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Pesquisa : D03.633.100.612 [Categoria DeCS]
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  1 / 2725 MEDLINE  
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[PMID]:29318287
[Au] Autor:Abu-Melha S
[Ti] Título:Synthesis and Biological Evaluation of Some Novel 1,8-Naphthyridine Derivatives.
[So] Source:Acta Chim Slov;64(4):919-930, 2017 Dec.
[Is] ISSN:1318-0207
[Cp] País de publicação:Slovenia
[La] Idioma:eng
[Ab] Resumo:A series of substituted 1,8-naphthyridine derivatives was synthesized to be used as cytotoxic and antioxidant agents by applying 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbohydrazide (1) as the starting material. Compound 1 was reacted with different reagents to afford the corresponding 3-heterarylcarbonyl-1,8-naphthyridine derivatives 3-19 which were tested for their in vitro cytotoxicity against Ehrlich Ascites Carcinoma, and antioxidant activity. Compound 15 showed the best cytotoxicity and antioxidant activity.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Antioxidantes/síntese química
Naftiridinas/síntese química
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Antioxidantes/farmacologia
Carcinoma de Ehrlich/tratamento farmacológico
Naftiridinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Antioxidants); 0 (Naphthyridines)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


  2 / 2725 MEDLINE  
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[PMID]:29329306
[Au] Autor:Mason JS; Wileman T; Chapman T
[Ad] Endereço:School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
[Ti] Título:Lifespan extension without fertility reduction following dietary addition of the autophagy activator Torin1 in Drosophila melanogaster.
[So] Source:PLoS One;13(1):e0190105, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan. Ideally, such manipulations should be specific and minimise off-target effects, and it is important to discover additional methods for 'clean' lifespan manipulation. Here we report an initial study into the effect of up-regulating autophagy on lifespan and fertility in Drosophila melanogaster by dietary addition of Torin1. Activation of autophagy using this selective TOR inhibitor was associated with significantly increased lifespan in both sexes. Torin1 induced a dose-dependent increase in lifespan in once-mated females. There was no evidence of a trade-off between longevity and fecundity or fertility. Torin1-fed females exhibited significantly elevated fecundity, but also elevated egg infertility, resulting in no net change in overall fertility. This supports the idea that lifespan can be extended without trade-offs in fertility and suggest that Torin1 may be a useful tool with which to pursue anti-ageing research.
[Mh] Termos MeSH primário: Autofagia
Drosophila melanogaster/fisiologia
Fertilidade
Naftiridinas/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one); 0 (Naphthyridines)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180210
[Lr] Data última revisão:
180210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190105


  3 / 2725 MEDLINE  
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[PMID]:28468969
[Au] Autor:Gibson SA; Yang W; Yan Z; Liu Y; Rowse AL; Weinmann AS; Qin H; Benveniste EN
[Ad] Endereço:Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294; and.
[Ti] Título:Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation.
[So] Source:J Immunol;198(11):4244-4254, 2017 06 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4 T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4 T cell activation. Targeting the catalytic activity of CK2 using the next-generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3 regulatory T cells (Tregs). These findings were associated with suppression of PI3K/Akt/mTOR activation and STAT3 phosphorylation upon CX-4945 treatment. Furthermore, we demonstrate that CX-4945 treatment inhibits the maturation of Th17 cells into inflammatory IFN-γ-coproducing effector cells. The Th17/Treg axis and maturation of Th17 cells are major contributing factors to the pathogenesis of many autoimmune disorders, including multiple sclerosis. Using a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrate that in vivo administration of CX-4945 targets Akt/mTOR signaling in CD4 T cells and the Th17/Treg axis throughout disease. Importantly, CX-4945 treatment after disease initiation significantly reduced disease severity, which was associated with a significant decrease in the frequency of pathogenic IFN-γ and GM-CSF Th17 cells in the CNS. Our data implicate CK2 as a regulator of the Th17/Treg axis and Th17 cell maturation and suggest that CK2 could be targeted for the treatment of Th17 cell-driven autoimmune disorders.
[Mh] Termos MeSH primário: Caseína Quinase II/metabolismo
Linfócitos T Reguladores/imunologia
Células Th17/imunologia
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/metabolismo
Caseína Quinase II/antagonistas & inibidores
Caseína Quinase II/genética
Diferenciação Celular
Encefalomielite Autoimune Experimental/imunologia
Regulação da Expressão Gênica
Seres Humanos
Interferon gama/biossíntese
Interferon gama/imunologia
Ativação Linfocitária
Camundongos
Esclerose Múltipla/imunologia
Esclerose Múltipla/fisiopatologia
Naftiridinas/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais
Linfócitos T Reguladores/fisiologia
Células Th1/imunologia
Células Th17/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid); 0 (Naphthyridines); 0 (STAT3 Transcription Factor); 0 (Stat3 protein, mouse); 82115-62-6 (Interferon-gamma); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (Pik3cd protein, mouse); EC 2.7.11.1 (Casein Kinase II); EC 2.7.11.1 (casein kinase 2, alpha, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601912


  4 / 2725 MEDLINE  
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[PMID]:29197731
[Au] Autor:Tang Q; Duan Y; Wang L; Wang M; Ouyang Y; Wang C; Mei H; Tang S; Xiong Y; Zheng P; Gong P; Zhu W
[Ad] Endereço:Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pha
[Ti] Título:Synthesis and antiproliferative activity of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety.
[So] Source:Eur J Med Chem;143:266-275, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety were synthesized, and evaluated for their antiproliferative activity against four cancer cell lines (HT-29, A549, H460, and U87MG) and six tyrosine kinases (c-Met, Flt-3, PDGFR-ß, VEGFR-2, EGFR, and c-Kit) inhibitory activities in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 32 showing Flt-3/c-Met IC value of 1.16/1.92 nM. Structure-activity relationship studies indicated that the hydrogen atom served as R group was benefited to the potency, and mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring (such as R = 4-F) showed a higher preference for antiproliferative activity.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Naftiridinas/farmacologia
Piridinas/farmacologia
Pirróis/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Naftiridinas/química
Piridinas/síntese química
Piridinas/química
Pirróis/síntese química
Pirróis/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1,8-naphthyridin-2(1H)-one); 0 (Antineoplastic Agents); 0 (Naphthyridines); 0 (Pyridines); 0 (Pyrroles); QX4465NR9T (pyrrolo(2, 3-b)pyridine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE


  5 / 2725 MEDLINE  
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[PMID]:28926607
[Au] Autor:Dutzmann J; Musmann RJ; Haertlé M; Daniel JM; Sonnenschein K; Schäfer A; Kolkhof P; Bauersachs J; Sedding DG
[Ad] Endereço:Dept. of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
[Ti] Título:The novel mineralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury.
[So] Source:PLoS One;12(9):e0184888, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive. PURPOSE: The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo. METHODS AND RESULTS: In vitro, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay. In vivo, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury. CONCLUSION: Finerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling.
[Mh] Termos MeSH primário: Lesões das Artérias Carótidas/tratamento farmacológico
Antagonistas de Receptores de Mineralocorticoides/uso terapêutico
Naftiridinas/uso terapêutico
[Mh] Termos MeSH secundário: Aldosterona/toxicidade
Animais
Apoptose/efeitos dos fármacos
Artérias Carótidas/patologia
Lesões das Artérias Carótidas/etiologia
Lesões das Artérias Carótidas/patologia
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Modelos Animais de Doenças
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Leucócitos/citologia
Leucócitos/imunologia
Leucócitos/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Antagonistas de Receptores de Mineralocorticoides/farmacologia
Músculo Liso Vascular/citologia
Músculo Liso Vascular/metabolismo
Naftiridinas/farmacologia
Neointima/patologia
Neointima/prevenção & controle
Neovascularização Fisiológica/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BAY 94-8862); 0 (Mineralocorticoid Receptor Antagonists); 0 (Naphthyridines); 4964P6T9RB (Aldosterone)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184888


  6 / 2725 MEDLINE  
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[PMID]:28918901
[Au] Autor:Nofal M; Zhang K; Han S; Rabinowitz JD
[Ad] Endereço:Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
[Ti] Título:mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein.
[So] Source:Mol Cell;67(6):936-946.e5, 2017 Sep 21.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Scavenging of extracellular protein via macropinocytosis is an alternative to monomeric amino acid uptake. In pancreatic cancer, macropinocytosis is driven by oncogenic Ras signaling and contributes substantially to amino acid supply. While Ras signaling promotes scavenging, mTOR signaling suppresses it. Here, we present an integrated experimental-computational method that enables quantitative comparison of protein scavenging rates across cell lines and conditions. Using it, we find that, independently of mTORC1, amino acid scarcity induces protein scavenging and that under such conditions the impact of mTOR signaling on protein scavenging rate is minimal. Nevertheless, mTOR inhibition promotes growth of cells reliant on eating extracellular protein. This growth enhancement depends on mTORC1's canonical function in controlling translation rate: mTOR inhibition slows translation, thereby matching protein synthesis to the limited amino acid supply. Thus, paradoxically, in amino acid-poor conditions the pro-anabolic effects of mTORC1 are functionally opposed to growth.
[Mh] Termos MeSH primário: Aminoácidos/metabolismo
Metabolismo Energético/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
Naftiridinas/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Proteínas/metabolismo
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Mh] Termos MeSH secundário: Aminoácidos/deficiência
Animais
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Simulação por Computador
Fibroblastos/enzimologia
Alvo Mecanístico do Complexo 1 de Rapamicina
Camundongos
Modelos Biológicos
Complexos Multiproteicos/antagonistas & inibidores
Complexos Multiproteicos/metabolismo
Mutação
Pinocitose/efeitos dos fármacos
Proteólise
Proteínas Proto-Oncogênicas p21(ras)/genética
Interferência de RNA
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/metabolismo
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one); 0 (Amino Acids); 0 (Multiprotein Complexes); 0 (Naphthyridines); 0 (Protein Kinase Inhibitors); 0 (Proteins); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 3.6.5.2 (Kras2 protein, mouse); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[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:170919
[St] Status:MEDLINE


  7 / 2725 MEDLINE  
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[PMID]:28873435
[Au] Autor:Lustri AM; Di Matteo S; Fraveto A; Costantini D; Cantafora A; Napoletano C; Bragazzi MC; Giuliante F; De Rose AM; Berloco PB; Grazi GL; Carpino G; Alvaro D
[Ad] Endereço:Medico-surgical Sciences and Biotechnologies, Sapienza University of Rome, RM, ROMA, Italy.
[Ti] Título:TGF-ß signaling is an effective target to impair survival and induce apoptosis of human cholangiocarcinoma cells: A study on human primary cell cultures.
[So] Source:PLoS One;12(9):e0183932, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cholangiocarcinoma (CCA) and its subtypes (mucin- and mixed-CCA) arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the biliary tree. CCA has a high mortality rate owing to its aggressiveness, late diagnosis and high resistance to radiotherapy and chemotherapeutics. We have demonstrated that CCA is enriched for cancer stem cells which express epithelial to mesenchymal transition (EMT) traits, with these features being associated with aggressiveness and drug resistance. TGF-ß signaling is upregulated in CCA and involved in EMT. We have recently established primary cell cultures from human mucin- and mixed-intrahepatic CCA. In human CCA primary cultures with different levels of EMT trait expression, we evaluated the anticancer effects of: (i) CX-4945, a casein kinase-2 (CK2) inhibitor that blocks TGF-ß1-induced EMT; and (ii) LY2157299, a TGF-ß receptor I kinase inhibitor. We tested primary cell lines expressing EMT trait markers (vimentin, N-cadherin and nuclear catenin) but negative for epithelial markers, and cell lines expressing epithelial markers (CK19-positive) in association with EMT traits. Cell viability was evaluated by MTS assays, apoptosis by Annexin V FITC and cell migration by wound-healing assay. RESULTS: at a dose of 10 µM, CX4945 significantly decreased cell viability of primary human cell cultures from both mucin and mixed CCA, whereas in CK19-positive cell cultures, the effect of CX4945 on cell viability required higher concentrations (>30µM). At the same concentrations, CX4945 also induced apoptosis (3- fold increase vs controls) which correlated with the expression level of CK2 in the different CCA cell lines (mucin- and mixed-CCA). Indeed, no apoptotic effects were observed in CK19-positive cells expressing lower CK2 levels. The effects of CX4945 on viability and apoptosis were associated with an increased number of γ-H2ax (biomarker for DNA double-strand breaks) foci, suggesting the active role of CK2 as a repair mechanism in CCAs. LY2157299 failed to influence cell proliferation or apoptosis but significantly inhibited cell migration. At a 50 µM concentration, in fact, LY2157299 significantly impaired (at 24, 48 and 120 hrs) the wound-healing of primary cell cultures from both mucin-and mixed-CCA. In conclusion, we demonstrated that CX4945 and LY2157299 exert relevant but distinct anticancer effects against human CCA cells, with CX4945 acting on cell viability and apoptosis, and LY2157299 impairing cell migration. These results suggest that targeting the TGF-ß signaling with a combination of CX-4945 and LY2157299 could have potential benefits in the treatment of human CCA.
[Mh] Termos MeSH primário: Apoptose
Colangiocarcinoma/metabolismo
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Movimento Celular
Sobrevivência Celular
Colangiocarcinoma/patologia
Resistência a Medicamentos Antineoplásicos
Transição Epitelial-Mesenquimal
Seres Humanos
Naftiridinas/química
Células-Tronco Neoplásicas/citologia
Cultura Primária de Células
Pirazóis/química
Quinolinas/química
Transdução de Sinais
Cicatrização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid); 0 (Naphthyridines); 0 (Pyrazoles); 0 (Quinolines); 0 (Transforming Growth Factor beta); 700874-72-2 (LY-2157299)
[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:170906
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183932


  8 / 2725 MEDLINE  
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[PMID]:28823556
[Au] Autor:Korb E; Herre M; Zucker-Scharff I; Gresack J; Allis CD; Darnell RB
[Ad] Endereço:Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
[Ti] Título:Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition.
[So] Source:Cell;170(6):1209-1223.e20, 2017 Sep 07.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism. FXS results from the loss of function of fragile X mental retardation protein (FMRP), which represses translation of target transcripts. Most of the well-characterized target transcripts of FMRP are synaptic proteins, yet targeting these proteins has not provided effective treatments. We examined a group of FMRP targets that encode transcriptional regulators, particularly chromatin-associated proteins. Loss of FMRP in mice results in widespread changes in chromatin regulation and aberrant gene expression. To determine if targeting epigenetic factors could reverse phenotypes associated with the disorder, we focused on Brd4, a BET protein and chromatin reader targeted by FMRP. Inhibition of Brd4 function alleviated many of the phenotypes associated with FXS. We conclude that loss of FMRP results in significant epigenetic misregulation and that targeting transcription via epigenetic regulators like Brd4 may provide new treatments for FXS.
[Mh] Termos MeSH primário: Azepinas/farmacologia
Proteína do X Frágil de Retardo Mental/metabolismo
Síndrome do Cromossomo X Frágil/tratamento farmacológico
Síndrome do Cromossomo X Frágil/metabolismo
Proteínas Nucleares/antagonistas & inibidores
Proteínas Nucleares/metabolismo
Fatores de Transcrição/antagonistas & inibidores
Fatores de Transcrição/metabolismo
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Epigênese Genética
Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Histonas/metabolismo
Camundongos
Camundongos Knockout
Naftiridinas/farmacologia
Neurônios/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((+)-JQ1 compound); 0 (5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid); 0 (Azepines); 0 (Brd4 protein, mouse); 0 (Fmr1 protein, mouse); 0 (Histones); 0 (Naphthyridines); 0 (Nuclear Proteins); 0 (Transcription Factors); 0 (Triazoles); 139135-51-6 (Fragile X Mental Retardation Protein)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE


  9 / 2725 MEDLINE  
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[PMID]:28821607
[Au] Autor:Tripathi SK; Xu T; Feng Q; Avula B; Shi X; Pan X; Mask MM; Baerson SR; Jacob MR; Ravu RR; Khan SI; Li XC; Khan IA; Clark AM; Agarwal AK
[Ad] Endereço:From the National Center for Natural Products Research.
[Ti] Título:Two plant-derived aporphinoid alkaloids exert their antifungal activity by disrupting mitochondrial iron-sulfur cluster biosynthesis.
[So] Source:J Biol Chem;292(40):16578-16593, 2017 Oct 06.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eupolauridine and liriodenine are plant-derived aporphinoid alkaloids that exhibit potent inhibitory activity against the opportunistic fungal pathogens and However, the molecular mechanism of this antifungal activity is unknown. In this study, we show that eupolauridine 9591 (E9591), a synthetic analog of eupolauridine, and liriodenine methiodide (LMT), a methiodide salt of liriodenine, mediate their antifungal activities by disrupting mitochondrial iron-sulfur (Fe-S) cluster synthesis. Several lines of evidence supported this conclusion. First, both E9591 and LMT elicited a transcriptional response indicative of iron imbalance, causing the induction of genes that are required for iron uptake and for the maintenance of cellular iron homeostasis. Second, a genome-wide fitness profile analysis showed that yeast mutants with deletions in iron homeostasis-related genes were hypersensitive to E9591 and LMT. Third, treatment of wild-type yeast cells with E9591 or LMT generated cellular defects that mimicked deficiencies in mitochondrial Fe-S cluster synthesis including an increase in mitochondrial iron levels, a decrease in the activities of Fe-S cluster enzymes, a decrease in respiratory function, and an increase in oxidative stress. Collectively, our results demonstrate that E9591 and LMT perturb mitochondrial Fe-S cluster biosynthesis; thus, these two compounds target a cellular pathway that is distinct from the pathways commonly targeted by clinically used antifungal drugs. Therefore, the identification of this pathway as a target for antifungal compounds has potential applications in the development of new antifungal therapies.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Aporfinas/farmacologia
Candida albicans
Proteínas Fúngicas
Indenos/farmacologia
Proteínas com Ferro-Enxofre
Proteínas Mitocondriais
Naftiridinas/farmacologia
[Mh] Termos MeSH secundário: Antifúngicos/química
Aporfinas/química
Candida albicans/genética
Candida albicans/crescimento & desenvolvimento
Cryptococcus neoformans/genética
Cryptococcus neoformans/crescimento & desenvolvimento
Proteínas Fúngicas/genética
Proteínas Fúngicas/metabolismo
Estudo de Associação Genômica Ampla
Indenos/química
Proteínas com Ferro-Enxofre/genética
Proteínas com Ferro-Enxofre/metabolismo
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Naftiridinas/química
Estresse Oxidativo/efeitos dos fármacos
Estresse Oxidativo/genética
Consumo de Oxigênio/efeitos dos fármacos
Consumo de Oxigênio/genética
Saccharomyces cerevisiae
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Aporphines); 0 (Fungal Proteins); 0 (Indenes); 0 (Iron-Sulfur Proteins); 0 (Mitochondrial Proteins); 0 (Naphthyridines); 58786-39-3 (eupolauridine); E134R7X4O9 (liriodenine)
[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:170820
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.781773


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[PMID]:28737946
[Au] Autor:Zhao XZ; Smith SJ; Maskell DP; Métifiot M; Pye VE; Fesen K; Marchand C; Pommier Y; Cherepanov P; Hughes SH; Burke TR
[Ti] Título:Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors.
[So] Source:J Med Chem;60(17):7315-7332, 2017 Sep 14.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
[Mh] Termos MeSH primário: Inibidores de Integrase de HIV/química
Inibidores de Integrase de HIV/farmacologia
Integrase de HIV/metabolismo
HIV-1/efeitos dos fármacos
Naftiridinas/química
Naftiridinas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Cristalografia por Raios X
Farmacorresistência Viral
Infecções por HIV/tratamento farmacológico
Infecções por HIV/virologia
Integrase de HIV/química
Integrase de HIV/genética
HIV-1/enzimologia
HIV-1/genética
HIV-1/fisiologia
Seres Humanos
Modelos Moleculares
Mutação
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Integrase Inhibitors); 0 (Naphthyridines); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00596



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