کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8270226 | 1534970 | 2014 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts
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کلمات کلیدی
Dnmt1PSCeIF2αRT-qPCRPDIATFNrf2LECDNA methyltransferase 1GLO-1TET1nuclear factor erythroid-2-related factor 2Ero1ER oxidoreductin 12′,7′-dichlorodihydrofluorescein diacetate - 2 '، 7'-dichlorodihydrofluorescein diacetate5-mC - 5 سانتیمتر5-Aza-2′-deoxycytidine - 5-Aza-2'-deoxycytidine5-Methylcytosine - 5-متیل سیتوزین5-Aza - 5-نهkeap1 - buy1C/EBP-homologous protein - C / EBP-homologous proteinIRE1α - IRE1aPKR-like endoplasmic reticulum kinase - PKR-like reticulum kinase endoplasmicROS - ROSAge-related cataract - آب مروارید وابسته به سنinositol-requiring enzyme 1α - آنزیم 1α مورد نیاز به آنزیم استCHOP - تکه کردنreal-time quantitative PCR - زمان واقعی PCR کمیLens epithelial cell - سلول اپیتلیال لنزHuman lens epithelial cell - سلول اپیتلیال لنز انسانیAge - سنendoplasmic reticulum - شبکه آندوپلاسمی eukaryotic translation initiation factor 2α - عامل آغازگر ترجمه یوکاریوتی 2αantioxidant-response element - عنصر پاسخ آنتی اکسیدانیActivation-induced deaminase - فعال سازی deaminase ناشی ازactivating transcription factor - فعال کردن عامل رونویسیArc - قوسMethylglyoxal - متیل گلی اکسالAdvanced glycation end-product - محصول نهایی پیشرفته glycationMgO - منیزیم اکسید ARE - هستندprotein disulfide isomerase - پروتئین دیسولفید ایزومرازKelch-like ECH-associated protein 1 - پروتئین مرتبط با ECH کلچ 1PERK - پرکposterior subcapsular cataract - کاتاراکت زیر کپسول خلفیAID - کمکglutathione reductase - گلوتاتیون ردوکتازGlyoxalase 1 - گلیوکسیلاز 1Reactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
Age-related cataracts are a leading cause of blindness. Previously, we have demonstrated the association of the unfolded protein response with various cataractogenic stressors. However, DNA methylation alterations leading to suppression of lenticular antioxidant protection remains unclear. Here, we report the methylglyoxal-mediated sequential events responsible for Keap1 promoter DNA demethylation in human lens epithelial cells, because Keap1 is a negative regulatory protein that regulates the Nrf2 antioxidant protein. Methylglyoxal induces endoplasmic reticulum stress and activates the unfolded protein response leading to overproduction of reactive oxygen species before human lens epithelial cell death. Methylglyoxal also suppresses Nrf2 and DNA methyltransferases but activates the DNA demethylation pathway enzyme TET1. Bisulfite genomic DNA sequencing confirms the methylglyoxal-mediated Keap1 promoter DNA demethylation leading to overexpression of Keap1 mRNA and protein. Similarly, bisulfite genomic DNA sequencing shows that human clear lenses (n = 15) slowly lose 5-methylcytosine in the Keap1 promoter throughout life, at a rate of 1% per year. By contrast, diabetic cataractous lenses (n = 21) lose an average of 90% of the 5-methylcytosine regardless of age. Overexpressed Keap1 protein is responsible for decreasing Nrf2 by proteasomal degradation, thereby suppressing Nrf2-dependent stress protection. This study demonstrates for the first time the associations of unfolded protein response activation, Nrf2-dependent antioxidant system failure, and loss of Keap1 promoter methylation because of altered active and passive DNA demethylation pathway enzymes in human lens epithelial cells by methylglyoxal. As an outcome, the cellular redox balance is altered toward lens oxidation and cataract formation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 72, July 2014, Pages 134-148
Journal: Free Radical Biology and Medicine - Volume 72, July 2014, Pages 134-148
نویسندگان
Periyasamy Palsamy, Keshore R. Bidasee, Masahiko Ayaki, Robert C. Augusteyn, Jefferson Y. Chan, Toshimichi Shinohara,