Search

Burn is one of the most common types of injuries worldwide, which remains a clinical challenge due to its progressive exacerbation caused by inflammation and edema that impede the growth and differentiation of fibroblast. To solve this problem, in this study, the anti-inflammatory Gelsvirine (Gs), as a specific STING inhibitor for rheumatoid arthritis pain, is used for inflammation control in burn wound healing. Meanwhile, to improve fibroblast migration, proliferation, and differentiation, the natural protein silk fibroin (SF) was used due to its demonstrated capacity to promote the proliferation of epidermal cells and fibroblasts, facilitate collagen synthesis and further improve wound repair. Through our rational design, a functional dressing for the co-delivery of Gs and SF is developed to improve burn wound healing. A multilayer composite dressing of Polycaprolactone(PCL)/Gs-loaded sodium alginate (SA)/SF-gelatin (Gs@SFD) was prepared using the combination of electrospinning and extrusion method, which contained four layers: PCL-dense barrier layer (to prevent infection), SA-hydrogel layer (to load Gs and keep wound moisture), PCL-loosen support layer (to prevent deformation of bioactive layer and to facilitate Gs release into trauma) and SF/gelatin bioactive layer (to contact with trauma and bioactively induce wound healing). Our data showed that the hydrogel layer realized the sustained release of Gs. As a specific inhibitor of STING signaling pathway, the released Gs inhibited the inflammatory response of macrophages and further reduced the fibroblast damage both in vitro and in vivo. In addition, the bioactive layer promoted cell proliferation, facilitated collagen synthesis, and further improved wound healing in animal model of burn trauma. Therefore, this study provides a novel multilayer composite dressing (Gs@SFD) to facilitate burn wound healing via efficient inflammation control with the sustained release of Gs, and improvement on wound healing due to the bioactive components of silk fibroin, which could serve as a potential therapeutic approach in the future. In addition, our multilayer dressing design provides an advanced drug delivery strategy for burn wound healing. [ABSTRACT FROM AUTHOR]

[Display omitted] Low-grade and chronic inflammation is recognized as an important mediator of the pathogenesis of osteoarthritis (OA). The aim of current work was to test the therapeutic effects of gelsevirine on age-related and surgically induced OA in mice and elucidate the underlying mechanism. The in vitro studies revealed that gelsevirine treatment mitigated IL-1β-induced inflammatory response and degeneration in cultured chondrocytes, evidenced by reduced apoptosis and expression of MMP3 , MMP9 , MMP13 , IFNβ , TNFɑ , and Il6 , and increased expression of Col2A and Il10. Furthermore, gelsevirine treatment in IL-1β-stimulated chondrocytes reduced the protein expression of stimulator of IFN genes (STING, also referred to Tmem173) and p-TBK1. Importantly, gelsevirine treatment did not provide further protection in STING-deficient chondrocytes against IL-1β stimulation. The in vivo studies revealed that gelsevirine treatment mitigated articular cartilage destruction in age-related and destabilization of the medial meniscus (DMM)-induced OA. Similarly, gelsevirine treatment did not provide further beneficial effects against OA in STING deficient mice. Mechanistically, gelsevirine promoted STING K48-linked poly-ubiquitination and MG-132 (a proteasome inhibitor) reversed the inhibitive effects of gelsevirine on IL-1β-induced activation of STING/TBK1 pathway in chondrocytes. Collectively, we identify that gelsevirine targets STING for K48 ubiquitination and degradation and improves age-related and surgically induced OA in mice. [ABSTRACT FROM AUTHOR]

Abstract: Alkaloids in Gelsemium elegans possess a variety of therapeutic properties, including tumor suppression, analgesic and anti-inflammatory effects. In China, G. elegans has been used for centuries to treat a variety of medical conditions, including chronic pain and skin ulcer. Methods currently used to separate the active components of G. elegans are time-consuming and have low recovery. In the present study, we used pH-zone-refining counter-current chromatography to separate major alkaloids from a crude extract of G. elegans. The two-phase solvent system was methyl tert-butyl ether (MtBE)/acetonitrile/water (3:1.5:4, v/v). Triethylamine (20mM) was added to the upper organic stationary phase as a retainer. Hydrochloric acid (10mM) was added to the lower aqueous phase as an eluter. From 1.5g of crude extract, we obtained 312mg gelsemine, 420mg koumine and 195mg gelsevirine, with purities at 94.8%, 95.9% and 96.7%, respectively, which were determined by HPLC at 256nm. The chemical identity of the isolated compounds was verified by electrospray ionization-mass spectrometry (ESI-MS), 1H NMR and 13C NMR. These results demonstrated that pH-zone-refining counter-current chromatography is an effective method to separate and purify major alkaloids from G. elegans. [Copyright &y& Elsevier]