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.
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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DOI：
10.1016/j.prostaglandins.2017.08.003
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发表时间：
2017-11
影响因子：
2.9
通讯作者：
Hammock BD
中科院分区：
文献类型：
--
作者：
Inceoglu B;Bettaieb A;Haj FG;Gomes AV;Hammock BD
花生四烯酸级联可以说是最广为人知的生物调控途径。在涉及其环加氧酶和脂加氧酶分支的开创性发现几十年后，对这一级联的研究仍然是一个活跃的研究领域。第三个鲜为人知的分支，细胞色素P450途径导致高活性的氧合脂质介质，环氧脂肪酸（EpFAs）和羟基二碳四烯酸（HETEs），它们与前列腺素和白三烯具有相似的效力。与COX和LOX分支不同，目前还没有针对P450分支的药物上市。然而，数据支持调节这些调节性脂质介质的治疗益处。这是通过稳定或模仿epfa甚至通过改变饮食来实现的。这些方法对广泛的明显不相关的状态产生了主要有益的影响，导致这一小群天然化学介质如何产生如此不同的影响成为一个谜。EpFAs被可溶性环氧化物水解酶（sEH）降解，并通过抑制该酶来稳定。在这篇综述中，我们重点介绍了EpFAs和可溶性环氧化物水解酶抑制剂（sEHI）作用机制的相互联系方面。sEHI和EpFAs通常在病理条件下保持稳态，而在正常生理条件下保持中性。在这里，我们提供了一个概念框架的独特和广泛的生物活性归因于环氧脂肪酸。我们认为，它们的作用机制取决于它们预防线粒体功能障碍、减少随后ROS形成和阻断由此产生的细胞信号级联反应（主要是内质网应激）的能力。通过稳定线粒体- ROS -内质网应激轴，EpFAs和sEHI的活性范围与糖尿病、纤维化、慢性疼痛、心血管和神经退行性疾病等疾病重叠，上述机制在这些疾病中发挥关键作用。
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.
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DOI：
10.18632/aging.100459
发表时间：
2012-05
期刊：
Aging
影响因子：
--
作者：
Favaloro B;Allocati N;Graziano V;Di Ilio C;De Laurenzi V
通讯作者：
De Laurenzi V
影响因子：
--
作者：
Fulda S;Gorman AM;Hori O;Samali A
通讯作者：
Samali A
影响因子：
4.7
作者：
Fessel, JP;Hulette, C;Zhang, J
通讯作者：
Zhang, J
影响因子：
1.5
作者：
Adachi, Yusuke;Yamamoto, Keisuke;Mori, Kazutoshi
通讯作者：
Mori, Kazutoshi
影响因子：
4
作者：
Eletto, Davide;Chevet, Eric;Appenzeller-Herzog, Christian
通讯作者：
Appenzeller-Herzog, Christian