<div>Abstract<p>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. Pharmacologic inhibition or genetic ablation of CYP monooxygenases suppressed AOM/DSS-induced colon tumorigenesis <i>in vivo</i>. In addition, treatment with 12,13-epoxyoctadecenoic acid (EpOME), which is a metabolite of CYP monooxygenase produced from linoleic acid, increased cytokine production and JNK phosphorylation <i>in vitro</i> and exacerbated AOM/DSS-induced colon tumorigenesis <i>in vivo</i>. Together, these results demonstrate that the previously unappreciated CYP monooxygenase pathway is upregulated in colon cancer, contributes to its pathogenesis, and could be therapeutically explored for preventing or treating colon cancer.</p>Significance:<p>This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis.</p></div>
<p>SF1: CYP monooxygenase expression in human colon cancer cells; SF2: gene expression of Cyp2e1 in the liver of Cyp2c+/+, Cyp2c+/-, and Cyp2c-/- mice; SF3: liver inflammation in Cyp2c+/+, Cyp2c+/-, and Cyp2c-/- mice; SF4: survival curve of the AOM/DSS-stimulated Cyp2c+/+, Cyp2c+/-, and Cyp2c-/- mice; SF5: pharmacological inhibition of CYP monooxygenases suppresses AOM/DSS-induced colon tumorigenesis in mice; SF6: effects of 12,13-EpOME on MC38 tumor growth in C57BL/6 mice; SF7: mRNA expression levels of CYP monooxygenases in control subjects and colon cancer patients</p>
Benzalkonium chloride (BAC), benzethonium chloride (BET), and chloroxylenol (PCMX) are antimicrobial ingredients used in many consumer products and are frequently detected in the environment. In 2016, the U.S. Food and Drug Administration removed 19 antimicrobial ingredients from consumer antiseptic wash products, but deferred rulemaking for BAC, BET, and PCMX to allow additional time to develop new safety and efficacy data for these 3 antimicrobials. Therefore, it is important and timely to better understand the effects of these 3 compounds on human health. Here, we report that exposure to low doses of these antimicrobial compounds, in particular BAC, increases dextran sodium sulfate (DSS)-induced colonic inflammation and azoxymethane/DSS-induced colon tumorigenesis in mice. In addition, we find that exposure to BAC increases activation of Toll-like receptor 4 signaling in the systemic circulation, by disrupting intestinal barrier function and thus enhancing circulating levels of bacterial products. Together, our results suggest that these widely used antimicrobial compounds could exaggerate disease development of inflammatory bowel disease and associated colon cancer. Further studies are urgently needed to better characterize the impacts of these compounds on gut diseases.
Pregnancy induces unique changes in maternal immune responses and metabolism. Drastic physiologic adaptations, in an intricately coordinated fashion, allow the maternal body to support the healthy growth of the fetus. The gut microbiome plays a central role in the regulation of the immune system, metabolism, and resistance to infections. Studies have reported changes in the maternal microbiome in the gut, vagina, and oral cavity during pregnancy; it remains unclear whether/how these changes might be related to maternal immune responses, metabolism, and susceptibility to infections during pregnancy. Our understanding of the concerted adaption of these different aspects of the human physiology to promote a successful pregnant remains limited. Here, we provide a comprehensive documentation and discussion of changes in the maternal microbiome in the gut, oral cavity, and vagina during pregnancy, metabolic changes and complications in the mother and newborn that may be, in part, driven by maternal gut dysbiosis, and, lastly, common infections in pregnancy. This review aims to shed light on how dysregulation of the maternal microbiome may underlie obstetrical metabolic complications and infections.
Substantial pre-clinical and human studies have shown that curcumin, a dietary compound from turmeric, has a variety of health-promoting biological activities. A better understanding of the biochemical mechanisms for the health-promoting effects of curcumin could facilitate the development of effective strategies for disease prevention. Recent studies have shown that in aqueous buffer, curcumin rapidly degrades and leads to formation of various degradation products. In this review, we summarized and discussed the biological activities of chemical degradation products of curcumin, including alkaline hydrolysis products (such as ferulic acid, vanillin, ferulaldehyde, and feruloyl methane), and autoxidation products (such as bicyclopentadione). Though many of these degradation products are biologically active, they are substantially less-active compared to curcumin, supporting that chemical degradation has a limited contribution to the biological activities of curcumin.
The prevalence of nonalcoholic fatty liver disease (NAFLD) in western countries is 20–30%; it is of critical importance to identify new therapeutic target, in order to reduce the risks of NAFLD and associated diseases. Here, we report that the expression of soluble epoxide hydrolase (sEH) is increased in liver tissues of a high‐fat diet‐induced NAFLD model; in addition, pharmacological inhibition or genetic ablation of sEH attenuates high‐fat diet‐induced NAFLD, suggesting that sEH could be a novel therapeutic target of NAFLD. We find that after 8‐week dietary feeding of high‐fat diet (60%cal), the expression of sEH is dramatically increased in liver. To explore the roles of sEH in obesity‐induced NAFLD, we test whether pharmacological inhibition or genetic ablation of sEH affects the development of NAFLD. We find that oral administration of TPPU and t‐ TUCB, which are two different sEH inhibitors, attenuates high‐fat diet‐induced fat accumulation in liver (assess by liver triglyceride analysis, oil red o staining and H&E histology staining), and reduces expressions of pro‐inflammatory genes in liver ( Mcp‐1 and Tnf‐α ). Similar results are observed in sEH knockout mice. Regarding the mechanisms, we find that pharmacological inhibition or genetic ablation of sEH suppresses the expression of Srebf1 , Ppar‐γ , Cd36 and Dgat2 , which play critical roles in lipid synthesis; and increases the expression of Ppar‐α , regulating fatty acid β‐oxidation. Together, these results support that sEH could be a promising therapeutic target for NAFLD, suppressing fat accumulation and inflammation in liver. This could lead to rapid human translations, because the pharmacological inhibitors of sEH are being evaluated in human clinical trials targeting multiple disorders. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.
Significance Defective intestinal barrier function and enhanced lipopolysaccharide (LPS)/bacterial translocation is a key pathogenic factor in many human diseases, including obesity. To date, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) could be a novel therapeutic target of obesity-induced intestinal barrier dysfunction and LPS/bacterial translocation, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other disorders, could be promising agents for prevention or treatment.
Abstract The gut microbiome promotes immune system development in early life, but the neonatal gut metabolome remains undefined. Here, we demonstrate that, distinct from adults, the neonatal mouse gut is enriched with neurotransmitters, and specific bacteria produce serotonin directly while downregulating monoamine oxidase A to limit serotonin breakdown. Serotonin inhibits mTOR activation to promote regulatory T cells and suppress T cell responses both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice leads to long-term immune tolerance toward both dietary antigens and commensal bacteria as well as alterations of the gut microbiome. Together, our study has uncovered unique microbiome-dependent mechanisms to maximize serotonin in the neonatal gut and a novel role for intestinal serotonin to promote immune tolerance in early life.
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