Oxylipin

Last updated
The structural formulae of selected oxylipins Oxylipins.jpg
The structural formulae of selected oxylipins

Oxylipins constitute a family of oxygenated natural products which are formed from fatty acids by pathways involving at least one step of dioxygen-dependent oxidation. [1] These small polar lipid compounds are metabolites of polyunsaturated fatty acids (PUFAs) including omega-3 fatty acids and omega-6 fatty acids. [2] [3] Oxylipins are formed by enyzmatic or non-enzymatic oxidation of PUFAs. [2]

Contents

In animal species, four main pathways of oxylipin production prevail: lipoxygenases (LOXs) pathway, cyklooxygenases (COXs) route, cytochrome P450 (CYPs) pathway, and reactive oxygen species (ROS) route. [4] These pathways result in formation of many different oxylipin molecules which are important for number of processes in living organisms. The processes include inflamation, blood flow, energy metabolism, cellular life, cell signaling, or muscle contractions. [2] [3] [4] Oxylipins have both pro- and anti-inflamatory roles. [5]

Oxylipins are widespread in aerobic organisms including plants, animals and fungi. Many of oxylipins have physiological significance. [6] [7] Typically, oxylipins are not stored in tissues but are formed on demand by liberation of precursor fatty acids from esterified forms.

Biosynthesis

Biosynthesis of oxylipins is initiated by dioxygenases or monooxygenases; however also non-enzymatic autoxidative processes contribute to oxylipin formation (phytoprostanes, isoprostanes). Dioxygenases include lipoxygenases (plants, animals, fungi), heme-dependent fatty acid oxygenases (plants, fungi), and cyclooxygenases (animals). Fatty acid hydroperoxides or endoperoxides are formed by action of these enzymes. Monooxygenases involved in oxylipin biosynthesis are members of the cytochrome P450 superfamily and can oxidize double bonds with epoxide formation or saturated carbons forming alcohols. Nature has evolved numerous enzymes which metabolize oxylipins into secondary products, many of which possess strong biological activity. Of special importance are the cytochrome P450 enzymes in animals, including CYP5A1 (thromboxane synthase), CYP8A1 (prostacyclin synthase), and the CYP74 family of hydroperoxide-metabolizing enzymes in plants, lower animals and bacteria. In the plant and animal kingdoms the C18 and C20 polyenoic fatty acids, respectively, are the major precursors of oxylipins.

Structure and function

Oxylipins in animals, referred to as eicosanoids (Greek icosa; twenty) because of their formation from twenty-carbon essential fatty acids, have potent and often opposing effects on e.g. smooth muscle (vasculature, myometrium) and blood platelets. Certain eicosanoids (leukotrienes B4 and C4) are proinflammatory whereas others (resolvins, protectins) are antiinflammatory and are involved in the resolution process which follows tissue injury. Plant oxylipins are mainly involved in control of ontogenesis, reproductive processes and in the resistance to various microbial pathogens and other pests.

Oxylipins most often act in an autocrine or paracrine manner, notably in targeting peroxisome proliferator-activated receptors (PPARs) to modify adipocyte formation and function. [8]

Most oxylipins in the body are derived from linoleic acid or alpha-linolenic acid. Linoleic acid oxylipins are usually present in blood and tissue in higher concentrations than any other PUFA oxylipin, despite the fact that alpha-linolenic acid is more readily metabolized to oxylipin. [9]

Linoleic acid oxylipins can be anti-inflammatory, but are more often pro-inflammatory, associated with atherosclerosis, non-alcoholic fatty liver disease, and Alzheimer's disease. [9] Centenarians have shown reduced levels of linoleic acid oxylipins in their blood circulation. [10] Lowering dietary linoleic acid results in fewer linoleic acid oxylipins in humans. [11] From 1955 to 2005 the linoleic acid content of human adipose tissue has risen an estimated 136% in the United States. [12]

In general, oxylipins derived from omega-6 fatty acids are more pro-inflammatory, vasoconstrictive, and proliferative than those derived from omega-3 fatty acids. [9] The omega-3 eicosapentaenoic acid (EPA)-derived and docosahexaenoic acid (DHA)-derived oxylipins are anti-inflammatory and vasodilatory. [9] In a clinical trial of men with high triglycerides, 3 grams daily of DHA compared with placebo (olive oil) given for 91 days nearly tripled the DHA in red blood cells while reducing oxylipins in those cells. [13] Both groups were given Vitamin C (ascorbyl palmitate) and Vitamin E (mixed tocopherol) supplements. [13]

Oxylipins and disease

Oxylipins play important role in many diseases, for example, diabetes, obesity, cardiovascular diseases, cancer, COVID-19, or neurodegenerative disorders. Changes in oxylipin metabolism have been reported in these diseases. [3] [4] [14] [15] [16] [17] In 2021, Alzheimer's disease was associated with changes in oxylipin levels in plasma and cerebrospinal fluid (CSF) for the first time. [18] Interestingly, improvement in neurodegenerative diseases and also cardiovascular diseases may be achieved by using inhibitors of an enzyme (soluble epoxide hydrolase) involved in formation of oxylipins. [19] [20] In Parkinson's disease, oxylipin profiles reflect the stage of the disease. This should be taken into consideration when choosing the suitable medication for Parkinson's disease. [15]

Related Research Articles

Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health, but cannot synthesize them.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk, fatty fish, fish oil, or algae oil. The consumption of DHA contributes to numerous physiological benefits, including cognition. As the primary structural component of nerve cells in the brain, the function of DHA is to support neuronal conduction and to allow optimal function of neuronal membrane proteins.

<span class="mw-page-title-main">Resolvin</span> Class of chemical compounds

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, soluble epoxide hydrolase (sEH), also termed epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

<span class="mw-page-title-main">Essential fatty acid interactions</span>

There are many fatty acids found in nature. Two types of fatty acids considered essential for human health are the omega-3 and omega-6 types. These two essential fatty acids are necessary for some cellular signalling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

<span class="mw-page-title-main">CYP2J2</span> Gene of the species Homo sapiens

Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.

<span class="mw-page-title-main">CYP2C18</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.

<span class="mw-page-title-main">CYP4A11</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substrate of the CYP epoxylgenases is arachidonic acid. This polyunsaturated fatty acid is metabolized by cyclooxygenases to various prostaglandin, thromboxane, and prostacyclin metabolites in what has been termed the first pathway of eicosanoid production; it is also metabolized by various lipoxygenases to hydroxyeicosatetraenoic acids and leukotrienes in what has been termed the second pathway of eicosanoid production. The metabolism of arachidonic acid to epoxyeicosatrienoic acids by the CYP epoxygenases has been termed the third pathway of eicosanoid metabolism. Like the first two pathways of eicosanoid production, this third pathway acts as a signaling pathway wherein a set of enzymes metabolize arachidonic acid to a set of products that act as secondary signals to work in activating their parent or nearby cells and thereby orchestrate functional responses. However, none of these three pathways is limited to metabolizing arachidonic acid to eicosanoids. Rather, they also metabolize other polyunsaturated fatty acids to products that are structurally analogous to the eicosanoids but often have different bioactivity profiles. This is particularly true for the CYP epoxygenases which in general act on a broader range of polyunsaturated fatty acids to form a broader range of metabolites than the first and second pathways of eicosanoid production. Furthermore, the latter pathways form metabolites many of which act on cells by binding with and thereby activating specific and well-characterized receptor proteins; no such receptors have been fully characterized for the epoxide metabolites. Finally, there are relatively few metabolite-forming lipoxygenases and cyclooxygenases in the first and second pathways and these oxygenase enzymes share similarity between humans and other mammalian animal models. The third pathway consists of a large number of metabolite-forming CYP epoxygenases and the human epoxygenases have important differences from those of animal models. Partly because of these differences, it has been difficult to define clear roles for the epoxygenase-epoxide pathways in human physiology and pathology.

<span class="mw-page-title-main">Epoxide hydrolase 2</span> Protein-coding gene in the species Homo sapiens

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding diols. A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia.

<span class="mw-page-title-main">Coronaric acid</span> Chemical compound

Coronaric acid (leukotoxin or leukotoxin A) is a mono-unsaturated, epoxide derivative of the di-saturated fatty acid, linoleic acid (i.e. 9(Z),12(Z) octadecadienoic acid). It is a mixture of the two optically active isomers of 12(Z) 9,10-epoxy-octadecenoic acid. This mixture is also termed 9,10-epoxy-12Z-octadecenoic acid or 9(10)-EpOME and when formed by or studied in mammalians, leukotoxin.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides. These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

<span class="mw-page-title-main">Epoxyeicosatetraenoic acid</span> Chemical compound

Epoxyeicosatetraenoic acids are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

References

  1. ↑ Wasternack C (October 2007). "Jasmonates: an update on biosynthesis, signal transduction and action in plant stress response, growth and development". Annals of Botany. 100 (4): 681–697. doi:10.1093/aob/mcm079. PMC   2749622 . PMID   17513307.
  2. 1 2 3 Camunas-Alberca SM, Moran-Garrido M, Sáiz J, Villaseñor A, Taha AY, Barbas C (July 2023). "The role of oxylipins and their validation as biomarkers in the clinical context". TrAC Trends in Analytical Chemistry. 164: 117065. doi:10.1016/j.trac.2023.117065.
  3. 1 2 3 Watrous JD, Niiranen TJ, Lagerborg KA, Henglin M, Xu YJ, Rong J, et al. (March 2019). "Directed Non-targeted Mass Spectrometry and Chemical Networking for Discovery of Eicosanoids and Related Oxylipins". Cell Chemical Biology. 26 (3): 433–442.e4. doi:10.1016/j.chembiol.2018.11.015. PMC   6636917 . PMID   30661990.
  4. 1 2 3 Liang N, Harsch BA, Zhou S, Borkowska A, Shearer GC, Kaddurah-Daouk R, et al. (January 2024). "Oxylipin transport by lipoprotein particles and its functional implications for cardiometabolic and neurological disorders". Progress in Lipid Research. 93: 101265. doi:10.1016/j.plipres.2023.101265. PMID   37979798.
  5. ↑ Wolfer AM, Gaudin M, Taylor-Robinson SD, Holmes E, Nicholson JK (December 2015). "Development and Validation of a High-Throughput Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry Approach for Screening of Oxylipins and Their Precursors". Analytical Chemistry. 87 (23): 11721–11731. doi:10.1021/acs.analchem.5b02794. PMID   26501362.
  6. ↑ Zhao J, Davis LC, Verpoorte R (June 2005). "Elicitor signal transduction leading to production of plant secondary metabolites". Biotechnology Advances. 23 (4): 283–333. doi:10.1016/j.biotechadv.2005.01.003. PMID   15848039.
  7. ↑ Bolwell GP, Bindschedler LV, Blee KA, Butt VS, Davies DR, Gardner SL, et al. (May 2002). "The apoplastic oxidative burst in response to biotic stress in plants: a three-component system". Journal of Experimental Botany. 53 (372): 1367–1376. doi:10.1093/jexbot/53.372.1367. PMID   11997382.
  8. ↑ Barquissau V, Ghandour RA, Ailhaud G, Klingenspor M, Langin D, Amri EZ, et al. (May 2017). "Control of adipogenesis by oxylipins, GPCRs and PPARs" (PDF). Biochimie. 136: 3–11. doi:10.1016/j.biochi.2016.12.012. PMID   28034718.
  9. 1 2 3 4 Gabbs M, Leng S, Devassy JG, Monirujjaman M, Aukema HM (September 2015). "Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs". Advances in Nutrition. 6 (5): 513–540. doi:10.3945/an.114.007732. PMC   4561827 . PMID   26374175.
  10. ↑ Collino S, Montoliu I, Martin FP, Scherer M, Mari D, Salvioli S, et al. (2013). "Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism". PLOS ONE. 8 (3): e56564. Bibcode:2013PLoSO...856564C. doi: 10.1371/journal.pone.0056564 . PMC   3590212 . PMID   23483888.
  11. ↑ Ramsden CE, Ringel A, Feldstein AE, Taha AY, MacIntosh BA, Hibbeln JR, et al. (2012). "Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 87 (4–5): 135–141. doi:10.1016/j.plefa.2012.08.004. PMC   3467319 . PMID   22959954.
  12. ↑ Guyenet SJ, Carlson SE (November 2015). "Increase in adipose tissue linoleic acid of US adults in the last half century". Advances in Nutrition. 6 (6): 660–664. doi:10.3945/an.115.009944. PMC   4642429 . PMID   26567191.
  13. 1 2 Shichiri M, Adkins Y, Ishida N, Umeno A, Shigeri Y, Yoshida Y, et al. (November 2014). "DHA concentration of red blood cells is inversely associated with markers of lipid peroxidation in men taking DHA supplement". Journal of Clinical Biochemistry and Nutrition. 55 (3): 196–202. doi:10.3164/jcbn.14-22. PMC   4227822 . PMID   25411526.
  14. ↑ Biagini D, Oliveri P, Baj A, Gasperina DD, Ferrante FD, Lomonaco T, et al. (December 2023). "The effect of SARS-CoV-2 variants on the plasma oxylipins and PUFAs of COVID-19 patients". Prostaglandins & Other Lipid Mediators. 169: 106770. doi:10.1016/j.prostaglandins.2023.106770. PMID   37633481.
  15. 1 2 Chistyakov DV, Azbukina NV, Lopachev AV, Goriainov SV, Astakhova AA, Ptitsyna EV, et al. (April 2024). "Plasma oxylipin profiles reflect Parkinson's disease stage". Prostaglandins & Other Lipid Mediators. 171: 106788. doi:10.1016/j.prostaglandins.2023.106788. PMID   37866654.
  16. ↑ Chaves-Filho AB, Diniz LS, Santos RS, Lima RS, Oreliana H, Pinto IF, et al. (November 2023). "Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis". Free Radical Biology & Medicine. 208: 285–298. doi:10.1016/j.freeradbiomed.2023.08.019. PMID   37619957.
  17. ↑ Tans R, Bande R, van Rooij A, Molloy BJ, Stienstra R, Tack CJ, et al. (September 2020). "Evaluation of cyclooxygenase oxylipins as potential biomarker for obesity-associated adipose tissue inflammation and type 2 diabetes using targeted multiple reaction monitoring mass spectrometry". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 160: 102157. doi:10.1016/j.plefa.2020.102157. PMID   32629236.
  18. ↑ Borkowski K, Pedersen TL, Seyfried NT, Lah JJ, Levey AI, Hales CM, et al. (September 2021). "Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer's disease". Alzheimer's Research & Therapy. 13 (1): 149. doi: 10.1186/s13195-021-00893-6 . PMC   8422756 . PMID   34488866.
  19. ↑ Imig JD, Hammock BD (October 2009). "Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases". Nature Reviews. Drug Discovery. 8 (10): 794–805. doi:10.1038/nrd2875. PMC   3021468 . PMID   19794443.
  20. ↑ Wagner KM, McReynolds CB, Schmidt WK, Hammock BD (December 2017). "Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases". Pharmacology & Therapeutics. 180: 62–76. doi:10.1016/j.pharmthera.2017.06.006. PMC   5677555 . PMID   28642117.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.