2024-03-28T16:02:17Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1729182021-07-20T11:30:23Zcom_10261_22com_10261_1com_10261_38com_10261_5col_10261_275col_10261_291
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
Alcalde-Estévez, Elena
Arroba, Ana I.
Sánchez-Fernández, Elena M.
Ortiz-Mellet, Carmen
García Fernández, José Manuel
Masgrau, Laura
Valverde, Ángela M.
Ministerio de Economía y Competitividad (España)
European Commission
Instituto de Salud Carlos III
Banco Santander
Universidad Autónoma de Barcelona
Diabetic retinopathy
Inflammation
p38α MAPK
sp2-iminosugar
Glycolipid
Heme oxygenase-1
Neuroinflammation 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.
2018-12-04T08:35:43Z
2018-12-04T08:35:43Z
2018
artículo
Food and Chemical Toxicology 111: 454-466 (2018)
0278-6915
http://hdl.handle.net/10261/172918
10.1016/j.fct.2017.11.050
1873-6351
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100011104
http://dx.doi.org/10.13039/100010784
29191728
eng
Postprint
https://doi.org/10.1016/j.fct.2017.11.050
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-65267-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76083-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2015-64425-C2-1-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2014-53144-P
info:eu-repo/grantAgreement/EC/H2020/721236
http://creativecommons.org/licenses/by-nc-nd/4.0/
openAccess
Elsevier