Department of Chemistry and Biochemistry, Université de Moncton, Moncton, Canada (M.S.D., J.-L.J., S.J.P., M.C., J.L.L., M.E.S., N.P., M.T., L.H.B.) and Centre de Recherche, Département de Médecine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada (S.J.P.).
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, Canada (M.S.D., J.-L.J., S.J.P., M.C., J.L.L., M.E.S., N.P., M.T., L.H.B.) and Centre de Recherche, Département de Médecine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada (S.J.P.)
Mol Pharmacol. 2019 Jan;95(1):139-150. doi: 10.1124/mol.118.113480. Epub 2018 Nov 7.
The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12()-hydroxyeicosatetraenoic acid [12()-HETE] lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12()-lipoxygenase pathway. The effects of the abundance of 12()-HETE and its contribution to several chronic inflammatory diseases have been well studied over the last few years. While most developed compounds primarily target the 5-lipoxygenase (5-LO) or the cyclooxygenase (COX) pathways, very few compounds selectively inhibiting the 12-lipoxygenase (12-LO) pathway are known. In this study, we examined whether the distribution of hydroxyl groups among flavones could influence their potency as 12-LO inhibitors. Using human platelets, the human embryonic kidney 293 (HEK293) cell line expressing 5-LO, and human polymorphonuclear leukocytes (PMNLs) we investigated the effects of these compounds on several inflammatory pathways, namely, 12-LO, 5-LO, and COX. Using high-resolution respirometry and flow cytometry, we also evaluated some normal cell functions that could be modulated by our compounds. We identified a peracetylated quercetin (compound ) that exerts potent inhibitory activity toward the platelet 12-LO pathway (IC = 1.53 M) while having a lesser affinity toward the COX pathway. This study characterizes the peracetylated quercetin (compound ) as a more selective platelet-type 12-LO inhibitor than baicalein, with no measurable nontargeted effects on the platelet's activation or overall cell's oxygen consumption.
炎症反应是宿主防御病原体所必需的；然而，前列腺素类物质的不受控制或不受调节的产生与几种慢性炎症性疾病有关。因此，参与前列腺素类物质产生的酶被作为潜在治疗方法的靶点也就不足为奇了。12（）-羟基二十碳四烯酸[12（）-HETE]脂质介质是在各种疾病中大量产生的炎症分子之一，主要通过 12（）-脂氧合酶途径生物合成。在过去的几年中，大量研究了 12（）-HETE 的丰度及其对几种慢性炎症性疾病的贡献。虽然大多数已开发的化合物主要针对 5-脂氧合酶（5-LO）或环氧化酶（COX）途径，但已知很少有化合物可选择性抑制 12-脂氧合酶（12-LO）途径。在这项研究中，我们研究了黄酮类化合物中羟基的分布是否会影响其作为 12-LO 抑制剂的效力。使用人血小板、表达 5-LO 的人胚肾 293（HEK293）细胞系和人多形核白细胞（PMN），我们研究了这些化合物对几种炎症途径（即 12-LO、5-LO 和 COX）的影响。使用高分辨率呼吸测量法和流式细胞术，我们还评估了一些可能被我们的化合物调节的正常细胞功能。我们确定了一种具有活性的乙酰化槲皮素（化合物），其对血小板 12-LO 途径具有强烈的抑制作用（IC = 1.53 M），而对 COX 途径的亲和力较低。这项研究将乙酰化槲皮素（化合物）描述为比黄芩素更具选择性的血小板 12-LO 抑制剂，对血小板的激活或细胞整体耗氧量没有可测量的非靶向作用。
