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[PMID]:29242061
[Au] Autor:Kaito Y; Kataoka R; Mihara T; Takechi K; Takahira A; Watanabe S; Han F; Tamura M
[Ad] Endereço:Department of Applied Chemistry, Graduate School of Science and Engineering, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577, Japan.
[Ti] Título:Phosphorylation of Ser-525 in ßPix impairs Nox1-activating ability in Caco-2 cells.
[So] Source:Arch Biochem Biophys;638:58-65, 2018 01 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ßPix activates Nox1, an O -generating NADPH oxidase, through Rac activation. In this study, we found that S525E mutation of ßPix eliminated its Nox1-activating ability in transfected Caco-2 cells. Unexpectedly, affinity for Rac was not diminished but rather enhanced by S525E mutation, and guanine nucleotide exchange factor (GEF) activity was not altered. The N-terminal fragment (amino acids 1-400) showed similar Rac-binding and GEF activity to wild-type ßPix. In contrast, the C-terminal fragment (amino acids 408-646) had higher Rac-binding activity, particularly for Rac-GTP, than wild-type ßPix, and showed no GEF activity. These data suggest that a second Rac-binding site within the C-terminal region is opened by phosphorylation of Ser-525. The site may bind not only Rac-GDP but also Rac-GTP released from the N-terminal catalytic region, which interrupts Rac-GTP translocation to the membrane where Nox1 resides. If one considers that S340E mutation enhances Nox1 activation (Kaito et al., 2014), the present study suggests that ßPix can also play an inhibitory role in O production, depending on the sites of phosphorylation.
[Mh] Termos MeSH primário: Mutação de Sentido Incorreto
NADPH Oxidase 1/metabolismo
Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
Superóxidos/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Células CACO-2
Ativação Enzimática/genética
Seres Humanos
NADPH Oxidase 1/genética
Fosforilação/genética
Domínios Proteicos
Fatores de Troca de Nucleotídeo Guanina Rho/genética
Proteínas rac de Ligação ao GTP/genética
Proteínas rac de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Rho Guanine Nucleotide Exchange Factors); 11062-77-4 (Superoxides); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NOX1 protein, human); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


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[PMID]:27771433
[Au] Autor:Wilson A; Yakovlev VA
[Ad] Endereço:Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298, United States.
[Ti] Título:Cells redox environment modulates BRCA1 expression and DNA homologous recombination repair.
[So] Source:Free Radic Biol Med;101:190-201, 2016 12.
[Is] ISSN:1873-4596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS. However, increase in oxidative DNA lesions does not always lead to malignancy. Hence, additional ROS-dependent, pro-carcinogenic mechanisms must be important. Our recent study demonstrated that Tyr nitration of PP2A stimulates its activity and leads to downregulation of BRCA1 expression. This provides a mechanism for chromosomal instability essential for tumor progression. In the present work, we demonstrated that inhibition of ROS production by generating mitochondrial-electron-transport-deficient cell lines (ρ cells) or by inhibition of NOX activity with a selective peptide inhibitor significantly reduced PP2A Tyr nitration and its activity in different cancer cell lines. As a result of the decreased PP2A activity, BRCA1 expression was restored along with a significantly enhanced level of DNA HRR. We used TCGA database to analyze the correlation between expressions of the NOX regulatory subunits, NOS isoforms, and BRCA1 in the 3 cancer research studies: breast invasive carcinoma, ovarian cystadenocarcinoma, and lung adenocarcinoma. TCGA database analysis demonstrated that the high expression levels of most of the NOX regulatory subunits responsible for stimulation of NOX1-NOX4 were associated with significant downregulation of BRCA1 expression.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica
NADPH Oxidase 1/genética
Óxido Nítrico Sintase Tipo III/genética
Fosfoproteínas Fosfatases/genética
Reparo de DNA por Recombinação
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Células A549
Adenocarcinoma/genética
Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/genética
Carcinoma Ductal de Mama/metabolismo
Carcinoma Ductal de Mama/patologia
Instabilidade Cromossômica
Cistadenocarcinoma Seroso/genética
Cistadenocarcinoma Seroso/metabolismo
Cistadenocarcinoma Seroso/patologia
Bases de Dados Genéticas
Transporte de Elétrons
Feminino
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Células MCF-7
Mitocôndrias/metabolismo
Mitocôndrias/patologia
NADPH Oxidase 1/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
Neoplasias Ovarianas/genética
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Oxirredução
Estresse Oxidativo
Fosfoproteínas Fosfatases/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Ubiquitina-Proteína Ligases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Reactive Oxygen Species); EC 1.14.13.39 (NOS3 protein, human); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NOX1 protein, human); EC 2.3.2.27 (BRAP protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.1.3.16 (Phosphoprotein Phosphatases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:29227594
[Au] Autor:Bazalii AV; Horak IR; Pasi chn yk GV; Komisarenko SV; Drobot LB
[Ti] Título:Transcriptional regulation of NOX genes express ion in human breast adenocarcinoma MCF-7 cells is modulated by adaptor protein Ruk/CIN 85.
[So] Source:Ukr Biochem J;88(1):119-25, 2016 Jan-Feb.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:NADPH oxidases are key components of redox-dependent signaling networks involved in the control of cancer cell proliferation, survival and invasion. The data have been accumulated that demonstrate specific expression patterns and levels of NADPH oxidase homologues (NOXs) and accessory genes in human cancer cell lines and primary tumors as well as modulation of these parameters by extracellular cues. Our previous studies revealed that ROS production by human colorectal adenocarcinoma HT-29 cells is positively correlated with adaptor protein Ruk/CIN85 expression while increased levels of Ruk/CIN85 in weakly invasive human breast adenocarcinoma MC F-7 cells contribute to their malignant phenotype through the constitutive activation of Src/Akt pathway. In this study, to investigate whether overexpression of Ruk/CIN85 in MC F-7 cells can influence transcriptional regulation of NOXs genes, the subclones of MCF-7 cells with different levels of Ruk/CIN85 were screened for NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 as well as for regulatory subunit p22Phox mRNA contents by quantitative RT-PCR (qPCR). Systemic multidirectional changes in mRNA levels for NOX1, NOX2, NOX5, DUOX2 and p22Phox were revealed in Ruk/CIN85 overexpressing cells in comparison to control WT cells. Knocking down of Ruk/CIN85 using technology of RNA-interference resulted in the reversion of these changes. Further studies are necessary to elucidate, by which molecular mechanisms Ruk/CIN85 could affect transcriptional regulation of NOXs genes.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
Regulação Neoplásica da Expressão Gênica
NADPH Oxidase 1/genética
Espécies Reativas de Oxigênio/metabolismo
Transcrição Genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Células Clonais
Oxidases Duais/genética
Oxidases Duais/metabolismo
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Células MCF-7
NADPH Oxidase 1/metabolismo
NADPH Oxidases/genética
NADPH Oxidases/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Isoenzymes); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 0 (SH3KBP1 protein, human); EC 1.11.1.- (Dual Oxidases); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (NOX1 protein, human); EC 1.6.3.1 (CYBA protein, human); EC 1.6.3.1 (DUOX1 protein, human); EC 1.6.3.1 (DUOX2 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.01.119


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[PMID]:27773825
[Au] Autor:García-Redondo AB; Aguado A; Briones AM; Salaices M
[Ad] Endereço:Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid, Spain.
[Ti] Título:NADPH oxidases and vascular remodeling in cardiovascular diseases.
[So] Source:Pharmacol Res;114:110-120, 2016 Dec.
[Is] ISSN:1096-1186
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Reactive oxygen species (ROS) are key signaling molecules that regulate vascular function and structure in physiological conditions. A misbalance between the production and detoxification of ROS increases oxidative stress that is involved in the vascular remodeling associated with cardiovascular diseases such as hypertension by affecting inflammation, hypertrophy, migration, growth/apoptosis and extracellular matrix protein turnover. The major and more specific source of ROS in the cardiovascular system is the NADPH oxidase (NOX) family of enzymes composed of seven members (NOX1-5, DUOX 1/2). Vascular cells express several NOXs being NOX-1 and NOX-4 the most abundant NOXs present in vascular smooth muscle cells. This review focuses on specific aspects of NOX-1 and NOX-4 isoforms including information on regulation, function and their role in vascular remodeling. In order to obtain a more integrated view about the role of the different NOX isoforms in different types of vascular remodeling, we discuss the available literature not only on hypertension but also in atherosclerosis, restenosis and aortic dilation.
[Mh] Termos MeSH primário: Doenças Cardiovasculares/enzimologia
Doenças Cardiovasculares/patologia
NADPH Oxidases/metabolismo
Remodelação Vascular
[Mh] Termos MeSH secundário: Animais
Doenças Cardiovasculares/metabolismo
Movimento Celular
Proliferação Celular
Seres Humanos
NADPH Oxidase 1/análise
NADPH Oxidase 1/metabolismo
NADPH Oxidase 4/análise
NADPH Oxidase 4/metabolismo
NADPH Oxidases/análise
Isoformas de Proteínas/análise
Isoformas de Proteínas/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Protein Isoforms); 0 (Reactive Oxygen Species); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NADPH Oxidase 4); EC 1.6.3.- (NADPH Oxidases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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Vassallo, Dalton Valentim
Texto completo
[PMID]:28826906
[Au] Autor:Martinez CS; Piagette JT; Escobar AG; Martín Á; Palacios R; Peçanha FM; Vassallo DV; Exley C; Alonso MJ; Miguel M; Salaices M; Wiggers GA
[Ad] Endereço:Postgraduate Program in Biochemistry, Universidade Federal do Pampa, BR 472 - Km 592 - PO box 118, Zip Code: 97500-970, Uruguaiana, Rio Grande do Sul, Brazil.
[Ti] Título:Aluminum exposure at human dietary levels promotes vascular dysfunction and increases blood pressure in rats: A concerted action of NAD(P)H oxidase and COX-2.
[So] Source:Toxicology;390:10-21, 2017 Sep 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Aluminum (Al) is a non-essential metal and a significant environmental contaminant and is associated with a number of human diseases including cardiovascular disease. We investigated the effects of Al exposure at doses similar to human dietary levels on the cardiovascular system over a 60day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60days as follows: a) Untreated - ultrapure water; b) AlCl at a dose of 8.3mg/kg bw for 60days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42days as follows: C) Untreated - ultrapure water; d) AlCl at 100mg/kg bw for 42days, representing a high level of human exposure to Al. Effects on systolic blood pressure (SBP) and vascular function of aortic and mesenteric resistance arteries (MRA) were studied. Endothelium and smooth muscle integrity were evaluated by concentration-response curves to acetylcholine (ACh) and sodium nitroprusside. Vasoconstrictor responses to phenylephrine (Phe) in the presence and absence of endothelium and in the presence of the NOS inhibitor L-NAME, the potassium channels blocker TEA, the NAD(P)H oxidase inhibitor apocynin, superoxide dismutase (SOD), the non-selective COX inhibitor indomethacin and the selective COX-2 inhibitor NS 398 were analyzed. Vascular reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity, were measured. The mRNA expressions of eNOS, NAD(P)H oxidase 1 and 2, SOD1, COX-2 and thromboxane A2 receptor (TXA-2 R) were also investigated. Al exposure at human dietary levels impaired the cardiovascular system and these effects were almost the same as Al exposure at much higher levels. Al increased SBP, decreased ACh-induced relaxation, increased response to Phe, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide (NO), the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric arteries. Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Our results point to an excess of ROS mainly from NAD(P)H oxidase after Al exposure and the increased vascular prostanoids from COX-2 acting in concert to decrease NO bioavailability, thus inducing vascular dysfunction and increasing blood pressure. Therefore, 60-day chronic exposure to Al, which reflects common human dietary Al intake, appears to pose a risk for the cardiovascular system.
[Mh] Termos MeSH primário: Compostos de Alumínio/toxicidade
Pressão Sanguínea/efeitos dos fármacos
Cloretos/toxicidade
Ciclo-Oxigenase 2/metabolismo
Dieta
Endotélio Vascular/efeitos dos fármacos
Hipertensão/induzido quimicamente
NADH NADPH Oxirredutases/metabolismo
Vasoconstrição/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Inibidores de Ciclo-Oxigenase 2/farmacologia
Relação Dose-Resposta a Droga
Endotélio Vascular/enzimologia
Endotélio Vascular/fisiopatologia
Seres Humanos
Hipertensão/enzimologia
Hipertensão/genética
Hipertensão/fisiopatologia
Peroxidação de Lipídeos/efeitos dos fármacos
Masculino
NADH NADPH Oxirredutases/antagonistas & inibidores
NADH NADPH Oxirredutases/genética
NADPH Oxidase 1
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Ratos Wistar
Receptores de Tromboxano A2 e Prostaglandina H2/efeitos dos fármacos
Receptores de Tromboxano A2 e Prostaglandina H2/genética
Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo
Medição de Risco
Transdução de Sinais/efeitos dos fármacos
Superóxido Dismutase-1/genética
Superóxido Dismutase-1/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aluminum Compounds); 0 (Chlorides); 0 (Cyclooxygenase 2 Inhibitors); 0 (Receptors, Thromboxane A2, Prostaglandin H2); 31C4KY9ESH (Nitric Oxide); 3CYT62D3GA (aluminum chloride); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.14.13.39 (Nos3 protein, rat); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (Ptgs2 protein, rat); EC 1.15.1.1 (Sod1 protein, rat); EC 1.15.1.1 (Superoxide Dismutase-1); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidase 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE


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[PMID]:28684629
[Au] Autor:Thompson JA; Larion S; Mintz JD; Belin de Chantemèle EJ; Fulton DJ; Stepp DW
[Ad] Endereço:From the Vascular Biology Center (J.A.T., S.L., J.D.M., E.J.B.d.C., D.J.F., D.W.S.), Department of Physiology (D.W.S), Department of Pharmacology (D.J.F.), and Department of Medicine (S.L., E.J.B.d.C.), Augusta University, GA.
[Ti] Título:Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease.
[So] Source:Circ Res;121(5):502-511, 2017 Aug 18.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase isoforms remains ill defined. OBJECTIVE: Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease. METHODS AND RESULTS: Four genotypes were generated by breeding Nox1 knockout mice with mice: lean (H W ), lean Nox1 knockout (H K ), obese (K W ), and obese KK (K K ). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW ( <0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved ( <0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion. CONCLUSIONS: Nox1 deletion reduces oxidant load and restores microvascular health in mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.
[Mh] Termos MeSH primário: Deleção de Genes
Doenças Metabólicas/genética
Microvasos/fisiologia
Músculo Liso Vascular/fisiologia
NADH NADPH Oxirredutases/deficiência
NADH NADPH Oxirredutases/genética
[Mh] Termos MeSH secundário: Animais
Glicemia/metabolismo
Masculino
Doenças Metabólicas/enzimologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Obesos
NADPH Oxidase 1
Estresse Oxidativo/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NOX1 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.116.309965


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[PMID]:28623179
[Au] Autor:El-Tanbouly DM; Wadie W; Sayed RH
[Ad] Endereço:Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
[Ti] Título:Modulation of TGF-ß/Smad and ERK signaling pathways mediates the anti-fibrotic effect of mirtazapine in mice.
[So] Source:Toxicol Appl Pharmacol;329:224-230, 2017 Aug 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and α alpha smooth muscle actin expression. Moreover, hepatic collagen deposition was markedly decreased in mirtazapine-treated mice as evaluated by Masson's trichrome staining. Mirtazapine provided an antifibrotic environment by decreasing the liver content of transforming growth factor-ß1 (TGF-ß1), and protein kinase C as well as the expression of phosphorylated-Smad3 (p-Smad) and phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2). Additionally, oxidative stress was largely mitigated by mirtazapine as manifested by decreased liver lipid peroxidation and NADPH oxidase 1 along with glutathione replenishment. The current study indicates that mirtazapine suppressed 5-HT-mediated TGF-ß1/Smad3 and ERK1/2 signaling pathways as well as oxidative stress that contribute to the progression of liver fibrosis.
[Mh] Termos MeSH primário: Cirrose Hepática Experimental/prevenção & controle
Fígado/efeitos dos fármacos
Mianserina/análogos & derivados
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
Transdução de Sinais/efeitos dos fármacos
Proteína Smad3/metabolismo
Fator de Crescimento Transformador beta1/metabolismo
[Mh] Termos MeSH secundário: Animais
Antioxidantes/farmacologia
Colágeno/metabolismo
Glutationa/metabolismo
Células Estreladas do Fígado/efeitos dos fármacos
Células Estreladas do Fígado/metabolismo
Células Estreladas do Fígado/patologia
Hipertensão Portal/induzido quimicamente
Hipertensão Portal/metabolismo
Hipertensão Portal/prevenção & controle
Peroxidação de Lipídeos/efeitos dos fármacos
Fígado/metabolismo
Fígado/patologia
Cirrose Hepática Experimental/induzido quimicamente
Cirrose Hepática Experimental/metabolismo
Cirrose Hepática Experimental/patologia
Masculino
Mianserina/farmacologia
Camundongos
NADH NADPH Oxirredutases/metabolismo
NADPH Oxidase 1
Estresse Oxidativo/efeitos dos fármacos
Fosforilação
Proteína Quinase C/metabolismo
Receptor 5-HT2A de Serotonina/efeitos dos fármacos
Receptor 5-HT2A de Serotonina/metabolismo
Serotonina/metabolismo
Tioacetamida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Receptor, Serotonin, 5-HT2A); 0 (Serotonin 5-HT2 Receptor Antagonists); 0 (Smad3 Protein); 0 (Smad3 protein, mouse); 0 (Tgfb1 protein, mouse); 0 (Transforming Growth Factor beta1); 075T165X8M (Thioacetamide); 250PJI13LM (Mianserin); 333DO1RDJY (Serotonin); 9007-34-5 (Collagen); A051Q2099Q (mirtazapine); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidase 1); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.24 (Mapk1 protein, mouse); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3); GAN16C9B8O (Glutathione)
[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]:28600286
[Au] Autor:Lee AJ; Ro M; Cho KJ; Kim JH
[Ad] Endereço:College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea; and.
[Ti] Título:Lipopolysaccharide/TLR4 Stimulates IL-13 Production through a MyD88-BLT2-Linked Cascade in Mast Cells, Potentially Contributing to the Allergic Response.
[So] Source:J Immunol;199(2):409-417, 2017 Jul 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In an experimental asthma model, the activation of TLR4 by bacterial LPS occasionally exacerbates allergic inflammation through the production of Th2 cytokines, and mast cells have been suggested to play a central role in this response. However, the detailed mechanism underlying how LPS/TLR4 stimulates the production of Th2 cytokines, especially IL-13, remains unclear in mast cells. In the current study, we observed that the expression levels of leukotriene B4 receptor-2 (BLT2) and the synthesis of its ligands were highly upregulated in LPS-stimulated bone marrow-derived mast cells and that BLT2 blockade with small interfering RNA or a pharmacological inhibitor completely abolished IL-13 production, suggesting a mediatory role of the BLT2 ligand-BLT2 axis in LPS/TLR4 signaling to IL-13 synthesis in mast cells. Moreover, we demonstrated that MyD88 lies upstream of the BLT2 ligand-BLT2 axis and that this MyD88-BLT2 cascade leads to the generation of reactive oxygen species through NADPH oxidase 1 and the subsequent activation of NF-κB, thereby mediating IL-13 synthesis. Interestingly, we observed that costimulation of LPS/TLR4 and IgE/FcεRI caused greatly enhanced IL-13 synthesis in mast cells, and blockading BLT2 abolished these effects. Similarly, in vivo, the IL-13 level was markedly enhanced by LPS administration in an OVA-induced asthma model, and injecting a BLT2 antagonist beforehand clearly attenuated this increase. Together, our findings suggest that a BLT2-linked cascade plays a pivotal role in LPS/TLR4 signaling for IL-13 synthesis in mast cells, thereby potentially exacerbating allergic response. Our findings may provide insight into the mechanisms underlying how bacterial infection worsens allergic inflammation under certain conditions.
[Mh] Termos MeSH primário: Hipersensibilidade/imunologia
Interleucina-13/biossíntese
Lipopolissacarídeos/imunologia
Mastócitos/imunologia
Fator 88 de Diferenciação Mieloide/metabolismo
Receptores do Leucotrieno B4/metabolismo
Receptor 4 Toll-Like/imunologia
[Mh] Termos MeSH secundário: Animais
Asma/imunologia
Asma/metabolismo
Linhagem Celular Tumoral
Modelos Animais de Doenças
Mastócitos/efeitos dos fármacos
Mastócitos/metabolismo
Camundongos
NADH NADPH Oxirredutases/metabolismo
NADPH Oxidase 1
Espécies Reativas de Oxigênio/metabolismo
Receptores do Leucotrieno B4/deficiência
Receptores do Leucotrieno B4/genética
Transdução de Sinais/imunologia
Receptor 4 Toll-Like/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-13); 0 (Lipopolysaccharides); 0 (Ltb4r2 protein, mouse); 0 (Myd88 protein, mouse); 0 (Myeloid Differentiation Factor 88); 0 (Reactive Oxygen Species); 0 (Receptors, Leukotriene B4); 0 (Toll-Like Receptor 4); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidase 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170611
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1602062


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[PMID]:28534509
[Au] Autor:Kesanakurti D; Maddirela D; Banasavadi-Siddegowda YK; Lai TH; Qamri Z; Jacob NK; Sampath D; Mohanam S; Kaur B; Puduvalli VK
[Ad] Endereço:Division of Neuro-oncology, The Dardinger Center for Neuro-oncology and Neurosciences, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
[Ti] Título:A novel interaction of PAK4 with PPARγ to regulate Nox1 and radiation-induced epithelial-to-mesenchymal transition in glioma.
[So] Source:Oncogene;36(37):5309-5320, 2017 Sep 14.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tumor recurrence in glioblastoma (GBM) is, in part, attributed to increased epithelial-to-mesenchymal transition (EMT) and enhanced tumor cell dissemination in adjacent brain parenchyma after ionizing radiation (IR). EMT is associated with aggressive behavior, increased stem-like characteristics and treatment resistance in malignancies; however, the underlying signaling mechanisms that regulate EMT are poorly understood. We identified grade-dependent p21-activated kinases 4 (PAK4) upregulation in gliomas and further determined its role in mesenchymal transition and radioresistance. IR treatment significantly elevated expression and nuclear localization of PAK4 in correlation with induction of reactive oxygen species (ROS) and mesenchymal transition in GBM cells. Stable PAK4 overexpression promoted mesenchymal transition by elevating EMT marker expression in these cells. Of note, transcription factor-DNA-binding arrays and chromatin immunoprecipitation experiments identified the formation of a novel nuclear PAK4/PPARγ complex which was recruited to the promoter of Nox1, a peroxisome proliferator-activated receptor gamma (PPARγ) target gene. In addition, IR further elevated PAK4/PPARγ complex co-recruitment to Nox1 promoter, and increased Nox1 expression and ROS levels associated with mesenchymal transition in these cells. Conversely, specific PAK4 downregulation decreased PPARγ-mediated Nox1 expression and suppressed EMT in IR-treated cells. In vivo orthotopic tumor experiments showed inhibition of growth and suppression of IR-induced PPARγ and Nox1 expression by PAK4 downregulation in tumors. Our results provide the first evidence of a novel role for PAK4 in IR-induced EMT and suggest potential therapeutic efficacy of targeting PAK4 to overcome radioresistance in gliomas.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/patologia
Transição Epitelial-Mesenquimal/efeitos da radiação
Glioma/patologia
NADPH Oxidases/metabolismo
PPAR gama/metabolismo
Quinases Ativadas por p21/metabolismo
[Mh] Termos MeSH secundário: Animais
Neoplasias Encefálicas/genética
Neoplasias Encefálicas/metabolismo
Feminino
Glioma/genética
Glioma/metabolismo
Seres Humanos
Camundongos
Camundongos Nus
NADPH Oxidase 1
NADPH Oxidases/biossíntese
NADPH Oxidases/genética
PPAR gama/genética
Regiões Promotoras Genéticas
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Transfecção
Quinases Ativadas por p21/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PPAR gamma); 0 (Reactive Oxygen Species); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (NOX1 protein, human); EC 2.7.1.11 (PAK4 protein, human); EC 2.7.11.1 (p21-Activated Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.261


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[PMID]:28522681
[Au] Autor:Ghouleh IA; Sahoo S; Meijles DN; Amaral JH; de Jesus DS; Sembrat J; Rojas M; Goncharov DA; Goncharova EA; Pagano PJ
[Ad] Endereço:Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
[Ti] Título:Endothelial Nox1 oxidase assembly in human pulmonary arterial hypertension; driver of Gremlin1-mediated proliferation.
[So] Source:Clin Sci (Lond);131(15):2019-2035, 2017 Aug 01.
[Is] ISSN:1470-8736
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pulmonary arterial hypertension (PAH) is a rapidly degenerating and devastating disease of increased pulmonary vessel resistance leading to right heart failure. Palliative modalities remain limited despite recent endeavors to investigate the mechanisms underlying increased pulmonary vascular resistance (PVR), i.e. aberrant vascular remodeling and occlusion. However, little is known of the molecular mechanisms responsible for endothelial proliferation, a root cause of PAH-associated vascular remodeling. Lung tissue specimens from PAH and non-PAH patients and hypoxia-exposed human pulmonary artery endothelial cells (ECs) (HPAEC) were assessed for mRNA and protein expression. Reactive oxygen species (ROS) were measured using cytochrome and Amplex Red assays. Findings demonstrate for the first time an up-regulation of NADPH oxidase 1 (Nox1) at the transcript and protein level in resistance vessels from PAH compared with non-PAH patients. This coincided with an increase in ROS production and expression of bone morphogenetic protein (BMP) antagonist Gremlin1 (Grem1). In HPAEC, hypoxia induced Nox1 subunit expression, assembly, and oxidase activity leading to elevation in sonic hedgehog (SHH) and Grem1 expression. Nox1 gene silencing abrogated this cascade. Moreover, loss of either Nox1, SHH or Grem1 attenuated hypoxia-induced EC proliferation. Together, these data support a Nox1-SHH-Grem1 signaling axis in pulmonary vascular endothelium that is likely to contribute to pathophysiological endothelial proliferation and the progression of PAH. These findings also support targeting of Nox1 as a viable therapeutic option to combat PAH.
[Mh] Termos MeSH primário: Proliferação Celular
Hipertensão Pulmonar/enzimologia
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
NADPH Oxidases/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Células Endoteliais/citologia
Células Endoteliais/metabolismo
Feminino
Proteínas Hedgehog/genética
Proteínas Hedgehog/metabolismo
Seres Humanos
Hipertensão Pulmonar/genética
Hipertensão Pulmonar/metabolismo
Hipertensão Pulmonar/fisiopatologia
Peptídeos e Proteínas de Sinalização Intercelular/genética
Masculino
Meia-Idade
NADPH Oxidase 1
NADPH Oxidases/genética
Artéria Pulmonar/enzimologia
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GREM1 protein, human); 0 (Hedgehog Proteins); 0 (Intercellular Signaling Peptides and Proteins); 0 (Reactive Oxygen Species); 0 (SHH protein, human); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (NOX1 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1042/CS20160812



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