HIF-prolyl hydroxylase is a potential molecular target for esculetin-mediated anti-colitic effects

Fitoterapia
Soohwan YumYunjin Jung

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.

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Citations

Feb 13, 2018·Molecular and Cellular Biochemistry·Renganathan SelvasundaramRadhakrishnan Murali Naidu
Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Luiz C Di Stasi
Oct 19, 2021·Cell Biology International·Jiuheng YinHua Yang
Nov 23, 2021·Phytotherapy Research : PTR·Linlin ZhangXiaofang Li

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