Substantial human and animal studies support the beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) on colonic inflammation and colorectal cancer (CRC). However, there are inconsistent results, which have shown that ω-3 PUFAs have no effect or even detrimental effects, making it difficult to effectively implement ω-3 PUFAs for disease prevention. A better understanding of the molecular mechanisms for the anti-inflammatory and anticancer effects of ω-3 PUFAs will help to clarify their potential health-promoting effects, provide a scientific base for cautions for their use, and establish dietary recommendations. In this review, we summarize recent studies of ω-3 PUFAs on colonic inflammation and CRC and discuss the potential roles of ω-3 PUFA-metabolizing enzymes, notably the cytochrome P450 monooxygenases, in mediating the actions of ω-3 PUFAs.

Severe coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their roles in COVID-19 are poorly characterized. Arachidonic acid-derived epoxyeicosatrienoic acids could alleviate the systemic hyperinflammatory response in COVID-19 infection by modulating endoplasmic reticulum stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous epoxyeicosatrienoic acid levels, exhibit potent anti-inflammatory activity and inhibit various pathologic processes in preclinical disease models, including pulmonary fibrosis, thrombosis, and acute respiratory distress syndrome. Therefore, targeting eicosanoids and sEH could be a novel therapeutic approach in combating COVID-19. In this review, we discuss the predominant role of eicosanoids in regulating the inflammatory cascade and propose the potential application of sEH inhibitors in alleviating COVID-19 symptoms. The host-protective action of omega-3 fatty acid-derived epoxyeicosanoids and specialized proresolving mediators in regulating anti-inflammation and antiviral response is also discussed. Future studies determining the eicosanoid profile in COVID-19 patients or preclinical models are pivotal in providing novel insights into coronavirus-host interaction and inflammation modulation.

Epidemiological and pre-clinical studies support the anti-tumor effects of ω-3 PUFAs; however, the results from human trials are mixed, making it difficult to provide dietary guidelines or recommendations of ω-3 PUFAs for disease prevention or treatment. Understanding the molecular mechanisms by which ω-3 PUFAs inhibit cancer could lead to better nutritional paradigms and human trials to clarify their health effects. The ω-3 PUFAs exert their biological activities mainly through the formation of bioactive lipid metabolites. Here we discuss the biology of cyclooxygenase, lipoxygenase and cytochrome P450 enzymes-derived ω-3-series lipid metabolites on angiogenesis, inflammation and cancer.

Obesity is a serious health problem in the US and is associated with increased risks of various human diseases. To date, the mechanisms by which obesity increases the risks of a wide range of human diseases are not well understood. Here we used a LC-MS/MS-based lipidomics, which can analyze >100 bioactive lipid mediators produced by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes, to analyze plasma profiles of lipid mediators in high-fat diet induced obesity in C57BL/6 mice. Our results show that the plasma concentrations of epoxyoctadecenoic acids (EpOMEs, also termed as leukotoxins) are significantly increased in plasma of high-fat diet-fed mice, in addition, EpOMEs are among the most abundant lipid mediators detected in mouse plasma. Since substantial studies have shown that EpOMEs and their metabolites have a large array of detrimental effects on health, enhanced levels of EpOMEs could contribute to the pathology of obesity.

Parkinson's disease (PD) is an increasingly common neurodegenerative movement disorder with contributing factors that are still largely unexplored and currently no effective intervention strategy. Epidemiological and pre-clinical studies support the close association between environmental toxicant exposure and PD incidence. Aflatoxin B₁ (AFB₁), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world. Previous evidence suggests that chronic exposure to AFB₁ leads to neurological disorders as well as cancer. However, whether and how aflatoxin B₁ contributes to the pathogenesis of PD is poorly understood. Here, oral exposure to AFB₁ is shown to induce neuroinflammation, trigger the α-synuclein pathology, and cause dopaminergic neurotoxicity. This was accompanied by the increased expression and enzymatic activity of soluble epoxide hydrolase (sEH) in the mouse brain. Importantly, genetic deletion or pharmacological inhibition of sEH alleviated the AFB₁-induced neuroinflammation by reducing microglia activation and suppressing pro-inflammatory factors in the brain. Furthermore, blocking the action of sEH attenuated dopaminergic neuron dysfunction caused by AFB₁ in vivo and in vitro. Together, our findings suggest a contributing role of AFB₁ to PD etiology and highlight sEH as a potential pharmacological target for alleviating PD-related neuronal disorders caused by AFB₁ exposure.

Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers p21, p16, Tp53, and β-galactosidase in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators Perk and Ire1 as well as the downstream pro-apoptotic effectors Chop and Gadd34. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon.

Objective

Enzymatic metabolism of polyunsaturated fatty acids leads to formation of bioactive lipid metabolites (LMs). Previous studies have shown that obesity leads to deregulation of LMs in adipose tissues. However, most previous studies have focused on a single or limited number of LMs, and few systematical analyses have been carried out.

Methods

A LC-MS/MS-based lipidomics approach was used, which can analyze >100 LMs produced by cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) enzymes, to analyze the profile of LMs in high-fat diet-induced obesity in mice.

Results

LC-MS/MS showed that high-fat feeding significantly modulated profiles of LMs in adipose tissues. Among the three major polyunsaturated fatty acid metabolizing pathways (cyclooxygenase, lipoxygenase, and CYP), CYP-derived fatty acid epoxides were the most dramatically altered LMs. Almost all types of fatty acid epoxides were reduced by 70% to 90% in adipose tissues of high-fat diet-fed mice. Consistent with the reduced levels of fatty acid epoxides, the gene expression of several CYP epoxygenases, including Cyp2j5, Cyp2j6, and Cyp2c44, was significantly reduced in adipose tissues of high-fat diet-fed mice.

Conclusions

Results show that CYP-derived fatty acid epoxides are the most responsive LMs in high-fat diet-induced obesity, suggesting that these LMs could play critical roles in obesity.

Aflatoxin B₁ (AFB₁) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB₁ via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB₁ toxicity are still unclear. Here, we showed that AFB₁ disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB₁ immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB₁-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and α-defensin-3 in mice. Altogether, our study demonstrates that AFB₁ exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB₁ global contamination.

Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. Considering the obesity epidemic in Western countries, it is important to identify novel therapeutic targets for obesity-induced colonic inflammation, to develop targeted strategies for prevention. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using an LC-MS/MS-based lipidomics approach, we find that obesity-induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. Furthermore, we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols, attenuates obesity-induced colonic inflammation, and decreases obesity-induced activation of Wnt signaling in mice. Together, these results support that sEH could be a novel therapeutic target for obesity-induced colonic inflammation and associated diseases.

Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.