In vitro, the role of CONPs in human hypertrophic scar fibroblasts (HSFs) apoptosis and proliferation were evaluated by Tunnel assay, Annexin V/PI staining, cell cycle analysis, and EdU proliferation assay. The endocytosis of CONPs by fibroblasts were detected through transmission electron microscopy (TEM) and the mitochondrial membrane potential and ROS production were also detected.In vivo, intralesional injections of CONPs could significantly improve the scar appearance and collagen arrangement, and decreased scar elevation index (SEI). In vitro, CONPs could prominently inhibit proliferation and induce apoptosis in HSFs in a concentration-dependent manner. In addition, CONPs could be endocytosed into mitochondria，damage the mitochondrial membrane potential and increase ROS production.CONPs possessed the therapeutic potential in the treatment of hypertrophic scar by inhibiting HSFs proliferation and inducing HSFs apoptosis.
Abstract Alumina is one of the most common and stable metal oxides in nature, which has been developed as a novel adsorbent in enrichment of biomolecules due to its excellent affinity to phosphor or amino groups. In this study, ordered mesoporous alumina (OMA) with interconnected mesopores and surface acidic property is synthesized through a solvent evaporation induced co‐assembly process using poly(ethylene oxide)‐ b ‐polystyrene (PEO‐ b ‐PS) diblock copolymer as a template and aluminium acetylacetonate (Al(acac) 3 ) as the aluminium source. The pore size (12.1–19.7 nm), pore window size (3.5–9.0 nm) and surface acidity (0.092–0.165 mmol g −1 ) can be precisely adjusted. The highly porous structure endows the OMA materials with high hemoglobin (Hb) immobilization capacity (170 mg g −1 ). The obtained Hb@OMA composite is used as an electrocatalyst of biosensor for convienet and fast detection of hydrogen peroxide (H 2 O 2 ) with a low H 2 O 2 detection limit of 1.7 × 10 −8 m and a wide linear range of 2.5 × 10 −8 to 5.0 × 10 −5 m . Moreover, the Hb@OMA sensors show a good performance in real time detection of H 2 O 2 released from Homo sapiens bone osteosarcoma, indicating their potential application in complex biological processes.
AbstractBackground: Copper oxide nanoparticles (CuO NPs) have demonstrated versatile applications in antitumor and antibacterial contexts, however, their potential as an anti- angiogenesis agent remains unexplored. This study aims to comprehensively investigate the efficacy of CuO NPs in the treatment of pathological angiogenic retinopathy. Results We demonstrated that CuO NPs possess nano-sized dimensions and exhibit well biocompatibility. In vitro experiments revealed that CuO NPs impede the proliferation, tube formation, migration, and sprouting of HUVECs dose-dependently. Subsequently, in vivo findings showed that CuO NPs effectively suppressed the development of retinal vasculature in a mouse model, as well as alleviate pathological retinal angiogenesis in an oxygen-induced retinopathy (OIR) model. Furthermore, RNA-seq and metabolomic analysis revealed that CuO NPs disrupt the tricarboxylic acid (TCA) cycle and induce cuproptosis. These results were further supported by the evaluation of metabolites and the expression of cuproptosis-related proteins. Conclusions The CuO NPs exhibit potential as effective anti-angiogenic platforms for the treatment of pathological retinal angiogenesis.
Abstract Pathological retinal neovascularization (RNV) is one of the leading causes of blindness worldwide; however, its underlying mechanism remains unclear. Here, we found that the expression of endothelial protein C receptor (EPCR) was increased during RNV, and its ligand was elevated in the serum or vitreous body of patients with proliferative diabetic retinopathy. Deleting endothelial Epcr or using an EPCR neutralizing antibody ameliorated pathological retinal angiogenesis. EPCR promoted endothelial heme catabolism and carbon monoxide release through heme oxygenase 1 (HO-1). Inhibition of heme catabolism by deleting of endothelial Ho-1or using an HO-1 inhibitor suppressed pathological angiogenesis in retinopathy. Conversely, supplementation with CO rescued the angiogenic defects after endothelial Epcr or Ho-1 deletion. Our results identified EPCR-dependent endothelial heme catabolism as an important contributor to pathological angiogenesis, which may serve as a potential target for treating vasoproliferative retinopathy.
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