Department of Food Science and Technology, Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, 30100 Campus de Espinardo, Murcia, Spain.
Br J Nutr. 2010 Aug;104(4):503-12. doi: 10.1017/S0007114510000826. Epub 2010 Mar 26.
Previous studies have reported the anti-inflammatory properties of pomegranate extracts, suggesting that ellagitannins (ET) and ellagic acid (EA) are the main anti-inflammatory compounds. However, both ET and EA are metabolised in vivo by the gut microbiota to yield urolithins (Uro) which can be found in the gut and in systemic bloodstream. The present study was carried out to evaluate the individual effect of EA and their microbiota-derived metabolites Uro on colon fibroblasts upon IL-1beta treatment as an in vitro inflammation model. Uro-A and Uro-B (10 microm) inhibited PGE2 production (85 and 40 %, respectively) after IL-1beta stimulation, whereas EA did not show any effect. Uro-A, but not Uro-B, down-regulated cyclo-oxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) mRNA expression and protein levels. Both Uro inhibited NF-kappaB translocation to nucleus. Slight but significant effects were found in the activation of mitogen-activated protein kinase (MAPK) pathways. Uro-A lowered c-Jun N-terminal kinase phosphorylation state, and both Uro inhibited p38 activation. No metabolites derived from Uro or EA were found in the cell media upon incubation of EA or Uro with the cells, and only traces of the compounds were found inside the cells. The present results suggest that Uro, mainly Uro-A, are the main compounds that are responsible for the pomegranate anti-inflammatory properties. The mechanism of action implicated seems to be via the inhibition of activation of NF-kappaB and MAPK, down-regulation of COX-2 and mPGES-1 expressions, and consequently,via the reduction of PGE2 production. Taking into account that Uro did not enter the cells, a competitive binding for IL-1beta membrane receptor cannot be discarded.
先前的研究报告表明，石榴提取物具有抗炎特性，提示鞣花单宁（ET）和鞣花酸（EA）是主要的抗炎化合物。然而，ET 和 EA 在体内均由肠道微生物群代谢为尿石素（Uro），可在肠道和全身血液系统中找到。本研究旨在评估 EA 及其微生物群衍生代谢物 Uro 对 IL-1β刺激的结肠成纤维细胞的单独作用，作为体外炎症模型。Uro-A 和 Uro-B（10 微摩尔）抑制 PGE2 的产生（分别为 85%和 40%），而 EA 没有显示出任何作用。Uro-A 但不是 Uro-B 下调环氧化酶-2（COX-2）和微粒体 PGE 合酶-1（mPGES-1）mRNA 表达和蛋白水平。两者均抑制 NF-κB 向核内易位。MAPK 途径的激活也发现了轻微但显著的影响。Uro-A 降低 c-Jun N 末端激酶磷酸化状态，两者均抑制 p38 激活。在 EA 或 Uro 与细胞孵育时，在细胞培养基中未发现源自 Uro 或 EA 的任何代谢物，并且仅在细胞内发现化合物的痕迹。目前的结果表明，Uro，主要是 Uro-A，是石榴抗炎特性的主要化合物。所涉及的作用机制似乎是通过抑制 NF-κB 和 MAPK 的激活、下调 COX-2 和 mPGES-1 的表达，从而减少 PGE2 的产生。考虑到 Uro 未进入细胞，不能排除其对 IL-1β 膜受体的竞争性结合。
