Endothelial cell-derived exosomes boost and maintain repair-related phenotypes of Schwann cells via miR199-5p to promote nerve regeneration.

BACKGROUND: Schwann cells (SCs) respond to nerve injury by transforming into the repair-related cell phenotype, which can provide the essential signals and spatial cues to promote axonal regeneration and induce target reinnervation. Endothelial cells (ECs) contribute to intraneural angiogenesis contributing to creating a permissive microenvironment. The coordination between ECs and SCs within injury sites is crucial in the regeneration process, however, it still unclear. As the intercellular vital information mediators in the nervous system, exosomes have been proposed to take a significant role in regulating regeneration. Thus, the main purpose of this study is to determine the facilitative effect of ECs-derived exosomes on SCs and to seek the underlying mechanism. RESULTS: In the present study, we collected exosomes from media of ECs. We demonstrated that exosomes derived from ECs possessed the favorable neuronal affinity both in vitro and in vivo. Further research indicated that EC-exosomes (EC-EXO) could boost and maintain repair-related phenotypes of SCs, thereby enhancing axonal regeneration, myelination of regenerated axons and neurologically functional recovery of the injured nerve. MiRNA sequencing in EXO-treated SCs and control SCs indicated that EC-EXO significantly up-regulated expression of miR199-5p. Furthermore, this study demonstrated that EC-EXO drove the conversion of SC phenotypes in a PI3K/AKT/PTEN-dependent manner. CONCLUSION: In conclusion, our research indicates that the internalization of EC-EXO in SCs can promote nerve regeneration by boosting and maintaining the repair-related phenotypes of SCs. And the mechanism may be relevant to the up-regulated expression of miR199-5p and activation of PI3K/AKT/PTEN signaling pathway.

Novel targeted pH-responsive drug delivery systems based on PEGMA-modified bimetallic Prussian blue analogs for breast cancer chemotherapy.

The development of novel nanoparticle-based drug delivery systems (nano-DDSs) with high loading capacity, low toxicity, precise targeting, and excellent biocompatibility remains urgent and important for the treatment of breast cancer (BC). Herein, novel BC-targeted nano-DDSs based on bimetallic Prussian blue analogs (PBA-DDSs) for intracellular doxorubicin (DOX) delivery and pH-responsive release were developed. Two kinds of bimetallic PBA, namely CuFe (copper-iron) PBA and CoFe (cobalt-iron) PBA, were synthesized by a coprecipitation method, followed by modification with polyethyleneglycol methacrylate (PEGMA) via surface-initiated atom transfer radical polymerization and immobilization with the AS1411 aptamer to obtain two kinds of novel BC-targeted nano-DDS. CuFePBA@PEGMA@AS1411 and CoFePBA@PEGMA@AS1411 showed high drug loading efficiency of 80% and 84%, respectively, for DOX, while 56.0% and 75.9% DOX release could be achieved under acidic pH conditions. In vitro cell viability and in vivo experiments proved the good biocompatibility of both PBA-DDSs. Cellular uptake and in vivo distribution suggested that both PBA-DDSs had efficient nucleolin-targeting capability, indicating the targeted delivery of DOX in tumor tissues. In vivo evaluation of anti-BC efficacy further confirmed that the obtained PBA-DDSs exhibited excellent therapeutic efficacy with limited side-effects. Therefore, the proposed novel PBA-DDSs can be used as secure and effective drug nano-DDSs for BC chemotherapy.

Impedimetric aptasensor based on porphyrin-based covalent-organic framework for determination of diethylstilbestrol.

An impedimetric sensing strategy was developed for sensitively determining diethylstilbestrol (DES) based on a platform of porphyrin-containing covalent-organic framework (p-COF). The p-COF was synthesized using 5,10,15,20-tetra (4-aminophenyl) porphyrin (TAPP) and 1,3,6,8-tetrakis(4-formylphenyl) pyrene (TFPy) as building blocks via condensation reaction, for which p-COF was named as TAPP-TFPy-COF. Considering the large specific surface area (302.9 m2 g-1), high porosity, rich nitrogen functionality, superior electrochemical activity, and strong bioaffinity toward DNA strands, the TAPP-TFPy-COF-based platform exhibited enhanced, non-label, and amplified electrochemical signal, large number of immobilized DES-targeted aptamer strands, and fast-response toward the analyte. Electrochemical results reveal that the TAPP-TFPy-COF-based aptasensor promoted the sensing performance for the detection of DES, resulting in an extremely low limit of detection of 0.42 fg mL-1 within a DES concentration ranging from 1 fg mL-1 to 0.1 pg mL-1, which was substantially lower than those of most reported DES sensors. Furthermore, the TAPP-TFPy-COF-based aptasensor possessed outperformed stability, high selectivity, ascendant reproducibility, and acceptable applicability in diverse environments. The recovery values for DES detection in milk, tap water, and frozen shrimp were in the range 91.80-118.50% with low relative standard deviation of 0.11-4.26%. This work provides a new sensing electrochemical approach based on COF network for DES detection and shows a deep insight into the construction of COF-based biosensors, which can be extended to be used for other target compounds.

Radix Astragalus Polysaccharide Accelerates Angiogenesis by Activating AKT/eNOS to Promote Nerve Regeneration and Functional Recovery.

Peripheral nerve injury (PNI) results in loss of neural control and severe disabilities in patients. Promoting functional nerve recovery by accelerating angiogenesis is a promising neuroprotective treatment strategy. Here, we identified a bioactive Radix Astragalus polysaccharide (RAP) extracted from traditional Chinese medicine (TCM) as a potent enhancer of axonal regeneration and remyelination. Notably, RAP promoted functional recovery and delayed gastrocnemius muscle atrophy in a rat model of sciatic nerve crush injury. Further, RAP treatment may induce angiogenesis in vivo. Moreover, our in vitro results showed that RAP promotes endothelial cell (EC) migration and tube formation. Altogether, our results show that RAP can enhance functional recovery by accelerating angiogenesis, which was probably related to the activation of AKT/eNOS signaling pathway, thereby providing a polysaccharide-based therapeutic strategy for PNI.

Determination of VEGF165 using impedimetric aptasensor based on cyclohexanehexone-melem covalent-organic framework.

A porous nanostructured covalent-organic framework (COF) has been prepared via condensation polymerization between the two building blocks of melem and hexaketocyclohexane octahydrate (represented as M-HO-COF). Basic characterizations revealed that the M-HO-COF network was composed of C=N and highly conjugated aromatic moieties, along with a high surface area, large pore size, remarkable electrochemical activity, and strong bioaffinity toward aptamer strands. Given that the vascular endothelial growth factor 165 (VEGF165)-targeted aptamer was stably anchored over M-HO-COF via weak intermolecular forces, the prepared M-HO-COF network exhibited great potential as a sensitive and selective platform for the impedimetric VEGF165 aptasensor. Consequently, the M-HO-COF-based aptasensor displayed an ultralow limit of detection of 0.18 fg mL-1 within a wide range of VEGF165 concentrations from 1 fg mL-1 to 10 ng mL-1. Considering its strong fluorescence performance, excellent biocompatibility, and small nanosheet-like structure, the obtained COF-based aptasensor showed a superior sensing performance and regeneration capability after 7 regeneration cycles for the detection of osteosarcoma cells (K7M2 cells), which overexpressed with VEGF165, with a low limit of detection of 49 cells mL-1. For real f human serum samples, the obtained COF-based aptasensor exhibits acceptable mean apparent recoveries of 97.41% with a relative standard deviation of 4.60%. Furthermore, the proposed bifunctional aptasensor for the detection VEGF165 and K7M2 cells exhibited good stability, appropriate selectivity toward other biomarkers or normal cells, acceptable reproducibility, and applicability. A bifunctional sensing system was constructed for detecting osteosarcoma cells (K7M2 cells) and VEGF165 based on the a porous nanostructured covalent-organic framework (M-HO-COF) via condensation polymerization between melem and hexaketocyclohexane octahydrate. The M-HO-COF-based aptasensor displayed ultralow detection limit of 0.18 fg mL-1 toward VEGF165 and 49 cell mL-1 for K7M2 cells with high selectivity, acceptable reproducibility, and good stability.