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The sp2-iminosugar glycolipid 1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO2-ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

AutorAlcalde-Estévez, Elena; Arroba, Ana I. ; Sánchez-Fernández, Elena M. ; Ortiz-Mellet, Carmen; García Fernández, José Manuel ; Masgrau, Laura; Valverde, Ángela M.
Palabras claveDiabetic retinopathy
Inflammation
p38α MAPK
sp2-iminosugar
Glycolipid
Heme oxygenase-1
Fecha de publicación2018
EditorElsevier
CitaciónFood and Chemical Toxicology 111: 454-466 (2018)
ResumenNeuroinflammation is an early event during diabetic retinopathy (DR) that impacts the dynamics of microglia polarization. Gliosis is a hallmark of DR and we have reported the beneficial effects of 1R-DSO-ONJ, a member of the sp2-iminosugar glycolipid (sp2-IGL) family, in targeting microglia and reducing gliosis in diabetic db/db mice. Herein, we analyzed the effect of DSO2-ONJ, another family compound incorporating a sulfone group that better mimics the phosphate group of phosphatidylinositol ether lipid analogues (PIAs), in Bv.2 microglial cells treated with bacterial lipopolysaccaride (LPS) and in retinal explants from db/db mice. In addition to decreasing iNOS and inflammasome activation, the anti-inflammatory effect of DSO2-ONJ was mediated by direct p38α MAPK activation. Computational docking experiments demonstrated that DSO2-ONJ binds to p38α MAPK at the same site where PIAs and the alkyl phospholipid perifosine activators do, suggesting similar mechanism of action. Moreover, treatment of microglial cells with DSO2-ONJ increased both heme-oxygenase (HO)-1 and Il10 expression regardless the presence of LPS. In retinal explants from db/db mice, DSO2-ONJ also induced HO-1 and reduced gliosis. Since IL-10-mediated induction of HO-1 expression is mediated by p38α MAPK activation, our results suggest that this molecular mechanism is involved in the anti-inflammatory effects of DSO2-ONJ in microglia.
Versión del editorhttps://doi.org/10.1016/j.fct.2017.11.050
URIhttp://hdl.handle.net/10261/172918
DOI10.1016/j.fct.2017.11.050
ISSN0278-6915
E-ISSN1873-6351
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