title: HIF-prolyl hydroxylase is a potential molecular target for esculetin-mediated anti-colitic effects.
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.
authors: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors: Soohwan
authors: S
authors: Yum
authors: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors: Seongkeun
authors: S
authors: Jeong
authors: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors: Sunyoung
authors: S
authors: Lee
authors: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors: Wooseong
authors: W
authors: Kim
authors: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors: Joon
authors: J
authors: Nam
authors: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea. Electronic address: jungy@pusan.ac.kr.
authors: Yunjin
authors: Y
authors: Jung
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014468:Umbelliferones / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014468:Umbelliferones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C007628:esculetin
keywords: 2-Ketoglutarate (PubChem CID: 164533); Anti-colitic mechanism; Ascorbic acid (PubChem CID: 54670067); Catechol (PubChem CID: 289); Colitis; Coumarin (PubChem CID: 323); Esculetin; Esculetin (PubChem CID: 5281416); HIF-prolyl hydroxylase; Hypoxia inducible factor-1; Pharmacophore; Scopoletin (PubChem CID: 5280460)