Alcalde-Estévez, ElenaArroba, Ana ISánchez-Fernández, Elena MMellet, Carmen OrtizGarcía Fernández, Jose MMasgrau, LauraValverde, Ángela M2023-01-252023-01-252017-11-27http://hdl.handle.net/10668/11861Neuroinflammation 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.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Diabetic retinopathyGlycolipidHeme oxygenase-1Inflammationp38α MAPKsp(2)-iminosugarAnimalsAnti-Inflammatory AgentsCell LineGene Expression Regulation, EnzymologicGlycolipidsHeme Oxygenase-1LipopolysaccharidesMiceMice, Inbred NODMicrogliaRetinaTissue Culture TechniquesThe 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.research article29191728open access10.1016/j.fct.2017.11.0501873-6351https://digital.csic.es/bitstream/10261/172918/1/FCT-S-17-01952.pdf