Review

Authors: Dipak Panigrahy, Emily R Greene, Ambra Pozzi...

Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cell Transformation, Neoplastic; Cytochrome P-450 Enzyme System; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Microenvironment

PubMed: 22009066
DOI: 10.1007/s10555-011-9315-y

Review

Authors: Hiroshi Kawashima, Katsuhiko Yoshizawa

Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws little attention. MA is distributed in various normal tissues and can be converted to several specific lipid mediators by lipoxygenase and cyclooxygenase. Recent pathological and epidemiological studies on MA raise the possibility of its effects on inflammation, cancer, dermatitis and cystic fibrosis, suggesting it is an endogenous multifunctional PUFA. This review summarizes the biosynthesis, presence, metabolism and physiological roles of MA and its relation to various diseases, as well as the significance of MA in PUFA metabolism.

Topics: Humans; Fatty Acids, Unsaturated; 8,11,14-Eicosatrienoic Acid; Inflammation

PubMed: 37838679
DOI: 10.1186/s12944-023-01937-6

Review

Authors: William B Campbell, John D Imig, James M Schmitz...

Biologically active epoxyeicosatrienoic acid (EET) regioisomers are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial, and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size after ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance, and reduce the renal injury. These actions of EETs emphasize their therapeutic potential. To minimize metabolic inactivation, 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates were developed. In preclinical rat models, a subset of agonist analogs, termed EET-A, EET-B, and EET-C22, are orally active with good pharmacokinetic properties. These orally active EET agonists lower blood pressure and reduce cardiac and renal injury in spontaneous and angiotensin hypertension. Other beneficial cardiovascular actions include improved endothelial function and cardiac antiremodeling actions. In rats, EET analogs effectively combat acute and chronic kidney disease including drug- and radiation-induced kidney damage, hypertension and cardiorenal syndrome kidney damage, and metabolic syndrome and diabetes nephropathy. The compelling preclinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Administration, Oral; Animals; Blood Pressure; Cardiovascular Diseases; Fatty Acids, Monounsaturated; Humans; Hypertension; Kidney Diseases; Muscle, Smooth, Vascular; Structure-Activity Relationship; Vasodilation

PubMed: 28937442
DOI: 10.1097/FJC.0000000000000523

Authors: Eun Ju Kim, Min-Kyoung Kim, Xing-Ji Jin...

We investigated the alterations of major fatty acid components in epidermis by natural aging and photoaging processes, and by acute ultraviolet (UV) irradiation in human skin. Interestingly, we found that 11,14,17-eicosatrienoic acid (ETA), which is one of the omega-3 polyunsaturated acids, was significantly increased in photoaged human epidermis in vivo and also in the acutely UV-irradiated human skin in vivo, while it was significantly decreased in intrinsically aged human epidermis. The increased ETA content in the epidermis of photoaged human skin and acute UV-irradiated human skin is associated with enhanced expression of human elongase 1 and calcium-independent phosphodiesterase A(2). We demonstrated that ETA inhibited matrix metalloproteinase (MMP)-1 expression after UV-irradiation, and that inhibition of ETA synthesis using EPTC and NA-TCA, which are elongase inhibitors, increased MMP-1 expression. Therefore, our results suggest that the UV increases the ETA levels, which may have a photoprotective effect in the human skin.

Topics: 8,11,14-Eicosatrienoic Acid; Acetyltransferases; Adult; Aged; Cell Line; Epidermis; Fatty Acid Elongases; Fatty Acids; Humans; Keratinocytes; Matrix Metalloproteinase 1; Phospholipases A2, Calcium-Independent; Skin Aging; Thiocarbamates; Ultraviolet Rays; Young Adult

PubMed: 20514327
DOI: 10.3346/jkms.2010.25.6.980

Comparative Study

Authors: A A AbuGhazaleh, L D Holmes, B N Jacobson...

Previous research found that docosahexaenoic acid (C22:6n-3) was a component of fish oil that promotes trans-C18:1 accumulation in ruminal cultures when incubated with linoleic acid. The objective of this study was to determine if eicosatrienoic acid (C20:3n-3) and docosatrienoic acid (C22:3n-3), n-3 fatty acids in fish oil, promote accumulation of trans-C18:1, vaccenic acid (VA) in particular, using cultures of mixed ruminal microorganisms. Treatments consisted of control, control plus 5 mg of C20:3n-3 (ETA), control plus 5 mg of C22:3n-3 (DTA), control plus 15 mg of linoleic acid (LA), control plus 5 mg of C20:3n-3 and 15 mg of linoleic acid (ETALA), and control plus 5 mg of C22:3n-3 and 15 mg of linoleic acid (DTALA). Treatments were incubated in triplicate in 125-mL flasks, and 5 mL of culture contents was taken at 0 and 24 h for fatty acid analysis by gas-liquid chromatography. After 24 h of incubation, the concentrations of trans-C18:1 (0.87, 0.88, and 0.99 mg/culture), and VA (0.52, 0.56, and 0.62 mg/culture) were similar for the control, ETA, and DTA cultures, respectively. The concentrations of trans-C18:1 (5.51, 5.41, and 5.36 mg/culture), and VA (4.78, 4.62, and 4.59 mg/culture) were also similar between LA, ETALA, and DTALA cultures, respectively. These data suggest that C20:3n-3 and C22:3n-3 are not the active components in fish oil that promote VA accumulation when incubated with linoleic acid.

Topics: Animals; Arachidonic Acids; Cattle; Erucic Acids; Fatty Acids; Fatty Acids, Omega-3; Female; Linoleic Acid; Oleic Acids; Rumen

PubMed: 17033021
DOI: 10.3168/jds.S0022-0302(06)72480-8

Review

Authors: William S Powell, Joshua Rokach

5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is formed from the 5-lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). The cofactor NADP(+) is a limiting factor in the synthesis of 5-oxo-ETE because of its low concentrations in unperturbed cells. Activation of the respiratory burst in phagocytic cells, oxidative stress, and cell death all dramatically elevate both intracellular NADP(+) levels and 5-oxo-ETE synthesis. 5-HEDH is widely expressed in inflammatory, structural, and tumor cells. Cells devoid of 5-lipoxygenase can synthesize 5-oxo-ETE by transcellular biosynthesis using inflammatory cell-derived 5-HETE. 5-Oxo-ETE is a chemoattractant for neutrophils, monocytes, and basophils and promotes the proliferation of tumor cells. However, its primary target appears to be the eosinophil, for which it is a highly potent chemoattractant. The actions of 5-oxo-ETE are mediated by the highly selective OXE receptor, which signals by activating various second messenger pathways through the release of the βγ-dimer from Gi/o proteins to which it is coupled. Because of its potent effects on eosinophils, 5-oxo-ETE may be an important mediator in asthma, and, because of its proliferative effects, may also contribute to tumor progression. Selective OXE receptor antagonists, which are currently under development, could be useful therapeutic agents in asthma and other allergic diseases.

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Asthma; Eosinophils; Humans; Neoplasms; Receptors, Eicosanoid; Signal Transduction; Structure-Activity Relationship

PubMed: 24056189
DOI: 10.1016/j.plipres.2013.09.001

Authors: Yasushi Endo, Kumiko Tsunokake, Ikuo Ikeda...

We investigated effects of the non-methylene-interrupted polyunsaturated fatty acid, sciadonic acid (all-cis-5,11,14-eicosatrienoic acid), on the lipid metabolism in rats, to identify the mechanism for the plasma and hepatic triacylglycerol-lowering effects of Japanese torreya (Torreya nucifera) seed oil. Sciadonic acid was isolated from torreya seed oil by the combination of urea-adduct with lipase-esterification. Sprague-Dawley (SD) male rats were fed with experimental diets containing 5% and 10% sciadonic acid based on corn oil for 2 weeks. The serum and liver triacylglycerol levels were lower in the rats fed with sciadonic acid. Considerable amounts of sciadonic acid were detected in the triacylglycerol and phospholipid in both the serum and liver of the rats fed with sciadonic acid. These observations demonstrate that sciadonic acid could modify the lipid metabolism in rats.

Topics: Animals; Arachidonic Acids; Body Weight; Eating; Enzymes; Lipid Metabolism; Lipids; Liver; Male; Plant Oils; Rats; Rats, Sprague-Dawley; Seeds; Taxaceae; Triglycerides

PubMed: 19270392
DOI: 10.1271/bbb.80646

Review

Authors: Anne-Mari Mustonen, Petteri Nieminen

Dihomo--linolenic acid (DGLA) has emerged as a significant molecule differentiating healthy and inflamed tissues. Its position at a pivotal point of metabolic pathways leading to anti-inflammatory derivatives or via arachidonic acid (ARA) to pro-inflammatory lipid mediators makes this n-6 polyunsaturated fatty acid (PUFA) an intriguing research subject. The balance of ARA to DGLA is probably a critical factor affecting inflammatory processes in the body. The aim of this narrative review was to examine the potential roles of DGLA and related n-6 PUFAs in inflammatory conditions, such as obesity-associated disorders, rheumatoid arthritis, atopic dermatitis, asthma, cancers, and diseases of the gastrointestinal tract. DGLA can be produced by cultured fungi or be obtained via endogenous conversion from -linolenic acid (GLA)-rich vegetable oils. Several disease states are characterized by abnormally low DGLA levels in the body, while others can feature elevated levels. A defect in the activity of ∆6-desaturase and/or ∆5-desaturase may be one factor in the initiation and progression of these conditions. The potential of GLA and DGLA administrations as curative or ameliorating therapies in inflammatory conditions and malignancies appears modest at best. Manipulations with ∆6- and ∆5-desaturase inhibitors or combinations of long-chain PUFA supplements with n-3 PUFAs could provide a way to modify the body's DGLA and ARA production and the concentrations of their pro- and anti-inflammatory mediators. However, clinical data remain scarce and further well-designed studies should be actively promoted.

Topics: Humans; 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Arachidonic Acid; Fatty Acid Desaturases; Fatty Acids, Omega-6; Inflammation; Chronic Disease

PubMed: 36768438
DOI: 10.3390/ijms24032116

Authors: Alexandra I Galler, Kristaps Klavins, Iwan A Burgener...

Perturbations of metabolite profiles in human and canine enteropathies have been reported before. However, data in dogs are scarce and inconsistent. Currently, the metabolite profile in Yorkshire Terrier enteropathy (YTE) and the impact of treatment is unknown. The objective of this study was to investigate the plasma metabolome of 13 Yorkshire Terriers with YTE and compare it to 20 healthy Yorkshire Terriers. Furthermore, we studied the impact of treatment on the metabolome. In this prospective observational study, plasma metabolite profiles were analyzed by flow injection analysis-tandem mass spectrometry (FIA-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a targeted metabolomics kit. Metabolite analysis revealed that YTE is accompanied by changes in lipid and bile acid metabolism. YTE was associated with a significant decrease of long-chain fatty acids (octadecenoic acid, eicosadienoic acid, eicosatrienoic acid) and lower levels of long-chain acylcarnitines (tetradecanoylcarnitine, hexadecanoylcarnitine, hexadecenoylcarnitine, octadecenoylcarnitine) compared with healthy controls. Furthermore, taurodeoxycholic acid, a secondary bile acid, was decreased in plasma from YTE patients. These changes might be breed-specific and might be involved in the pathogenesis of YTE. Interestingly, changes in metabolite levels were not recovered after treatment and differed considerably from healthy controls.

PubMed: 35323707
DOI: 10.3390/metabo12030264

Review

Authors: John D Imig

The development of pharmacological, genetic, and biochemical tools have allowed for detailed studies to determine the contribution of cytochrome P450 (CYP) metabolites of arachidonic acid to renal microvascular function. Renal microvessels can generate CYP hydroxylase metabolites including 20-hydroxyeicosatetraenoic acid (20-HETE) and CYP epoxygenase metabolites, epoxyeicosatrienoic acids (EETs). 20-HETE constricts afferent arterioles and contributes to renal blood flow autoregulation. EETs act as endothelium-dependent hyperpolarizing factors (EDHFs) on the renal microcirculation. 20-HETE inhibits whereas EETs activate renal microvascular smooth muscle cell large-conductance calcium-activated K(+) channels (KCa). Likewise, 20-HETE renal microvascular actions are pro-hypertensive and EET actions are anti-hypertensive. These findings in the renal microvasculature and those of others have provided impetus for the development of enzymatic inhibitors, agonists, and antagonists for 20-HETE and EETs to determine their potential therapeutic value. Initial genetic studies and experimental studies with soluble epoxide hydrolase inhibitors to increase EETs, EET analogs, and 20-HETE inhibitors have demonstrated improved renal microvascular function in hypertension. These findings have demonstrated the important contributions that 20-HETE and EETs play in the regulation of renal microvascular function.

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Endothelial Cells; Endothelium, Vascular; Epoxide Hydrolases; Humans; Hydroxyeicosatetraenoic Acids; Hypertension, Renal; Kidney; Large-Conductance Calcium-Activated Potassium Channels; Microcirculation; Small Molecule Libraries; Vasoconstriction; Vasodilation

PubMed: 23333581
DOI: 10.1016/j.prostaglandins.2013.01.002