3,108 results on '"Zeldin, Darryl C."'
Search Results
2. attenuates allergic lung inflammation through regulation of Th2, Th9, and Treg differentiation
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Li, Hong, Bradbury, J. Alyce, Edin, Matthew L., Gruzdev, Artiom, Li, Huiling, Graves, Joan P., DeGraff, Laura M., Lih, Fred B., Feng, Chiguang, Wolf, Erin R., Bortner, Carl D., London, Stephanie J., Sparks, Matthew A., Coffman, Thomas M., and Zeldin, Darryl C.
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Thromboxanes -- Physiological aspects -- Health aspects ,Immune response -- Health aspects -- Physiological aspects ,Asthma -- Development and progression -- Prevention -- Care and treatment ,Health care industry - Abstract
In lung, thromboxane [A.sub.2] ([TXA.sub.2]) activates the TP receptor to induce proinflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and [TXA.sub.2] 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. Herein, we found that [TXA.sub.2] reduces Th9 cell differentiation during allergic lung inflammation. Th9 cells were decreased approximately 2-fold and airway hyperresponsiveness was attenuated in lungs of allergic mice treated with [TXA.sub.2]. Naive [CD4.sup.+] T cell differentiation to Th9 cells and IL-9 production were inhibited dose-dependently by [TXA.sub.2] in vitro. TP receptor-deficient mice had an approximately 2-fold increase in numbers of Th9 cells in lungs in vivo after OVA exposure compared with wild-type mice. Naive [CD4.sup.+] T cells from TP- deficient mice exhibited increased Th9 cell differentiation and IL-9 production in vitro compared with [CD4.sup.+] T cells from wild-type mice. [TXA.sub.2] also suppressed Th2 and enhanced Treg differentiation both in vitro and in vivo. Thus, in contrast to its acute, proinflammatory effects, [TXA.sub.2] also has longer-lasting immunosuppressive effects that attenuate the Th9 differentiation that drives asthma progression. These findings may explain the paradoxical failure of anti-thromboxane therapies in the treatment of asthma., Introduction Development of allergic lung inflammation is a complex process involving both immune and inflammatory events. In the immune phase, allergens are taken up and processed by antigen-presenting cells such [...]
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- 2024
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3. Overexpression of soluble epoxide hydrolase reduces post-ischemic recovery of cardiac contractile function
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Edin, Matthew L., Gruzdev, Artiom, Bradbury, J. Alyce, Graves, Joan P., Muse, Ginger W., Goulding, David R., Lih, Fred B., DeGraff, Laura M., and Zeldin, Darryl C.
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- 2024
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4. 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
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Hateley, Charlotte, Olona, Antoni, Halliday, Laura, Edin, Matthew L., Ko, Jeong-Hun, Forlano, Roberta, Terra, Ximena, Lih, Fred B., Beltrán-Debón, Raúl, Manousou, Penelopi, Purkayastha, Sanjay, Moorthy, Krishna, Thursz, Mark R., Zhang, Guodong, Goldin, Robert D., Zeldin, Darryl C., Petretto, Enrico, and Behmoaras, Jacques
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- 2024
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5. Predictors of upstream inflammation and oxidative stress pathways during early pregnancy
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Welch, Barrett M., Bommarito, Paige A., Cantonwine, David E., Milne, Ginger L., Motsinger-Reif, Alison, Edin, Matthew L., Zeldin, Darryl C., Meeker, John D., McElrath, Thomas F., and Ferguson, Kelly K.
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- 2024
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6. Environmental management of asthma in clinical practice: Results from the 2012 National Ambulatory Medical Care Survey
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Salo, Paivi M., Akinbami, Lara J., Cloutier, Michelle M., Wilkerson, Jesse C., Elward, Kurtis S., Mazurek, Jacek M., Diette, Gregory B., Mitchell, Tracey A., Williams, Sonja, and Zeldin, Darryl C.
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- 2024
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7. Soluble epoxide hydrolase deficiency attenuates lipotoxic cardiomyopathy via upregulation of AMPK-mTORC mediated autophagy
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Wang, Luyun, Zhao, Daqiang, Tang, Liangqiu, Li, Huihui, Liu, Zhaoyu, Gao, Jingwei, Edin, Matthew L, Zhang, Huanji, Zhang, Kun, Chen, Jie, Zhu, Xinhong, Wang, Daowen, Zeldin, Darryl C, Hammock, Bruce D, Wang, Jingfeng, and Huang, Hui
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Biochemistry and Cell Biology ,Biological Sciences ,Heart Disease ,Cardiovascular ,Nutrition ,2.1 Biological and endogenous factors ,Aetiology ,AMP-Activated Protein Kinases ,Animals ,Autophagy ,Biomarkers ,Cardiomyopathies ,Disease Models ,Animal ,Disease Susceptibility ,Epoxide Hydrolases ,Lipid Metabolism ,Mice ,Mice ,Knockout ,Myocardium ,TOR Serine-Threonine Kinases ,AMPK-mTORC pathway ,Cardiac lipid accumulation ,Lipotoxic cardiomyopathy ,Soluble epoxide hydrolase ,Cardiorespiratory Medicine and Haematology ,Medical Physiology ,Cardiovascular System & Hematology ,Biochemistry and cell biology ,Cardiovascular medicine and haematology ,Medical physiology - Abstract
Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6 J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. Palmitic acid (PA) was utilized to induce lipotoxicity to cardiomyocytes for in vitro study. We found sEH KO, independent of plasma lipid and blood pressures, significantly attenuated HFD-induced myocardial lipid accumulation and cardiac dysfunction in vivo. HFD-induced lipotoxic cardiomyopathy and dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin complex (AMPK-mTORC) signaling mediated lipid autophagy in heart were restored by sEH KO. In primary neonatal mouse cardiomyocytes, both sEH KO and sEH substrate EETs plus sEH inhibitor AUDA treatments attenuated PA-induced lipid accumulation. These effects were blocked by inhibition of AMPK or autophagy. The outcomes were supported by the results that sEH KO and EETs plus AUDA rescued HFD- and PA-induced impairment of autophagy upstream signaling of AMPK-mTORC, respectively. These findings revealed that sEH deficiency played an important role in attenuating myocardial lipid accumulation and provided new insights into treating lipotoxic cardiomyopathy. Regulation of autophagy via AMPK-mTORC signaling pathway is one of the underlying mechanisms.
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- 2021
8. Global and endothelial G-protein coupled receptor 75 (GPR75) knockout relaxes pulmonary artery and mitigates hypoxia-induced pulmonary hypertension
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D'Addario, Catherine A., Matsumura, Shun, Kitagawa, Atsushi, Lainer, Gregg M., Zhang, Frank, D'silva, Melinee, Khan, Mohammad Y., Froogh, Ghezal, Gruzdev, Artiom, Zeldin, Darryl C., Schwartzman, Michal L., and Gupte, Sachin A.
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- 2023
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9. Natural Products in the Prevention of Metabolic Diseases: Lessons Learned from the 20th KAST Frontier Scientists Workshop
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Baek, Seung J, Hammock, Bruce D, Hwang, In-Koo, Li, Qingxiao, Moustaid-Moussa, Naima, Park, Yeonhwa, Safe, Stephen, Suh, Nanjoo, Yi, Sun-Shin, Zeldin, Darryl C, Zhong, Qixin, Bradbury, Jennifer Alyce, Edin, Matthew L, Graves, Joan P, Jung, Hyo-Young, Jung, Young-Hyun, Kim, Mi-Bo, Kim, Woosuk, Lee, Jaehak, Li, Hong, Moon, Jong-Seok, Yoo, Ik-Dong, Yue, Yiren, Lee, Ji-Young, and Han, Ho-Jae
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Biomedical and Clinical Sciences ,Nutrition and Dietetics ,Clinical Sciences ,Prevention ,Complementary and Integrative Health ,Nutrition ,Good Health and Well Being ,Animals ,Anti-Inflammatory Agents ,Antioxidants ,Biological Products ,Dietary Supplements ,Humans ,Metabolic Diseases ,Mice ,Nanoparticles ,Obesity ,Oxidative Stress ,Rats ,obesity ,inflammation-related diseases ,cancer ,aging ,natural products ,bioactive food components ,nanoparticles ,antioxidants ,anti-inflammation ,Food Sciences ,Clinical sciences ,Nutrition and dietetics ,Public health - Abstract
The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases.
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- 2021
10. Soluble Epoxide Hydrolase in Aged Female Mice and Human Explanted Hearts Following Ischemic Injury
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Jamieson, K Lockhart, Darwesh, Ahmed M, Sosnowski, Deanna K, Zhang, Hao, Shah, Saumya, Zhabyeyev, Pavel, Yang, Jun, Hammock, Bruce D, Edin, Matthew L, Zeldin, Darryl C, Oudit, Gavin Y, Kassiri, Zamaneh, and Seubert, John M
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Biochemistry and Cell Biology ,Biological Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Microbiology ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,Aging ,Animals ,Case-Control Studies ,Cytochrome P450 Family 2 ,Disease Models ,Animal ,Enzyme Inhibitors ,Epoxide Hydrolases ,Female ,Heart ,Humans ,Metabolome ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myocardial Ischemia ,Myocardial Reperfusion Injury ,Survival Rate ,Tandem Mass Spectrometry ,soluble epoxide hydrolase ,ischemic injury ,failing heart ,explanted hearts ,sex differences ,aging ,Other Chemical Sciences ,Genetics ,Other Biological Sciences ,Chemical Physics ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
Myocardial infarction (MI) accounts for a significant proportion of death and morbidity in aged individuals. The risk for MI in females increases as they enter the peri-menopausal period, generally occurring in middle-age. Cytochrome (CYP) 450 metabolizes N-3 and N-6 polyunsaturated fatty acids (PUFA) into numerous lipid mediators, oxylipids, which are further metabolised by soluble epoxide hydrolase (sEH), reducing their activity. The objective of this study was to characterize oxylipid metabolism in the left ventricle (LV) following ischemic injury in females. Human LV specimens were procured from female patients with ischemic cardiomyopathy (ICM) or non-failing controls (NFC). Female C57BL6 (WT) and sEH null mice averaging 13-16 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD) to induce myocardial infarction. WT (wild type) mice received vehicle or sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB), in their drinking water ad libitum for 28 days. Cardiac function was assessed using echocardiography and electrocardiogram. Protein expression was determined using immunoblotting, mitochondrial activity by spectrophotometry, and cardiac fibre respiration was measured using a Clark-type electrode. A full metabolite profile was determined by LC-MS/MS. sEH was significantly elevated in ischemic LV specimens from patients, associated with fundamental changes in oxylipid metabolite formation and significant decreases in mitochondrial enzymatic function. In mice, pre-treatment with tAUCB or genetic deletion of sEH significantly improved survival, preserved cardiac function, and maintained mitochondrial quality following MI in female mice. These data indicate that sEH may be a relevant pharmacologic target for women with MI. Although future studies are needed to determine the mechanisms, in this pilot study we suggest targeting sEH may be an effective strategy for reducing ischemic injury and mortality in middle-aged females.
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- 2021
11. Preface
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Zeldin, Darryl C., primary and Seubert, John M., additional
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- 2023
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12. Vascular Lipidomic Profiling of Potential Endogenous Fatty Acid PPAR Ligands Reveals the Coronary Artery as Major Producer of CYP450-Derived Epoxy Fatty Acids
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Edin, Matthew L, Lih, Fred B, Hammock, Bruce D, Thomson, Scott, Zeldin, Darryl C, and Bishop-Bailey, David
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Biomedical and Clinical Sciences ,Prevention ,Heart Disease ,Atherosclerosis ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Anti-Inflammatory Agents ,Coronary Vessels ,Fatty Acids ,Female ,Hydroxyeicosatetraenoic Acids ,Inflammation ,Ligands ,Lipidomics ,Lipopolysaccharides ,Myocytes ,Smooth Muscle ,Peroxisome Proliferator-Activated Receptors ,Swine ,CYP450 ,PPARs ,coronary artery ,eicosanoids ,inflammation ,lipidomics ,vascular ,Biological sciences ,Biomedical and clinical sciences - Abstract
A number of oxylipins have been described as endogenous PPAR ligands. The very short biological half-lives of oxylipins suggest roles as autocrine or paracrine signaling molecules. While coronary arterial atherosclerosis is the root of myocardial infarction, aortic atherosclerotic plaque formation is a common readout of in vivo atherosclerosis studies in mice. Improved understanding of the compartmentalized sources of oxylipin PPAR ligands will increase our knowledge of the roles of PPAR signaling in diverse vascular tissues. Here, we performed a targeted lipidomic analysis of ex vivo-generated oxylipins from porcine aorta, coronary artery, pulmonary artery and perivascular adipose. Cyclooxygenase (COX)-derived prostanoids were the most abundant detectable oxylipin from all tissues. By contrast, the coronary artery produced significantly higher levels of oxylipins from CYP450 pathways than other tissues. The TLR4 ligand LPS induced prostanoid formation in all vascular tissue tested. The 11-HETE, 15-HETE, and 9-HODE were also induced by LPS from the aorta and pulmonary artery but not coronary artery. Epoxy fatty acid (EpFA) formation was largely unaffected by LPS. The pig CYP2J homologue CYP2J34 was expressed in porcine vascular tissue and primary coronary artery smooth muscle cells (pCASMCs) in culture. Treatment of pCASMCs with LPS induced a robust profile of pro-inflammatory target genes: TNFα, ICAM-1, VCAM-1, MCP-1 and CD40L. The soluble epoxide hydrolase inhibitor TPPU, which prevents the breakdown of endogenous CYP-derived EpFAs, significantly suppressed LPS-induced inflammatory target genes. In conclusion, PPAR-activating oxylipins are produced and regulated in a vascular site-specific manner. The CYP450 pathway is highly active in the coronary artery and capable of providing anti-inflammatory oxylipins that prevent processes of inflammatory vascular disease progression.
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- 2020
13. Soluble Epoxide Hydrolase Inhibition by t-TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity
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Overby, Haley, Yang, Yang, Xu, Xinyun, Graham, Katherine, Hildreth, Kelsey, Choi, Sue, Wan, Debin, Morisseau, Christophe, Zeldin, Darryl C, Hammock, Bruce D, Wang, Shu, Bettaieb, Ahmed, and Zhao, Ling
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Biochemistry and Cell Biology ,Biological Sciences ,Nutrition ,Obesity ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Cardiovascular ,Cancer ,Metabolic and endocrine ,Stroke ,Adipocytes ,Brown ,Adipogenesis ,Adipose Tissue ,Brown ,Animals ,Benzoates ,Cell Line ,Enzyme Inhibitors ,Epoxide Hydrolases ,Humans ,Male ,Mice ,Mice ,Inbred C57BL ,Phenylurea Compounds ,Triglycerides ,soluble epoxide hydrolase ,soluble epoxide hydrolase inhibitor ,t-TUCB ,brown adipose tissue ,brown adipogenesis ,Other Chemical Sciences ,Genetics ,Other Biological Sciences ,Chemical Physics ,Biochemistry and cell biology ,Microbiology ,Medicinal and biomolecular chemistry - Abstract
Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH and sEHI in brown adipogenesis and BAT activity in treating diet-induced obesity (DIO) have not been reported. sEH expression was studied in in vitro models of brown adipogenesis and the fat tissues of DIO mice. The effects of the sEHI, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy-benzoic acid (t-TUCB), were studied in vitro and in the obese mice via mini osmotic pump delivery. sEH expression was increased in brown adipogenesis and the BAT of the DIO mice. t-TUCB promoted brown adipogenesis in vitro. Although t-TCUB did not change body weight, fat pad weight, or glucose and insulin tolerance in the obese mice, it decreased serum triglycerides and increased protein expression of genes important for lipid metabolism in the BAT. Our results suggest that sEH may play a critical role in brown adipogenesis, and sEHI may be beneficial in improving BAT protein expression involved in lipid metabolism. Further studies using the sEHI combined with EpFA generating diets for obesity treatment and prevention are warranted.
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- 2020
14. Furin cleavage of the SARS-CoV-2 spike is modulated by O -glycosylation
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Zhang, Liping, Mann, Matthew, Syed, Zulfeqhar A., Reynolds, Hayley M., Tian, E., Samara, Nadine L., Zeldin, Darryl C., Tabak, Lawrence A., and Hagen, Kelly G. Ten
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- 2021
15. Preface to the Special Issue
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Zeldin, Darryl C., Honn, Kenneth, and Volpe, Caryn
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- 2023
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16. Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS‐CoV‐2‐infected mice
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Edin, Matthew L., primary, Gruzdev, Artiom, additional, Graves, Joan P., additional, Lih, Fred B., additional, Morisseau, Christophe, additional, Ward, James M., additional, Hammock, Bruce D., additional, Bosio, Catharine M., additional, and Zeldin, Darryl C., additional
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- 2024
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17. Targeted metabolomics identifies the cytochrome P450 monooxygenase eicosanoid pathway as a novel therapeutic target of colon tumorigenesis
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Wang, Weicang, Yang, Jun, Edin, Matthew L, Wang, Yuxin, Luo, Ying, Wan, Debin, Yang, Haixia, Song, Chun-Qing, Xue, Wen, Sanidad, Katherine Z, Song, Mingyue, Bisbee, Heather A, Bradbury, Jennifer A, Nan, Guanjun, Zhang, Jianan, Shih, Pei-An Betty, Lee, Kin Sing Stephen, Minter, Lisa M, Kim, Daeyoung, Xiao, Hang, Liu, Jun-Yan, Hammock, Bruce D, Zeldin, Darryl C, and Zhang, Guodong
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Medical Biochemistry and Metabolomics ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Colo-Rectal Cancer ,Digestive Diseases ,Cancer ,Animals ,Antifungal Agents ,Apoptosis ,Azoxymethane ,Carcinogenesis ,Cell Proliferation ,Clotrimazole ,Colonic Neoplasms ,Cytochrome P-450 Enzyme System ,Dextran Sulfate ,Eicosanoids ,Enzyme Inhibitors ,Humans ,Male ,Metabolomics ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Proadifen ,RNA ,Small Interfering ,Tumor Cells ,Cultured ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
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 in vivo. 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 in vitro and exacerbated AOM/DSS-induced colon tumorigenesis in vivo. 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. SIGNIFICANCE: This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis.
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- 2019
18. Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice
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Gong, Yan, Tomita, Yohei, Edin, Matthew L., Ren, Anli, Ko, Minji, Yang, Jay, Bull, Edward, Zeldin, Darryl C., Hellström, Ann, Fu, Zhongjie, and Smith, Lois E.H.
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- 2022
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19. Serum antioxidant vitamins and respiratory morbidity and mortality: a pooled analysis
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Salo, Paivi M., Mendy, Angelico, Wilkerson, Jesse, Molsberry, Samantha A., Feinstein, Lydia, London, Stephanie J., Fessler, Michael B., Thorne, Peter S., and Zeldin, Darryl C.
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- 2022
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20. Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism.
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Foo, Alexander C.Y., Edin, Matthew L., Lin, Wan-Chi, Lih, Fred B., Gabel, Scott A., Uddin, Mohammad N., Fessler, Michael B., Zeldin, Darryl C., and Mueller, Geoffrey A.
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- 2024
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21. Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia
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Bettaieb, Ahmed, Koike, Shinichiro, Hsu, Ming-Fo, Ito, Yoshihiro, Chahed, Samah, Bachaalany, Santana, Gruzdev, Artiom, Calvo-Rubio, Miguel, Lee, Kin Sing Stephen, Inceoglu, Bora, Imig, John D, Villalba, Jose M, Zeldin, Darryl C, Hammock, Bruce D, and Haj, Fawaz G
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Biochemistry and Cell Biology ,Biological Sciences ,Kidney Disease ,Nutrition ,Diabetes ,Aetiology ,2.1 Biological and endogenous factors ,Renal and urogenital ,Animals ,Apoptosis ,Autophagy ,Diabetes Mellitus ,Experimental ,Diabetic Nephropathies ,Endoplasmic Reticulum Stress ,Enzyme Inhibitors ,Epoxide Hydrolases ,Humans ,Hyperglycemia ,Kidney ,Mice ,Podocytes ,Diabetic nephropathy ,soluble epoxide hydrolase ,podocyte ,knockout mice ,autophagy ,endoplasmic reticulum stress ,Pharmacology and Pharmaceutical Sciences ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
BackgroundDiabetic nephropathy (DN) is the leading cause of renal failure, and podocyte dysfunction contributes to the pathogenesis of DN. Soluble epoxide hydrolase (sEH, encoded by Ephx2) is a conserved cytosolic enzyme whose inhibition has beneficial effects on renal function. The aim of this study is to investigate the contribution of sEH in podocytes to hyperglycemia-induced renal injury.Materials and methodsMice with podocyte-specific sEH disruption (pod-sEHKO) were generated, and alterations in kidney function were determined under normoglycemia, and high-fat diet (HFD)- and streptozotocin (STZ)-induced hyperglycemia.ResultssEH protein expression increased in murine kidneys under HFD- and STZ-induced hyperglycemia. sEH deficiency in podocytes preserved renal function and glucose control and mitigated hyperglycemia-induced renal injury. Also, podocyte sEH deficiency was associated with attenuated hyperglycemia-induced renal endoplasmic reticulum (ER) stress, inflammation and fibrosis, and enhanced autophagy. Moreover, these effects were recapitulated in immortalized murine podocytes treated with a selective sEH pharmacological inhibitor. Furthermore, pharmacological-induced elevation of ER stress or attenuation of autophagy in immortalized podocytes mitigated the protective effects of sEH inhibition.ConclusionsThese findings establish sEH in podocytes as a significant contributor to renal function under hyperglycemia.General significanceThese data suggest that sEH is a potential therapeutic target for podocytopathies.
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- 2017
22. Lipid Mediators: Leukotrienes
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Card, Jeffrey W., primary, Edin, Matthew L., additional, and Zeldin, Darryl C., additional
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- 2022
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23. Proteome and functional decline as platelets age in the circulation
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Allan, Harriet E., Hayman, Melissa A., Marcone, Simone, Chan, Melissa V., Edin, Matthew L., Maffucci, Tania, Joshi, Abhishek, Menke, Laura, Crescente, Marilena, Mayr, Manuel, Zeldin, Darryl C., Armstrong, Paul C., and Warner, Timothy D.
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- 2021
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24. TXA2 attenuates allergic lung inflammation through regulation of Th2, Th9 and Treg differentiation
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Li, Hong, primary, Bradbury, J. Alyce, additional, Edin, Matthew L., additional, Gruzdev, Artiom, additional, Li, Huiling, additional, Graves, Joan P., additional, DeGraff, Laura M., additional, Lih, Fred B., additional, Feng, Chiguang, additional, Wolf, Erin R., additional, Bortner, Carl D., additional, London, Stephanie J., additional, Sparks, Matthew A., additional, Coffman, Thomas M., additional, and Zeldin, Darryl C., additional
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- 2024
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25. Regulation of cardiovascular biology by microsomal epoxide hydrolase
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Edin, Matthew L. and Zeldin, Darryl C.
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- 2021
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26. Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization
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Hasegawa, Eiichi, Inafuku, Saori, Mulki, Lama, Okunuki, Yoko, Yanai, Ryoji, Smith, Kaylee E, Kim, Clifford B, Klokman, Garrett, Bielenberg, Diane R, Puli, Narender, Falck, John R, Husain, Deeba, Miller, Joan W, Edin, Matthew L, Zeldin, Darryl C, Lee, Kin Sing Stephen, Hammock, Bruce D, Schunck, Wolf-Hagen, and Connor, Kip M
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Macular Degeneration ,Neurosciences ,Aging ,Eye Disease and Disorders of Vision ,Neurodegenerative ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Eye ,Animals ,Choroidal Neovascularization ,Cytochrome P-450 CYP2C8 ,Cytochrome P-450 Enzyme System ,Disease Models ,Animal ,Endothelial Cells ,Epoxide Hydrolases ,Fatty Acids ,Unsaturated ,Leukocytes ,Lipid Metabolism ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Second Messenger Systems ,P450 ,choroidal neovascularization ,oxylipin ,omega-3 fatty acids ,lipid metabolites - Abstract
Age-related macular degeneration (AMD) is the most common cause of blindness for individuals age 50 and above in the developed world. Abnormal growth of choroidal blood vessels, or choroidal neovascularization (CNV), is a hallmark of the neovascular (wet) form of advanced AMD and leads to significant vision loss. A growing body of evidence supports a strong link between neovascular disease and inflammation. Metabolites of long-chain polyunsaturated fatty acids derived from the cytochrome P450 (CYP) monooxygenase pathway serve as vital second messengers that regulate a number of hormones and growth factors involved in inflammation and vascular function. Using transgenic mice with altered CYP lipid biosynthetic pathways in a mouse model of laser-induced CNV, we characterized the role of these lipid metabolites in regulating neovascular disease. We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of the monooxygenase CYP2C8 or genetic ablation or inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development. In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost. We found that these molecules work in part through their ability to regulate the expression of key leukocyte adhesion molecules, on both leukocytes and endothelial cells, thereby mediating leukocyte recruitment. These results suggest that CYP lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases.
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- 2017
27. Reduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor (t-AUCB): Role of adenosine A2A receptor and plasma oxylipins
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Hanif, Ahmad, Edin, Matthew L, Zeldin, Darryl C, Morisseau, Christophe, Falck, John R, Ledent, Catherine, Tilley, Stephen L, and Nayeem, Mohammed A
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Medical Physiology ,Biomedical and Clinical Sciences ,Cardiovascular ,Heart Disease ,Adenosine A2 Receptor Antagonists ,Animals ,Benzoates ,Coronary Vessels ,Enzyme Inhibitors ,Epoxide Hydrolases ,Hyperemia ,Mice ,Mice ,Inbred C57BL ,Oxylipins ,Receptor ,Adenosine A2A ,Solubility ,Urea ,Adenosine A(2A) receptor ,Coronary reactive hyperemia ,omega-hydroxylases ,Soluble epoxide hydrolase ,Heart perfusate oxylipins ,Plasma oxylipins ,ω-hydroxylases ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics - Abstract
Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR-deficient (A2AAR-/-) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH-inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR-/- and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR-/- mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or ω-hydroxylases-inhibition. Compared to WT mice, A2AAR-/- mice had attenuated CRH and changed oxylipin profiles, which were consistent between plasma and heart perfusate samples, including decreased EET/DHET ratios, and increased hydroxyeicosatetraenoic acids (HETEs). Plasma oxylipns in A2AAR-/- mice indicated an increased proinflammatory state including increased ω-terminal HETEs, decreased epoxyoctadecaenoic/dihydroxyoctadecaenoic acids (EpOMEs/DiHOMEs) ratios, increased 9-hydroxyoctadecadienoic acid, and increased prostanoids. Inhibition of either sEH or ω-hydroxylases reversed the reduced CRH in A2AAR-/- mice. In WT and sEH-/- mice, blocking A2AAR decreased CRH. These data demonstrate that A2AAR-deletion was associated with changes in oxylipin profiles, which may contribute to the attenuated CRH. Also, inhibition of sEH and ω-hydroxylases reversed the reduction in CRH.
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- 2017
28. Podocyte‐specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury
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Bettaieb, Ahmed, Koike, Shinichiro, Chahed, Samah, Zhao, Yi, Bachaalany, Santana, Hashoush, Nader, Graham, James, Fatima, Huma, Havel, Peter J, Gruzdev, Artiom, Zeldin, Darryl C, Hammock, Bruce D, and Haj, Fawaz G
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Biomedical and Clinical Sciences ,Clinical Sciences ,Kidney Disease ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,Renal and urogenital ,Acute Kidney Injury ,Animals ,Blood Urea Nitrogen ,Cells ,Cultured ,Cytokines ,Epoxide Hydrolases ,Gene Expression Regulation ,Immunoblotting ,Kidney ,Lipopolysaccharides ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mice ,Transgenic ,Microscopy ,Fluorescence ,Phenylurea Compounds ,Piperidines ,Podocytes ,Proteinuria ,Reverse Transcriptase Polymerase Chain Reaction ,Signal Transduction ,Solubility ,knockout mice ,podocyte ,proteinuria ,soluble epoxide hydrolase ,Medicinal and Biomolecular Chemistry ,Biochemistry and Cell Biology ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics ,Medicinal and biomolecular chemistry - Abstract
Podocytes play an important role in maintaining glomerular function, and podocyte injury is a significant component in the pathogenesis of proteinuria. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose genetic deficiency and pharmacological inhibition have beneficial effects on renal function, but its role in podocytes remains unexplored. The objective of this study was to investigate the contribution of sEH in podocytes to lipopolysaccharide (LPS)-induced kidney injury. We report increased sEH transcript and protein expression in murine podocytes upon LPS challenge. To determine the function of sEH in podocytes in vivo we generated podocyte-specific sEH-deficient (pod-sEHKO) mice. Following LPS challenge, podocyte sEH-deficient mice exhibited lower kidney injury, proteinuria, and blood urea nitrogen concentrations than controls suggestive of preserved renal function. Also, renal mRNA and serum concentrations of inflammatory cytokines IL-6, IL-1β, and TNFα were significantly lower in LPS-treated pod-sEHKO than control mice. Moreover, podocyte sEH deficiency was associated with decreased LPS-induced NF-κB and MAPK activation and attenuated endoplasmic reticulum stress. Furthermore, the protective effects of podocyte sEH deficiency in vivo were recapitulated in E11 murine podocytes treated with a selective sEH pharmacological inhibitor. Altogether, these findings identify sEH in podocytes as a contributor to signaling events in acute renal injury and suggest that sEH inhibition may be of therapeutic value in proteinuria.EnzymesSoluble epoxide hydrolase: EC 3.3.2.10.
- Published
- 2017
29. Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice
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Hanif, Ahmad, Edin, Matthew L, Zeldin, Darryl C, Morisseau, Christophe, Falck, John R, and Nayeem, Mohammed A
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Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Cardiovascular ,Heart Disease - Coronary Heart Disease ,Animals ,Arachidonic Acid ,Cytochrome P-450 CYP2J2 ,Cytochrome P-450 CYP4A ,Cytochrome P-450 Enzyme System ,Dinoprost ,Endothelium ,Vascular ,Female ,Heart ,Humans ,Hyperemia ,Male ,Mice ,Mice ,Inbred C57BL ,Myocardium ,Oxylipins ,Reperfusion Injury ,General Science & Technology - Abstract
Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects. Post-ischemic vasodilation in the heart, known as coronary reactive hyperemia (CRH), protects against potential damage to the heart muscle caused by ischemia. The relationship among CRH response to ischemia, in mice with altered levels of CYP2J epoxygenases has not yet been investigated. Therefore, we evaluated the effect of endothelial overexpression of the human cytochrome P450 epoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. Additionally, we evaluated the effect of pharmacologic inhibition of CYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that CRH would be enhanced in isolated mouse hearts with vascular endothelial overexpression of human CYP2J2 through modulation of oxylipin profiles. Similarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, whereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, Tie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of ω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 Tr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 significantly changed oxylipin profiles, including increased EETs (P < 0.05), increased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of CYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a decrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < 0.05). These data demonstrate that vascular endothelial overexpression of CYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP epoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH.
- Published
- 2017
30. Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ω-Hydroxylases
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Hanif, Ahmad, Edin, Matthew L, Zeldin, Darryl C, Morisseau, Christophe, Falck, John R, and Nayeem, Mohammed A
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Heart Disease ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,Animals ,Chromatography ,Liquid ,Coronary Disease ,Endothelium ,Vascular ,Epoxide Hydrolases ,Humans ,Hydroxyeicosatetraenoic Acids ,Hyperemia ,Mice ,Mice ,Inbred C57BL ,Oxylipins ,PPAR gamma ,Tandem Mass Spectrometry ,General Science & Technology - Published
- 2017
31. Use of National Asthma Guidelines by Allergists and Pulmonologists: A National Survey
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Cloutier, Michelle M., Akinbami, Lara J., Salo, Paivi M., Schatz, Michael, Simoneau, Tregony, Wilkerson, Jesse C., Diette, Gregory, Elward, Kurtis S., Fuhlbrigge, Anne, Mazurek, Jacek M., Feinstein, Lydia, Williams, Sonja, and Zeldin, Darryl C.
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- 2020
- Full Text
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32. Cytochrome P450 Oxidase 2C Inhibition Adds to &ohgr;-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization
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Gong, Yan, Fu, Zhongjie, Edin, Matthew L, Liu, Chi-Hsiu, Wang, Zhongxiao, Shao, Zhuo, Fredrick, Thomas W, Saba, Nicholas J, Morss, Peyton C, Burnim, Samuel B, Meng, Steven S, Lih, Fred B, Lee, Kin Sing Stephen, Moran, Elizabeth P, SanGiovanni, John Paul, Hellström, Ann, Hammock, Bruce D, Zeldin, Darryl C, and Smith, Lois EH
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Neurosciences ,Aging ,Eye Disease and Disorders of Vision ,Macular Degeneration ,Neurodegenerative ,Metabolic and endocrine ,Eye ,Cardiovascular ,Acetates ,Angiogenesis Inhibitors ,Animals ,Aorta ,Cells ,Cultured ,Choroidal Neovascularization ,Cyclopropanes ,Cytochrome P-450 CYP2C8 ,Cytochrome P-450 CYP2C8 Inhibitors ,Disease Models ,Animal ,Endothelial Cells ,Fatty Acids ,Omega-3 ,Genotype ,Humans ,Hyperoxia ,Lasers ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Neovascularization ,Physiologic ,Phenotype ,Quinolines ,Retinal Neovascularization ,Retinopathy of Prematurity ,Sulfides ,Tissue Culture Techniques ,arachidonic acid ,choroidal neovascularization ,CYP2C inhibitor ,diabetic retinopathy ,docosahexaenoic acid ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
ObjectivePathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases.Approach and resultsThe mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast.ConclusionsInhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.
- Published
- 2016
33. Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ
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Hanif, Ahmad, Edin, Matthew L, Zeldin, Darryl C, Morisseau, Christophe, and Nayeem, Mohammed A
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Medical Physiology ,Biomedical and Clinical Sciences ,Heart Disease ,Cardiovascular ,Heart Disease - Coronary Heart Disease ,Animals ,Chromatography ,Liquid ,Coronary Disease ,Epoxide Hydrolases ,Hyperemia ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Oxylipins ,PPAR gamma ,Rosiglitazone ,Tandem Mass Spectrometry ,Thiazolidinediones ,General Science & Technology - Abstract
Coronary reactive hyperemia (CRH) is a physiological response to ischemic insult that prevents the potential harm associated with an interruption of blood supply. The relationship between the pharmacologic inhibition of soluble epoxide hydrolase (sEH) and CRH response to a brief ischemia is not known. sEH is involved in the main catabolic pathway of epoxyeicosatrienoic acids (EETs), which are converted into dihydroxyeicosatrienoic acids (DHETs). EETs protect against ischemia/reperfusion injury and have numerous beneficial physiological effects. We hypothesized that inhibition of sEH by t-AUCB enhances CRH in isolated mouse hearts through changing the oxylipin profiles, including an increase in EETs/DHETs ratio. Compared to controls, t-AUCB-treated mice had increased CRH, including repayment volume (RV), repayment duration, and repayment/debt ratio (p < 0.05). Treatment with t-AUCB significantly changed oxylipin profiles, including an increase in EET/DHET ratio, increase in EpOME/DiHOME ratio, increase in the levels of HODEs, decrease in the levels of mid-chain HETEs, and decrease in prostanoids (p < 0.05). Treatment with MS-PPOH (CYP epoxygenase inhibitor) reduced CRH, including RV (p < 0.05). Involvement of PPARγ in the modulation of CRH was demonstrated using a PPARγ-antagonist (T0070907) and a PPARγ-agonist (rosiglitazone). T0070907 reduced CRH (p < 0.05), whereas rosiglitazone enhanced CRH (p < 0.05) in isolated mouse hearts compared to the non-treated. These data demonstrate that sEH inhibition enhances, whereas CYP epoxygenases-inhibition attenuates CRH, PPARγ mediate CRH downstream of the CYP epoxygenases-EET pathway, and the changes in oxylipin profiles associated with sEH-inhibition collectively contributed to the enhanced CRH.
- Published
- 2016
34. Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study
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Oni-Orisan, Akinyemi, Edin, Matthew L, Lee, John Andrew, Wells, Michael A, Christensen, Erin S, Vendrov, Kimberly C, Lih, Fred B, Tomer, Kenneth B, Bai, Xue, Taylor, Joan M, Stouffer, George A, Zeldin, Darryl C, and Lee, Craig R
- Subjects
Medical Biochemistry and Metabolomics ,Biomedical and Clinical Sciences ,Atherosclerosis ,Heart Disease ,Clinical Research ,Cardiovascular ,Heart Disease - Coronary Heart Disease ,8 ,11 ,14-Eicosatrienoic Acid ,Adult ,Aged ,Arachidonic Acid ,Arachidonic Acids ,Biomarkers ,Coronary Angiography ,Coronary Artery Disease ,Cytochrome P-450 Enzyme System ,Female ,Humans ,Hydroxyeicosatetraenoic Acids ,Inflammation ,Male ,Metabolomics ,Middle Aged ,arachidonic acid ,atherosclerosis ,eicosanoids ,heart ,inflammation ,pharmacometabolomics ,precision medicine ,Biochemistry and Cell Biology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics - Abstract
Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.
- Published
- 2016
35. Environmental Management of Asthma in Clinical Practice: Results from the 2012 National Ambulatory Medical Care Survey
- Author
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Salo, Paivi M., primary, Akinbami, Lara J., additional, Cloutier, Michelle M., additional, Wilkerson, Jesse C., additional, Elward, Kurtis S., additional, Mazurek, Jacek M., additional, Diette, Gregory B., additional, Mitchell, Tracey A., additional, Williams, Sonja, additional, and Zeldin, Darryl C., additional
- Published
- 2023
- Full Text
- View/download PDF
36. Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases
- Author
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Hanif, Ahmad, Edin, Matthew L., Zeldin, Darryl C., and Nayeem, Mohammed A.
- Published
- 2020
- Full Text
- View/download PDF
37. Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins
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Thomson, Scott, Edin, Matthew L, Lih, Fred B, Davies, Michael, Yaqoob, Muhammad M, Hammock, Bruce D, Gilroy, Derek, Zeldin, Darryl C, and Bishop-Bailey, David
- Subjects
Biochemistry and Cell Biology ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biological Sciences ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Cell Line ,Cytochrome P-450 Enzyme System ,Humans ,Inflammation ,Muscle ,Smooth ,Vascular ,Oxylipins ,Real-Time Polymerase Chain Reaction ,Rodentia ,Swine ,Tunica Intima ,Epoxygenase ,LPS ,Oxylipin ,Smooth muscle cell ,Soluble epoxide hydrolase ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
Vascular pathologies are associated with changes in the presence and expression of morphologically distinct vascular smooth muscle cells. In particular, in complex human vascular lesions and models of disease in pigs and rodents, an intimal smooth muscle cell (iSMC) which exhibits a stable epithelioid or rhomboid phenotype in culture is often found to be present in high numbers, and may represent the reemergence of a distinct developmental vascular smooth muscle cell phenotype. The CYP450-oxylipin - soluble epoxide hydrolase (sEH) pathway is currently of great interest in targeting for cardiovascular disease. sEH inhibitors limit the development of hypertension, diabetes, atherosclerosis and aneurysm formation in animal models. We have investigated the expression of CYP450-oxylipin-sEH pathway enzymes and their metabolites in paired intimal (iSMC) and medial (mSMC) cells isolated from rat aorta. iSMC basally released significantly larger amounts of epoxy-oxylipin CYP450 products from eicosapentaenoic acid > docosahexaenoic acid > arachidonic acid > linoleic acid, and expressed higher levels of CYP2C12, CYP2B1, but not CYP2J mRNA compared to mSMC. When stimulated with the pro-inflammatory TLR4 ligand LPS, epoxy-oxylipin production did not change greatly in iSMC. In contrast, LPS induced epoxy-oxylipin products in mSMC and induced CYP2J4. iSMC and mSMC express sEH which metabolizes primary epoxy-oxylipins to their dihydroxy-counterparts. The sEH inhibitors TPPU or AUDA inhibited LPS-induced NFκB activation and iNOS induction in mSMC, but had no effect on NFκB nuclear localization or inducible nitric oxide synthase in iSMC; effects which were recapitulated in part by addition of authentic epoxy-oxylipins. iSMCs are a rich source but not a sensor of anti-inflammatory epoxy-oxylipins. Complex lesions that contain high levels of iSMCs may be more resistant to the protective effects of sEH inhibitors.
- Published
- 2015
38. Sinus Surgery Is Associated with a Decrease in Aspirin-Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease
- Author
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Jerschow, Elina, Edin, Matthew L., Chi, Yuling, Hurst, Beth, Abuzeid, Waleed M., Akbar, Nadeem A., Gibber, Marc, Fried, Marvin P., Han, Weiguo, Pelletier, Teresa, Ren, Zhen, Keskin, Taha, Roizen, Gigia, Lih, Fred B., Gruzdev, Artiom, Bradbury, J. Alyce, Schuster, Victor, Spivack, Simon, Rosenstreich, David, and Zeldin, Darryl C.
- Published
- 2019
- Full Text
- View/download PDF
39. Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy
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Lee, Kin Sing Stephen, Liu, Jun-Yan, Wagner, Karen M, Pakhomova, Svetlana, Dong, Hua, Morisseau, Christophe, Fu, Samuel H, Yang, Jun, Wang, Peng, Ulu, Arzu, Mate, Christina A, Nguyen, Long V, Hwang, Sung Hee, Edin, Matthew L, Mara, Alexandria A, Wulff, Heike, Newcomer, Marcia E, Zeldin, Darryl C, and Hammock, Bruce D
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Peripheral Neuropathy ,Pain Research ,Neurodegenerative ,Chronic Pain ,Diabetes ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Metabolic and endocrine ,Administration ,Oral ,Amines ,Analgesics ,Animals ,Biological Availability ,Chemistry Techniques ,Synthetic ,Crystallography ,X-Ray ,Cyclohexanecarboxylic Acids ,Diabetes Mellitus ,Type 1 ,Diabetic Neuropathies ,Drug Design ,Enzyme Inhibitors ,Epoxide Hydrolases ,Gabapentin ,Humans ,Male ,Mice ,Molecular Targeted Therapy ,Neuralgia ,Rats ,Sprague-Dawley ,Solubility ,Structure-Activity Relationship ,Time Factors ,gamma-Aminobutyric Acid ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
- Published
- 2014
40. Exposure and Sensitization to Pets Modify Endotoxin Association with Asthma and Wheeze
- Author
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Mendy, Angelico, Wilkerson, Jesse, Salo, Päivi M., Cohn, Richard D., Zeldin, Darryl C., and Thorne, Peter S.
- Published
- 2018
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41. Overexpression of Human Soluble Epoxide Hydrolase Exacerbates Coronary Reactive Hyperemia Reduction in Angiotensin-II-Treated Mouse Hearts.
- Author
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Hanif, Ahmad, Edin, Matthew L., Zeldin, Darryl C., and Nayeem, Mohammed A.
- Published
- 2024
- Full Text
- View/download PDF
42. Overexpression of human soluble epoxide hydrolase exacerbates coronary reactive hyperemia reduction in Angiotensin-II treated mouse hearts
- Author
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Hanif, Ahmad, primary, Edin, Matthew L., additional, Zeldin, Darryl C., additional, and Nayeem, Mohammed A., additional
- Published
- 2023
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43. Introduction
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Honn, Kenneth V., Zeldin, Darryl C., Cohen, Irun R., Editorial Board Member, Lajtha, Abel, Editorial Board Member, Lambris, John D., Editorial Board Member, Paoletti, Rodolfo, Editorial Board Member, Rezaei, Nima, Editorial Board Member, Honn, Kenneth V., editor, and Zeldin, Darryl C., editor
- Published
- 2019
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44. Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis
- Author
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Olona, Antoni, Terra, Ximena, Ko, Jeong-Hun, Grau-Bové, Carme, Pinent, Montserrat, Ardevol, Anna, Diaz, Ana Garcia, Moreno-Moral, Aida, Edin, Matthew, Bishop-Bailey, David, Zeldin, Darryl C., Aitman, Timothy J., Petretto, Enrico, Blay, Mayte, and Behmoaras, Jacques
- Published
- 2018
- Full Text
- View/download PDF
45. Clinician Agreement, Self-Efficacy, and Adherence with the Guidelines for the Diagnosis and Management of Asthma
- Author
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Cloutier, Michelle M., Salo, Paivi M., Akinbami, Lara J., Cohn, Richard D., Wilkerson, Jesse C., Diette, Gregory B., Williams, Sonja, Elward, Kurtis S., Mazurek, Jacek M., Spinner, Jovonni R., Mitchell, Tracey A., and Zeldin, Darryl C.
- Published
- 2018
- Full Text
- View/download PDF
46. Sensitization and Exposure to Pets: The Effect on Asthma Morbidity in the US Population
- Author
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Gergen, Peter J., Mitchell, Herman E., Calatroni, Agustin, Sever, Michelle L., Cohn, Richard D., Salo, Pӓivi M., Thorne, Peter S., and Zeldin, Darryl C.
- Published
- 2018
- Full Text
- View/download PDF
47. Epoxyeicosanoids promote organ and tissue regeneration
- Author
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Panigrahy, Dipak, Kalish, Brian T, Huang, Sui, Bielenberg, Diane R, Le, Hau D, Yang, Jun, Edin, Matthew L, Lee, Craig R, Benny, Ofra, Mudge, Dayna K, Butterfield, Catherine E, Mammoto, Akiko, Mammoto, Tadanori, Inceoglu, Bora, Jenkins, Roger L, Simpson, Mary A, Akino, Tomoshige, Lih, Fred B, Tomer, Kenneth B, Ingber, Donald E, Hammock, Bruce D, Falck, John R, Manthati, Vijaya L, Kaipainen, Arja, D’Amore, Patricia A, Puder, Mark, Zeldin, Darryl C, and Kieran, Mark W
- Subjects
Biomedical and Clinical Sciences ,Engineering ,Biomedical Engineering ,Regenerative Medicine ,Eye Disease and Disorders of Vision ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,Cardiovascular ,Animals ,Chromatography ,Liquid ,Eicosanoids ,Endothelial Cells ,Epoxide Hydrolases ,Epoxy Compounds ,Eye ,Immunohistochemistry ,Kidney ,Liver ,Lung ,Mice ,Mice ,Transgenic ,Neovascularization ,Physiologic ,Receptor ,TIE-2 ,Regeneration ,Tandem Mass Spectrometry ,autacoid ,organ regeneration ,small molecule mediator ,angiocrine ,VEGF - Abstract
Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.
- Published
- 2013
48. Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice
- Author
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Oni-Orisan, Akinyemi, Deng, Yangmei, Schuck, Robert N, Theken, Katherine N, Edin, Matthew L, Lih, Fred B, Molnar, Kimberly, DeGraff, Laura, Tomer, Kenneth B, Zeldin, Darryl C, and Lee, Craig R
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Aetiology ,2.1 Biological and endogenous factors ,8 ,11 ,14-Eicosatrienoic Acid ,Acute Disease ,Animals ,Cyclooxygenase Inhibitors ,Cytochrome P-450 CYP2J2 ,Cytochrome P-450 Enzyme System ,Endothelium ,Vascular ,Endotoxins ,Epoxide Hydrolases ,Female ,Gene Expression Regulation ,Indomethacin ,Inflammation ,Liver ,Lung ,Male ,Mice ,Mice ,Transgenic ,Peroxidase ,Prostaglandin-Endoperoxide Synthases ,CYP2J2 ,Soluble epoxide hydrolase ,Cyclooxygenase ,Vascular inflammation ,Epoxyeicosatrienoic acid ,Prostaglandin ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics - Abstract
Cyclooxygenase (COX)-derived prostaglandins and cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids are important regulators of inflammation; however, functional interactions between these pathways in the regulation of vascular inflammation in vivo have not been studied. We investigated the relative and additive effects of endothelial CYP2J2 overexpression (Tie2-CYP2J2-Tr), global sEH disruption (Ephx2(-/-)), and pharmacologic COX inhibition with indomethacin on the acute vascular inflammatory response to endotoxin in mice. Compared to vehicle-treated wild-type C57BL/6 controls, induction of myeloperoxidase (MPO) activity in lung and liver was similarly attenuated in Tie2-CYP2J2-Tr mice, Ephx2(-/-) mice and wild-type mice treated with moderate dose indomethacin. Dual modulation of both pathways, however, did not produce an additive anti-inflammatory effect. These findings demonstrate that both COX and CYP epoxygenase-mediated eicosanoid metabolism are important regulators of the acute vascular inflammatory response in vivo, and suggest that the anti-inflammatory effects of modulating each pathway may be mediated, at least in part, by overlapping mechanisms.
- Published
- 2013
49. Dust Weight and Asthma Prevalence in the National Survey of Lead and Allergens in Housing (NSLAH)
- Author
-
Elliott, Leslie, Arbes,, Samuel J., Lee, Robert C., Cohn, Richard D., London, Stephanie J., and Zeldin, Darryl C.
- Published
- 2007
50. National Prevalence and Exposure Risk for Cockroach Allergen in U.S. Households
- Author
-
Cohn, Richard D., Arbes, Samuel J., Jaramillo, Renee, Reid, Laura H., and Zeldin, Darryl C.
- Published
- 2006
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