Vav1 is a guanine nucleotide exchange factor that is expressed specifically in hematopoietic cells and plays important roles in T cell development and activation. Vav1 consists of multiple structural domains so as to facilitate both its guanine nucleotide exchange activity and scaffold function following T cell antigen receptor ( Stimulation of the T cell antigen receptor (TCR)2 initiates a cascade of signaling events that lead to T cell activation. Calcium plays a central role in this process and has been studied intensively (1-4). Engagement of TCR triggers the activation and accumulation of enzymes and adapter molecules to the proximal membrane (5, 6), such as tyrosine phosphorylation and activation of phospholipase-C␥1 (PLC-␥1), thereby increasing the production of inositol 1,4,5-trisphosphate (IP 3 ). IP 3 binds to and activates the inositol 1,4,5-trisphosphate receptor (IP 3 R), which results in Ca 2ϩ release from the endoplasmic reticulum (ER) and the subsequent calcium influx from Ca 2ϩ release-activated Ca 2ϩ channel (CRAC) (1, 7). The elevated cytoplasmic [Ca 2ϩ ] i evokes a multitude of cellular responses, such as the NFAT-mediated gene expressions and the cell proliferation (8, 9).Vav1 is expressed specifically in hematopoietic cells as a 95-kDa protein, which plays pivotal roles as a guanine exchange factor (GEF) for small GTPases as well as a scaffold protein in the activation of hematopoietic cells (10 -12). The importance of Vav1 is because of its multiple structural elements, including a calponin homology (CH) domain, an acidic motif, a Dbl homology domain, a pleckstrin homology (PH) domain, a cysteine-rich motif, and one single SH2 domain flanked by two SH3 domains responsible for signaling protein assembly (12, 13). Upon TCR engagement, Vav1 is phosphorylated on the key tyrosine residues in the acidic motif, leading to the exposure of active Dbl homology domain for GDP/GTP exchange activity (14). Studies on vav1 Ϫ/Ϫ T cells isolated from knock-out mice demonstrated that Vav1 is essential for normal T cell activation and proliferation (15)(16)(17). In addition, the vav1-null cell line, J.Vav1, derived from Jurkat cells by somatic gene targeting approach, also exhibits pleiotropic defects in TCR-mediated signaling pathways (18).T cell stimulation evokes a biphasic calcium flux as follows: calcium release from intracellular stores followed by calcium influx across the plasma membrane (7,19). IP 3 Rs dominantly control the initiation of IP 3 -induced calcium release, demonstrated by using antisense knockdown of IP 3 R to block calcium release from the ER (20). Jurkat T cells express three IP 3 R isoforms, IP 3 R-1, IP 3 R-2, and IP 3 R-3 (21), which differ significantly in their sensitivity to IP 3 (22,23). A tyrosine kinase, Fyn, was suggested to modulate IP 3 R channel activities (24,25). Interactions between IP 3 R and other proteins, such as calmodulin (CaM), were reported to control the channel opening. Although some observations viewed CaM as an inhibitory protein of IP 3 R (26 -28), more...
Human umbilical cord mesenchymal stem cells (hUC‑MSCs) hold great potential in the search for therapies to treat refractory diseases, including rheumatoid arthritis (RA), due to their potential regenerative ability and extensive source. However, the role of hUC‑MSCs in vivo and the repair mechanisms for RA remain to be fully elucidated. The present study aimed to determine whether hUC‑MSCs exert immunomodulatory effects and have anti‑inflammatory capabilities in the treatment of embolisms. Following the transplantation of hUC‑MSCs into collagen type Ⅱ‑induced arthritic (CIA) model rats, magnetic resonance imaging (MRI) in vivo was performed, and the levels of interleukin (IL)‑1, IL‑17, tumor necrosis factor (TNF)‑α, vascular endothelial growth factor (VEGF), tissue factor (TF), CD4+CD25+ T cells (Treg) and antithrombin (AT) were measured. Bromodeoxyuridine staining was performed for histopathological examinations. As revealed by immunofluorescence and MRI experiments, the injected hUC‑MSCs preferentially migrated to the inflammatory joint sites of the rats. The Treg cell percentage and AT levels in the hUC‑MSC‑treated group were markedly increased, whereas the levels of IL‑1, IL‑17, TNF‑α, VEGF and TF were decreased compared with those in the CIA model group. The values determined for these parameters in the hUC‑MSC‑treated group returned to approximately the identical values as those of the control group on day 35 post‑therapy. Superparamagnetic iron oxide nanoparticles (SPIONs) may serve as an effective, non‑invasive method for tracking transplanted cells in vivo. The present study provided direct evidence that hUC‑MSCs in the CIA rat model migrated to the inflammatory joint sites, effectively promoting recovery from collagen type II damage and thereby improving the immune‑associated prothrombotic state.
Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.
The aim of this study was to prepare chitosan-collagen (CS/COL) scaffolds that could release fibroblast growth factor-2 (FGF-2) and bone morphogenetic protein 2 (BMP-2), and to study the effect of this scaffold on bone repair. By improving the double emulsion/solvent evaporation technique, BMP-2 was encapsulated in poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PELA) microcapsules, to the surface of which FGF-2 was attached. The CS/COL scaffold carrying the microcapsules was prepared by freeze-drying. Periosteum derived cells (PDCs) were extracted and cultured on the scaffolds to study their proliferation and differentiation on the scaffolds. In addition, the effects of the scaffolds were investigated on rats with skull defects by micro-computed tomography and histology. We successfully prepared PELA microcapsules with external adherence to FGF-2 and encapsulated with BMP-2. The CS/COL scaffolds were porous and PDCs adhered, proliferated and underwent osteogenic differentiation on the scaffolds. The sequential release of FGF-2/BMP-2 had better osteogenic efficacy than other groups. Our results suggest that CS/COL scaffolds that bind FGF-2 and BMP-2 in combination with PDCs could be a promising new strategy for tissue engineering periosteum.
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