Promyelocytic leukemia zinc finger-retinoic acid receptor a (PLZF-RARa), a fusion receptor generated as a result of a variant t(11;17) chromosomal translocation that occurs in a small subset of acute promyelocytic leukemia (APL) patients, has been shown to display a dominantnegative effect against the wild-type RARa/retinoid X receptor a (RXRa). We now show that its N-terminal region ( (Fig. 1A): C.I, deletion of amino acids 172-348 containing 4 proline-dependent phosphorylation sites; C.II, deletion of amino acids 403-432 corresponding to the first zinc finger structure of PLZF; C.III, deletion of amino acids 432-455, thus lacking the second zinc
MaR1 is a therapeutic target for RA, likely operating through effects on the imbalanced Treg/Th17 ratio found in the disease.
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint stiffness, finally leading to tissue destruction. Connective tissue growth factor (CTGF) is a critical factor in RA progression, which promotes fibroblast-like synoviocyte (FLS) proliferation, pannus formation, and the damage of cartilage as well as bone. Resolvin D1 (RvD1) can promote inflammation resolution in acute inflammatory diseases, and recently, effects of RvD1 on chronic inflammatory diseases also attracted attention. This study aimed to examine the effect of RvD1 on pannus formation in RA and the underlying mechanism. Methods: Serum levels of RvD1 and CTGF were determined in RA patients and healthy persons by UPLC-MS/MS and ELISA respectively. The levels of CTGF and inflammatory factors were assessed by qRT-PCR and ELISA. MicroRNA expression profile was determined by miRNA microarray. The effects of CTGF, RvD1, and miR-146a-5p on angiogenesis were evaluated with tube formation and chick chorioallantoic membrane (CAM) assays. Collagen-induced arthritis (CIA) mice were constructed to detect the effects of RvD1 and miR146a-5p on RA. STAT3 activation was determined by Western blotting. Results: RvD1 levels decreased while CTGF levels increased in RA patients' serum, and an inverse correlation of the concentrations of RvD1 and CTGF in the serum of RA patients was synchronously observed. In CIA mice, RvD1 suppressed angiopoiesis and decreased the expression of CTGF. Simultaneously, RvD1 significantly decreased CTGF and proinflammation cytokines levels in RA FLS. Furthermore, CTGF suppressed angiopoiesis and RvD1 inhibited the proliferation and migration of RA FLS and angiopoiesis. MiRNA microarray and qRT-PCR results showed that RvD1 upregulated miRNA-146a-5p. The transfection experiments demonstrated that miRNA-146a-5p could decrease inflammatory factors and CTGF levels. Moreover, miRNA-146a-5p decreased the proliferation of FLS and angiogenesis in vivo. MiRNA-146a-5p also suppressed angiogenesis and downregulated the expression of CTGF in CIA mice. Finally, Western blot results revealed that miRNA-146a-5p inhibited the activation of STAT3.
Peripheral nerve injuries represent one of the most common causes of permanent disabilities. Therapeutic electrical stimulation has been widely used in neural regeneration for decades. Combined with the implantation of a nerve cuff, several outcomes have proven effectiveness and feasibility in neuroprosthetic applications. However, the current electrical stimulation strategy fails to complete nerve repair. There is a lack of research on long‐term implantable nanogenerators in the neurostimulation scenario. Especially considering many disease models, those devices may not reach the in vitro simulative working setting. Thus, an implanted sciatic nerve stimulation system that spontaneously generates biphasic electric pulses in response to rats’ movement is developed. The electric signals generated by this device could stimulate injured sciatic nerve by cuff electrode. This work introduces an implantable self‐regulated neural electrical stimulation system generated by a contact separation triboelectric nanogenerator with a nerve cuff electrode and compares it with chronic therapeutic electrical stimulation for sciatic nerve restoration effect. Neural function restoration is observed in gait and histological analysis. Moreover, the upregulation of growth associated protein 43 can be a protentional target. This could have potential clinical application in facilitating closed‐loop energy harvesting for long‐term electrical stimulation.
Objective: Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (γδTreg)/γδT17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process. Methods: We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, γδTreg/γδT17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. Nlrp 3 -/- mice were introduced to assess the influence of NLRP3 on γδT17 cell activation in RA. Results: TOF treatment decreased levels of γδT17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the γδTreg/γδT17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1β via downregulation of NLRP3. Furthermore, experiments using Nlrp3 -/- mice verified that the NLRP3 inflammasome mediated the effect of TOF on γδT17 cell activation. Conclusions: Recovery of γδTreg/γδT17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated γδT17 cell activation.
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