Yum Soohwan, Jeong Seongkeun, Lee Sunyoung, Kim Wooseong, Nam Joon, Jung Yunjin
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea.
Fitoterapia. 2015 Jun;103:55-62. doi: 10.1016/j.fitote.2015.03.013. Epub 2015 Mar 20.
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.
我们研究了七叶亭（6,7 - 二羟基香豆素）抗结肠炎作用的潜在分子靶点。经直肠给予七叶亭可有效改善三硝基苯磺酸（TNBS）诱导的大鼠结肠炎，并减弱炎症结肠中促炎介质的表达。在人结肠癌HCT116细胞中，七叶亭诱导缺氧诱导因子 - 1α（HIF - 1α），导致血管内皮生长因子分泌，血管内皮生长因子是一种参与胃肠道黏膜溃疡愈合的HIF - 1靶基因产物。七叶亭直接抑制HIF脯氨酰羟化酶 - 2（HPH - 2），该酶在负向调节HIF - 1α蛋白稳定性中起主要作用。随着抗坏血酸或2 - 酮戊二酸（该酶所需的因子）剂量的增加，七叶亭对HPH的抑制作用以及随后对HIF - 1α的诱导作用均减弱。在结构上，七叶亭中的儿茶酚部分是抑制HPH所必需的。总体而言，HPH可能是七叶亭介导的抗结肠炎作用的分子靶点，且七叶亭中的儿茶酚部分是抑制HPH的药效基团。
