1. HIF-prolyl hydroxylase is a potential molecular target for esculetin-mediated anti-colitic effects.
- Author
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Yum, Soohwan, Jeong, Seongkeun, Lee, Sunyoung, Kim, Wooseong, Nam, Joon, and Jung, Yunjin
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PEPTIC ulcer prevention , *COLITIS prevention , *ALTERNATIVE medicine , *ANIMAL experimentation , *ANTI-inflammatory agents , *BIOLOGICAL models , *BIOPHYSICS , *ENZYME inhibitors , *INTESTINAL mucosa , *RESEARCH methodology , *RATS , *RECTAL medication , *PLANT extracts , *VASCULAR endothelial growth factors , *DESCRIPTIVE statistics , *IN vitro studies , *PHARMACODYNAMICS - Abstract
We investigated a potential molecular target for anti-colitic effects of esculetin, 6,7-dihydroxycoumarin. Esculetin administered rectally effectively ameliorated TNBS-induced rat colitis and attenuated the expression of pro-inflammatory mediators in the inflamed colon. In human colon carcinoma HCT116 cells, esculetin induced hypoxia-inducible factor-1α (HIF-1α), leading to secretion of vascular endothelial growth factor, a HIF-1 target gene product involved in ulcer healing of the gastrointestinal mucosa. Esculetin directly inhibited HIF prolyl hydroxylase-2 (HPH-2), an enzyme playing a major role in negatively regulating HIF-1α protein stability. Esculetin inhibition of HPH and consequent induction of HIF-1α were attenuated by escalating dose of either ascorbate or 2-ketoglutarate, the required factors of the enzyme. Structurally, the catechol moiety in esculetin was required for HPH inhibition. Collectively, HPH may be a molecular target for esculetin-mediated anti-colitic effects and the catechol moiety in esculetin is the pharmacophore for HPH inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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