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[PMID]:29330456
[Au] Autor:Tunaru S; Bonnavion R; Brandenburger I; Preussner J; Thomas D; Scholich K; Offermanns S
[Ad] Endereço:Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231, Bad Nauheim, Germany.
[Ti] Título:20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1.
[So] Source:Nat Commun;9(1):177, 2018 01 12.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The long-chain fatty acid receptor FFAR1 is highly expressed in pancreatic ß-cells. Synthetic FFAR1 agonists can be used as antidiabetic drugs to promote glucose-stimulated insulin secretion (GSIS). However, the physiological role of FFAR1 in ß-cells remains poorly understood. Here we show that 20-HETE activates FFAR1 and promotes GSIS via FFAR1 with higher potency and efficacy than dietary fatty acids such as palmitic, linoleic, and α-linolenic acid. Murine and human ß-cells produce 20-HETE, and the ω-hydroxylase-mediated formation and release of 20-HETE is strongly stimulated by glucose. Pharmacological inhibition of 20-HETE formation and blockade of FFAR1 in islets inhibits GSIS. In islets from type-2 diabetic humans and mice, glucose-stimulated 20-HETE formation and 20-HETE-dependent stimulation of GSIS are strongly reduced. We show that 20-HETE is an FFAR1 agonist, which functions as an autocrine positive feed-forward regulator of GSIS, and that a reduced glucose-induced 20-HETE formation contributes to inefficient GSIS in type-2 diabetes.
[Mh] Termos MeSH primário: Glucose/farmacologia
Ácidos Hidroxieicosatetraenoicos/metabolismo
Células Secretoras de Insulina/efeitos dos fármacos
Insulina/secreção
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Adulto
Animais
Comunicação Autócrina/efeitos dos fármacos
Células COS
Linhagem Celular
Linhagem Celular Tumoral
Células Cultivadas
Cercopithecus aethiops
Diabetes Mellitus Tipo 2/genética
Diabetes Mellitus Tipo 2/metabolismo
Feminino
Seres Humanos
Ácidos Hidroxieicosatetraenoicos/sangue
Ácidos Hidroxieicosatetraenoicos/farmacologia
Células Secretoras de Insulina/metabolismo
Masculino
Camundongos Knockout
Camundongos Obesos
Meia-Idade
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (FFAR1 protein, human); 0 (Hydroxyeicosatetraenoic Acids); 0 (Insulin); 0 (Receptors, G-Protein-Coupled); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02539-4


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[PMID]:29192828
[Au] Autor:Randell SH; Zeldin DC
[Ad] Endereço:1 Department of Cell Biology and Physiology.
[Ti] Título:A Slippery Cause of a Slimy Problem: Mucin Induction by an Esterified Lipid.
[So] Source:Am J Respir Cell Mol Biol;57(6):633-634, 2017 12.
[Is] ISSN:1535-4989
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Asma/metabolismo
Bronquite Crônica/metabolismo
Fibrose Cística/metabolismo
Células Caliciformes/metabolismo
Ácidos Hidroxieicosatetraenoicos/metabolismo
Fibrose Pulmonar Idiopática/metabolismo
Mucinas/biossíntese
[Mh] Termos MeSH secundário: Animais
Asma/patologia
Bronquite Crônica/patologia
Fibrose Cística/patologia
Células Caliciformes/patologia
Seres Humanos
Fibrose Pulmonar Idiopática/patologia
[Pt] Tipo de publicação:EDITORIAL
[Nm] Nome de substância:
0 (Hydroxyeicosatetraenoic Acids); 0 (Mucins); 73945-47-8 (15-hydroxy-5,8,11,13-eicosatetraenoic acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE
[do] DOI:10.1165/rcmb.2017-0275ED


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[PMID]:29206843
[Au] Autor:Contreras GA; Strieder-Barboza C; de Souza J; Gandy J; Mavangira V; Lock AL; Sordillo LM
[Ad] Endereço:Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States of America.
[Ti] Título:Periparturient lipolysis and oxylipid biosynthesis in bovine adipose tissues.
[So] Source:PLoS One;12(12):e0188621, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The periparturient period of dairy cows is characterized by intense lipolysis in adipose tissues (AT), which induces the release of free fatty acids (FFA) into circulation. Among FFA, polyunsaturated fatty acids are susceptible to oxidation and can modulate inflammatory responses during lipolysis within AT. Linoleic and arachidonic acid oxidized products (oxylipids) such as hydroxy-octadecadienoic acids (HODE) and hydroxy-eicosatetraenoic acids (HETE), were recently identified as products of lipolysis that could modulate AT inflammation during lipolysis. However, the effect of lipolysis intensity during the transition from gestation to lactation on fatty acid substrate availability and subsequent AT oxylipid biosynthesis is currently unknown. We hypothesized that in periparturient dairy cows, alterations in AT and plasma fatty acids and oxylipid profiles coincide with changes in lipolysis intensity and stage of lactation. Blood and subcutaneous AT samples were collected from periparturient cows at -27±7 (G1) and -10±5 (G2) d prepartum and at 8±3 d postpartum (PP). Targeted lipidomic analysis was performed on plasma and AT using HPLC-MS/MS. We report that FFA concentrations increased as parturition approached and were highest at PP. Cows exhibiting high lipolysis rate at PP (FFA>1.0 mEq/L) had higher body condition scores at G1 compared to cows with low lipolysis rate (FFA<1.0 mEq/L). Concentrations of plasma linoleic and arachidonic acids were increased at PP. In AT, 13-HODE, and 5-, 11- and 15-HETE were increased at PP compared to G1 and G2. Concentrations of beta hydroxybutyrate were positively correlated with those of 13-HODE and 15-HETE in AT. Plasma concentrations of 5- and 20-HETE were increased at PP. These data demonstrate that prepartum adiposity predisposes cows to intense lipolysis post-partum and may exacerbate AT inflammation because of increased production of pro-inflammatory oxylipids including 5- and 15-HETE and 13-HODE. These results support a role for certain linoleic and arachidonic acid-derived oxylipids as positive and negative modulators of AT inflammation during periparturient lipolysis.
[Mh] Termos MeSH primário: Tecido Adiposo/metabolismo
Ácidos Hidroxieicosatetraenoicos/biossíntese
Lipólise
Parto
[Mh] Termos MeSH secundário: Animais
Bovinos
Cromatografia Líquida de Alta Pressão
Indústria de Laticínios
Feminino
Ácidos Hidroxieicosatetraenoicos/sangue
Gravidez
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxyeicosatetraenoic Acids); 467RNW8T91 (5-hydroxy-6,8,11,14-eicosatetraenoic acid); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188621


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[PMID]:28724635
[Au] Autor:Kotla S; Singh NK; Kirchhofer D; Rao GN
[Ad] Endereço:From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
[Ti] Título:Heterodimers of the transcriptional factors NFATc3 and FosB mediate tissue factor expression for 15( )-hydroxyeicosatetraenoic acid-induced monocyte trafficking.
[So] Source:J Biol Chem;292(36):14885-14901, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tissue factor (TF) is expressed in vascular and nonvascular tissues and functions in several pathways, including embryonic development, inflammation, and cell migration. Many risk factors for atherosclerosis, including hypertension, diabetes, obesity, and smoking, increase TF expression. To better understand the TF-related mechanisms in atherosclerosis, here we investigated the role of 12/15-lipoxygenase (12/15-LOX) in TF expression. 15( )-hydroxyeicosatetraenoic acid (15( )-HETE), the major product of human 15-LOXs 1 and 2, induced TF expression and activity in a time-dependent manner in the human monocytic cell line THP1. Moreover, TF suppression with neutralizing antibodies blocked 15( )-HETE-induced monocyte migration. We also found that NADPH- and xanthine oxidase-dependent reactive oxygen species (ROS) production, calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation, and interactions between nuclear factor of activated T cells 3 (NFATc3) and FosB proto-oncogene, AP-1 transcription factor subunit (FosB) are involved in 15( )-HETE-induced TF expression. Interestingly, NFATc3 first induced the expression of its interaction partner FosB before forming the heterodimeric NFATc3-FosB transcription factor complex, which bound the proximal AP-1 site in the TF gene promoter and activated TF expression. We also observed that macrophages from 12/15-LOX mice exhibit diminished migratory response to monocyte chemotactic protein 1 (MCP-1) and lipopolysaccharide compared with WT mouse macrophages. Similarly, compared with WT macrophages, monocytes from 12/15-LOX mice displayed diminished trafficking, which was rescued by prior treatment with 12( )-HETE, in a peritonitis model. These observations indicate that 15( )-HETE-induced monocyte/macrophage migration and trafficking require ROS-mediated CaMKIV activation leading to formation of NFATc3 and FosB heterodimer, which binds and activates the TF promoter.
[Mh] Termos MeSH primário: Araquidonato 12-Lipoxigenase/metabolismo
Araquidonato 15-Lipoxigenase/metabolismo
Movimento Celular/efeitos dos fármacos
Ácidos Hidroxieicosatetraenoicos/farmacologia
Monócitos/efeitos dos fármacos
Fatores de Transcrição NFATC/metabolismo
Proteínas Proto-Oncogênicas c-fos/metabolismo
Tromboplastina/genética
[Mh] Termos MeSH secundário: Animais
Araquidonato 12-Lipoxigenase/deficiência
Araquidonato 12-Lipoxigenase/genética
Araquidonato 15-Lipoxigenase/deficiência
Araquidonato 15-Lipoxigenase/genética
Células Cultivadas
Seres Humanos
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Monócitos/citologia
Monócitos/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Tromboplastina/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (12-15-lipoxygenase); 0 (FOSB protein, human); 0 (Hydroxyeicosatetraenoic Acids); 0 (NFATC Transcription Factors); 0 (NFATC3 protein, human); 0 (Proto-Oncogene Proteins c-fos); 0 (Reactive Oxygen Species); 9035-58-9 (Thromboplastin); EC 1.13.11.31 (Arachidonate 12-Lipoxygenase); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.804344


  5 / 3168 MEDLINE  
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[PMID]:28641720
[Au] Autor:Sporková A; Certíková Chábová V; Dolezelová S; Jíchová S; Kopkan L; Vanourková Z; Kompanowska-Jezierska E; Sadowski J; Maxová H; Cervenka L
[Ad] Endereço:Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
[Ti] Título:Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20-Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney.
[So] Source:Am J Med Sci;353(6):568-579, 2017 Jun.
[Is] ISSN:1538-2990
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: There is vast evidence that the renin-angiotensin system is not the sole determinant of blood pressure (BP) elevation in human renovascular hypertension or the relevant experimental models. This study tested the hypothesis that kidney deficiency of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent ω-hydroxylase pathway of arachidonic acid metabolism, is important in the pathophysiology of the maintenance phase of 2-kidney, 1-clip (2K1C) Goldblatt hypertension. MATERIALS AND METHODS: In 2K1C Goldblatt rats with established hypertension, angiotensin II, angiotensin 1-7, 20-HETE concentrations and gene expression of CYP4A1 enzyme (responsible for 20-HETE formation) of the nonclipped kidney were determined. We examined if 14 days׳ administration of fenofibrate, a lipid-lowering drug, would increase CYP4A1 gene expression and renal 20-HETE formation, and if increased 20-HETE concentrations in the nonclipped kidney would decrease BP (telemetric measurements). RESULTS: CYP4A1 gene expression, 20-HETE and angiotensin 1-7 concentrations were lower and angiotensin II levels were higher in the nonclipped kidney of 2K1C rats than in sham-operated rats. Fenofibrate increased CYP4A1 gene expression and 20-HETE concentration in the nonclipped kidney and significantly decreased BP in 2K1C rats but did not restore it to normotensive range. The treatment did not change BP in sham-operated rats. CONCLUSIONS: Our results suggest that alterations in the RAS and CYP-dependent ω-hydroxylase metabolites of arachidonic acid in the nonclipped kidneys are both important in the pathophysiology of the maintenance phase of 2K1C Goldblatt hypertension. Therefore, fenofibrate treatment effectively attenuated hypertension, probably via stimulation of 20-HETE formation in the nonclipped kidney.
[Mh] Termos MeSH primário: Fenofibrato/farmacologia
Fenofibrato/uso terapêutico
Ácidos Hidroxieicosatetraenoicos/deficiência
Hipertensão Renovascular/tratamento farmacológico
Rim/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Hipertensão Renovascular/fisiopatologia
Hipolipemiantes/farmacologia
Hipolipemiantes/uso terapêutico
Rim/metabolismo
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxyeicosatetraenoic Acids); 0 (Hypolipidemic Agents); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170628
[Lr] Data última revisão:
170628
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE


  6 / 3168 MEDLINE  
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[PMID]:28602979
[Au] Autor:Wang C; Li Y; Chen H; Zhang J; Zhang J; Qin T; Duan C; Chen X; Liu Y; Zhou X; Yang J
[Ad] Endereço:Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
[Ti] Título:Inhibition of CYP4A by a novel flavonoid FLA-16 prolongs survival and normalizes tumor vasculature in glioma.
[So] Source:Cancer Lett;402:131-141, 2017 Aug 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Glioblastomas rapidly become refractory to anti-VEGF therapies. We previously showed that cytochrome P450 (CYP) 4A-derived 20-hydroxyeicosatetraenoic acid (20-HETE) promotes angiogenesis. Here, we tested whether a novel flavonoid (FLA-16) prolongs survival and normalizes tumor vasculature in glioma through CYP4A inhibition. FLA-16 improved survival, reduced tumor burden, and normalized vasculature, accompanied with the decreased secretion of 20-HETE, VEGF and TGF-ß in tumor-associated macrophages (TAMs) and endothelial progenitor cells (EPCs) in C6 and U87 gliomas. FLA-16 attenuated vascular abnormalization induced by co-implantation of GL261 glioma cells with CYP4A10 macrophages or EPCs. Mechanistically, the conditional medium from TAMs and EPCs treated with FLA-16 enhanced the migration of pericyte cells, and decreased the proliferation and migration of endothelial cells, which were reversed by CYP4A overexpression or exogenous addition of 20-HETE, VEGF and TGF-ß. Furthermore, FLA-16 prevented crosstalk between TAMs and EPCs during angiogenesis. These results suggest that CYP4A inhibition by FLA-16 prolongs survival and normalizes vasculature in glioma through decreasing production of TAMs and EPCs-derived VEGF and TGF-ß. This may represent a potential therapeutic strategy to overcome resistance to anti-VEGF treatment by effects on vessels and immune cells.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia
Neoplasias Encefálicas/tratamento farmacológico
Chalconas/farmacologia
Citocromo P-450 CYP4A/antagonistas & inibidores
Inibidores das Enzimas do Citocromo P-450/farmacologia
Células Progenitoras Endoteliais/efeitos dos fármacos
Flavonoides/farmacologia
Glioma/tratamento farmacológico
Macrófagos/efeitos dos fármacos
Neovascularização Patológica
[Mh] Termos MeSH secundário: Animais
Neoplasias Encefálicas/irrigação sanguínea
Neoplasias Encefálicas/enzimologia
Neoplasias Encefálicas/patologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Meios de Cultivo Condicionados/metabolismo
Citocromo P-450 CYP4A/metabolismo
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos
Células Progenitoras Endoteliais/enzimologia
Células Progenitoras Endoteliais/patologia
Glioma/irrigação sanguínea
Glioma/enzimologia
Glioma/patologia
Seres Humanos
Ácidos Hidroxieicosatetraenoicos/metabolismo
Macrófagos/enzimologia
Macrófagos/patologia
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Camundongos Nus
Comunicação Parácrina/efeitos dos fármacos
Pericitos/efeitos dos fármacos
Pericitos/metabolismo
Pericitos/patologia
Ratos Wistar
Fatores de Tempo
Fator de Crescimento Transformador beta/metabolismo
Carga Tumoral/efeitos dos fármacos
Microambiente Tumoral
Fator A de Crescimento do Endotélio Vascular/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Chalcones); 0 (Culture Media, Conditioned); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (FLA-16 compound); 0 (Flavonoids); 0 (Hydroxyeicosatetraenoic Acids); 0 (Transforming Growth Factor beta); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid); EC 1.14.15.3 (Cytochrome P-450 CYP4A)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE


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[PMID]:28566277
[Au] Autor:Uderhardt S; Ackermann JA; Fillep T; Hammond VJ; Willeit J; Santer P; Mayr M; Biburger M; Miller M; Zellner KR; Stark K; Zarbock A; Rossaint J; Schubert I; Mielenz D; Dietel B; Raaz-Schrauder D; Ay C; Gremmel T; Thaler J; Heim C; Herrmann M; Collins PW; Schabbauer G; Mackman N; Voehringer D; Nadler JL; Lee JJ; Massberg S; Rauh M; Kiechl S; Schett G; O'Donnell VB; Krönke G
[Ad] Endereço:Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
[Ti] Título:Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease.
[So] Source:J Exp Med;214(7):2121-2138, 2017 Jul 03.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.
[Mh] Termos MeSH primário: Araquidonato 12-Lipoxigenase/metabolismo
Araquidonato 15-Lipoxigenase/metabolismo
Coagulação Sanguínea
Eosinófilos/metabolismo
Hemostasia
Lipídeos/análise
Trombose/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Araquidonato 12-Lipoxigenase/genética
Araquidonato 15-Lipoxigenase/genética
Aterosclerose/diagnóstico
Aterosclerose/metabolismo
Western Blotting
Células Cultivadas
Proteína Catiônica de Eosinófilo/metabolismo
Seres Humanos
Ácidos Hidroxieicosatetraenoicos/metabolismo
Modelos Logísticos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Meia-Idade
Oxirredução
Fosfatidiletanolaminas/metabolismo
Estudos Prospectivos
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Fatores de Risco
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (12-15-lipoxygenase); 0 (Hydroxyeicosatetraenoic Acids); 0 (Lipids); 0 (Phosphatidylethanolamines); EC 1.13.11.31 (Arachidonate 12-Lipoxygenase); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase); EC 3.1.27.- (Eosinophil Cationic Protein); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20161070


  8 / 3168 MEDLINE  
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[PMID]:28550179
[Au] Autor:Hashimoto R; Joshi SR; Jiang H; Capdevila JH; McMurtry IF; Laniado Schwartzman M; Gupte SA
[Ad] Endereço:Department of Pharmacology, and Translation Cardiovascular Institute, School of Medicine, New York Medical College, Valhalla, New York.
[Ti] Título: gene disruption is associated with increased hematopoietic stem cells: implication in chronic hypoxia-induced pulmonary hypertension.
[So] Source:Am J Physiol Heart Circ Physiol;313(2):H293-H303, 2017 Aug 01.
[Is] ISSN:1522-1539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have recently demonstrated that disruption of the murine cytochrome -450 2c44 gene ( exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found that gene disruption also increases hematopoietic stem cell (HSC) numbers in bone marrow and blood. Therefore, the objective of the present study was to investigate whether CYP2C44-derived eicosanoids regulate HSC proliferation/cell growth and whether increased HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries in knockout mice. Our findings demonstrated that lack of CYP2C44 epoxygenase, which catalyzed the oxidation of arachidonic acid to epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic (HETE) acids, increases the numbers of ) HSCs (CD34 , CD117 , and CD133 ), ) proangiogenic (CD34 CD133 and CD34 CD117 CD133 ) cells, and ) immunogenic/inflammatory (CD34 CD11b , CD133 CD11b , F4/80 , CD11b , and F4/80 CD11b ) macrophages in bone marrow and blood compared with wild-type mice. Among the various CYP2C44-derived arachidonic acids, only 15-HETE decreased CD117 cell numbers when applied to bone marrow cell cultures. Interestingly, CD133 and von Willebrand factor-positive cells, which are derived from proangiogenic stem cells, are increased in the bone marrow, blood, and lungs of mice exposed to chronic hypoxia and in remodeled and occluded pulmonary arteries of CYP2C44-deficient mice. In conclusion, our results demonstrate that CYP2C44-derived 15-HETE plays a critical role in downregulating HSC proliferation and growth, because disruption of the gene increased HSCs that potentially contribute to chronic hypoxia-induced pulmonary arterial remodeling and occlusion. This study demonstrates that cytochrome -450 2C44 plays a critical role in controlling the phenotype of hematopoietic stem cells and that when this enzyme is knocked out, stem cells are differentiated. These stem cells give rise to increased circulating monocytes and macrophages and contribute to the pathogenesis of chronic hypoxia-induced pulmonary artery remodeling and hypertension.
[Mh] Termos MeSH primário: Proliferação Celular
Família 2 do Citocromo P450/deficiência
Células-Tronco Hematopoéticas/enzimologia
Ácidos Hidroxieicosatetraenoicos/metabolismo
Hipertensão Pulmonar/enzimologia
Hipóxia/complicações
Artéria Pulmonar/enzimologia
Remodelação Vascular
[Mh] Termos MeSH secundário: Antígeno AC133/metabolismo
Animais
Antígenos CD34/metabolismo
Antígenos de Diferenciação/metabolismo
Antígeno CD11b/metabolismo
Diferenciação Celular
Células Cultivadas
Doença Crônica
Família 2 do Citocromo P450/genética
Modelos Animais de Doenças
Feminino
Predisposição Genética para Doença
Hipertensão Pulmonar/genética
Hipertensão Pulmonar/patologia
Hipertensão Pulmonar/fisiopatologia
Macrófagos/enzimologia
Masculino
Camundongos da Linhagem 129
Camundongos Knockout
Monócitos/enzimologia
Fenótipo
Proteínas Proto-Oncogênicas c-kit/metabolismo
Artéria Pulmonar/patologia
Artéria Pulmonar/fisiopatologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AC133 Antigen); 0 (Antigens, CD34); 0 (Antigens, Differentiation); 0 (CD11b Antigen); 0 (Hydroxyeicosatetraenoic Acids); 0 (Prom1 protein, mouse); 0 (monocyte-macrophage differentiation antigen); 73945-47-8 (15-hydroxy-5,8,11,13-eicosatetraenoic acid); EC 1.14.14.1 (Cyp2c44 protein, mouse); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE
[do] DOI:10.1152/ajpheart.00785.2016


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[PMID]:28533430
[Au] Autor:Albertolle ME; Kim D; Nagy LD; Yun CH; Pozzi A; Savas Ü; Johnson EF; Guengerich FP
[Ad] Endereço:From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
[Ti] Título:Heme-thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition.
[So] Source:J Biol Chem;292(27):11230-11242, 2017 Jul 07.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 (P450, CYP) 4A11 is a human fatty acid ω-hydroxylase that catalyzes the oxidation of arachidonic acid to the eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE), which plays important roles in regulating blood pressure regulation. Variants of P450 4A11 have been associated with high blood pressure and resistance to anti-hypertensive drugs, and 20-HETE has both pro- and antihypertensive properties relating to increased vasoconstriction and natriuresis, respectively. These physiological activities are likely influenced by the redox environment, but the mechanisms are unclear. Here, we found that reducing agents ( dithiothreitol and tris(2-carboxyethyl)phosphine) strongly enhanced the catalytic activity of P450 4A11, but not of 10 other human P450s tested. Conversely, added H O attenuated P450 4A11 catalytic activity. Catalytic roles of five of the potentially eight implicated Cys residues of P450 4A11 were eliminated by site-directed mutagenesis. Using an isotope-coded dimedone/iododimedone-labeling strategy and mass spectrometry of peptides, we demonstrated that the heme-thiolate cysteine (Cys-457) is selectively sulfenylated in an H O concentration-dependent manner. This sulfenylation could be reversed by reducing agents, including dithiothreitol and dithionite. Of note, we observed heme ligand cysteine sulfenylation of P450 4A11 e in kidneys and livers derived from transgenic mice. We also detected sulfenylation of murine P450 4a12 and 4b1 heme peptides in kidneys. To our knowledge, reversible oxidation of the heme thiolate has not previously been observed in P450s and may have relevance for 20-HETE-mediated functions.
[Mh] Termos MeSH primário: Citocromo P-450 CYP4A/química
Ditiotreitol/química
Heme/química
Peróxido de Hidrogênio/química
[Mh] Termos MeSH secundário: Animais
Catálise
Citocromo P-450 CYP4A/genética
Citocromo P-450 CYP4A/metabolismo
Ditiotreitol/metabolismo
Heme/genética
Heme/metabolismo
Seres Humanos
Peróxido de Hidrogênio/metabolismo
Ácidos Hidroxieicosatetraenoicos/biossíntese
Ácidos Hidroxieicosatetraenoicos/química
Ácidos Hidroxieicosatetraenoicos/genética
Rim/enzimologia
Fígado/enzimologia
Camundongos
Camundongos Transgênicos
Oxirredução
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxyeicosatetraenoic Acids); 42VZT0U6YR (Heme); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid); BBX060AN9V (Hydrogen Peroxide); EC 1.14.15.3 (CYP4A11 protein, human); EC 1.14.15.3 (Cytochrome P-450 CYP4A); T8ID5YZU6Y (Dithiothreitol)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.792200


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[PMID]:28403941
[Au] Autor:Pickens CA; Sordillo LM; Zhang C; Fenton JI
[Ad] Endereço:Department of Food Science and Human Nutrition, East Lansing, MI, United States.
[Ti] Título:Obesity is positively associated with arachidonic acid-derived 5- and 11-hydroxyeicosatetraenoic acid (HETE).
[So] Source:Metabolism;70:177-191, 2017 May.
[Is] ISSN:1532-8600
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Oxylipids are oxygenated polyunsaturated fatty acid (PUFA) metabolites that are responsible for the onset and resolution of the inflammatory response. Enzymatic oxygenation through the lipoxygenase (LOX) or cytochrome P450 (CYP) pathways can form oxylipids that have either proinflammatory or proresolving functions depending on the type of PUFA substrate and degree of metabolism. The objective of this study was to determine how PUFA substrates and their corresponding oxylipids are associated with obesity. METHODS: Plasma non-esterified FA and oxylipids were isolated from 123 Caucasian males using solid phase extraction and quantified using high performance liquid chromatography-tandem mass spectrometry. Statistical analyses included linear regressions and polytomous logistic regressions, and the responses were body mass index (BMI) and waist circumference (WC), and serum leptin, total adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-peptide. Models were adjusted for age and smoking, and p-values were corrected for false discovery per Benjamini-Hochberg and Bonferroni. RESULTS: We report that BMI, WC, and several serum cytokines were highly associated arachidonic acid (ARA)-derived hydroxyeicosatetraenoic acids (HETEs), and vicinal diols (i.e., alcohols on adjacent carbon atoms) derived from several PUFAs. There was a significant linear relationship between BMI, WC, and serum leptin, and ARA-derived 5-, 11-, and 15-HETE. Specifically, BMI and WC were positively associated with proinflammatory 5- and 11-hydroxyeicosatetraenoic acid (HETE), even after normalization to ARA concentrations and false discovery p-value correction. Individuals with 5-HETE concentrations >5.01nmol/L or 11-HETE concentrations and >0.89nmol/L were over 5 times more likely to be obese compared to those with ≤1.86nmol/L and ≤0.39nmol/L, respectively. Vicinal diols from linoleic, eicosapentaenoic, and docosahexaenoic acid were inversely associated with obesity. Across all statistical tests, vicinal diols were inversely associated with obesity whether normalized to parent PUFA concentrations or normalized to precursor epoxides. Interestingly, the proinflammatory cytokines IL-6 and TNF-α were not associated with any oxylipids. Since 5-HETE is a 5LOX product, 11-HETE is marker of lipid peroxidation, and vicinal diols are formed through soluble epoxide hydrolase (sEH) metabolism of CYP epoxygenated PUFAs, therefore, these results indicate that obesity is likely associated with altered metabolism with distinct oxygenating pathways. Taken together, our results indicate that obesity is associated with specific oxylipids indicative of altered PUFA metabolism through several pathways (i.e., LOX, reactive oxygen species, and sEH and CYP epoxygenase), rather than attributed solely to altered dietary PUFA intake.
[Mh] Termos MeSH primário: Ácido Araquidônico/metabolismo
Ácidos Hidroxieicosatetraenoicos/sangue
Obesidade/metabolismo
[Mh] Termos MeSH secundário: Idoso
Biomarcadores/sangue
Estudos Transversais
Sistema Enzimático do Citocromo P-450/metabolismo
Grupo com Ancestrais do Continente Europeu
Ácidos Graxos Insaturados/sangue
Ácidos Graxos Insaturados/metabolismo
Seres Humanos
Inflamação/diagnóstico
Lipoxigenase/metabolismo
Masculino
Redes e Vias Metabólicas
Meia-Idade
Obesidade/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Fatty Acids, Unsaturated); 0 (Hydroxyeicosatetraenoic Acids); 27YG812J1I (Arachidonic Acid); 467RNW8T91 (5-hydroxy-6,8,11,14-eicosatetraenoic acid); 73151-66-3 (11-hydroxy-5,8,12,14-eicosatetraenoic acid); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.13.11.12 (Lipoxygenase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170419
[Lr] Data última revisão:
170419
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE



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