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Publication
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.
Authors Inceoglu B, Bettaieb A, Haj FG, Gomes AV, Hammock BD
Submitted By Submitted Externally on 11/16/2018
Status Published
Journal Prostaglandins & other lipid mediators
Year 2017
Date Published 11/1/2017
Volume : Pages 133 : 68 - 78
PubMed Reference 28847566
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.




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