Oxidized polyunsaturated fatty acid promotes colitis and colitis-associated tumorigenesis in mice.

Background And Aims: Human studies suggest that a high intake of polyunsaturated fatty acid (PUFA) is associated with an increased risk of inflammatory bowel disease (IBD). PUFA is highly prone to oxidation. To date, it is unclear whether unoxidized or oxidized PUFA is involved in the development of IBD.

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.

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase.

Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation.

Aflatoxin B Increases Soluble Epoxide Hydrolase in the Brain and Induces Neuroinflammation and Dopaminergic Neurotoxicity.

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 B (AFB), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world.

Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon.

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.

Aflatoxin B exposure disrupts the intestinal immune function via a soluble epoxide hydrolase-mediated manner.

Aflatoxin B (AFB) 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 AFB via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB toxicity are still unclear. Here, we showed that AFB disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells.

ω-3 Polyunsaturated Fatty Acids on Colonic Inflammation and Colon Cancer: Roles of Lipid-Metabolizing Enzymes Involved.

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.

Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression.

Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer.

Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)?

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.

Foodborne Titanium Dioxide Nanoparticles Induce Stronger Adverse Effects in Obese Mice than Non-Obese Mice: Gut Microbiota Dysbiosis, Colonic Inflammation, and Proteome Alterations.

The recent ban of titanium dioxide (TiO ) as a food additive (E171) in France intensified the controversy on safety of foodborne-TiO nanoparticles (NPs). This study determines the biological effects of TiO NPs and TiO (E171) in obese and non-obese mice. Oral consumption (0.

Soluble epoxide hydrolase is an endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation.

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.

Click chemistry-based imaging to study the tissue distribution of the curcumin-protein complex in mice.

Previous studies have shown that curcumin, a bioactive dietary compound with a thiol-reactive α,β-unsaturated carbonyl moiety, can covalently modify protein thiols. However, most of the previous studies were performed in cultured cells or cell-free enzyme systems, and so it remains unknown whether curcumin could covalently modify proteins after oral administration in vivo. Using click chemistry-based fluorescence imaging, here we show that oral administration of dialkyne-curcumin (Di-Cur), a "click" probe mimicking curcumin, results in covalent modifications of cellular proteins in colon and liver tissues, but not in other tissues, in mice.

trans, trans-2,4-Decadienal, a lipid peroxidation product, induces inflammatory responses via Hsp90- or 14-3-3ζ-dependent mechanisms.

Peroxidation of polyunsaturated fatty acids leads to the formation of a large array of lipid-derived electrophiles (LDEs), many of which are important signaling molecules involved in the pathogenesis of human diseases. Previous research has shown that one of such LDEs, trans, trans-2,4-decadienal (tt-DDE), increases inflammation, however, the underlying mechanisms are not well understood. Here we used click chemistry-based proteomics to identify the cellular targets which are required for the pro-inflammatory effects of tt-DDE.

Triclocarban Exposure Exaggerates Spontaneous Colonic Inflammation in Il-10-/- Mice.

Triclocarban (3,4,4'-trichlorocarbanilide, TCC) is a high-volume chemical used as an antimicrobial ingredient in many consumer and personal care products. In 2016, the Food and Drug Administration removed TCC from over-the-counter hand washing products. However, TCC remains approved to use in many other products and is a ubiquitous contaminant in the environment; furthermore, many common food crops can efficiently accumulate environmental TCC, resulting in potential human exposure through oral ingestion of contaminated food products.

Triclocarban exposure exaggerates colitis and colon tumorigenesis: roles of gut microbiota involved.

Triclocarban (TCC) is a widely used antimicrobial ingredient in consumer products and is a ubiquitous contaminant in the environment. In 2016, the FDA removed TCC from over-the-counter handwashing products, but this compound is still approved for use in many other personal care products. A better understanding of its impact on human health could lead to significant impact for public health and regulatory policies.

Mapping of Pesticide Transmission on Biological Tissues by Surface Enhanced Raman Microscopy with a Gold Nanoparticle Mirror.

We presented an improved surface-enhanced Raman scattering (SERS) mapping technique for the imaging of pesticides on biological samples including tomato leaves, fruits, and mouse skin using a gold nanoparticle mirror as the SERS substrate. The gold nanoparticle mirror was fabricated using 50 nm commercial citrate-capped gold nanoparticles upon the interface of water and a mediating solvent that was prepared using acetonitrile and hexane. The properties of the gold nanoparticle mirror were compared with gold nanoparticles, and the mirror displayed higher sensitivity with a limit of detection of 0.

Cytochrome P450 Eicosanoid Signaling Pathway in Colorectal Tumorigenesis.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. It is important to discover novel cellular targets which are crucial in the pathogenesis of CRC, which could facilitate development of mechanism-based strategies to reduce the risks of CRC. Emerging studies support that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH) pathway and their eicosanoid metabolites play critical roles in colonic inflammation and CRC, and could be therapeutically explored for treating or preventing CRC.

REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells.

Interleukin-17A (IL-17A)-producing helper T (Th17) cells are a subset of CD4 T cells that play important pathological roles in autoimmune diseases. Although the intrinsic pathways of Th17 cell differentiation have been well described, how instructive signals derived from the innate immune system trigger the Th17 response and inflammation remains poorly understood. Here, we report that mice deficient in REGγ, a proteasome activator belonging to the 11S family, exhibit significantly deteriorated autoimmune neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model with augmented Th17 cell polarization in vivo.

An anaerobic bacterium host system for heterologous expression of natural product biosynthetic gene clusters.

Anaerobic bacteria represent an overlooked rich source of biological and chemical diversity. Due to the challenge of cultivation and genetic intractability, assessing the capability of their biosynthetic gene clusters (BGCs) for secondary metabolite production requires an efficient heterologous expression system. However, this kind of host system is still unavailable.

Click chemistry approach to characterize curcumin-protein interactions in vitro and in vivo.

Curcumin, a bis-α, β-unsaturated β-diketon dietary compound from turmeric, is among the most promising dietary compounds for preventing chronic diseases. Previous research has shown that curcumin is highly reactive toward protein thiols to form curcumin-protein adducts, however, the interactions of curcumin with proteins are under-studied. Here we report the design and synthesis of "click" chemistry probes of curcumin, mono-propargyl curcumin (mono-Cur) and di-propargyl curcumin (di-Cur), and use the click probes to study curcumin-proteins interactions in vitro and in vivo.

Dietary Intake of Whole Strawberry Inhibited Colonic Inflammation in Dextran-Sulfate-Sodium-Treated Mice via Restoring Immune Homeostasis and Alleviating Gut Microbiota Dysbiosis.

Strawberry () is a major edible berry with various potential health benefits. This study determined the protective effects of whole strawberry (WS) against dextran-sulfate-sodium-induced colitis in mice. In colitic mice, dietary WS reduced the disease activity index, prevented the colon shortening and spleen enlargement, and alleviated the colonic tissue damages.

Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis.

Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, emphasizing the need for the discovery of new cellular targets. Using a metabolomics approach, we report here that epoxygenated fatty acids (EpFA), which are eicosanoid metabolites produced by cytochrome P450 (CYP) monooxygenases, were increased in both the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice. CYP monooxygenases were overexpressed in colon tumor tissues and colon cancer cells.

Intraperitoneal injection of 4-hydroxynonenal (4-HNE), a lipid peroxidation product, exacerbates colonic inflammation through activation of Toll-like receptor 4 signaling.

Human and animal studies have shown that the colonic concentrations of lipid peroxidation products, such as 4-hydroxynonenal (4-HNE), are elevated in inflammatory bowel disease (IBD). However, the actions and mechanisms of these compounds on the development of IBD are unknown. Here, we show that a systemic treatment of low-dose 4-HNE exacerbates dextran sulfate sodium (DSS)-induced IBD in C57BL/6 mice, suggesting its pro-IBD actions in vivo.

Consumer Antimicrobials on Gut Microbiota and Gut Health.

Triclosan (TCS) is a high-volume chemical used as an antimicrobial ingredient in over 2000 consumer products such as toothpastes, cosmetics, and toys. Due to its widespread use, it causes ubiquitous contamination in the environment and is frequently detected in the human body, raising concerns about its impact on environmental pollution and human health. Our recent study showed that short-time exposure to low-dose TCS causes colonic inflammation, increases severity of colitis, and exacerbates colitis-associated colon tumorigenesis in mice, through gut microbiota- and Toll-like receptor 4 (TLR4)-dependent mechanisms.

Eicosanoid signaling in carcinogenesis of colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the USA. It is of practical importance to identify novel therapeutic targets of CRC to develop new anti-cancer drugs and to discover novel biomarkers of CRC to develop new detection methods. Eicosanoids, which are metabolites of polyunsaturated fatty acids produced by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, are important lipid-signaling molecules involved in the regulation of inflammation and tumorigenesis.