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[PMID]:29317615
[Au] Autor:An JU; Song YS; Kim KR; Ko YJ; Yoon DY; Oh DK
[Ad] Endereço:Department of Integrative Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
[Ti] Título:Biotransformation of polyunsaturated fatty acids to bioactive hepoxilins and trioxilins by microbial enzymes.
[So] Source:Nat Commun;9(1):128, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hepoxilins (HXs) and trioxilins (TrXs) are involved in physiological processes such as inflammation, insulin secretion and pain perception in human. They are metabolites of polyunsaturated fatty acids (PUFAs), including arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, formed by 12-lipoxygenase (LOX) and epoxide hydrolase (EH) expressed by mammalian cells. Here, we identify ten types of HXs and TrXs, produced by the prokaryote Myxococcus xanthus, of which six types are new, namely, HXB , HXD , HXE , TrXB , TrXD and TrXE . We succeed in the biotransformation of PUFAs into eight types of HXs (>35% conversion) and TrXs (>10% conversion) by expressing M. xanthus 12-LOX or 11-LOX with or without EH in Escherichia coli. We determine 11-hydroxy-eicosatetraenoic acid, HXB , HXB , HXD , TrXB and TrXD as potential peroxisome proliferator-activated receptor-γ partial agonists. These findings may facilitate physiological studies and drug development based on lipid mediators.
[Mh] Termos MeSH primário: Ácido 8,11,14-Eicosatrienoico/análogos & derivados
Ácidos Graxos Insaturados/metabolismo
Myxococcus xanthus/enzimologia
[Mh] Termos MeSH secundário: Ácido 8,11,14-Eicosatrienoico/química
Ácido 8,11,14-Eicosatrienoico/metabolismo
Araquidonato 12-Lipoxigenase/genética
Araquidonato 12-Lipoxigenase/metabolismo
Araquidonato Lipoxigenases/genética
Araquidonato Lipoxigenases/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Biotransformação
Epóxido Hidrolases/genética
Epóxido Hidrolases/metabolismo
Ácidos Graxos Insaturados/química
Redes e Vias Metabólicas/genética
Estrutura Molecular
Myxococcus xanthus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Fatty Acids, Unsaturated); 68860-46-8 (8,11,12-trihydroxy-5,9,14-eicosatrienoic acid); 7324-41-6 (8,11,14-Eicosatrienoic Acid); 85589-24-8 (8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid); EC 1.13.11.- (11-lipoxygenase); EC 1.13.11.- (Arachidonate Lipoxygenases); EC 1.13.11.31 (Arachidonate 12-Lipoxygenase); EC 3.3.2.- (Epoxide Hydrolases)
[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:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02543-8


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[PMID]:28743492
[Au] Autor:Ichimaru Y; Fujii T; Saito H; Sano M; Uchiyama T; Miyairi S
[Ad] Endereço:School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
[Ti] Título:5-Bromoindirubin 3'-(O-oxiran-2-ylmethyl)oxime: A long-acting anticancer agent and a suicide inhibitor for epoxide hydrolase.
[So] Source:Bioorg Med Chem;25(17):4665-4676, 2017 09 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Indirubin 3'-oxime (Indox (1b)) suppresses cancer cell growth (IC : 15µM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases and glycogen synthase kinase-3ß. We have previously reported that the conjugation of 1b with oxirane, a protein-reactive component, enhanced the cytotoxic activity of Indox as determined from the IC value (1.7µM) of indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind (1c)). Here we prepared Epox/Ind derivatives with one or two halogen atoms or a methoxy group on the aromatic ring(s) of an Indox moiety and studied the structure-activity relationships of the substituent(s). We found that bromine-substitution at the 5-position on 1c or any Epox/Ind derivative(s) having bromine on the aromatic ring except Epox/6'-Br-Ind was efficient to improving anticancer activity. Of the 22 Epox/Ind derivatives, 5-bromoindirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/5-Br-Ind (2c)) was the best anticancer agent in both short- (24h) (IC : 0.67µM) and extended-duration (72h) cultures. The high anticancer activity of 2c was partly due to it being a poor substrate and a suicide inhibitor for epoxide hydrolase as epoxide hydrolase was identified as the enzyme primarily responsible for the metabolism of 2c.
[Mh] Termos MeSH primário: Antineoplásicos/química
Epóxido Hidrolases/antagonistas & inibidores
Indóis/química
Oximas/química
[Mh] Termos MeSH secundário: Antineoplásicos/metabolismo
Antineoplásicos/farmacologia
Sítios de Ligação
Bromo/química
Sobrevivência Celular/efeitos dos fármacos
Epóxido Hidrolases/metabolismo
Células Hep G2
Seres Humanos
Indóis/metabolismo
Indóis/farmacologia
Cinética
Simulação de Acoplamento Molecular
Oximas/metabolismo
Oximas/farmacologia
Estrutura Terciária de Proteína
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Indoles); 0 (Oximes); 0 (indirubin 3'-(O-oxiran-2-ylmethyl)oxime); EC 3.3.2.- (Epoxide Hydrolases); SBV4XY874G (Bromine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


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[PMID]:29054760
[Au] Autor:Chung JE; Lee KE; Chang BC; Gwak HS
[Ad] Endereço:School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Suwan si, Gyeonggi-do 16419, Republic of Korea.
[Ti] Título:Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses.
[So] Source:Gene;641:68-73, 2018 Jan 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses.
[Mh] Termos MeSH primário: Anticoagulantes/administração & dosagem
Anticoagulantes/uso terapêutico
Epóxido Hidrolases/genética
Vitamina K Epóxido Redutases/genética
Varfarina/administração & dosagem
Varfarina/uso terapêutico
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Feminino
Frequência do Gene
Implante de Prótese de Valva Cardíaca
Seres Humanos
Masculino
Meia-Idade
Polimorfismo de Nucleotídeo Único/genética
Vitamina K/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticoagulants); 12001-79-5 (Vitamin K); 5Q7ZVV76EI (Warfarin); EC 1.17.4.4 (VKORC1L1 protein, human); EC 1.17.4.4 (Vitamin K Epoxide Reductases); EC 3.3.2.- (Epoxide Hydrolases); EC 3.3.2.9 (EPHX1 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171022
[St] Status:MEDLINE


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[PMID]:28867330
[Au] Autor:Zhao J; Zhou Y; Li X; Cai W; Hua H
[Ad] Endereço:Hubei Insect Resources Utilisation and Sustainable Pest Management Key Laboratory, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China.
[Ti] Título:Silencing of juvenile hormone epoxide hydrolase gene (Nljheh) enhances short wing formation in a macropterous strain of the brown planthopper, Nilaparvata lugens.
[So] Source:J Insect Physiol;102:18-26, 2017 Oct.
[Is] ISSN:1879-1611
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The rice brown planthopper, Nilaparvata lugens, is an important migratory pest in many rice planting areas of Asia. The typical wing dimorphism of N. lugens gives them flexibility to adapt to different environmental cues. As an important hormone in the insect's endocrine regulation, juvenile hormone (JH) has previously been shown to participate in the wing morph determination of N. lugens. In this paper, we investigated the possible wing morph determination roles of two JH metabolic enzymes, JH esterase (JHE) and JH epoxide hydrolase (JHEH). A 1957-bp full-length cDNA sequence encoding JHEH in N. lugens (NlJHEH) was first cloned from a hemipteran insect. Except for an uncertain transmembrane segment prediction, the deduced 454-amino-acid sequence of Nljheh has all of the conserved domains of JHEHs such as the H GWP , Tyr293 and Tyr368 motif corresponding to the oxyanion hole and the residues Asp222, Glu398, and His425 in the catalytic triad. qRT-PCR results showed that both Nljhe and Nljheh had different expression timeframes between a predominantly brachypterous strain (BS) and a macropterous strain (MS) of N. lugens, indicating that these two enzymes may participate in wing dimorphism regulation in brown planthopper. Silencing Nljheh expression by dsRNA injection enhanced short wing formation in the macropterous strain of N. lugens, while the brachypterizing individuals were mainly females. Compared to the dsgfp injection control, silencing Nljhe had no brachypterizing effect. Our results indicated that NlJHEH plays an important role in the wing morph determination of N. lugens.
[Mh] Termos MeSH primário: Epóxido Hidrolases/genética
Hemípteros/genética
Proteínas de Insetos/genética
Asas de Animais/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Clonagem Molecular
DNA Complementar/genética
DNA Complementar/metabolismo
Epóxido Hidrolases/química
Epóxido Hidrolases/metabolismo
Feminino
Regulação da Expressão Gênica no Desenvolvimento
Inativação Gênica
Hemípteros/crescimento & desenvolvimento
Hemípteros/metabolismo
Proteínas de Insetos/química
Proteínas de Insetos/metabolismo
Masculino
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Alinhamento de Sequência
Asas de Animais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Complementary); 0 (Insect Proteins); 0 (RNA, Messenger); EC 3.3.2.- (Epoxide Hydrolases); EC 3.3.2.- (juvenile hormone epoxide hydrolase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28845983
[Au] Autor:Schmidt J; Rotter M; Weiser T; Wittmann S; Weizel L; Kaiser A; Heering J; Goebel T; Angioni C; Wurglics M; Paulke A; Geisslinger G; Kahnt A; Steinhilber D; Proschak E; Merk D
[Ad] Endereço:Institute of Pharmaceutical Chemistry, Goethe University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany.
[Ti] Título:A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis.
[So] Source:J Med Chem;60(18):7703-7724, 2017 Sep 28.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the disease's multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Inibidores Enzimáticos/farmacologia
Epóxido Hidrolases/antagonistas & inibidores
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
Receptores Citoplasmáticos e Nucleares/agonistas
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios/química
Descoberta de Drogas
Inibidores Enzimáticos/química
Epóxido Hidrolases/metabolismo
Células HeLa
Células Hep G2
Seres Humanos
Fígado/efeitos dos fármacos
Fígado/enzimologia
Fígado/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Simulação de Acoplamento Molecular
Hepatopatia Gordurosa não Alcoólica/enzimologia
Hepatopatia Gordurosa não Alcoólica/metabolismo
Receptores Citoplasmáticos e Nucleares/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Enzyme Inhibitors); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); EC 3.3.2.- (Epoxide Hydrolases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00398


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[PMID]:28789952
[Au] Autor:Naidoo P; Naidoo RN; Ramkaran P; Asharam K; Chuturgoon AA
[Ad] Endereço:Discipline of Medical Biochemistry and Chemical Pathology, Howard College Campus, University of KwaZulu-Natal, Durban, South Africa.
[Ti] Título:The Tyr113His T/C rs1051740 and 'very slow' phenotype of the EPHX1 gene alters miR-26b-5p and miR-1207-5p expression in pregnancy.
[So] Source:Gene;633:71-81, 2017 Oct 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Environmental insults and microsomal epoxide hydrolase 1 (EPHX1) single nucleotide polymorphisms (SNPs), Tyr113His T/C rs1051740 and His139Arg A/G rs2234922, aberrantly alters microRNA (miR) expression and are linked to low birthweights (LBW). OBJECTIVES: To investigate the interplay between pollution, EPHX1 SNPs and miRs during pregnancy and associated LBW outcomes. METHODS: South African pregnant women (n=241) were recruited in the MACE birth cohort study in Durban, a city with high levels of industry and traffic related pollutants. EPHX1 SNPs were genotyped using PCR-RFLP and grouped into their respective phenotypes, i.e. normal (N), slow (S), very slow (VS) and fast (F). EPHX1, miR-26b-5p, miR-193b-3p and miR-1207-5p expression were determined using quantitative PCR. RESULTS: Mothers with the Tyr113His SNP had low iron levels [TT vs. TC+CC: mean difference (MD)=0.67g/dl; p=0.0167], LBW [TT vs. TC+CC: MD=189.30g; p=0.0067], and low EPHX1 expression; p<0.0001. miR-26b-5p and miR-1207-5p expression were significantly higher in the CC genotypes compared to TT+TC groups; p<0.0001. The opposite trend occurred for miR-193b-3p; p=0.0045. Mothers with the VS phenotype had low iron levels [N vs. VS and VS vs. F: MD=2.03 and -1.96g/dl; p=0.0021, respectively], decreased gestational age [VS vs. F: MD=-2.14weeks; p=0.0051, respectively], and LBW [N vs. VS, VS vs. F and S vs. VS: MD=1000, -940.30 and 968.80g; p<0.0001, respectively]; F phenotype had the highest EPHX1 expression [N vs. F, VS vs. F and S vs. F: MD=-1.067, -1.854 and -1.379; p=0.0002, respectively]; and N phenotype had low miR-26b-5p [N vs. VS: MD=-0.6100; p=0.0159] and miR-1207-5p [N vs. VS and VS vs. F: MD=-0.834 and 1.103; p=0.0007, respectively] expression. miR-193b-3p expression between phenotypes remained unchanged. CONCLUSION: The Tyr113His T/C variant of rs1051740 and VS phenotype alters EPHX1, miR-26b-5p and miR-1207-5p expression, and contributes towards low blood iron levels and LBW.
[Mh] Termos MeSH primário: Epóxido Hidrolases/genética
Recém-Nascido de Baixo Peso
Ferro/deficiência
Exposição Materna
MicroRNAs/metabolismo
[Mh] Termos MeSH secundário: Adulto
Estudos de Coortes
Feminino
Genótipo
Histidina/genética
Seres Humanos
Ferro/sangue
MicroRNAs/genética
Fenótipo
Polimorfismo de Nucleotídeo Único
Gravidez
África do Sul
Tirosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN1207 microRNA, human); 0 (MIRN193 microRNA, human); 0 (MIRN26A microRNA, human); 0 (MicroRNAs); 42HK56048U (Tyrosine); 4QD397987E (Histidine); E1UOL152H7 (Iron); EC 3.3.2.- (Epoxide Hydrolases); EC 3.3.2.9 (EPHX1 protein, human)
[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:170810
[St] Status:MEDLINE


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[PMID]:28707660
[Au] Autor:Abramova TO; Ryazanova MA; Antonov EV; Redina OE; Markel AL
[Ad] Endereço:Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia.
[Ti] Título:[Increase in the concentration of sEH protein in renal medulla of ISIAH rats with inherited stress-induced arterial hypertension].
[So] Source:Mol Biol (Mosk);51(3):442-446, 2017 May-Jun.
[Is] ISSN:0026-8984
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:The concentration of soluble epoxide hydrolase (sEH) protein was studied in renal medulla of adult rats from hypertensive ISIAH strain and normotensive WAG strain. The sEH is a key enzyme in metabolism of epoxyeicosatrienoic acids capable of activating endothelial NO-synthase and nitrogen oxide formation, and therefore being vasodilators. An increase in the sEH protein concentration (that we found) allows one to assume that the oxidative stress is increased in the renal medulla of hypertensive rats, and the bloodflow is decreased.
[Mh] Termos MeSH primário: Epóxido Hidrolases/biossíntese
Estresse Oxidativo/genética
Estresse Fisiológico/genética
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea
Modelos Animais de Doenças
Epóxido Hidrolases/isolamento & purificação
Seres Humanos
Hipertensão/enzimologia
Hipertensão/patologia
Medula Renal/enzimologia
Medula Renal/patologia
Masculino
Óxido Nítrico Sintase/genética
Óxidos de Nitrogênio/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitrogen Oxides); EC 1.14.13.39 (Nitric Oxide Synthase); EC 3.3.2.- (Epoxide Hydrolases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.7868/S0026898417020021


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[PMID]:28694203
[Au] Autor:Dong XW; Jia YL; Ge LT; Jiang B; Jiang JX; Shen J; Jin YC; Guan Y; Sun Y; Xie QM
[Ad] Endereço:Key Laboratory of Respiratory Drugs Research, Zhejiang University School of Medicine, Hangzhou 310058, China.
[Ti] Título:Soluble epoxide hydrolase inhibitor AUDA decreases bleomycin-induced pulmonary toxicity in mice by inhibiting the p38/Smad3 pathways.
[So] Source:Toxicology;389:31-41, 2017 Aug 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Bleomycin (BLM) has potent tumor cell-killing properties that have given it an important place in cancer chemotherapy, but pulmonary toxicity is its major adverse effect. Soluble epoxide hydrolase (sEH) inhibitors have been reported to have protective effects in fibrosis models, but the effects of AUDA, an sEH inhibitor of BLM-induced pulmonary toxicity and fibrosis, remain to be researched. In this study, we assessed the effects of AUDA on the BLM-induced pulmonary fibrosis in a mouse model, and transforming growth factor (TGF)-ß -induced epithelial proliferation and epithelial-mesenchymal transition (EMT) in vitro by monitoring changes in pulmonary function, inflammatory response, fibrotic remodeling, and signaling pathways. AUDA was administered by intragastric administration (i.g) daily for three weeks, starting at seven days after intratracheal instillation of BLM. All examinations were performed 24h after the last i.g. In vivo, AUDA significantly improved BLM-induced decline in lung function and body weight, and inhibited inflammatory cell accumulation and the mRNA and protein expression of interleukin (IL)-1ß, TGF-ß , and matrix metalloproteinase 9 (MMP-9) in lung tissue. Moreover, AUDA attenuated BLM-induced deposition of collagen fibers, destruction of alveolar structures, and pulmonary parenchyma. Additionally, AUDA regulated the expression of α-smooth muscle actin (α-SMA) and E-cadherin by inhibiting the Smad3/p38 signaling pathway. In vitro, AUDA significantly inhibited TGF-ß -induced epithelial cells and fibroblast proliferation, reduced sEH expression and α-SMA expression, and increased epoxyeicosatrienoic acid (EET) levels and E-cadherin expression in epithelial cells. These effects were blocked by AUDA by downregulating the Smad3 and p38 signaling pathways. Taken together, these data indicate that treatment with sEH inhibitors may improve BLM-induced pulmonary toxicity.
[Mh] Termos MeSH primário: Adamantano/análogos & derivados
Bleomicina
Inibidores Enzimáticos/farmacologia
Epóxido Hidrolases/antagonistas & inibidores
Ácidos Láuricos/farmacologia
Pulmão/efeitos dos fármacos
Fibrose Pulmonar/prevenção & controle
Proteína Smad3/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Adamantano/farmacologia
Animais
Biomarcadores/metabolismo
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Colágeno/metabolismo
Citocinas/metabolismo
Citoproteção
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Epóxido Hidrolases/metabolismo
Feminino
Seres Humanos
Mediadores da Inflamação/metabolismo
Pulmão/enzimologia
Pulmão/patologia
Pulmão/fisiopatologia
Camundongos Endogâmicos ICR
Pneumonia/induzido quimicamente
Pneumonia/enzimologia
Pneumonia/prevenção & controle
Fibrose Pulmonar/induzido quimicamente
Fibrose Pulmonar/enzimologia
Fibrose Pulmonar/patologia
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (12-(3-adamantan-1-ylureido)dodecanoic acid); 0 (Biomarkers); 0 (Cytokines); 0 (Enzyme Inhibitors); 0 (Inflammation Mediators); 0 (Lauric Acids); 0 (Smad3 Protein); 0 (Smad3 protein, mouse); 11056-06-7 (Bleomycin); 9007-34-5 (Collagen); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.3.2.- (Epoxide Hydrolases); PJY633525U (Adamantane)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE


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[PMID]:28658259
[Au] Autor:Vincent WJB; Harvie EA; Sauer JD; Huttenlocher A
[Ad] Endereço:Microbiology Doctoral Training Program, Department of Medical Microbiology and Immunology, University of Wisconsin-Madison; Madison, WI; United States of America.
[Ti] Título:Neutrophil derived LTB4 induces macrophage aggregation in response to encapsulated Streptococcus iniae infection.
[So] Source:PLoS One;12(6):e0179574, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Immune cells sense and react to a multitude of factors including both host and microbe-derived signals. Understanding how cells translate these cues into particular cellular behaviors is a complex yet critical area of study. We have previously shown that both neutrophils and macrophages are important for controlling the fish pathogen Streptococcus iniae. Here, we report both host and bacterial determinants leading to the formation of organized macrophage aggregates as part of the host inflammatory response in a subset of infected larvae. Streptococcal capsule was a required signal for aggregate formation. Macrophage aggregation coincided with NFκB activity, and the formation of these aggregates is mediated by leukotriene B4 (LTB4) produced by neutrophils. Depletion, inhibition, or genetic deletion of leukotriene A4 hydrolase (Lta4h), which catalyzes the last step in LTB4 synthesis, resulted in the absence of macrophage aggregation. Larvae with impaired neutrophil function also had impaired macrophage aggregation; however, aggregate formation was partially rescued with the addition of exogenous LTB4. Neutrophil-specific expression of lta4h was sufficient to rescue macrophage aggregation in Lta4h-deficient larvae and increased host survival following infection. In summary, our findings highlight a novel innate immune response to infection in which specific bacterial products drive neutrophils that modulate macrophage behavior through eicosanoid signaling.
[Mh] Termos MeSH primário: Leucotrieno B4/metabolismo
Macrófagos/metabolismo
Neutrófilos/metabolismo
Infecções Estreptocócicas/metabolismo
[Mh] Termos MeSH secundário: Animais
Epóxido Hidrolases/genética
Epóxido Hidrolases/metabolismo
Deleção de Genes
Imunidade Inata
Inflamação/metabolismo
NF-kappa B/metabolismo
Streptococcus iniae
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NF-kappa B); 1HGW4DR56D (Leukotriene B4); EC 3.3.2.- (Epoxide Hydrolases); EC 3.3.2.- (leukotriene A4 hydrolase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171118
[Lr] Data última revisão:
171118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179574


  10 / 3058 MEDLINE  
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[PMID]:28575166
[Au] Autor:Oi N; Yamamoto H; Langfald A; Bai R; Lee MH; Bode AM; Dong Z
[Ad] Endereço:The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA.
[Ti] Título:LTA4H regulates cell cycle and skin carcinogenesis.
[So] Source:Carcinogenesis;38(7):728-737, 2017 Jul 01.
[Is] ISSN:1460-2180
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Leukotriene A4 hydrolase (LTA4H), a bifunctional zinc metallo-enzyme, is reportedly overexpressed in several human cancers. Our group has focused on LTA4H as a potential target for cancer prevention and/or therapy. In the present study, we report that LTA4H is a key regulator of cell cycle at the G0/G1 phase acting by negatively regulating p27 expression in skin cancer. We found that LTA4H is overexpressed in human skin cancer tissue. Knocking out LTA4H significantly reduced skin cancer development in the 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin cancer mouse model. LTA4H depletion dramatically decreased anchorage-dependent and -independent skin cancer cell growth by inducing cell cycle arrest at the G0/G1 phase. Moreover, our findings showed that depletion of LTA4H enhanced p27 protein stability, which was associated with decreased phosphorylation of CDK2 at Thr160 and inhibition of the CDK2/cyclin E complex, resulting in down-regulated p27 ubiquitination. These findings indicate that LTA4H is critical for skin carcinogenesis and is an important mediator of cell cycle and the data begin to clarify the mechanisms of LTA4H's role in cancer development.
[Mh] Termos MeSH primário: Carcinogênese/genética
Ciclo Celular/genética
Epóxido Hidrolases/genética
Neoplasias Cutâneas/genética
[Mh] Termos MeSH secundário: 9,10-Dimetil-1,2-benzantraceno/toxicidade
Animais
Quinase 2 Dependente de Ciclina/biossíntese
Quinase 2 Dependente de Ciclina/genética
Epóxido Hidrolases/biossíntese
Fase G1
Seres Humanos
Camundongos
Fosforilação
Antígeno Nuclear de Célula em Proliferação/biossíntese
Piridinas/toxicidade
Neoplasias Cutâneas/induzido quimicamente
Neoplasias Cutâneas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proliferating Cell Nuclear Antigen); 0 (Pyridines); 0 (p27 antigen); 0 (tris(2-pyridylmethyl)amine); 57-97-6 (9,10-Dimethyl-1,2-benzanthracene); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); EC 3.3.2.- (Epoxide Hydrolases); EC 3.3.2.- (leukotriene A4 hydrolase)
[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:170603
[St] Status:MEDLINE
[do] DOI:10.1093/carcin/bgx049



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