Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells.

BACKGROUND: Reduced supplies of oxygen and nutrients caused by vascular injury lead to difficult-to-heal pressure ulcers (PU) in clinical practice. Rapid vascular repair in the skin wound is the key to the resolution of this challenge, but clinical measures are still limited. We described the beneficial effects of extracellular vesicle-derived silk fibroin nanoparticles (NPs) loaded with milk fat globule EGF factor 8 (MFGE8) on accelerating skin blood vessel and PU healing by targeting CD13 in the vascular endothelial cells (VECs). METHODS: CD13, the specific targeting protein of NGR, and MFGE8, an inhibitor of ferroptosis, were detected in VECs and PU tissues. Then, NPs were synthesized via silk fibroin, and MFGE8-coated NPs (NPs@MFGE8) were assembled via loading purified protein MFGE8 produced by Chinese hamster ovary cells. Lentivirus was used to over-express MFGE8 in VECs and obtained MFGE8-engineered extracellular vesicles (EVs-MFGE8) secreted by these VECs. The inhibitory effect of EVs-MFGE8 or NPs@MFGE8 on ferroptosis was detected in vitro. The NGR peptide cross-linked with NPs@MFGE8 was assembled into NGR-NPs@MFGE8. Collagen and silk fibroin were used to synthesize the silk fibroin/collagen hydrogel. After being loaded with NGR-NPs@MFGE8, silk fibroin/collagen hydrogel sustained-release carrier was synthesized to investigate the repair effect on PU in vivo. RESULTS: MFGE8 was decreased, and CD13 was increased in PU tissues. Similar to the effect of EVs-MFGE8 on inhibiting ferroptosis, NPs@MFGE8 could inhibit the mitochondrial autophagy-induced ferroptosis of VECs. Compared with the hydrogels loaded with NPs or NPs@MFGE8, the hydrogels loaded with NGR-NPs@MFGE8 consistently released NGR-NPs@MFGE8 targeting CD13 in VECs, thereby inhibiting mitochondrial autophagy and ferroptosis caused by hypoxia and accelerating wound healing effectively in rats. CONCLUSIONS: The silk fibroin/collagen hydrogel sustained-release carrier loaded with NGR-NPs@MFGE8 was of great significance to use as a wound dressing to inhibit the ferroptosis of VECs by targeting CD13 in PU tissues, preventing PU formation and promoting wound healing.

N-acetylcysteine attenuates the incidence of phlebitis induced by carbomer/vinorelbine gel.

Background: The high incidence and severe clinical manifestations of phlebitis pose a complex and urgent clinical challenge. The rapid and simple establishment of animal phlebitis models and the development of preventive strategies are crucial to resolving this problem. Methods: In this study, we established such models by mixing vinorelbine ditartrate (VNR) and carbomer to form a sustained-release gel carrier, and then injected it around the veins rather than inside the vessels. Furthermore, we analyzed the efficacy of the carbomer/VNR gel in inducing phlebitis by monitoring the morphology of the veins using HE staining, immunohistochemical and immunofluorescence staining, and western blotting. Reactive oxygen species (ROS) and lipid peroxidation levels were determined using flow cytometry. Finally, we evaluated the inhibitory effect of N-acetylcysteine (NAC) on VNR-induced phlebitis in rabbits and rats. Results: Our findings suggested that the carbomer/VNR gel rapidly and easily induced phlebitis due to by retention of the gel in situ, wrapping the veins, and the prolonged release of VNR. NAC alleviated the VNR-induced oxidative stress response and expression of inflammatory cytokines by attenuating mitochondrial damage in venous endothelial cells, thereby preventing the occurrence of phlebitis in rabbits and rats. Conclusion: The in situ carbomer/VNR gel provides a rapid and simple method for establishing an animal model to study the pathogenesis of phlebitis. Furthermore, the observed therapeutic effect of NAC highlights its novel and efficacious role in preventing and treating phlebitis.

Identification of ADAM23 as a Potential Signature for Psoriasis Using Integrative Machine-Learning and Experimental Verification.

Background: Psoriasis is a common chronic, recurrent, and inflammatory skin disease. Identifying novel and potential biomarkers is valuable in the treatment and diagnosis of psoriasis. The goal of this study was to identify novel key biomarkers of psoriasis and analyze the potential underlying mechanisms. Methods: Psoriasis-related datasets were downloaded from the Gene Expression Omnibus database to screen differential genes in the datasets. Functional and pathway enrichment analyses were performed on the differentially expressed genes (DEGs). Candidate biomarkers for psoriasis were identified from the GSE30999 and GSE6710 datasets using four machine learning algorithms, namely, random forest (RF), least absolute shrinkage and selection operator (LASSO) logistic regression, weighted gene co-expression network analysis (WGCNA), and support vector machine recursive feature elimination (SVM-RFE), and were validated using the GSE41662 dataset. Next, we used CIBERSORT and single-cell RNA analysis to explore the relationship between ADAM23 and immune cells. Finally, we validated the expression of the identified biomarkers expressions in human and mouse experiments. Results: A total of 709 overlapping DEGs were identified, including 426 upregulated and 283 downregulated genes. Enhanced by enrichment analysis, the differentially expressed genes (DEGs) were spatially arranged in relation to immune cell involvement, immune-activating processes, and inflammatory signals. Based on the enrichment analysis, the DEGs were mapped to immune cell involvement, immune-activating processes, and inflammatory signals. Four machine learning strategies and single-cell RNA sequencing analysis showed that ADAM23, a disintegrin and metalloprotease, may be a unique, critical biomarker with high diagnostic accuracy for psoriasis. Based on CIBERSORT analysis, ADAM23 was found to be associated with a variety of immune cells, such as macrophages and mast cells, and it was upregulated in the macrophages of psoriatic lesions in patients and mice. Conclusion: ADAM23 may be a potential biomarker in the diagnosis of psoriasis and may contribute to the pathogenesis by regulating immunological activity in psoriatic lesions.