Eupatilin with Heme Oxygenase-1-Inducing Ability Protects Cultured Feline Esophageal Epithelial Cells from Cell Damage Caused by Indomethacin
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- Song Hyun Ju
- Department of Pharmacology, College of Pharmacy, Chung Ang University
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- Shin Chang Yell
- Research Laboratory, Dong-A Pharmaceutical Co., Ltd.
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- Oh Tae Young
- Research Laboratory, Dong-A Pharmaceutical Co., Ltd.
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- Min Young Sil
- Department of Pharmacology, College of Pharmacy, Chung Ang University
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- Park Eon Sub
- Department of Pathology, College of Medicine, Chung Ang University
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- Sohn Uy Dong
- Department of Pharmacology, College of Pharmacy, Chung Ang University
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Abstract
We previously reported that eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) extracted from Artemisia asiaitica, augmented the cellular antioxidant defense capacity through induction of the antioxidant protein heme oxygenase-1 (HO-1), thereby protecting ileal smooth muscle cells from nonsteroidal anti-inflammatory drug (NSAID)-induced intestinal toxicity. In the present study, we used cultured feline esophageal epithelial cells (EEC) to investigate the ability of eupatilin to induce expression of HO-1 and to analyze its cytoprotective effect against indomethacin-induced damage, since NSAID users have a higher risk of esophageal ulcers or esophagitis than non-NSAID users. A culture of EEC from cat was prepared. The identity of the cultures was confirmed by immunocytochemistry using cytokeratin antibodies. Western blot analysis showed a concentration- and time- dependent expression of HO-1 in response to eupatilin. Phosphorylation of extracellular regulating protein kinase (ERKs) and Akt, and nuclear translocation of nuclear related factor 2 (Nrf2) were induced by 150 μM eupatilin in a time-dependent manner. Eupatilin-induced HO-1 expression and Nrf2 were partly attenuated by MEK inhibitor PD98059 and almost completely by phosphatidyl-inactiol 3 kinase (PI3K) inhibitor LY294002, but not by c-Jun N-terminal kinase (JNK) inhibitor SP600125 or p38 mitogen activated protein kinase (MAPK) inhibitor SB202190. MTT assay showed that treatment with 2 mM indomethacin for 2 h decreased cell viability to about 41%. Pre-treatment of cells with eupatilin resulted in the dose-dependent inhibition of indomethacin-induced cell damage. We confirmed that ZnPP, an HO-1 inhibitor, repressed eupatilin-induced HO-1 activity and showed the protective effect of eupatilin against indomethacin-induced cell injury. The data suggested that HO-1 was partly responsible for the eupatilin-mediated protective action of esophageal epithelial cells against indomethacin via both ERKs and PI3K/Akt pathways as well as Nrf2 translocation.
Journal
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- Biological and Pharmaceutical Bulletin
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Biological and Pharmaceutical Bulletin 32 (4), 589-596, 2009
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390282679600981888
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- NII Article ID
- 110007160697
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- NII Book ID
- AA10885497
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- COI
- 1:CAS:528:DC%2BD1MXmsVGmu70%3D
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- ISSN
- 13475215
- 09186158
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- NDL BIB ID
- 10194223
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- PubMed
- 19336889
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed