ABSTRACT
Rheumatoid arthritis (RA) is a worldwide chronic autoimmune inflammatory disease which is affecting approximately 1% of the total population. It is characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS) and increased production of proinflammatory cytokines. In the current study, we were aiming to investigate the role of ubiquitin-specific protease 5 (USP5) in the inflammatory process in RA-FLS. Expression of USP5 was found upregulated in RA-FLS compared with that in osteoarthritis- (OA-) FLS, and IL-1ß stimulation increased USP5 expression in a time-dependent manner. Furthermore, we found that USP5 overexpression significantly aggravated proinflammatory cytokine production and related nuclear factor κB (NF-κB) signaling activation. Consistently, silencing of USP5 decreased the release of cytokines and inhibited the activation of NF-κB. In addition, USP5 was found to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6) and remove its K48-linked polyubiquitination chains therefore stabilizing TRAF6. Our data showed that a USP5-positive cell regulates inflammatory processes in RA-FLS and suggested USP5 as a potential target for RA treatment.
Subject(s)
Arthritis, Rheumatoid/metabolism , Endopeptidases/metabolism , Fibroblasts/cytology , Synoviocytes/metabolism , Arthritis, Rheumatoid/immunology , Cells, Cultured , Endopeptidases/immunology , Humans , NF-kappa B/metabolism , Signal Transduction , Synoviocytes/immunology , TNF Receptor-Associated Factor 6/metabolismABSTRACT
Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26µM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , MAP Kinase Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , MAP Kinase Signaling System/drug effects , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/enzymology , Quantitative Structure-Activity RelationshipABSTRACT
Research on peripheral nervous injuries, especially the stretched injuries, is important to improve the clinical effectiveness and alleviate the patients's pain. In recent years, the biological changes and mechanics of stretched axons have been hot topics. This article reviews the recent advances in the morphological changes of axons as well as changes in cellular membrane, cytoskeleton, cellular metabolism, and action potential after axonal stretch.
