Document Details
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Document Type |
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Article In Journal |
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Document Title |
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Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation |
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Document Language |
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English |
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Abstract |
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Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for antioxidant and anti-inflammation enzymes that binds to its endogenous inhibitor protein, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1, in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses, such as ionizing radiation (IR), can disrupt the Nrf2-Kelch-like ECH-associated protein 1 complex. This allows Nrf2 to translocate from the cytoplasm into the nucleus to induce transcription of heme oxygenase-1 and other cytoprotective enzymes through binding to antioxidant responsive elements. However, how Nrf2 protects cells from IR-induced damage remains unclear. Here, we report that Nrf2 activation by the synthetic triterpenoids, bardoxolone methyl (BARD) and 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide, protects colonic epithelial cells against IR-induced damage, in part, by enhancing signaling of the DNA damage response. Pretreatment with BARD reduced the frequency of both G1 and S/G2 chromosome aberrations and enhanced the disappearance of repairosomes (C-terminal binding protein interacting protein, Rad51, and p53 binding protein-1 foci) after IR. BARD protected cells from IR toxicity in a Nrf2-dependent manner. The p53 binding protein-1 promoter contains three antioxidant responsive elements in which Nrf2 directly binds following BARD treatment. In addition, 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide provided before exposure to a lethal dose of whole-body irradiation protected WT mice from DNA damage and acute gastrointestinal toxicity, which resulted in improved overall survival. These results demonstrate that Nrf2 activation by synthetic triterpenoids is a promising candidate target to protect the gastrointestinal tract against acute IR in vitro and in vivo. |
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ISSN |
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0027-8424 |
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Journal Name |
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Proceedings of the National Academy of Sciences |
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Volume |
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109 |
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Issue Number |
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43 |
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Publishing Year |
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1433 AH
2012 AD |
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Article Type |
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Article |
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Added Date |
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Thursday, March 10, 2016 |
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Researchers
| Sang Bum Kim | Kim, Sang Bum | Investigator | | |
| Raj K Pandita | Pandita, Raj K | Researcher | | |
| Ugur Eskiocak | Eskiocak, Ugur | Researcher | | |
| Peter Ly | Ly, Peter | Researcher | | |
| Aadil Kaisani | Kaisani, Aadil | Researcher | | |
| Rakesh Kumar | Kumar, Rakesh | Researcher | | |
| Crystal Cornelius | Cornelius, Crystal | Researcher | | |
| Woodring E Wright | Wright, Woodring E | Researcher | | |
| Tej K Pandita | Pandita, Tej K | Researcher | | |
| Jerry W Shay | Shay, Jerry W | Researcher | | |
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