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首页> 外文期刊>Prostaglandins and Other Lipid Mediators >Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors
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Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

机译：线粒体功能障碍和内质网胁迫的调节是环氧脂肪酸和可溶性环氧化物水解酶抑制剂的宽范围作用的关键机制

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Highlights ? The mechanism of action of epoxy fatty acids and inhibitors of the soluble epoxide hydrolase pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. ? By stabilizing the mitochondrial – ROS – ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles. Abstract The arachidonic acid cascade is arguably the most widely known biologic regulatory pathway. Decades after the seminal discoveries involving its cyclooxygenase and lipoxygenase branches, studies of this cascade remain an active area of research. The third and less widely known branch, the cytochrome P450 pathway leads to highly active oxygenated lipid mediators, epoxy fatty acids (EpFAs) and hydroxyeicosatetraenoic acids (HETEs), which are of similar potency to prostanoids and leukotrienes. Unlike the COX and LOX branches, no pharmaceuticals currently are marketed targeting the P450 branch. However, data support therapeutic benefits from modulating these regulatory lipid mediators. This is being approached by stabilizing or mimicking the EpFAs or even by altering the diet. These approaches lead to predominantly beneficial effects on a wide range of apparently unrelated states resulting in an enigma of how this small group of natural chemical mediators can have such diverse effects. EpFAs are degraded by soluble epoxide hydrolase (sEH) and stabilized by inhibiting this enzyme. In this review, we focus on interconnected aspects of reported mechanisms of action of EpFAs and inhibitors of soluble epoxide hydrolase (sEHI). The sEHI and EpFAs are commonly reported to maintain homeostasis under pathological conditions while remaining neutral under normal physiological conditions. Here we provide a conceptual framework for the unique and broad range of biological activities ascribed to epoxy fatty acids. We argue that their mechanism of action pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. By stabilizing the mitochondrial – ROS – ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles.
机译：强调 ？环氧脂肪酸和可溶性环氧化物水解酶的抑制剂对其预防线粒体功能障碍的能力的作用机理，以减少随后的ROS形成和阻断导致蜂窝信号传导级联，主要是内质网应力。还通过稳定线粒体 - ROS - ER应力轴，EPFA和SEHI的活性范围显示出与糖尿病，纤维化，慢性疼痛，心血管和神经变性疾病的疾病病症重叠，上述概述机制起关键作用。摘要阿拉契酸级联可以说是已知最广泛的生物调节途径。涉及其环氧氧酶和脂氧合酶分支的精髓苷酸的初始发现，这级联的研究仍然是一个活跃的研究领域。三种众所周知的分支，细胞色素P450途径导致高活性的含氧脂质介质，环氧脂肪酸（EPFA）和羟基亚二甲醚（HETES），其对前列腺和白酮类的效力具有类似的效力。与COX和LOX分支不同，目前没有药物销售P450分支。然而，数据支持治疗益处调节这些调节脂质介质。通过稳定或模仿EPFA或甚至通过改变饮食来接近这一点。这些方法导致对广泛的明显无关状态产生的效果主要有益，导致这一小组自然化学介质的谜团可以具有这种多种不同的效果。 EPFA通过可溶的环氧化物水解酶（SEH）降解并通过抑制该酶稳定。在本文中，我们专注于互联的EPFAS和可溶性环氧化物水解酶（SEHI）的抑制剂的互联方面。据报道，SEHI和EPFA在病理条件下保持稳态，同时在正常生理条件下剩余中性。在这里，我们为归因于环氧脂肪酸的独特和广泛的生物活性提供了一种概念框架。我们认为，它们对预防线粒体功能障碍的能力进行动作枢转的机制，以减少随后的ROS形成和阻止产生的细胞信号传导级联，主要是内质网应力。通过稳定线粒体 - ROS - ER应力轴，EPFA和SEHI的活性范围显示出与糖尿病，纤维化，慢性疼痛，心血管和神经变性疾病的疾病病症重叠，上述概述机制起关键作用。

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