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[PMID]:28468971
[Au] Autor:Olson MR; Ulrich BJ; Hummel SA; Khan I; Meuris B; Cherukuri Y; Dent AL; Janga SC; Kaplan MH
[Ad] Endereço:Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; olsonmr@iupui.edu mkaplan2@iupui.edu.
[Ti] Título:Paracrine IL-2 Is Required for Optimal Type 2 Effector Cytokine Production.
[So] Source:J Immunol;198(11):4352-4359, 2017 06 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:IL-2 is a pleiotropic cytokine that promotes the differentiation of Th cell subsets, including Th1, Th2, and Th9 cells, but it impairs the development of Th17 and T follicular helper cells. Although IL-2 is produced by all polarized Th subsets to some level, how it impacts cytokine production when effector T cells are restimulated is unknown. We show in this article that Golgi transport inhibitors (GTIs) blocked IL-9 production. Mechanistically, GTIs blocked secretion of IL-2 that normally feeds back in a paracrine manner to promote STAT5 activation and IL-9 production. IL-2 feedback had no effect on Th1- or Th17-signature cytokine production, but it promoted Th2- and Th9-associated cytokine expression. These data suggest that the use of GTIs results in an underestimation of the presence of type 2 cytokine-secreting cells and highlight IL-2 as a critical component in optimal cytokine production by Th2 and Th9 cells in vitro and in vivo.
[Mh] Termos MeSH primário: Citocinas/biossíntese
Interleucina-2/metabolismo
Interleucina-9/biossíntese
Comunicação Parácrina
Células Th2/imunologia
[Mh] Termos MeSH secundário: Animais
Brefeldina A/farmacologia
Diferenciação Celular
Citocinas/imunologia
Interleucina-2/secreção
Interleucina-9/antagonistas & inibidores
Interleucina-9/imunologia
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos C57BL
Monensin/farmacologia
Inibidores da Síntese de Proteínas/farmacologia
Ionóforos de Próton/farmacologia
Fator de Transcrição STAT5/metabolismo
Células Th1/imunologia
Células Th17/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytokines); 0 (Interleukin-2); 0 (Interleukin-9); 0 (Protein Synthesis Inhibitors); 0 (Proton Ionophores); 0 (STAT5 Transcription Factor); 20350-15-6 (Brefeldin A); 906O0YJ6ZP (Monensin)
[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.1601792


  2 / 2424 MEDLINE  
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[PMID]:29107113
[Au] Autor:Guo J; Yang Z; Yang X; Li T; Liu M; Tang H
[Ad] Endereço:Tianjin Life Science Research Center, Department of Pathogen, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Clinical Laboratory of Guangdong Women and Children Hospital, Guangzhou, China.
[Ti] Título:miR-346 functions as a pro-survival factor under ER stress by activating mitophagy.
[So] Source:Cancer Lett;413:69-81, 2018 Jan 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which attempts to restore normal function of the ER. Both autophagy and miRNAs have been reported to participate in the process of ER stress, but the relationship between these two factors is still obscure. In this study, we demonstrated that miR-346, which was induced under ER stress, modulated autophagic flux in HeLa cells. By regulating the process of autophagy, miR-346 reduced the ROS level in the cells, thus protecting them from death following ER stress. Furthermore, we demonstrated that GSK3B was the target of miR-346 and participated in ER stress-related autophagy. miR-346 activated autophagy by interrupting the association between BCL2 and BECN1 in a GSK3B-dependent manner. Our findings shed new light on the role of miRNAs during ER stress and suggest a new mechanism for the induction of autophagy under ER stress.
[Mh] Termos MeSH primário: Autofagia
Estresse do Retículo Endoplasmático
Retículo Endoplasmático/metabolismo
MicroRNAs/metabolismo
Mitocôndrias/metabolismo
Degradação Mitocondrial
Neoplasias do Colo do Útero/metabolismo
[Mh] Termos MeSH secundário: Autofagia/efeitos dos fármacos
Beclina-1/metabolismo
Brefeldina A/farmacologia
Morte Celular
Relação Dose-Resposta a Droga
Retículo Endoplasmático/efeitos dos fármacos
Retículo Endoplasmático/patologia
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Feminino
Glicogênio Sintase Quinase 3 beta/metabolismo
Células HeLa
Seres Humanos
MicroRNAs/genética
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/patologia
Degradação Mitocondrial/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Fatores de Tempo
Ubiquitinação
Neoplasias do Colo do Útero/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2 protein, human); 0 (BECN1 protein, human); 0 (Beclin-1); 0 (MIRN346 microRNA, human); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Reactive Oxygen Species); 20350-15-6 (Brefeldin A); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171107
[St] Status:MEDLINE


  3 / 2424 MEDLINE  
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[PMID]:28462831
[Au] Autor:Huang H; Liu T; Guo J; Yu L; Wu X; He Y; Li D; Liu J; Zhang K; Zheng X; Goodin S
[Ad] Endereço:Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou 510006, China. Electronic address: hrhuang@gdut.edu.cn.
[Ti] Título:Brefeldin A enhances docetaxel-induced growth inhibition and apoptosis in prostate cancer cells in monolayer and 3D cultures.
[So] Source:Bioorg Med Chem Lett;27(11):2286-2291, 2017 06 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Docetaxel is a commonly used chemotherapeutic drug for patients with late stage prostate cancer. However, serious side effect and drug resistance limit its clinical success. Brefeldin A is a 16-membered macrolide antibiotic from mangrove-derived Fungus Aspergillus sp. (9Hu), which exhibited potent cytotoxicity against human cancer cells. In the present study, we determined the effect of brefeldin A on docetaxel-induced growth inhibition and apoptosis in human prostate cancer PC-3 cells. Brefeldin A in combination with docetaxel inhibited the growth of PC-3 cells in monolayer and in three dimensional cultures. The combination also potently stimulated apoptosis in PC-3 cells as determined by propidium iodide staining and morphological assessment. Mechanistic studies showed that growth inhibition and apoptosis in PC-3 cells treated with brefeldin A and docetaxel were associated with decrease in the level of Bcl-2. The present study indicates that combined brefeldin A with docetaxel may represent a novel approach for improving the efficacy of docetaxel, and Bcl-2 may serve as a target for brefeldin A to enhance the effects of docetaxel chemotherapy.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Brefeldina A/farmacologia
Proliferação Celular/efeitos dos fármacos
Neoplasias da Próstata/patologia
Taxoides/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Taxoids); 15H5577CQD (docetaxel); 20350-15-6 (Brefeldin A)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  4 / 2424 MEDLINE  
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[PMID]:28962860
[Au] Autor:Zhang N; Zhang L
[Ad] Endereço:MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100176, China.
[Ti] Título:Key components of COPI and COPII machineries are required for chikungunya virus replication.
[So] Source:Biochem Biophys Res Commun;493(3):1190-1196, 2017 Nov 25.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The infection of CHIKV is associated with cellular membranes; however whether early secretory pathways are involved in CHIKV replication remains unclear. In the present study, we have provided initial evidences that CHIKV requires both COPI and COPII for its replication. Small interfering RNAs against COPI components, including coatomer, ARFs or GBF1, suppress CHIKV replication. Moreover, CHIKV infection is abolished by the presence of ARF1 inhibitor brefeldin A or GBF1 inhibitor golgicide A. In addition, perturbation of COPII by silencing key components of COPII pathways leads to a reduction in CHIKV replication. Collectively, these observations demonstrate the importance of functional secretory pathways in the infectivity of CHIKV.
[Mh] Termos MeSH primário: Vírus Chikungunya/fisiologia
Complexo I de Proteína do Envoltório/metabolismo
Proteínas Virais/metabolismo
Replicação Viral/fisiologia
[Mh] Termos MeSH secundário: Fator 1 de Ribosilação do ADP/genética
Fator 1 de Ribosilação do ADP/metabolismo
Brefeldina A/farmacologia
Vírus Chikungunya/patogenicidade
Complexo I de Proteína do Envoltório/genética
Fatores de Troca do Nucleotídeo Guanina/genética
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Células HeLa
Seres Humanos
Piridinas/farmacologia
Quinolinas/farmacologia
RNA Interferente Pequeno
Proteínas Virais/genética
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Coat Protein Complex I); 0 (Guanine Nucleotide Exchange Factors); 0 (Pyridines); 0 (Quinolines); 0 (RNA, Small Interfering); 0 (Viral Proteins); 0 (golgicide A); 20350-15-6 (Brefeldin A); EC 3.6.5.2 (ADP-Ribosylation Factor 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171001
[St] Status:MEDLINE


  5 / 2424 MEDLINE  
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[PMID]:28858527
[Au] Autor:Benabdi S; Peurois F; Nawrotek A; Chikireddy J; Cañeque T; Yamori T; Shiina I; Ohashi Y; Dan S; Rodriguez R; Cherfils J; Zeghouf M
[Ad] Endereço:Laboratoire de Biologie et Pharmacologie Appliquée CNRS, Ecole Normale Supérieure Paris-Saclay , 61 avenue du président Wilson, 94235 Cachan, France.
[Ti] Título:Family-wide Analysis of the Inhibition of Arf Guanine Nucleotide Exchange Factors with Small Molecules: Evidence of Unique Inhibitory Profiles.
[So] Source:Biochemistry;56(38):5125-5133, 2017 Sep 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arf GTPases and their guanine nucleotide exchange factors (ArfGEFs) are major regulators of membrane traffic and organelle structure in cells. They are associated with a variety of diseases and are thus attractive therapeutic targets for inhibition by small molecules. Several inhibitors of unrelated chemical structures have been discovered, which have shown their potential in dissecting molecular pathways and blocking disease-related functions. However, their specificity across the ArfGEF family has remained elusive. Importantly, inhibitory responses in the context of membranes, which are critical determinants of Arf and ArfGEF cellular functions, have not been investigated. Here, we compare the efficiency and specificity of four structurally distinct ArfGEF inhibitors, Brefeldin A, SecinH3, M-COPA, and NAV-2729, toward six ArfGEFs (human ARNO, EFA6, BIG1, and BRAG2 and Legionella and Rickettsia RalF). Inhibition was assessed by fluorescence kinetics using pure proteins, and its modulation by membranes was determined with lipidated GTPases in the presence of liposomes. Our analysis shows that despite the intra-ArfGEF family resemblance, each inhibitor has a specific inhibitory profile. Notably, M-COPA is a potent pan-ArfGEF inhibitor, and NAV-2729 inhibits all GEFs, the strongest effects being against BRAG2 and Arf1. Furthermore, the presence of the membrane-binding domain in Legionella RalF reveals a strong inhibitory effect of BFA that is not measured on its GEF domain alone. This study demonstrates the value of family-wide assays with incorporation of membranes, and it should enable accurate dissection of Arf pathways by these inhibitors to best guide their use and development as therapeutic agents.
[Mh] Termos MeSH primário: Brefeldina A/farmacologia
Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores
Naftóis/farmacologia
Pirazóis/farmacologia
Piridinas/farmacologia
Pirimidinonas/farmacologia
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Fatores de Ribosilação do ADP/antagonistas & inibidores
Fatores de Ribosilação do ADP/genética
Fatores de Ribosilação do ADP/metabolismo
Membrana Celular
Fluorescência
Proteínas Ativadoras de GTPase/antagonistas & inibidores
Fatores de Troca do Nucleotídeo Guanina/genética
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Seres Humanos
Lipossomos/química
Soluções
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GTPase-Activating Proteins); 0 (Guanine Nucleotide Exchange Factors); 0 (IQSEC1 protein, human); 0 (Liposomes); 0 (N-(pyridine-3-ylmethyl)-5-(7-hydroxy-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-yl)-2-methylpenta-2,4-dienamide); 0 (NAV-2729); 0 (Naphthols); 0 (Pyrazoles); 0 (Pyridines); 0 (Pyrimidinones); 0 (RalF protein, Legionella pneumophila); 0 (SecinH3); 0 (Solutions); 0 (Triazoles); 0 (cytohesin-2); 20350-15-6 (Brefeldin A); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ADP-ribosylation factor 6)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00706


  6 / 2424 MEDLINE  
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[PMID]:28822840
[Au] Autor:Chakraborti S; Sarkar J; Chowdhury A; Chakraborti T
[Ad] Endereço:Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India. Electronic address: sajal_chakraborti@yahoo.com.
[Ti] Título:Role of ADP ribosylation factor6- Cytohesin1-PhospholipaseD signaling axis in U46619 induced activation of NADPH oxidase in pulmonary artery smooth muscle cell membrane.
[So] Source:Arch Biochem Biophys;633:1-14, 2017 Nov 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Treatment of human pulmonary artery smooth muscle cells (HPASMCs) with the thromboxane A2 receptor antagonist, SQ29548 inhibited U46619 stimulation of phospholipase D (PLD) and NADPH oxidase activities in the cell membrane. Pretreatment with apocynin inhibited U46619 induced increase in NADPH oxidase activity. The cell membrane contains predominantly PLD2 along with PLD1 isoforms of PLD. Pretreatment with pharmacological and genetic inhibitors of PLD2, but not PLD1, attenuated U46619 stimulation of NADPH oxidase activity. U46619 stimulation of PLD and NADPH oxidase activities were insensitive to BFA and Clostridium botulinum C3 toxin; however, pretreatment with secinH3 inhibited U46619 induced increase in PLD and NADPH oxidase activities suggesting a major role of cytohesin in U46619-induced increase in PLD and NADPH oxidase activities. Arf-1, Arf-6, cytohesin-1 and cytohesin-2 were observed in the cytosolic fraction, but only Arf-6 and cytohesin-1 were translocated to the cell membrane upon treatment with U46619. Coimmunoprecipitation study showed association of Arf-6 with cytohesin-1 in the cell membrane fraction. In vitro binding of GTPγS with Arf-6 required the presence of cytohesin-1 and that occurs in BFA insensitive manner. Overall, BFA insensitive Arf6-cytohesin1 signaling axis plays a pivotal role in U46619-mediated activation of PLD leading to stimulation of NADPH oxidase activity in HPASMCs.
[Mh] Termos MeSH primário: Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia
Fatores de Ribosilação do ADP/genética
Fatores de Troca do Nucleotídeo Guanina/genética
NADPH Oxidases/genética
Fosfolipase D/genética
Vasoconstritores/farmacologia
[Mh] Termos MeSH secundário: ADP Ribose Transferases/farmacologia
Fatores de Ribosilação do ADP/metabolismo
Acetofenonas/farmacologia
Antioxidantes/farmacologia
Toxinas Botulínicas/farmacologia
Brefeldina A/farmacologia
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Proteínas Ativadoras de GTPase/antagonistas & inibidores
Proteínas Ativadoras de GTPase/genética
Proteínas Ativadoras de GTPase/metabolismo
Regulação da Expressão Gênica
Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia
Seres Humanos
Hidrazinas/farmacologia
Miócitos de Músculo Liso/citologia
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
NADPH Oxidases/metabolismo
Fosfolipase D/antagonistas & inibidores
Fosfolipase D/metabolismo
Cultura Primária de Células
Inibidores da Síntese de Proteínas/farmacologia
Artéria Pulmonar/citologia
Artéria Pulmonar/efeitos dos fármacos
Artéria Pulmonar/metabolismo
Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores
Receptores de Tromboxano A2 e Prostaglandina H2/genética
Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo
Transdução de Sinais
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetophenones); 0 (Antioxidants); 0 (GTPase-Activating Proteins); 0 (Guanine Nucleotide Exchange Factors); 0 (Hydrazines); 0 (Protein Synthesis Inhibitors); 0 (Receptors, Thromboxane A2, Prostaglandin H2); 0 (SecinH3); 0 (Triazoles); 0 (Vasoconstrictor Agents); 0 (cytohesin-1); 0 (cytohesin-2); 20350-15-6 (Brefeldin A); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); 76898-47-0 (15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid); 98299-61-7 (SQ 29548); B6J7B9UDTR (acetovanillone); EC 1.6.3.- (NADPH Oxidases); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.- (exoenzyme C3, Clostridium botulinum); EC 3.1.4.- (phospholipase D2); EC 3.1.4.4 (Phospholipase D); EC 3.1.4.4 (phospholipase D1); EC 3.4.24.69 (Botulinum Toxins); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ADP-ribosylation factor 6)
[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:170821
[St] Status:MEDLINE


  7 / 2424 MEDLINE  
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[PMID]:28787571
[Au] Autor:Bartolowits MD; Brown W; Ali R; Pedley AM; Chen Q; Harvey KE; Wendt MK; Davisson VJ
[Ad] Endereço:Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
[Ti] Título:Selective Inhibition of STAT3 Phosphorylation Using a Nuclear-Targeted Kinase Inhibitor.
[So] Source:ACS Chem Biol;12(9):2371-2378, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The discovery of compounds that selectively modulate signaling and effector proteins downstream of EGFR could have important implications for understanding specific roles for pathway activation. A complicating factor for receptor tyrosine kinases is their capacity to be translocated to the nucleus upon ligand engagement. Once localized in subcellular compartments like the nucleus, the roles for EGFR take on additional features, many of which are still being revealed. Additionally, nuclear localization of EGFR has been implicated in downstream events that have significance for therapy resistance and disease progression. The challenges to addressing the differential roles for EGFR in the nucleus motivated experimental approaches that can selectively modulate its subcellular function. By adding modifications to the established EGFR kinase inhibitor gefitinib, an approach to small molecule conjugates with a unique nuclear-targeting peptoid sequence was tested in both human and murine breast tumor cell models for their capacity to inhibit EGF-stimulated activation of ERK1/2 and STAT3. While gefitinib alone inhibits both of these downstream effectors, data acquired here indicate that compartmentalization of the gefitinib conjugates allows for pathway specific inhibition of STAT3 while not affecting ERK1/2 signaling. The inhibitor conjugates offered a more direct route to evaluate the role of EGF-stimulated epithelial-to-mesenchymal transition in these breast cancer cell models. These conjugates revealed that STAT3 activation is not involved in EGF-induced EMT, and instead utilization of the cytoplasmic MAP kinase signaling pathway is critical to this process. This is the first example of a conjugate kinase inhibitor capable of partitioning to the nucleus and offers a new approach to enhancing kinase inhibitor specificity.
[Mh] Termos MeSH primário: Descoberta de Drogas
Fosforilação/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Fator de Transcrição STAT3/antagonistas & inibidores
[Mh] Termos MeSH secundário: Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/metabolismo
Brefeldina A/farmacologia
Linhagem Celular Tumoral
Sistemas de Liberação de Medicamentos
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Feminino
Seres Humanos
Peptoides/administração & dosagem
Peptoides/química
Peptoides/farmacologia
Inibidores de Proteínas Quinases/administração & dosagem
Inibidores de Proteínas Quinases/química
Inibidores da Síntese de Proteínas/farmacologia
Receptor do Fator de Crescimento Epidérmico/metabolismo
Fator de Transcrição STAT3/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptoids); 0 (Protein Kinase Inhibitors); 0 (Protein Synthesis Inhibitors); 0 (STAT3 Transcription Factor); 20350-15-6 (Brefeldin A); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00341


  8 / 2424 MEDLINE  
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[PMID]:28755500
[Au] Autor:Yamaguchi K; Zhu C; Ohsugi T; Yamaguchi Y; Ikenoue T; Furukawa Y
[Ad] Endereço:Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
[Ti] Título:Bidirectional reporter assay using HAL promoter and TOPFLASH improves specificity in high-throughput screening of Wnt inhibitors.
[So] Source:Biotechnol Bioeng;114(12):2868-2882, 2017 Dec.
[Is] ISSN:1097-0290
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Constitutive activation of Wnt signaling plays an important role in colorectal and liver tumorigenesis. Cell-based assays using synthetic TCF/LEF (T-cell factor/lymphoid enhancer factor) reporters, as readouts of ß-catenin/TCF-dependent transcriptional activity, have contributed greatly to the discovery of small molecules that modulate Wnt signaling. In the present study, we report a novel screening method, called a bidirectional dual reporter assay. Integrated transcriptome analysis identified a histidine ammonia-lyase gene (HAL) that was negatively regulated by ß-catenin/TCF-dependent transcriptional activity. We leveraged a promoter region of the HAL gene as another transcriptional readout of Wnt signaling. Cells stably expressing both an optimized HAL reporter and the TCF/LEF reporter enabled bidirectional reporter activities in response to Wnt signaling. Increased HAL reporter activity and decreased TCF/LEF reporter activity were observed simultaneously in the cells when ß-catenin/TCF7L2 was inhibited. Notably, this method could decrease the number of false positives observed when screening an inhibitor library compared with the conventional TCF/LEF assay. We found that Brefeldin A, a disruptor of the Golgi apparatus, inhibited the Wnt/ß-catenin signaling pathway. The utility of our system could be expanded to examine other disease-associated pathways beyond the Wnt/ß-catenin signaling pathway.
[Mh] Termos MeSH primário: Brefeldina A/administração & dosagem
Genes Reporter/genética
Ensaios de Triagem em Larga Escala/métodos
Histidina Amônia-Liase/genética
Regiões Promotoras Genéticas/genética
Proteínas Wnt/antagonistas & inibidores
Via de Sinalização Wnt/efeitos dos fármacos
[Mh] Termos MeSH secundário: Bioensaio
Desenho de Drogas
Avaliação Pré-Clínica de Medicamentos/métodos
Proteínas Wnt/genética
Via de Sinalização Wnt/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Wnt Proteins); 20350-15-6 (Brefeldin A); EC 4.3.1.3 (Histidine Ammonia-Lyase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170730
[St] Status:MEDLINE
[do] DOI:10.1002/bit.26394


  9 / 2424 MEDLINE  
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[PMID]:28549691
[Au] Autor:Kim BY; Son Y; Choi J; Eo SK; Park YC; Kim K
[Ad] Endereço:Department of Pharmacology, Pusan National University-School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea.
[Ti] Título:27-Hydroxycholesterol upregulates the production of heat shock protein 60 of monocytic cells.
[So] Source:J Steroid Biochem Mol Biol;172:29-35, 2017 Sep.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Investigating differentially expressed proteins in a milieu rich in cholesterol oxidation products, we found via mass spectrometry-based proteomics that surface levels of heat shock protein 60 (HSP60) were upregulated on monocytic cells in the presence of 27-hydroxycholesterol (27OHChol). The elevated levels of cytoplasmic membrane HSP60 were verified via Western blot analysis and visualized by confocal microscopy. Treatment with 27OHChol also resulted in increased levels of cellular HSP60 without altering its transcription. Cholesterol, however, did not affect cell-surface levels and cellular amount of HSP60. GSK 2033, an LXR antagonist, inhibited expression of live X receptor α, but not of HSP60, induced by 27OHChol. Treatment with 27OHChol also resulted in increased release of HSP60 from monocytic cells, but the release was significantly reduced by inhibitors of endoplasmic reticulum-Golgi protein trafficking, brefeldin A and monensin. Results of the current study indicate that 27OHChol upregulates not only cell-surface and cellular levels of HSP60 but also its release from monocytic cells, thereby contributing to activation of the immune system.
[Mh] Termos MeSH primário: Chaperonina 60/genética
Hidroxicolesteróis/farmacocinética
Proteínas Mitocondriais/genética
Monócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Brefeldina A/farmacologia
Linhagem Celular
Membrana Celular/efeitos dos fármacos
Membrana Celular/imunologia
Membrana Celular/metabolismo
Chaperonina 60/agonistas
Chaperonina 60/metabolismo
Retículo Endoplasmático/efeitos dos fármacos
Retículo Endoplasmático/imunologia
Retículo Endoplasmático/metabolismo
Regulação da Expressão Gênica
Complexo de Golgi/efeitos dos fármacos
Complexo de Golgi/imunologia
Complexo de Golgi/metabolismo
Seres Humanos
Hidroxicolesteróis/metabolismo
Imunidade Celular
Receptores X do Fígado/antagonistas & inibidores
Receptores X do Fígado/genética
Receptores X do Fígado/metabolismo
Proteínas Mitocondriais/agonistas
Proteínas Mitocondriais/metabolismo
Monensin/farmacologia
Monócitos/citologia
Monócitos/imunologia
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
Sulfonamidas/farmacologia
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2,4,6-trimethyl-N-((3'-(methylsulfonyl)-4-biphenylyl)methyl)-N-((5-(trifluoromethyl)-2-furanyl)methyl)benzenesulfonamide); 0 (Chaperonin 60); 0 (HSPD1 protein, human); 0 (Hydroxycholesterols); 0 (Liver X Receptors); 0 (Mitochondrial Proteins); 0 (Sulfonamides); 20350-15-6 (Brefeldin A); 6T2NA6P5SQ (27-hydroxycholesterol); 906O0YJ6ZP (Monensin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE


  10 / 2424 MEDLINE  
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[PMID]:28494251
[Au] Autor:Tian K; Xu F; Gao X; Han T; Li J; Pan H; Zang L; Li D; Li Z; Uchita T; Gao M; Hua H
[Ad] Endereço:Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
[Ti] Título:Nitric oxide-releasing derivatives of brefeldin A as potent and highly selective anticancer agents.
[So] Source:Eur J Med Chem;136:131-143, 2017 Aug 18.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of NO-donating mono- or diester derivatives of brefeldin A were designed, synthesized and biologically evaluated. Some derivatives exhibited potent antiproliferative activity with low IC values. The most potent NO-donating hybrid 13b exhibited stronger cytotoxicity against human prostate cancer PC-3 cells, human colon carcinoma HT-29 cells and human liver cancer HepG-2 cells than BFA with IC values of 25 nM, 160 nM and 180 nM, respectively. More importantly, compound 13b showed good selectivity between human normal and tumor liver cells with selectivity index of 33. Additionally, 13b released higher levels of NO in HepG-2 cells than L-02 cells. Further mechanism concerning cellular apoptosis showed that 13b induced apoptosis and S phase cell cycle arrest in HepG-2 cells. Incubation with 13b increased the number of HepG-2 cells with collapsed mitochondrial membrane at low concentrations in dose-dependent manner. In addition, by using the Human Apoptosis Protein Array kit, several apoptosis-related proteins, including HO-1, HO-2 and survivin, were found to be markedly downregulated by 13b in HepG-2 cells. Furthermore, in western blot assay, 13b increased the expression of Bax, Cyt c and caspase 3, and reduced the relative levels of Bcl-2, Bcl-xl and pro-caspase 3 in HepG-2 cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Brefeldina A/farmacologia
Óxido Nítrico/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Brefeldina A/síntese química
Brefeldina A/química
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Células Hep G2
Seres Humanos
Estrutura Molecular
Óxido Nítrico/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 20350-15-6 (Brefeldin A); 31C4KY9ESH (Nitric Oxide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE



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