The gut microbiota mediates epoxy eicosanoid metabolism in the colon.

The metabolism of polyunsaturated fatty acids by cytochrome P450 (CYP) mono-oxygenases generates fatty acid epoxides, which are endogenous lipid mediators with potent actions to regulate inflammation, immune responses, vascular tone, and other critical biological processes. While previous research about their biosynthesis has focused on host metabolic enzymes, the role of gut microbiota remains largely unknown. Here, we demonstrate that the gut microbiota directly participates in the metabolism of fatty acid epoxides in the colon by catalyzing their conversion to fatty acid diols, thereby modulating colonic concentrations of these lipid mediators and associated biological actions.

Technical recommendations for analyzing oxylipins by liquid chromatography-mass spectrometry.

Several oxylipins are potent lipid mediators that regulate diverse aspects of health and disease and whose quantitative analysis by liquid chromatography-mass spectrometry (LC-MS) presents substantial technical challenges. As members of the lipidomics community, we developed technical recommendations to ensure best practices when quantifying oxylipins by LC-MS.

Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy.

We analyzed the role of pro- and anti-inflammatory eicosanoids in the pathogenesis of arrhythmogenic cardiomyopathy (ACM). Lipidomics revealed reduced levels of anti-inflammatory oxylipins in plasma and increased levels of pro-inflammatory eicosanoids in hearts of Dsg2 mice, a preclinical model of ACM. Disease features were reversed in vitro in rat ventricular myocytes expressing mutant JUP by the anti-inflammatory epoxyeicosatrienoic acid 14-15-EET, whereas 14,15-EEZE, which antagonizes the 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin.

Consumer Product Chemical Mixtures and Oxylipin-Mediated Inflammation and Oxidative Stress during Early Pregnancy: Findings from a Large US Pregnancy Cohort.

Consumer product chemicals pose an environmental risk to public health. Exposure during pregnancy to consumer product chemicals, particularly phthalates and phenols, may increase the susceptibility to pregnancy disorders by dysregulating inflammation and oxidative stress. However, existing studies rely on downstream and nonmodifiable markers of these processes.

Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischaemic injury involves direct activation of mitochondrial sirtuin 3.

Aims: Although current clinical therapies following myocardial infarction (MI) have improved patient outcomes, morbidity, and mortality rates, secondary to ischaemic and ischaemia reperfusion (IR) injury remains high. Maintaining mitochondrial quality is essential to limit myocardial damage following cardiac ischaemia and IR injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial function and cardiac energy metabolism.

Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model.

Purpose: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function.

Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism.

The cockroach allergen Bla g 1 encloses an exceptionally large hydrophobic cavity, which allows it to bind and deliver unsaturated fatty acid ligands. Bla g 1-mediated delivery of naturally occurring (nMix) ligands has been shown to destabilize lipid membranes, contributing to its digestive/antiviral functions within the source organism. However, the consequences of this activity on Bla g 1 allergenicity following human exposure remain unknown.

Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS-CoV-2-infected mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves an initial viral infection phase followed by a host-response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti-viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti-inflammatory molecules called epoxyeicosatrienoic acids (EETs).

Overexpression of soluble epoxide hydrolase reduces post-ischemic recovery of cardiac contractile function.

Cytochromes P450 can metabolize endogenous fatty acids, such as arachidonic acid, to bioactive lipids such as epoxyeicosatrienoic acids (EETs) that have beneficial effects. EETs protect hearts against ischemic damage, heart failure or fibrosis; however, their effects are limited by hydrolysis to less active dihydroxy oxylipins by soluble epoxide hydrolase (sEH), encoded by the epoxide hydrolase 2 gene (EPHX2, EC 3.3.

Multi-tissue profiling of oxylipins reveal a conserved up-regulation of epoxide:diol ratio that associates with white adipose tissue inflammation and liver steatosis in obesity.

Background: Obesity drives maladaptive changes in the white adipose tissue (WAT) which can progressively cause insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated liver disease (MASLD). Obesity-mediated loss of WAT homeostasis can trigger liver steatosis through dysregulated lipid pathways such as those related to polyunsaturated fatty acid (PUFA)-derived oxylipins. However, the exact relationship between oxylipins and metabolic syndrome remains elusive and cross-tissue dynamics of oxylipins are ill-defined.

TXA2 attenuates allergic lung inflammation through regulation of Th2, Th9, and Treg differentiation.

In lung, thromboxane A2 (TXA2) activates the TP receptor to induce proinflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and TXA2 synthase inhibitors have been tested as potential asthma therapeutics in humans. Th9 cells play key roles in asthma and regulate the lung immune response to allergens.

Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy.

Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of mice, a well characterized mouse model of ACM.

Increased Perfluorooctanesulfonate (PFOS) Toxicity and Accumulation Is Associated with Perturbed Prostaglandin Metabolism and Increased Organic Anion Transport Protein (OATP) Expression.

Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver disease and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than those of Cyp2b-null mice, with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity.

Overexpression of Human Soluble Epoxide Hydrolase Exacerbates Coronary Reactive Hyperemia Reduction in Angiotensin-II-Treated Mouse Hearts.

Coronary reactive hyperemia (CRH) is impaired in cardiovascular diseases, and angiotensin-II (Ang-II) exacerbates it. However, it is unknown how Ang-II affects CRH in Tie2-sEH Tr (human-sEH-overexpressed) versus wild-type (WT) mice. sEH-overexpression resulted in CRH reduction in Tie2-sEH Tr versus WT.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects.

Dynamic expression of mucins and the genes controlling mucin-type O-glycosylation within the mouse respiratory system.

The COVID-19 global pandemic has underscored the need to understand how viruses and other pathogens are able to infect and replicate within the respiratory system. Recent studies have highlighted the role of highly O-glycosylated mucins in the protection of the respiratory system as well as how mucin-type O-glycosylation may be able to modify viral infectivity. Therefore, we set out to identify the specific genes controlling mucin-type O-glycosylation throughout the mouse respiratory system as well as determine how their expression and the expression of respiratory mucins is influenced by infection or injury.

Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts.

Cytochromes P450 metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which have numerous effects. After cardiac ischemia, EET-induced coronary vasodilation increases delivery of oxygen/nutrients to the myocardium, and EET-induced signaling protects cardiomyocytes against postischemic mitochondrial damage. Soluble epoxide hydrolase 2 (EPHX2) diminishes the benefits of EETs through hydrolysis to less active dihydroxyeicosatrienoic acids.

Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice.

Introduction: Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) leads to blindness. It has been widely reported that increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) diets reduce CNV. Of the three major pathways metabolizing ω-3 (and ω-6 LCPUFA), the cyclooxygenase and lipoxygenase pathways generally produce pro-angiogenic metabolites from ω-6 LCPUFA and anti-angiogenic ones from ω-3 LCPUFA.

Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy.

Objective: Metabolites derived from -3 and -6 polyunsaturated fatty acids (PUFAs) have both beneficial and detrimental effects on the heart. However, contribution of these lipid mediators to dilated cardiomyopathy (DCM)-associated mitochondrial dysfunction remains unknown. This study aimed to characterize DCM-specific alterations in the PUFA metabolome in conjunction with cardiac mitochondrial quality in human explanted heart tissues.

Inflammation and oxidative stress as mediators of the impacts of environmental exposures on human pregnancy: Evidence from oxylipins.

Inflammation and oxidative stress play major roles in healthy and pathological pregnancy. Environmental exposure to chemical pollutants may adversely affect maternal and fetal health in pregnancy by dysregulating these critical underlying processes of inflammation and oxidative stress. Oxylipins are bioactive lipids that play a major role in regulating inflammation and increasing lines of evidence point towards an importance in pregnancy.

sEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae.

Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown.

Proteome and functional decline as platelets age in the circulation.

Background: Platelets circulate in the blood of healthy individuals for approximately 7-10 days regulated by finely balanced processes of production and destruction. As platelets are anucleate we reasoned that their protein composition would change as they age and that this change would be linked to alterations in structure and function.

Objective: To isolate platelets of different ages from healthy individuals to test the hypothesis that changes in protein content cause alterations in platelet structure and function.

Regulation of cardiovascular biology by microsomal epoxide hydrolase.

Microsomal epoxide hydrolase/epoxide hydrolase 1 (mEH/EPHX1) works in conjunction with cytochromes P450 to metabolize a variety of compounds, including xenobiotics, pharmaceuticals and endogenous lipids. mEH has been most widely studied for its role in metabolism of xenobiotic and pharmaceutical compounds where it converts hydrophobic and reactive epoxides to hydrophilic diols that are more readily excreted. Inhibition or genetic disruption of mEH can be deleterious in the face of many industrial, environmental or pharmaceutical exposures and polymorphisms are associated with the development of exposure-related cancers.