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Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy
PURPOSE: Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR. METHODS: The tran...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The Association for Research in Vision and Ophthalmology
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633008/ https://www.ncbi.nlm.nih.gov/pubmed/28979999 http://dx.doi.org/10.1167/iovs.16-21402 |
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author | Deng, Guotao Moran, Elizabeth P. Cheng, Rui Matlock, Greg Zhou, Kelu Moran, David Chen, Danyang Yu, Qiang Ma, Jian-Xing |
author_facet | Deng, Guotao Moran, Elizabeth P. Cheng, Rui Matlock, Greg Zhou, Kelu Moran, David Chen, Danyang Yu, Qiang Ma, Jian-Xing |
author_sort | Deng, Guotao |
collection | PubMed |
description | PURPOSE: Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR. METHODS: The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model. RESULTS: A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPARα agonists, activated PPARα transcriptional activity and upregulated PPARα expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-κB signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model. CONCLUSIONS: Y-0452 is a novel PPARα agonist and has therapeutic potential for DR. |
format | Online Article Text |
id | pubmed-5633008 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Association for Research in Vision and Ophthalmology |
record_format | MEDLINE/PubMed |
spelling | pubmed-56330082017-10-18 Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy Deng, Guotao Moran, Elizabeth P. Cheng, Rui Matlock, Greg Zhou, Kelu Moran, David Chen, Danyang Yu, Qiang Ma, Jian-Xing Invest Ophthalmol Vis Sci Retina PURPOSE: Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR. METHODS: The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model. RESULTS: A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPARα agonists, activated PPARα transcriptional activity and upregulated PPARα expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-κB signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model. CONCLUSIONS: Y-0452 is a novel PPARα agonist and has therapeutic potential for DR. The Association for Research in Vision and Ophthalmology 2017-10 /pmc/articles/PMC5633008/ /pubmed/28979999 http://dx.doi.org/10.1167/iovs.16-21402 Text en Copyright 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
spellingShingle | Retina Deng, Guotao Moran, Elizabeth P. Cheng, Rui Matlock, Greg Zhou, Kelu Moran, David Chen, Danyang Yu, Qiang Ma, Jian-Xing Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy |
title | Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy |
title_full | Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy |
title_fullStr | Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy |
title_full_unstemmed | Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy |
title_short | Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy |
title_sort | therapeutic effects of a novel agonist of peroxisome proliferator-activated receptor alpha for the treatment of diabetic retinopathy |
topic | Retina |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633008/ https://www.ncbi.nlm.nih.gov/pubmed/28979999 http://dx.doi.org/10.1167/iovs.16-21402 |
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