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11 pages, 922 KiB

Open AccessArticle

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

by Eulambius M. Mlugu, Omary M. Minzi, Appolinary A. R. Kamuhabwa, Ulf Diczfalusy and Eleni Aklillu

Int. J. Mol. Sci. 2022, 23(23), 15168; https://doi.org/10.3390/ijms232315168 - 2 Dec 2022

Cited by 6 | Viewed by 1974

Abstract

Changes in cortisol and other hormones during pregnancy may alter CYP3A enzymes activity, but data from sub-Saharan Africa are sparse. We investigated the effect of pregnancy and CYP3A5 genotypes on CYP3A enzymes activity using the plasma 4β-hydroxycholesterol (4β-OHC)/cholesterol (Chol) ratio, a known endogenous [...] Read more.

Changes in cortisol and other hormones during pregnancy may alter CYP3A enzymes activity, but data from sub-Saharan Africa are sparse. We investigated the effect of pregnancy and CYP3A5 genotypes on CYP3A enzymes activity using the plasma 4β-hydroxycholesterol (4β-OHC)/cholesterol (Chol) ratio, a known endogenous biomarker. Tanzanian pregnant women (n = 110) and non-pregnant women (n = 59) controls were enrolled. Plasma 4β-OHC and Chol were determined in the second and third trimesters for pregnant women and once for non-pregnant women using gas chromatography–mass spectrometry. Genotyping for CYP3A5 (*3, *6, *7) was performed. Wilcoxon Signed-Rank Test and Mann–Whitney U test were used to compare the median 4β-OHC/Chol ratio between trimesters in pregnant women and between pregnant and non-pregnant women. Repeated-measure ANOVA was used to evaluate the effect of the CYP3A5 genotypes on the 4β-OHC/Chol ratio in pregnant women. No significant effect of the pregnancy status or the CYP3A5 genotype on the cholesterol level was observed. The plasma 4β-OHC/Chol ratio significantly increased by 7.3% from the second trimester to the third trimester (p = 0.02). Pregnant women had a significantly higher mean 4β-OHC/Chol ratio than non-pregnant women, (p < 0.001). In non-pregnant women, the mean 4β-OHC/Chol ratio was significantly lower in carriers of defective CYP3A5 alleles (*3, *6 or *7) as compared to women with the CYP3A5*1/*1 genotypes (p = 0.002). Pregnancy increases CYP3A enzymes activity in a gestational-stage manner. The CYP3A5 genotype predicts CYP3A enzymes activity in the black Tanzanian population, but not during pregnancy-mediated CYP3A enzyme induction. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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18 pages, 2665 KiB

Open AccessArticle

Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer′s Disease Neurodegeneration

by Clara Bartra, Alba Irisarri, Ainhoa Villoslada, Rubén Corpas, Samuel Aguirre, Elisa García-Lara, Cristina Suñol, Mercè Pallàs, Christian Griñán-Ferré and Coral Sanfeliu

Int. J. Mol. Sci. 2022, 23(23), 15151; https://doi.org/10.3390/ijms232315151 - 2 Dec 2022

Cited by 4 | Viewed by 2439

Abstract

Modulation of Alzheimer′s disease (AD) risk begins early in life. During embryo development and postnatal maturation, the brain receives maternal physiological influences and establishes epigenetic patterns that build its level of resilience to late-life diseases. The soluble epoxide hydrolase inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N′-[4-(trifluoromethoxy)phenyl] urea (TPPU), [...] Read more.

Modulation of Alzheimer′s disease (AD) risk begins early in life. During embryo development and postnatal maturation, the brain receives maternal physiological influences and establishes epigenetic patterns that build its level of resilience to late-life diseases. The soluble epoxide hydrolase inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N′-[4-(trifluoromethoxy)phenyl] urea (TPPU), reported as ant-inflammatory and neuroprotective against AD pathology in the adult 5XFAD mouse model of AD, was administered to wild-type (WT) female mice mated to heterozygous 5XFAD males during gestation and lactation. Two-month-old 5XFAD male and female offspring of vehicle-treated dams showed memory loss as expected. Remarkably, maternal treatment with TPPU fully prevented memory loss in 5XFAD. TPPU-induced brain epigenetic changes in both WT and 5XFAD mice, modulating global DNA methylation (5-mC) and hydroxymethylation (5-hmC) and reducing the gene expression of some histone deacetylase enzymes (Hdac1 and Hdac2), might be on the basis of the long-term neuroprotection against cognitive impairment and neurodegeneration. In the neuropathological analysis, both WT and 5XFAD offspring of TPPU-treated dams showed lower levels of AD biomarkers of tau hyperphosphorylation and microglia activation (Trem2) than the offspring of vehicle-treated dams. Regarding sex differences, males and females were similarly protected by maternal TPPU, but females showed higher levels of AD risk markers of gliosis and neurodegeneration. Taken together, our results reveal that maternal treatment with TPPU impacts in preventing or delaying memory loss and AD pathology by inducing long-term modifications in the epigenetic machinery and its marks. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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14 pages, 1593 KiB

Open AccessArticle

Oxylipins Associated with D3-Creatine Muscle Mass/Weight and Physical Performance among Community-Dwelling Older Men

by Megan M. Marron, Eric S. Orwoll, Peggy M. Cawthon, Nancy E. Lane, Anne B. Newman and Jane A. Cauley

Int. J. Mol. Sci. 2022, 23(21), 12857; https://doi.org/10.3390/ijms232112857 - 25 Oct 2022

Cited by 2 | Viewed by 1868

Abstract

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate [...] Read more.

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate polyunsaturated fatty-acid-related metabolites, i.e., oxylipins, and their associations with D3-creatine muscle mass/weight, gait speed, grip strength, and the Short Physical Performance Battery among 463 older men from the Osteoporotic Fractures in Men Study (MrOS). Oxylipins were measured in fasting serum using liquid chromatography–mass spectrometry. Muscle mass was estimated using D3-creatine dilution and adjusted for body size. We used linear regression to determine oxylipins associated with D3-creatine muscle mass/weight and physical performance, while adjusting for age, education, physical activity, Western dietary pattern, fish oil supplementation, and multiple comparisons. Among 42 oxylipins, none were associated with grip strength and 3 were associated with the Short Physical Performance Battery. In contrast, 18 and 17 oxylipins were associated with D3-creatine muscle mass/weight and gait speed, respectively. A subset of associations between oxylipins and gait speed were partially attenuated by D3-creatine muscle mass/weight. Higher levels of fatty acid alcohol and ketone oxylipins tended to be most strongly associated with gait speed and D3-creatine muscle mass/weight, potentially reflecting anti-inflammatory activity from these select oxylipins in MrOS older men. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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14 pages, 3113 KiB

Open AccessArticle

Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation

by Theresa Aliwarga, Jean C. Dinh, Scott Heyward, Bhagwat Prasad, Sina A. Gharib, Rozenn N. Lemaitre, Nona Sotoodehnia and Rheem A. Totah

Int. J. Mol. Sci. 2022, 23(20), 12433; https://doi.org/10.3390/ijms232012433 - 17 Oct 2022

Cited by 2 | Viewed by 1791

Abstract

CYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to cis-epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by EPHX2) or re-esterified back to the membrane. EETs [...] Read more.

CYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to cis-epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by EPHX2) or re-esterified back to the membrane. EETs have several cardioprotective properties and higher levels are usually associated with better cardiac outcomes/prognosis. This study investigates how cardiovascular disease (CVD) can influence total EET levels by altering protein expression and activity of enzymes involved in their biosynthesis and degradation. Diseased ventricular cardiac tissues were collected from patients receiving Left Ventricular Assist Device (LVAD) or heart transplants and compared to ventricular tissue from controls free of CVD. EETs, and enzymes involved in EETs biosynthesis and degradation, were measured using mass spectrometric assays. Terfenadine hydroxylation was used to probe CYP2J2 activity. Significantly higher cis- and trans-EET levels were observed in control cardiac tissue (n = 17) relative to diseased tissue (n = 24). Control cardiac tissue had higher CYP2J2 protein levels, which resulted in higher rate of terfenadine hydroxylation, compared to diseased cardiac tissues. In addition, levels of both NADPH-Cytochrome P450 oxidoreductase (POR) and sEH proteins were significantly higher in control versus diseased cardiac tissue. Overall, alterations in protein and activity of enzymes involved in the biosynthesis and degradation of EETs provide a mechanistic understanding for decreased EET levels in diseased tissues. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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16 pages, 2656 KiB

Open AccessArticle

Soluble Epoxide Hydrolase Is Associated with Postprandial Anxiety Decrease in Healthy Adult Women

by Nhien Nguyen, Christophe Morisseau, Dongyang Li, Jun Yang, Eileen Lam, D. Blake Woodside, Bruce D. Hammock and Pei-an Betty Shih

Int. J. Mol. Sci. 2022, 23(19), 11798; https://doi.org/10.3390/ijms231911798 - 5 Oct 2022

Cited by 3 | Viewed by 1947

Abstract

The metabolism of bioactive oxylipins by soluble epoxide hydrolase (sEH) plays an important role in inflammation, and sEH may be a risk modifier in various human diseases and disorders. The relationships that sEH has with the risk factors of these diseases remain elusive. [...] Read more.

The metabolism of bioactive oxylipins by soluble epoxide hydrolase (sEH) plays an important role in inflammation, and sEH may be a risk modifier in various human diseases and disorders. The relationships that sEH has with the risk factors of these diseases remain elusive. Herein, sEH protein expression and activity in white blood cells were characterized before and after a high-fat meal in healthy women (HW) and women with anorexia nervosa (AN). sEH expression and sEH activity were significantly correlated and increased in both groups two hours after consumption of the study meal. Fasting sEH expression and activity were positively associated with body mass index (BMI) in both groups, while an inverse association with age was found in AN only (p value < 0.05). sEH was not associated with anxiety or depression in either group at the fasting timepoint. While the anxiety score decreased after eating in both groups, a higher fasting sEH was associated with a lower postprandial anxiety decrease in HW (p value < 0.05). sEH characterization using direct measurements verified the relationship between the protein expression and in vivo activity of this important oxylipin modulator, while a well-controlled food challenge study design using HW and a clinical control group of women with disordered eating elucidated sEH’s role in the health of adult women. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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28 pages, 2033 KiB

Open AccessArticle

The Plasma Oxylipin Signature Provides a Deep Phenotyping of Metabolic Syndrome Complementary to the Clinical Criteria

by Céline Dalle, Jérémy Tournayre, Malwina Mainka, Alicja Basiak-Rasała, Mélanie Pétéra, Sophie Lefèvre-Arbogast, Jessica Dalloux-Chioccioli, Mélanie Deschasaux-Tanguy, Lucie Lécuyer, Emmanuelle Kesse-Guyot, Léopold K. Fezeu, Serge Hercberg, Pilar Galan, Cécilia Samieri, Katarzyna Zatońska, Philip C. Calder, Mads Fiil Hjorth, Arne Astrup, André Mazur, Justine Bertrand-Michel, Nils Helge Schebb, Andrzej Szuba, Mathilde Touvier, John W. Newman and Cécile Gladine Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(19), 11688; https://doi.org/10.3390/ijms231911688 - 2 Oct 2022

Cited by 7 | Viewed by 2745

Abstract

Metabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Oxylipins are a superfamily of lipid mediators regulating many cardiometabolic functions. Plasma oxylipin signature could provide a new clinical tool to enhance the phenotyping of MetS pathophysiology. A high-throughput validated [...] Read more.

Metabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Oxylipins are a superfamily of lipid mediators regulating many cardiometabolic functions. Plasma oxylipin signature could provide a new clinical tool to enhance the phenotyping of MetS pathophysiology. A high-throughput validated mass spectrometry method, allowing for the quantitative profiling of over 130 oxylipins, was applied to identify and validate the oxylipin signature of MetS in two independent nested case/control studies involving 476 participants. We identified an oxylipin signature of MetS (coined OxyScore), including 23 oxylipins and having high performances in classification and replicability (cross-validated AUC_ROC of 89%, 95% CI: 85–93% and 78%, 95% CI: 72–85% in the Discovery and Replication studies, respectively). Correlation analysis and comparison with a classification model incorporating the MetS criteria showed that the oxylipin signature brings consistent and complementary information to the clinical criteria. Being linked with the regulation of various biological processes, the candidate oxylipins provide an integrative phenotyping of MetS regarding the activation and/or negative feedback regulation of crucial molecular pathways. This may help identify patients at higher risk of cardiometabolic diseases. The oxylipin signature of patients with metabolic syndrome enhances MetS phenotyping and may ultimately help to better stratify the risk of cardiometabolic diseases. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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12 pages, 3121 KiB

Open AccessArticle

Epoxyeicosatrienoic Acid and Prostanoid Crosstalk at the Receptor and Intracellular Signaling Levels to Maintain Vascular Tone

by Pedro Felipe Malacarne, Justus Bezzenberger, Melina Lopez, Timothy Warwick, Niklas Müller, Ralf P. Brandes and Flávia Rezende

Int. J. Mol. Sci. 2022, 23(11), 5939; https://doi.org/10.3390/ijms23115939 - 25 May 2022

Cited by 5 | Viewed by 2057

Abstract

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by the cytochrome P450-(CYP450)-mediated epoxygenation of arachidonic acid. EETs have numerous biological effects on the vascular system, but aspects including their species specificity make their effects on vascular tone controversial. CYP450 enzymes require the 450-reductase (POR) [...] Read more.

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by the cytochrome P450-(CYP450)-mediated epoxygenation of arachidonic acid. EETs have numerous biological effects on the vascular system, but aspects including their species specificity make their effects on vascular tone controversial. CYP450 enzymes require the 450-reductase (POR) for their activity. We set out to determine the contribution of endothelial CYP450 to murine vascular function using isolated aortic ring preparations from tamoxifen-inducible endothelial cell-specific POR knockout mice (ecPOR^−/−). Constrictor responses to phenylephrine were similar between control (CTR) and ecPOR^−/− mice. Contrastingly, sensitivity to the thromboxane receptor agonist U46619 and prostaglandin E2 (PGE2) was increased following the deletion of POR. Ex vivo incubation with a non-hydrolyzable EET (14,15-EE-8(Z)-E, EEZE) reversed the increased sensitivity to U46619 to the levels of CTR. EETs had no effect on vascular tone in phenylephrine-preconstricted vessels, but dilated vessels contracted with U46619 or PGE2. As U46619 acts through RhoA-dependent kinase, this system was analyzed. The deletion of POR affected the expression of genes in this pathway and the inhibition of Rho-GTPase with SAR407899 decreased sensitivity to U46619. These data suggest that EET and prostanoid crosstalk at the receptor level and that lack of EET production sensitizes vessels to vasoconstriction via the induction of the Rho kinase system. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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Review

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14 pages, 846 KiB

Open AccessReview

The Role of α-Linolenic Acid and Its Oxylipins in Human Cardiovascular Diseases

by Lucia Cambiaggi, Akash Chakravarty, Nazek Noureddine and Martin Hersberger

Int. J. Mol. Sci. 2023, 24(7), 6110; https://doi.org/10.3390/ijms24076110 - 24 Mar 2023

Cited by 27 | Viewed by 4985

Abstract

α-linolenic acid (ALA) is an essential C-18 n-3 polyunsaturated fatty acid (PUFA), which can be elongated to longer n-3 PUFAs, such as eicosapentaenoic acid (EPA). These long-chain n-3 PUFAs have anti-inflammatory and pro-resolution effects either directly or through their oxylipin metabolites. However, there [...] Read more.

α-linolenic acid (ALA) is an essential C-18 n-3 polyunsaturated fatty acid (PUFA), which can be elongated to longer n-3 PUFAs, such as eicosapentaenoic acid (EPA). These long-chain n-3 PUFAs have anti-inflammatory and pro-resolution effects either directly or through their oxylipin metabolites. However, there is evidence that the conversion of ALA to the long-chain PUFAs is limited. On the other hand, there is evidence in humans that supplementation of ALA in the diet is associated with an improved lipid profile, a reduction in the inflammatory biomarker C-reactive protein (CRP) and a reduction in cardiovascular diseases (CVDs) and all-cause mortality. Studies investigating the cellular mechanism for these beneficial effects showed that ALA is metabolized to oxylipins through the Lipoxygenase (LOX), the Cyclooxygenase (COX) and the Cytochrome P450 (CYP450) pathways, leading to hydroperoxy-, epoxy-, mono- and dihydroxylated oxylipins. In several mouse and cell models, it has been shown that ALA and some of its oxylipins, including 9- and 13-hydroxy-octadecatrienoic acids (9-HOTrE and 13-HOTrE), have immunomodulating effects. Taken together, the current literature suggests a beneficial role for diets rich in ALA in human CVDs, however, it is not always clear whether the described effects are attributable to ALA, its oxylipins or other substances present in the supplemented diets. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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15 pages, 1108 KiB

Open AccessReview

Polymorphisms in Lymphotoxin-Alpha as the “Missing Link” in Prognosticating Favourable Response to Omega-3 Supplementation for Dry Eye Disease: A Narrative Review

by Benjamin Paik and Louis Tong

Int. J. Mol. Sci. 2023, 24(4), 4236; https://doi.org/10.3390/ijms24044236 - 20 Feb 2023

Cited by 2 | Viewed by 2598

Abstract

Elements of inflammation are found in almost all chronic ocular surface disease, such as dry eye disease. The chronicity of such inflammatory disease speaks to the dysregulation of innate and adaptive immunity. There has been a rising interest in omega-3 fatty acids to [...] Read more.

Elements of inflammation are found in almost all chronic ocular surface disease, such as dry eye disease. The chronicity of such inflammatory disease speaks to the dysregulation of innate and adaptive immunity. There has been a rising interest in omega-3 fatty acids to attenuate inflammation. While many cell-based (in vitro) studies verify the anti-inflammatory effects of omega-3, different human trials report discordant outcomes after supplementation. This may be due to underlying inter-individual differences in inflammatory cytokine metabolism (such as tumor necrosis factor alpha (TNF-α)), in which genetic differences might play a role, such as polymorphisms in the lymphotoxin alpha (LT-α) gene. Inherent TNF-α production affects omega-3 response and is also associated with LT-α genotype. Therefore, LT-α genotype might predict omega-3 response. Using the NIH dbSNP, we analyzed the relative frequency of LT-α polymorphisms among various ethnicities, each weighted by the genotype’s probability of positive response. While the probability of response for unknown LT-α genotypes are 50%, there is greater distinction in response rates between various genotypes. Hence, there is value in genetic testing to prognosticate an individual’s response to omega-3. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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31 pages, 2915 KiB

Open AccessReview

Therapeutic Potential of Plant Oxylipins

by Tatyana Savchenko, Evgeny Degtyaryov, Yaroslav Radzyukevich and Vlada Buryak

Int. J. Mol. Sci. 2022, 23(23), 14627; https://doi.org/10.3390/ijms232314627 - 23 Nov 2022

Cited by 20 | Viewed by 3642

Abstract

For immobile plants, the main means of protection against adverse environmental factors is the biosynthesis of various secondary (specialized) metabolites. The extreme diversity and high biological activity of these metabolites determine the researchers’ interest in plants as a source of therapeutic agents. Oxylipins, [...] Read more.

For immobile plants, the main means of protection against adverse environmental factors is the biosynthesis of various secondary (specialized) metabolites. The extreme diversity and high biological activity of these metabolites determine the researchers’ interest in plants as a source of therapeutic agents. Oxylipins, oxygenated derivatives of fatty acids, are particularly promising in this regard. Plant oxylipins, which are characterized by a diversity of chemical structures, can exert protective and therapeutic properties in animal cells. While the therapeutic potential of some classes of plant oxylipins, such as jasmonates and acetylenic oxylipins, has been analyzed thoroughly, other oxylipins are barely studied in this regard. Here, we present a comprehensive overview of the therapeutic potential of all major classes of plant oxylipins, including derivatives of acetylenic fatty acids, jasmonates, six- and nine-carbon aldehydes, oxy-, epoxy-, and hydroxy-derivatives of fatty acids, as well as spontaneously formed phytoprostanes and phytofurans. The presented analysis will provide an impetus for further research investigating the beneficial properties of these secondary metabolites and bringing them closer to practical applications. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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18 pages, 1530 KiB

Open AccessReview

Soluble Epoxide Hydrolase and Diabetes Complications

by Natasha Z. Anita and Walter Swardfager

Int. J. Mol. Sci. 2022, 23(11), 6232; https://doi.org/10.3390/ijms23116232 - 2 Jun 2022

Cited by 10 | Viewed by 4209

Abstract

Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute to macrovascular complications, such as heart failure, peripheral arterial disease, and large vessel stroke. T2DM also increases the risks of depression [...] Read more.

Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute to macrovascular complications, such as heart failure, peripheral arterial disease, and large vessel stroke. T2DM also increases the risks of depression and dementia for reasons that remain largely unclear. Perturbations in the cytochrome P450-soluble epoxide hydrolase (CYP-sEH) pathway have been implicated in each of these diabetes complications. Here we review evidence from the clinical and animal literature suggesting the involvement of the CYP-sEH pathway in T2DM complications across organ systems, and highlight possible mechanisms (e.g., inflammation, fibrosis, mitochondrial function, endoplasmic reticulum stress, the unfolded protein response and autophagy) that may be relevant to the therapeutic potential of the pathway. These mechanisms may be broadly relevant to understanding, preventing and treating microvascular complications affecting the brain and other organ systems in T2DM. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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15 pages, 1374 KiB

Open AccessReview

Soluble Epoxide Hydrolase as a Therapeutic Target for Neuropsychiatric Disorders

by Jiajing Shan and Kenji Hashimoto

Int. J. Mol. Sci. 2022, 23(9), 4951; https://doi.org/10.3390/ijms23094951 - 29 Apr 2022

Cited by 19 | Viewed by 3837

Abstract

It has been found that soluble epoxide hydrolase (sEH; encoded by the EPHX2 gene) in the metabolism of polyunsaturated fatty acids (PUFAs) plays a key role in inflammation, which, in turn, plays a part in the pathogenesis of neuropsychiatric disorders. Meanwhile, epoxy fatty [...] Read more.

It has been found that soluble epoxide hydrolase (sEH; encoded by the EPHX2 gene) in the metabolism of polyunsaturated fatty acids (PUFAs) plays a key role in inflammation, which, in turn, plays a part in the pathogenesis of neuropsychiatric disorders. Meanwhile, epoxy fatty acids such as epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxyeicosapentaenoic acids (EDPs) have been found to exert neuroprotective effects in animal models of neuropsychiatric disorders through potent anti-inflammatory actions. Soluble expoxide hydrolase, an enzyme present in all living organisms, metabolizes epoxy fatty acids into the corresponding dihydroxy fatty acids, which are less active than the precursors. In this regard, preclinical findings using sEH inhibitors or Ephx2 knock-out (KO) mice have indicated that the inhibition or deficiency of sEH can have beneficial effects in several models of neuropsychiatric disorders. Thus, this review discusses the current findings of the role of sEH in neuropsychiatric disorders, including depression, autism spectrum disorder (ASD), schizophrenia, Parkinson’s disease (PD), and stroke, as well as the potential mechanisms underlying the therapeutic effects of sEH inhibitors. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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