Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation. Various therapeutic strategies have been developed against inflammatory cytokines in RA in recent decades. Based on the migratory features of FLSs, we examined whether modulation of the migratory module attenuates RA severity. In this study, inflamed synovial fluid-stimulated FLSs exhibited enhanced migration and migratory apparatus expression, and sodium bicarbonate cotransporter n1 (NBCn1) was identified in primary cultured RA-FLSs for the first time. The NBC inhibitor S0859 attenuated the migration of FLSs induced with synovial fluid from patients with RA or with TNF-α stimulation. Inhibition of NBCs with S0859 in a collagen-induced arthritis (CIA) mouse model reduced joint swelling and destruction without blood, hepatic, or renal toxicity. Primary FLSs isolated from the CIA-induced mouse model also showed reduced migration in the presence of S0859. Our results suggest that inflammatory mediators in synovial fluid, including TNF-α, recruit NBCn1 to the plasma membrane of FLSs to provide dynamic properties and that modulation of NBCn1 could be developed into a therapeutic strategy for RA.
Dexmedetomidine (Dex), a highly selective α2-adrenoceptor agonist, attenuates inflammatory responses induced by lipopolysaccharide (LPS) and induces sedative and analgesic effects. Administration of Dex also reduces salivary secretion in human subjects and inhibits osmotic water permeability in rat cortical collecting ducts. However, little is known about the mechanisms underlying the effects of Dex on salivary glands fluid secretion. We demonstrated the α2-adrenoceptor expression in the basolateral membrane of mouse submandibular glands (SMG). To investigate fluid secretion upon treatment with Dex, we studied the effects of Dex on the activity of Na+-K+-2Cl− cotransporter1 (NKCC1) and Cl−/HCO3- exchange (CBE), and on downstream pro-inflammatory cytokine expression in isolated primary mouse SMG cells. Dex acutely increased CBE activity and NKCC1-mediated and independent NH4+ entry in SMG duct cells, and enhanced ductal fluid secretion in a sealed duct system. Dex showed differential effects on cholinergic/adrenergic stimulations and inflammatory mediators, histamine, and LPS, stimulations-induced Ca2+ in mouse SMG cells. Both, histamine- and LPS-induced intracellular Ca2+ increases were inhibited by Dex, whereas carbachol-stimulated Ca2+ signals were not. Long-lasting (2 h) treatment with Dex reduced CBE activity in SMG and in human submandibular glands (HSG) cells. Moreover, when isolated SMG cells were stimulated with Dex for 2 h, phosphodiesterase 4D (PDE4D) expression was enhanced. These results confirm the anti-inflammatory properties of Dex on LPS-mediated signaling. Further, Dex also inhibited mRNA expression of interleukin-6 and NADPH oxidase 4. The present study also showed that α2-adrenoceptor activation by Dex reduces salivary glands fluid secretion by increasing PDE4D expression, and subsequently reducing the concentration of cAMP. These findings reveal an interaction between the α2-adrenoceptor and PDE4D, which should be considered when using α2-adrenoceptor agonists as sedative or analgesics.
Diabetic heart dysfunctions during cardiac surgeries have revealed several clinical problems associated with ion imbalance. However, the mechanism of ion imbalance mediated by cardioplegia and a diabetic heart is largely unclear. We hypothesized that ion transporters might be regulated differently in the diabetic heart and that the differentially regulated ion transporters may involve in ion imbalance of the diabetic heart after cardioplegic arrest. In this study, we modified the Langendorff-free cardioplegia method and identified the involved ion transporters after cardioplegia-induced arrest between wild type and db/db heart. Enhanced expression of Na+-K+-2Cl− cotransporter 1 (NKCC1) was observed in the db/db heart compared to the wild type heart. Enhanced NKCC1 activity was observed in the left ventricle of db/db mice compared to that of wild type after cardioplegia-induced arrest. The expression and activity of Slc26a6, a dominant Cl−/HCO3− exchanger in cardiac tissues, were enhanced in left ventricle strips of db/db mice compared to that of wild type. The Cl− transporting activity in left ventricle strips of db/db mice was dramatically increased as compared to that of wild type. Interestingly, expression of Slc26a6, as well as carbonic anhydrase IV as a supportive enzyme of Slc26a6, was increased in db/db cardiac strips compared to wild type cardiac strips. Thus, the enhanced Cl− transporting activity and expression by NKCC1 and Slc26a6 in db/db cardiac tissues after cardioplegia-induced arrest provide greater insight into enhanced acidosis and Cl− movement-mediated db/db heart dysfunction. Thus, we suggested that enhanced Cl− influx and HCO3− efflux through NKCC1 and Slc26a6 offer more acidic circumstances in the diabetic heart after cardioplegic arrest. These transporters should be considered as potential therapeutic targets to develop the next generation of cardioplegia solution for protection against ischemia-reperfusion injury in diabetic hearts.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical and chronic polyarthritis. Fibroblast-like synoviocytes are mainly involved in joint inflammation and cartilage and bone destruction by inflammatory cytokines and matrix-degrading enzymes in RA. Approaches that induce various cellular growth alterations of synoviocytes are considered as potential strategies for treating RA. However, since synoviocytes play a critical role in RA, the mechanism and hyperplastic modulation of synoviocytes and their motility need to be addressed. In this review, we focus on the alteration of synoviocyte signalling and cell fate provided by signalling proteins, various antioxidant molecules, enzymes, compounds, clinical candidates, to understand the pathology of the synoviocytes, and finally to achieve developed therapeutic strategies of RA. Cite this article: Bone Joint Res 2021;10(4):285–297.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.