کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8258396 | 1534604 | 2018 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration
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کلمات کلیدی
AMDlecithin retinol acyltransferaseLRATSTGDA2EIRBPRPE65Light-induced retinal damageABCA4RPEIPMretinal pigment epithelium - اپیتلیوم رنگدانه شبکیهStargardt's disease - بیماری استارگاردAll-trans-retinol - تمام ترانس رتینولretinal degeneration - دژنراسیون شبکیهage-related macular degeneration - سن تخریب ماکولا مربوط به سن استEnzyme inhibitor - مهارکننده آنزیمInterphotoreceptor retinoid-binding protein - پروتئین اتصال دهنده رتینوئید اینترفوتوریسپتورVisual cycle - چرخه ویژوال
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
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چکیده انگلیسی
The retinoid visual cycle is an ocular retinoid metabolism specifically dedicated to support vertebrate vision. The visual cycle serves not only to generate light-sensitive visual chromophore 11-cis-retinal, but also to clear toxic byproducts of normal visual cycle (i.e. all-trans-retinal and its condensation products) from the retina, ensuring both the visual function and the retinal health. Unfortunately, various conditions including genetic predisposition, environment and aging may attribute to a functional decline of the all-trans-retinal clearance. To combat all-trans-retinal mediated retinal degeneration, we sought to slow down the retinoid influx from the RPE by inhibiting the visual cycle with a small molecule. The present study describes identification of CU239, a novel non-retinoid inhibitor of RPE65, a key enzyme in the visual cycle. Our data demonstrated that CU239 selectively inhibited isomerase activity of RPE65, with IC50 of 6â¯Î¼M. Further, our results indicated that CU239 inhibited RPE65 via competition with its substrate all-trans-retinyl ester. Mice with systemic injection of CU239 exhibited delayed chromophore regeneration after light bleach, and conferred a partial protection of the retina against injury from high intensity light. Taken together, CU239 is a potent visual cycle modulator and may have a therapeutic potential for retinal degeneration.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1864, Issue 7, July 2018, Pages 2420-2429
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1864, Issue 7, July 2018, Pages 2420-2429
نویسندگان
Younghwa Shin, Gennadiy Moiseyev, Konstantin Petrukhin, Christopher L. Cioffi, Parthasarathy Muthuraman, Yusuke Takahashi, Jian-xing Ma,