RESUMEN
Sacubitril/valsartan (Sac/Val) is a recently approved drug that is commonly used for treatment of heart failure. Several studies indicated that Sac/Val also regulated the secretion of inflammatory factors. However, the effect and mechanism of this drug modulation of inflammatory immune responses are uncertain. In this study, an experimental autoimmune myocarditis (EAM) mouse model was established by injection of α-myosin-heavy chain peptides. The effect of oral Sac/Val on EAM was evaluated by histological staining of heart tissues, measurements of cardiac troponin T and inflammatory markers (IL-6 and hsCRP). The effects of Sac/Val on NLRP3 inflammasome activation and Th1/Th17 cell differentiation were also determined. To further explore the signaling pathways, the expressions of cardiac soluble guanylyl cyclase (sGC) and NF-κB p65 were investigated. The results showed that Sac/Val downregulated the inflammatory response and attenuated the severity of EAM, but did not influence NLRP3 inflammasomes activation. Moreover, Sac/Val treatment inhibited cardiac Th17 cell differentiation, and this might be associated with sGC/NF-κB p65 signaling pathway. These findings indicate the potential use of Sac/Val for treatment of myocarditis.
RESUMEN
The opening of mitochondrial permeability transition pore (MPTP) plays a critical role in platelet activation. However, the potential trigger of the MPTP opening in platelet activation remains unknown. Inflammation is the crucial trigger of platelet activation. In this study, we aimed to explore whether and how the important inflammatory cytokine IL-17 is associated with MPTP opening in platelets activation by using MPTP inhibitor cyclosporine-A (CsA). The mitochondrial membrane potential (ΔΨm) was detected to reflect MPTP opening levels. And the platelet aggregation, activation, and the primary signaling pathway were also tested. The results showed that the MPTP opening levels were increased and Δψm reduced in platelets administrated with IL-17. Moreover, the levels of aggregation, CD62P, PAC-1, P53 and the phosphorylation of ERK2 were enhanced along with the MPTP opening in platelets pre-stimulated with IL-17. However, CsA attenuated these effects triggered by IL-17. It was suggested that IL-17 could induce MPTP opening through ERK2 and P53 signaling pathway in platelet activation and aggregation.
Asunto(s)
Plaquetas/efectos de los fármacos , Interleucina-17/farmacología , Proteínas de Transporte de Membrana Mitocondrial/agonistas , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Plaquetas/citología , Plaquetas/metabolismo , Separación Celular , Ciclosporina/farmacología , Fosfatasa 2 de Especificidad Dual/genética , Fosfatasa 2 de Especificidad Dual/metabolismo , Regulación de la Expresión Génica , Humanos , Interleucina-17/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Proteína Quinasa 1 Activada por Mitógenos/genética , Selectina-P/genética , Selectina-P/metabolismo , Fosforilación/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Cultivo Primario de Células , Transducción de Señal , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND/AIM: B10 cells are generally considered to inhibit the kidney injury in systemic lupus erythematosus (SLE) mouse models, but recently this function of B10 cells was denied by the lineage-specific deletion of IL-10 from B cells. Thus, this study aimed to determine whether and how B10 cells play a protective role in lupus nephritis (LN). METHODS: LN and non-LN SLE patients without receiving any treatments were recruited, and the percentages of circulating B10 cell were determined. Furthermore, the purified B10 cells were transferred into MRL/lpr SLE mice, and the exact effects of B10 cells on LN progression were investigated. RESULTS: The percentage of circulating B10 cells was significantly higher in patient than in healthy controls, while they were fewer in LN patients than non-LN SLE patients. Moreover, B10 cells rather than plasma IL-10 levels were negatively correlated with disease severity especially with kidney injury in LN patients. In animal experiments, the glomerular injuries including the proteinuria and pathological scores were significantly attenuated in SLE mice transferred with B10 cells, accompanied by the decreased glomerular endothelial cell CD54/CD106 expression, and glomerular p38 phosphorylation as well as increased SOCS3 expression. At the same time, the serum anti-dsDNA autoantibody, TNF-α and IFN-γ levels were also reduced, while there were no changes in serum IL-10 and IL-17 levels in B10 cell transferred mice. CONCLUSION: These findings suggest that B10 cells could - independent from IL-10 - ameliorate glomerular injury in LN through protection of glomerular endothelial cells.
