Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation

Hdl Handle:
http://hdl.handle.net/10675.2/604
Title:
Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation
Authors:
Ibrahim, Ahmed S. ( 0000-0001-8480-6252 ) ; El-Shishtawy, Mamdouh M.; Pena, Alejandro Jr.; Liou, Gregory I.
Abstract:
Purpose: Diabetic retinopathy (DR) is associated with microglial activation and increased levels of inflammatory cytokines. Genistein, a tyrosine kinase inhibitor, has been shown to possess anti-inflammatory potential that so far untested in animal models of diabetes. The aims of this study are to evaluate the efficacy of genistein for alleviation of diabetes-induced retinal inflammation and also to gain insight into the molecular mechanisms involved therein by analyzing the effect of genistein on concomitant microglia activation in the diabetic retina and in isolated cells.; Methods: Streptozotocin (STZ)-induced diabetic Sprague Dawley rats were used. After diabetes was established for two weeks a single intravitreal injection of genistein or vehicle was performed. Forty-eight hours later, rats were killed, their retinal and vitreal samples were processed for Quantitative Real Time-PCR (qRTâ PCR) and Enzyme-linked immunosorbent assay (ELISA) analyses, respectively. For the in vitro study, isolated microglial cells from retinas of newborn rats were used.; Results: mRNA as well as protein levels for tumor necrosis factor α (TNF-α), a robust marker of inflammation, were increased in the retina early in the course of diabetes. Moreover, diabetes resulted in elevation of ionized calcium binding adaptor molecule-1 (Iba1) mRNA, known to be upregulated in activated microglia. These effects of diabetes in retina were all reduced by intervention treatment with genistein. Using an in vitro bioassay, we demonstrated the release of TNF- α from microglia activated by glycated albumin, a risk factor for diabetic disorders. This inflammatory signal involves the activation of tyrosine kinase and its subsequent events, ERK and P38 MAPKs. Genistein represses the release of TNF- α and significantly inhibits ERK and P38 phosphorylation in activated microglial cells by acting as a tyrosine kinase inhibitor.; Conclusions: These findings show genistein to be effective in dampening diabetes-induced retinal inflammation by interfering with inflammatory signaling (ERK and P38 MAPKs) that occurs in activated microglia. This beneficial effect of genistein may represent a new intervention therapy to modulate early pathological pathways long before the occurrence of vision loss among diabetics.
Citation:
Mol Vis. 2010 Oct 8; 16:2033-2042
Issue Date:
8-Oct-2010
URI:
http://hdl.handle.net/10675.2/604
PubMed ID:
21042558
PubMed Central ID:
PMC2965567
Type:
Article
ISSN:
1090-0535
Appears in Collections:
Department of Ophthalmology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorIbrahim, Ahmed S.en_US
dc.contributor.authorEl-Shishtawy, Mamdouh M.en_US
dc.contributor.authorPena, Alejandro Jr.en_US
dc.contributor.authorLiou, Gregory I.en_US
dc.date.accessioned2012-10-26T16:26:51Z-
dc.date.available2012-10-26T16:26:51Z-
dc.date.issued2010-10-08en_US
dc.identifier.citationMol Vis. 2010 Oct 8; 16:2033-2042en_US
dc.identifier.issn1090-0535en_US
dc.identifier.pmid21042558en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/604-
dc.description.abstractPurpose: Diabetic retinopathy (DR) is associated with microglial activation and increased levels of inflammatory cytokines. Genistein, a tyrosine kinase inhibitor, has been shown to possess anti-inflammatory potential that so far untested in animal models of diabetes. The aims of this study are to evaluate the efficacy of genistein for alleviation of diabetes-induced retinal inflammation and also to gain insight into the molecular mechanisms involved therein by analyzing the effect of genistein on concomitant microglia activation in the diabetic retina and in isolated cells.en_US
dc.description.abstractMethods: Streptozotocin (STZ)-induced diabetic Sprague Dawley rats were used. After diabetes was established for two weeks a single intravitreal injection of genistein or vehicle was performed. Forty-eight hours later, rats were killed, their retinal and vitreal samples were processed for Quantitative Real Time-PCR (qRTâ PCR) and Enzyme-linked immunosorbent assay (ELISA) analyses, respectively. For the in vitro study, isolated microglial cells from retinas of newborn rats were used.en_US
dc.description.abstractResults: mRNA as well as protein levels for tumor necrosis factor α (TNF-α), a robust marker of inflammation, were increased in the retina early in the course of diabetes. Moreover, diabetes resulted in elevation of ionized calcium binding adaptor molecule-1 (Iba1) mRNA, known to be upregulated in activated microglia. These effects of diabetes in retina were all reduced by intervention treatment with genistein. Using an in vitro bioassay, we demonstrated the release of TNF- α from microglia activated by glycated albumin, a risk factor for diabetic disorders. This inflammatory signal involves the activation of tyrosine kinase and its subsequent events, ERK and P38 MAPKs. Genistein represses the release of TNF- α and significantly inhibits ERK and P38 phosphorylation in activated microglial cells by acting as a tyrosine kinase inhibitor.en_US
dc.description.abstractConclusions: These findings show genistein to be effective in dampening diabetes-induced retinal inflammation by interfering with inflammatory signaling (ERK and P38 MAPKs) that occurs in activated microglia. This beneficial effect of genistein may represent a new intervention therapy to modulate early pathological pathways long before the occurrence of vision loss among diabetics.en_US
dc.rightsCopyright © 2010 Molecular Vision.en_US
dc.subjectResearch Articleen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAnti-Inflammatory Agentsen_US
dc.subject.meshDiabetes Mellitus, Experimentalen_US
dc.subject.meshDiabetic Retinopathyen_US
dc.subject.meshEnzyme Activationen_US
dc.subject.meshExtracellular Signal-Regulated MAP Kinasesen_US
dc.subject.meshGenisteinen_US
dc.subject.meshInflammationen_US
dc.subject.meshIntravitreal Injectionsen_US
dc.subject.meshMaleen_US
dc.subject.meshMicrogliaen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProtein Kinase Inhibitorsen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshRetinaen_US
dc.subject.meshSerum Albuminen_US
dc.subject.meshTumor Necrosis Factor-alphaen_US
dc.subject.meshp38 Mitogen-Activated Protein Kinasesen_US
dc.titleGenistein attenuates retinal inflammation associated with diabetes by targeting of microglial activationen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2965567en_US
dc.contributor.corporatenameDepartment of Ophthalmology-
dc.contributor.corporatenameDepartment of Medicine-

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