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

作者：Yum Soohwan; Jeong Seongkeun; Lee Sunyoung; Kim Wooseong; Nam Joon; Jung Yunjin^*

来源：Fitoterapia, 2015, 103: 55-62.

DOI：10.1016/j.fitote.2015.03.013

• Esculetin
• Hypoxia inducible factor-1
• HIF-prolyl hydroxylase
• Colitis
• Pharmacophore
• Anti-colitic mechanism

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-1 alpha (HIF-1 alpha), 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-1 alpha protein stability. Esculetin inhibition of HPH and consequent induction of HIF-1 alpha 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.

• 出版日期2015-6