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      Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: An Emerging Therapeutic Target

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          Abstract

          Cytochrome P450-mediated metabolism of arachidonic acid (AA) is an important pathway for the formation of eicosanoids. The ω-hydroxylation of AA generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in various tissues. In the current review, we discussed the role of 20-HETE in the kidney, liver, lung, and brain during physiological and pathophysiological states. Moreover, we discussed the role of 20-HETE in tumor formation, metabolic syndrome and diabetes. In the kidney, 20-HETE is involved in modulation of preglomerular vascular tone and tubular ion transport. Furthermore, 20-HETE is involved in renal ischemia/reperfusion (I/R) injury and polycystic kidney diseases. The role of 20-HETE in the liver is not clearly understood although it represents 50%–75% of liver CYP-dependent AA metabolism, and it is associated with liver cirrhotic ascites. In the respiratory system, 20-HETE plays a role in pulmonary cell survival, pulmonary vascular tone and tone of the airways. As for the brain, 20-HETE is involved in cerebral I/R injury. Moreover, 20-HETE has angiogenic and mitogenic properties and thus helps in tumor promotion. Several inhibitors and inducers of the synthesis of 20-HETE as well as 20-HETE analogues and antagonists are recently available and could be promising therapeutic options for the treatment of many disease states in the future.

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          Epoxides and soluble epoxide hydrolase in cardiovascular physiology.

           John D. Imig (2011)
          Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that importantly contribute to vascular and cardiac physiology. The contribution of EETs to vascular and cardiac function is further influenced by soluble epoxide hydrolase (sEH) that degrades EETs to diols. Vascular actions of EETs include dilation and angiogenesis. EETs also decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis. Myocyte contraction and increased coronary blood flow are the two primary EET actions in the heart. EET cell signaling mechanisms are tissue and organ specific and provide significant evidence for the existence of EET receptors. Additionally, pharmacological and genetic manipulations of EETs and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases. Given the impact of EETs to cardiovascular physiology, there is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases.
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            The growth of acute kidney injury: a rising tide or just closer attention to detail?

            Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mortality, prolonged hospital stay, and accelerated chronic kidney disease (CKD). Over the past 2 decades, dramatic rises in the incidences of AKI have been reported, particularly within the United States. The question arises as to whether these changes reflect actual increases in disease incidence, or are potentially explained by the introduction of consensus definitions that rely on small standardized changes in serum creatinine, changes in coding and reimbursement, or increasingly available and more liberal use of dialysis. In this review, we explore the secular trends in AKI incidence in North America and Western Europe and its potential contributors.
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              Astrocyte control of the cerebrovasculature.

              The control of cerebral vessel diameter is of fundamental importance in maintaining healthy brain function because it is critical to match cerebral blood flow (CBF) to the metabolic demand of active neurons. Recent studies have shown that astrocytes are critical players in the regulation of cerebral blood vessel diameter and that there are several molecular pathways through which astrocytes can elicit these changes. Increased intracellular Ca(2+) in astrocytes has demonstrated a dichotomy in vasomotor responses by causing the constriction as well as the dilation of neighboring blood vessels. The production of arachidonic acid (AA) in astrocytes by Ca(2+) sensitive phospholipase A(2) (PLA(2)) has been shown to be common to both constriction and dilation mechanisms. Constriction results from the conversion of AA to 20-hydroxyeicosatetraenoic acid (20-HETE) and dilation from the production of prostaglandin E(2) (PGE2) or epoxyeicosatrienoic acid (EET) and the level of nitric oxide (NO) appears to dictate which of these two pathways is recruited. In addition the activation of Ca(2+) activated K(+) channels in astrocyte endfeet and the efflux of K(+) has also been suggested to modify vascular tone by hyperpolarization and relaxation of smooth muscle cells (SMCs). The wide range of putative pathways indicates that more work is needed to clarify the contributions of astrocytes to vascular dynamics under different cellular conditions. Nonetheless it is clear that astrocytes are important albeit complicated regulators of CBF.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                20 February 2017
                March 2017
                : 9
                : 1
                Affiliations
                [1 ]Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada; oshenawy@ 123456ualberta.ca (O.H.E.); shoieb@ 123456ualberta.ca (S.M.S.); anwarmoh@ 123456ualberta.ca (A.M.)
                [2 ]Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
                Author notes
                [* ]Correspondence: aelkadi@ 123456ualberta.ca ; Tel.: 780-492-3071; Fax: 780-492-1217
                Article
                pharmaceutics-09-00009
                10.3390/pharmaceutics9010009
                5374375
                28230738
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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