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Mridul Mukherji, VK Chaithanya Ponnaluri, Ramya Krishna Vadlapatla, Ashim K Mitra, Divya Teja Vavilala; Inhibitors of HIF-mediated Epigenetic Expression of Histone Demethylases for Diabetic Retinopathy Treatment. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3296.
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We have recently shown that hypoxia induces the expression of a number of histone lysine demethylases (KDMs) in retinal pigment epithelial cells. The objective of this study was to identify phytochemicals which inhibit the expression of these KDMs and therefore, can be used to treat a number of retinal diseases caused by hypoxia induces neovascularization.
Since retinal pigment epithelial cells are one of the major cell constituents and secretors of VEGF in the retina, a human retinal pigment epithelial cell line (D407) was used for these studies. The expressions of KDMs in D407 cells were compared using qPCR under the normoxic and hypoxic conditions. Using this assay a number of phytochemicals were screened to evaluate their efficacy as expression inhibitors of KDMs and pro-angiogenic factors. Further molecular characterizations of these phytochemicals were performed using immunoblot and cytotoxicity assays.
Using the above methods two phytochemicals, MM-1225 and MM-1226, were identified which inhibited HIF pathway and reduce the expression of KDMs and other pro-angiogenic genes in retinal pigment epithelial cells in a dose-dependent manner. The cytotoxicity assays suggest that these phytochemicals were nontoxic up to 20 microM and 50 microM concentrations, respectively.
This study demonstrates for the first time that MM-1225 and MM-1226 inhibit the epigenetic regulation mediated by HIF pathway. These findings suggest that therapeutic use of these phytochemicals can be a new avenue to treat retinal diseases caused by hypoxia induces neovascularization such as diabetic retinopathy.
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