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Pesquisa : D08.811.682.690.416.583.500.055 [Categoria DeCS]
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[PMID]:29302056
[Au] Autor:Werz O; Gerstmeier J; Libreros S; De la Rosa X; Werner M; Norris PC; Chiang N; Serhan CN
[Ad] Endereço:Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Road, BTM 3016, Boston, MA, 02115, USA. oliver.werz@uni-jena.de.
[Ti] Título:Human macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity.
[So] Source:Nat Commun;9(1):59, 2018 01 04.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Proinflammatory eicosanoids (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPM) are temporally regulated during infections. Here we show that human macrophage phenotypes biosynthesize unique lipid mediator signatures when exposed to pathogenic bacteria. E. coli and S. aureus each stimulate predominantly proinflammatory 5-lipoxygenase (LOX) and cyclooxygenase pathways (i.e., leukotriene B and prostaglandin E ) in M1 macrophages. These pathogens stimulate M2 macrophages to produce SPMs including resolvin D2 (RvD2), RvD5, and maresin-1. E. coli activates M2 macrophages to translocate 5-LOX and 15-LOX-1 to different subcellular locales in a Ca -dependent manner. Neither attenuated nor non-pathogenic E. coli mobilize Ca or activate LOXs, rather these bacteria stimulate prostaglandin production. RvD5 is more potent than leukotriene B at enhancing macrophage phagocytosis. These results indicate that M1 and M2 macrophages respond to pathogenic bacteria differently, producing either leukotrienes or resolvins that further distinguish inflammatory or pro-resolving phenotypes.
[Mh] Termos MeSH primário: Araquidonato 5-Lipoxigenase/metabolismo
Ácidos Docosa-Hexaenoicos/metabolismo
Leucotrieno B4/metabolismo
Ativação de Macrófagos
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Seres Humanos
Fagocitose
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (resolvin D5); 1HGW4DR56D (Leukotriene B4); 25167-62-8 (Docosahexaenoic Acids); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02538-5


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[PMID]:27770821
[Au] Autor:Zappavigna S; Scuotto M; Cossu AM; Ingrosso D; De Rosa M; Schiraldi C; Filosa R; Caraglia M
[Ad] Endereço:Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via L. De Crecchio 7, Naples, 80138, Italy.
[Ti] Título:The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells.
[So] Source:J Exp Clin Cancer Res;35(1):167, 2016 Oct 22.
[Is] ISSN:1756-9966
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms. METHODS: U87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique. RESULTS: Here, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway. CONCLUSIONS: RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets.
[Mh] Termos MeSH primário: Benzoquinonas/farmacologia
Neoplasias Encefálicas/metabolismo
Regulação para Baixo
Inibidores Enzimáticos/farmacologia
Glioblastoma/metabolismo
Proteínas Inibidoras de Apoptose/metabolismo
[Mh] Termos MeSH secundário: Araquidonato 5-Lipoxigenase/metabolismo
Ácido Araquidônico/metabolismo
Autofagia
Benzoquinonas/síntese química
Benzoquinonas/química
Neoplasias Encefálicas/tratamento farmacológico
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Glioblastoma/tratamento farmacológico
Seres Humanos
Ácido Linoleico/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Enzyme Inhibitors); 0 (Inhibitor of Apoptosis Proteins); 27YG812J1I (Arachidonic Acid); 9KJL21T0QJ (Linoleic Acid); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 1.3.11.34 (ALOX5 protein, human); SHC6U8F5ER (embelin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:28943042
[Au] Autor:Ye Q; Chourey S; Wang R; Chintam NR; Gravel S; Powell WS; Rokach J
[Ad] Endereço:Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901, USA.
[Ti] Título:Structure-activity relationship study of ß-oxidation resistant indole-based 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) receptor antagonists.
[So] Source:Bioorg Med Chem Lett;27(20):4770-4776, 2017 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed from 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by the 5-lipoxygenase (5-LO) pathway under conditions associated with oxidative stress. 5-Oxo-ETE is an important pro-inflammatory mediator, which stimulates the migration of eosinophils via a selective G-protein coupled receptor, known as the OXE receptor (OXE-R). Previously, we designed and synthesized structural mimics of 5-oxo-ETE such as 1 using an indole scaffold. In the present work, we added various substituents at C-3 of this moiety to block potential ß-oxidation of the 5-oxo-valerate side chain, and investigated the structure-activity relationships of the resulting novel ß-oxidation-resistant antagonists. Cyclopropyl and cyclobutyl substituents were well tolerated in this position, but were less potent as the highly active 3S-methyl compound. It seems likely that 3-alkyl substituents can affect the conformation of the 5-oxovalerate side chain containing the critical keto and carboxyl groups, thereby affecting interaction with the OXE-receptor.
[Mh] Termos MeSH primário: Indóis/metabolismo
Receptores Eicosanoides/antagonistas & inibidores
[Mh] Termos MeSH secundário: Araquidonato 5-Lipoxigenase/metabolismo
Desenho de Drogas
Eosinófilos/citologia
Eosinófilos/metabolismo
Seres Humanos
Indóis/química
Concentração Inibidora 50
Oxirredução
Receptores Eicosanoides/metabolismo
Eletricidade Estática
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Indoles); 0 (Receptors, Eicosanoid); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


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[PMID]:28865292
[Au] Autor:Abdelgawad MA; Labib MB; Abdel-Latif M
[Ad] Endereço:Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Sakaka, Aljouf 2014, Saudi Arabia. Electronic address: mohamedabdelwahab976@yahoo.com.
[Ti] Título:Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design, synthesis, biological evaluation, COX-1,2/5-LOX inhibition and docking study.
[So] Source:Bioorg Chem;74:212-220, 2017 Oct.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, H NMR, C NMR, MS spectral data and elemental analysis. IC values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC =0.67µM) and 4b (IC =0.58µM) showed better COX-2 inhibitory activity than celecoxib (IC =0.87µM) with selectivity index (SI=8.41, 10.55 in sequent) relative to celecoxib (SI=8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC =1.92, 2.31µM) higher than zileuton (IC =2.43µM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition=15-20%) at all doses when compared to reference drug celecoxib (% edema inhibition=15.7-17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia
Inibidores de Ciclo-Oxigenase/farmacologia
Desenho de Drogas
Hidrazonas/farmacologia
Inibidores de Lipoxigenase/farmacologia
Pirazóis/farmacologia
[Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/síntese química
Anti-Inflamatórios não Esteroides/química
Araquidonato 5-Lipoxigenase/metabolismo
Ciclo-Oxigenase 1/metabolismo
Ciclo-Oxigenase 2/metabolismo
Inibidores de Ciclo-Oxigenase/síntese química
Inibidores de Ciclo-Oxigenase/química
Relação Dose-Resposta a Droga
Seres Humanos
Hidrazonas/química
Inibidores de Lipoxigenase/síntese química
Inibidores de Lipoxigenase/química
Simulação de Acoplamento Molecular
Estrutura Molecular
Pirazóis/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Cyclooxygenase Inhibitors); 0 (Hydrazones); 0 (Lipoxygenase Inhibitors); 0 (Pyrazoles); 3QD5KJZ7ZJ (pyrazole); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Cyclooxygenase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


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[PMID]:28737505
[Au] Autor:Pace S; Pergola C; Dehm F; Rossi A; Gerstmeier J; Troisi F; Pein H; Schaible AM; Weinigel C; Rummler S; Northoff H; Laufer S; Maier TJ; Rådmark O; Samuelsson B; Koeberle A; Sautebin L; Werz O
[Ad] Endereço:Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, University Hospital Jena, Jena, Germany.
[Ti] Título:Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.
[So] Source:J Clin Invest;127(8):3167-3176, 2017 Aug 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.
[Mh] Termos MeSH primário: Androgênios/metabolismo
Leucotrienos/biossíntese
Fatores Sexuais
Testosterona/administração & dosagem
[Mh] Termos MeSH secundário: Proteínas Ativadoras de 5-Lipoxigenase/metabolismo
Animais
Araquidonato 5-Lipoxigenase/metabolismo
Di-Hidrotestosterona/metabolismo
Feminino
Seres Humanos
Hidroxiureia/análogos & derivados
Hidroxiureia/farmacologia
Leucócitos/metabolismo
Inibidores de Lipoxigenase/farmacologia
Masculino
Camundongos
Pirróis/administração & dosagem
Ratos
Ratos Wistar
Sulindaco/administração & dosagem
Sulindaco/análogos & derivados
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-Lipoxygenase-Activating Proteins); 0 (Androgens); 0 (Leukotrienes); 0 (Lipoxygenase Inhibitors); 0 (Pyrroles); 08J2K08A3Y (Dihydrotestosterone); 184SNS8VUH (Sulindac); 3XMK78S47O (Testosterone); 6UVA8S2DEY (sulindac sulfide); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); P5T6BYS22Y (licofelone); V1L22WVE2S (zileuton); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE


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[PMID]:28720504
[Au] Autor:Shen FQ; Wang ZC; Wu SY; Ren SZ; Man RJ; Wang BZ; Zhu HL
[Ad] Endereço:State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China; Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People's Republic of China.
[Ti] Título:Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX.
[So] Source:Bioorg Med Chem Lett;27(16):3653-3660, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC =0.23±0.16µM for COX-2, IC =0.87±0.07µM for 5-LOX, IC =4.48±0.57µM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC =0.41±0.28µM for COX-2, IC =7.68±0.55µM against A549) and Zileuton (IC =1.35±0.24µM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.
[Mh] Termos MeSH primário: Cumarínicos/química
Cumarínicos/farmacologia
Ciclo-Oxigenase 2/metabolismo
Pirazóis/química
Pirazóis/farmacologia
[Mh] Termos MeSH secundário: Células A549
Apoptose/efeitos dos fármacos
Araquidonato 5-Lipoxigenase/química
Araquidonato 5-Lipoxigenase/metabolismo
Sítios de Ligação
Domínio Catalítico
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Ciclo-Oxigenase 2/química
Inibidores de Ciclo-Oxigenase 2/síntese química
Inibidores de Ciclo-Oxigenase 2/química
Inibidores de Ciclo-Oxigenase 2/farmacologia
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Concentração Inibidora 50
Inibidores de Lipoxigenase/síntese química
Inibidores de Lipoxigenase/química
Inibidores de Lipoxigenase/farmacologia
Simulação de Acoplamento Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Coumarins); 0 (Cyclooxygenase 2 Inhibitors); 0 (Lipoxygenase Inhibitors); 0 (Pyrazoles); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 1.14.99.1 (Cyclooxygenase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE


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[PMID]:28637652
[Au] Autor:Lukic A; Larssen P; Fauland A; Samuelsson B; Wheelock CE; Gabrielsson S; Radmark O
[Ad] Endereço:Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
[Ti] Título:GM-CSF- and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures.
[So] Source:FASEB J;31(10):4370-4381, 2017 Oct.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:M1 and M2 activated macrophages (MÏ•s) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte MÏ• colony-stimulating factor (GM-CSF) or MÏ• colony-stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively. Lipid mediators released during resting conditions and produced in response to bacterial stimuli (LPS/ -formylmethionyl-leucyl-phenylalanine or peptidoglycan) were quantified by liquid chromatography-mass spectrometry. In resting conditions, both MÏ• phenotypes released primarily proresolving lipid mediators (prostaglandin E metabolite, lipoxin A , and 18-hydroxyeicosapentaenoic acid). A striking shift toward proinflammatory eicosanoids was observed when the same cells were exposed (30 min) to bacterial stimuli: M-CSF MÏ•s produced considerably more 5-lipoxygenase products, particularly leukotriene C , potentially linked to M2 functions in asthma. Prostaglandins were formed by both MÏ• types. In the M-CSF cells, there was also an enhanced release of arachidonic acid and activation of cytosolic phospholipase A However, GM-CSF cells expressed higher levels of 5-lipoxygenase and 5-lipoxygenase-activating protein, and in ionophore incubations these cells also produced the highest levels of 5-hydroxyeicosatetraenoic acid. In summary, GM-CSF and M-CSF MÏ•s displayed similar proresolving lipid mediator formation in resting conditions but shifted toward different proinflammatory eicosanoids upon bacterial stimuli. This demonstrates that preference for specific eicosanoid pathways is primed by CSFs before full M1/M2 activation.-Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., Radmark, O. GM-CSF- and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia
Metabolismo dos Lipídeos/efeitos dos fármacos
Fator Estimulador de Colônias de Macrófagos/farmacologia
Macrófagos/efeitos dos fármacos
Monócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Araquidonato 5-Lipoxigenase/metabolismo
Eicosanoides/metabolismo
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo
Seres Humanos
Inflamação/metabolismo
Fator Estimulador de Colônias de Macrófagos/metabolismo
Macrófagos/metabolismo
Monócitos/metabolismo
Neutrófilos/efeitos dos fármacos
Neutrófilos/metabolismo
Fator de Ativação de Plaquetas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eicosanoids); 0 (Platelet Activating Factor); 81627-83-0 (Macrophage Colony-Stimulating Factor); 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700319R


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[PMID]:28623130
[Au] Autor:Dolinska M; Piccini A; Wong WM; Gelali E; Johansson AS; Klang J; Xiao P; Yektaei-Karin E; Strömberg UO; Mustjoki S; Stenke L; Ekblom M; Qian H
[Ad] Endereço:Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
[Ti] Título:Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 CD38 stem and progenitor cells in chronic myeloid leukemia.
[So] Source:Biochem Biophys Res Commun;490(2):378-384, 2017 Aug 19.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABL CD34 CD38 cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long-term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34 CD38 cells from 7 CML patients. The majority of the single leukemic BCR-ABL CD34 CD38 cells expressed cysteinyl leukotriene receptors CYSLT1 and CYSLT2. However, montelukast, an inhibitor of CYSLT1, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLT1 signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients.
[Mh] Termos MeSH primário: ADP-Ribosil Ciclase 1/análise
Antígenos CD34/análise
Araquidonato 5-Lipoxigenase/imunologia
Células da Medula Óssea/patologia
Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
Células-Tronco Neoplásicas/patologia
Receptores de Leucotrienos/imunologia
[Mh] Termos MeSH secundário: ADP-Ribosil Ciclase 1/imunologia
Adulto
Antígenos CD34/imunologia
Células da Medula Óssea/imunologia
Proliferação Celular
Seres Humanos
Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia
Células-Tronco Neoplásicas/imunologia
Transdução de Sinais
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD34); 0 (Receptors, Leukotriene); 0 (leukotriene D4 receptor); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 1.3.11.34 (ALOX5 protein, human); EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170618
[St] Status:MEDLINE


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[PMID]:28569429
[Au] Autor:Kuhnert R; Sárosi MB; George S; Lönnecke P; Hofmann B; Steinhilber D; Murganic B; Mijatovic S; Maksimovic-Ivanic D; Hey-Hawkins E
[Ad] Endereço:Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany.
[Ti] Título:CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway.
[So] Source:ChemMedChem;12(13):1081-1086, 2017 Jul 06.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Araquidonato 5-Lipoxigenase/metabolismo
Compostos de Boro/farmacologia
Inibidores de Lipoxigenase/farmacologia
Quinolinas/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/toxicidade
Apoptose/efeitos dos fármacos
Compostos de Boro/síntese química
Compostos de Boro/toxicidade
Linhagem Celular Tumoral
Seres Humanos
Inibidores de Lipoxigenase/síntese química
Inibidores de Lipoxigenase/toxicidade
Simulação de Acoplamento Molecular
Óxido Nítrico/metabolismo
Quinolinas/síntese química
Quinolinas/química
Quinolinas/toxicidade
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Boron Compounds); 0 (Lipoxygenase Inhibitors); 0 (Quinolines); 0 (Reactive Oxygen Species); 101910-24-1 (alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol); 31C4KY9ESH (Nitric Oxide); EC 1.13.11.34 (Arachidonate 5-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:170602
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700309


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[PMID]:28566527
[Au] Autor:Gammelmark A; Lundbye-Christensen S; Tjønneland A; Schmidt EB; Overvad K; Nielsen MS
[Ad] Endereço:Department of Cardiology, anders.gammelmark@rn.dk.
[Ti] Título:Interactions between 5-Lipoxygenase Polymorphisms and Adipose Tissue Contents of Arachidonic and Eicosapentaenoic Acids Do Not Affect Risk of Myocardial Infarction in Middle-Aged Men and Women in a Danish Case-Cohort Study.
[So] Source:J Nutr;147(7):1340-1347, 2017 Jul.
[Is] ISSN:1541-6100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The 5-lipoxygenase pathway has been linked to atherothrombotic disease, and a functional tandem repeat polymorphism in the arachidonate lipoxygenase-5 ( ) gene has been associated with the risk of myocardial infarction (MI). Interestingly, 2 studies have reported an interaction between dietary intakes of the ALOX-5 substrates, arachidonic acid (AA) and eicosapentaenoic acid (EPA), and genotype. We investigated whether the interactions between the tandem repeat polymorphism (rs59439148) and adipose tissue AA and EPA were associated with incident MI. In the Danish Diet, Cancer and Health study, we conducted a case-cohort study including 3089 participants with incident MI identified from national registries and a randomly selected subcohort of 3000 participants. Participants were men and women with a median age of 56 y at baseline and no previous history of cancer. Adipose tissue and blood samples were collected at baseline along with comprehensive questionnaires on lifestyle and demographic data. The tandem repeat polymorphism was genotyped by multititer plate sequencing. Associations were analyzed by using Cox proportional hazards models. We observed a higher risk of MI for homozygous carriers of the variant alleles in the fifth quintile of AA content than for the reference group with the lowest quintile of AA and carrying the wild-type allele (HR: 3.02; 95% CI: 1.41, 6.44). In contrast, homozygotes for the variant alleles tended to have a higher risk of MI when comparing the lowest quintile of EPA content with the reference group with the highest quintile of EPA and carrying the wild-type allele (HR: 2.15; 95% CI: 0.91, 5.09; = 0.08). Although our results suggested interactions between the polymorphism and adipose tissue AA and EPA, a quantitative evaluation of interaction by calculating the relative excess risk due to interactions was not significant. Adipose tissue EPA and AA and the tandem repeat polymorphism did not significantly interact to affect the risk of MI. However, the results should be replicated in larger, heterogeneous populations.
[Mh] Termos MeSH primário: Tecido Adiposo/metabolismo
Araquidonato 5-Lipoxigenase/metabolismo
Ácido Araquidônico/química
Ácido Eicosapentaenoico/química
Infarto do Miocárdio/genética
Polimorfismo Genético
[Mh] Termos MeSH secundário: Tecido Adiposo/química
Araquidonato 5-Lipoxigenase/genética
Estudos de Casos e Controles
Dinamarca
Feminino
Regulação Enzimológica da Expressão Gênica/fisiologia
Predisposição Genética para Doença
Genótipo
Seres Humanos
Masculino
Meia-Idade
Regiões Promotoras Genéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
27YG812J1I (Arachidonic Acid); AAN7QOV9EA (Eicosapentaenoic Acid); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.3945/jn.117.247569



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