Department of Pathology and Microbiology, College of Medicine , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States.
ACS Chem Neurosci. 2020 Feb 5;11(3):356-366. doi: 10.1021/acschemneuro.9b00566. Epub 2020 Jan 17.
The glyoxalase pathway (GP) is an antioxidant defense system that detoxifies metabolic byproduct methylglyoxal (MG). Through sequential reactions, reduced glutathione (GSH), glyoxalase I (glo-1), and glyoxalase II (glo-2) convert MG into d-lactate. Spontaneous reactions involving MG alter the structure and function of cellular macromolecules through the formation of inflammatory advanced glycation endproducts (AGEs). Accumulation of MG and AGEs in neural cells contributes to oxidative stress (OS), a state of elevated inflammation commonly found in neurodegenerative diseases including Alzheimer's disease (AD). Morin is a common plant-produced flavonoid polyphenol that exhibits the ability to enhance the GP-mediated detoxification of MG. We hypothesize that structural modifications to morin will improve its inherent GP enhancing ability. Here we synthesized a morin derivative, dibromo-morin (DBM), formulated a morin encapsulated nanoparticle (MNP), and examined their efficacy in enhancing neural GP activity. Cultured mouse primary cerebellar neurons and were induced to a state of OS with MG and treated with morin, DBM, and MNP. Results indicated the morin derivatives were more effective compared to the parent compound in neural GP enhancement and preventing MG-mediated OS in an AD model.
乙二醛酶途径（GP）是一种抗氧化防御系统，可解毒代谢副产物甲基乙二醛（MG）。通过连续反应，还原型谷胱甘肽（GSH）、乙二醛酶 I（glo-1）和乙二醛酶 II（glo-2）将 MG 转化为 d-乳酸。涉及 MG 的自发反应通过形成炎症性晚期糖基化终产物（AGEs）改变细胞大分子的结构和功能。MG 和 AGEs 在神经细胞中的积累导致氧化应激（OS），这是一种在包括阿尔茨海默病（AD）在内的神经退行性疾病中常见的炎症升高状态。桑色素是一种常见的植物产生的类黄酮多酚，具有增强 GP 介导的 MG 解毒的能力。我们假设对桑色素进行结构修饰将提高其内在的 GP 增强能力。在这里，我们合成了一种桑色素衍生物，二溴桑色素（DBM），并制备了一种桑色素包裹的纳米颗粒（MNP），并研究了它们在增强神经 GP 活性方面的功效。用 MG 诱导培养的小鼠原代小脑神经元和 诱导 OS，并分别用桑色素、DBM 和 MNP 进行处理。结果表明，与母体化合物相比，这些桑色素衍生物在神经 GP 增强和预防 AD 模型中 MG 介导的 OS 方面更有效。
