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Pesquisa : A11.284.430.214.190.750.602 [Categoria DeCS]
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[PMID]:28471062
[Au] Autor:Rao AN; Patil A; Brodnik ZD; Qiang L; España RA; Sullivan KA; Black MM; Baas PW
[Ad] Endereço:Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
[Ti] Título:Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons.
[So] Source:Traffic;18(7):433-441, 2017 Jul.
[Is] ISSN:1600-0854
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Many veterans of the 1990-1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure.
[Mh] Termos MeSH primário: Anilidas/farmacologia
Substâncias para a Guerra Química/toxicidade
Ácidos Hidroxâmicos/farmacologia
Isoflurofato/toxicidade
Microtúbulos/efeitos dos fármacos
Neurônios/efeitos dos fármacos
Estresse Fisiológico
[Mh] Termos MeSH secundário: Acetilação
Animais
Transporte Biológico
Células Cultivadas
Corticosterona/farmacologia
Dopamina/secreção
Relação Dose-Resposta a Droga
Seres Humanos
Hidrocortisona/farmacologia
Microtúbulos/metabolismo
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Síndrome do Golfo Pérsico
Ratos
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anilides); 0 (Chemical Warfare Agents); 0 (Hydroxamic Acids); 0 (Tubulin); 02C2G1D30D (tubacin); 12UHW9R67N (Isoflurophate); VTD58H1Z2X (Dopamine); W980KJ009P (Corticosterone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1111/tra.12489


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[PMID]:29442036
[Au] Autor:Pivodová V; Zahler S; Karas D; Valentová K; Ulrichova J
[Ti] Título: study of 2,3-dehydrosilybin and its galloyl esters as potential inhibitors of angiogenesis.
[So] Source:Pharmazie;71(8):478-483, 2016 08 01.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:2,3-Dehydrosilybin exhibits substantial anticancer and antiangiogenic effects, which can be potentially improved by semi-synthetic modification such as esterification with gallic acid. The aim of this study was to examine the potential antiangiogenic effect of 2,3-dehydrosilybin and its galloyl esters (3-O-galloyl-2,3-dehydrosilybin; 7-O-galloyl-2,3-dehydrosilybin; 20-O-galloyl-2,3-dehydrosilybin and 23-O-galloyl-2,3-dehydrosilybin) and to determine which molecular mechanism could be responsible for their activity. The effect on cell proliferation, tube formation, signal transduction pathways (PI3K/Akt and ERK) and the cell cycle was studied in human microvascular endothelial cells (HMEC). The results showed that all compounds decreased the growth of HMEC, but the strongest effect was observed for 20-O-galloyl-2,3-dehydrosilybin at 5 µmol/l. In addition, at 5 and 10 µmol/l, this was the only compound that significantly inhibited HMEC tube formation. Based on an assessment of Akt and ERK1/2 expression, we suggest that 20-O-galloyl-2,3-dehydrosilybin influences the angiogenic process through the Akt pathway.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia
Silimarina/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/síntese química
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Endoteliais/efeitos dos fármacos
Ésteres/síntese química
Ésteres/farmacologia
Ácido Gálico/síntese química
Ácido Gálico/farmacologia
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Microtúbulos/efeitos dos fármacos
Neovascularização Patológica/tratamento farmacológico
Proteína Oncogênica v-akt/efeitos dos fármacos
Fosfatidilinositol 3-Quinases/efeitos dos fármacos
Silimarina/síntese química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Esters); 0 (Silymarin); 4RKY41TBTF (silybin); 632XD903SP (Gallic Acid); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Oncogene Protein v-akt)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6579


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[PMID]:28460485
[Au] Autor:Lv LX; Zhou ZX; Zhou Z; Zhang LJ; Yan R; Zhao Z; Yang LY; Bian XY; Jiang HY; Li YD; Sun YS; Xu QQ; Hu GL; Guan WJ; Li YQ
[Ad] Endereço:Institute of Pharmaceutical Biotechnology and College of Pharmaceutical Sciences, Zhejiang University, 310058 Hangzhou, China.
[Ti] Título:Hispidin induces autophagic and necrotic death in SGC-7901 gastric cancer cells through lysosomal membrane permeabilization by inhibiting tubulin polymerization.
[So] Source:Oncotarget;8(16):26992-27006, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hispidin and its derivatives are widely distributed in edible mushrooms. Hispidin is more cytotoxic to A549, SCL-1, Bel7402 and Capan-1 cancer cells than to MRC5 normal cells; by contrast, hispidin protects H9c2 cardiomyoblast cells from hydrogen peroxide-induced or doxorubicin-induced apoptosis. Consequently, further research on how hispidin affects normal and cancer cells may help treat cancer and reduce chemotherapy-induced side effects. This study showed that hispidin caused caspase-independent death in SGC-7901 cancer cells but not in GES-1 normal cells. Hispidin-induced increases in LC3-II occurred in SGC-7901 cells in a time independent manner. Cell death can be partially inhibited by treatment with ATG5 siRNA but not by autophagy or necroptosis inhibitors. Ultrastructural evidence indicated that hispidin-induced necrotic cell death involved autophagy. Hispidin-induced lysosomal membrane permeabilization (LMP) related to complex cell death occurred more drastically in SGC-7901 cells than in GES-1 cells. Ca2+ rather than cathepsins from LMP contributed more to cell death. Hispidin induced microtubule depolymerization, which can cause LMP, more drastically in SGC-7901 cells than in GES-1 cells. At 4.1 µM, hispidin promoted cell-free tubulin polymerization but at concentrations higher than 41 µM, hispidin inhibited polymerization. Hispidin did not bind to tubulin. Alterations in microtubule regulatory proteins, such as stathmin phosphorylation at Ser16, contributed to hispidin-induced SGC-7901 cell death. In conclusion, hispidin at concentrations higher than 41 µM may inhibit tubulin polymerization by modulating microtubule regulatory proteins, such as stathmin, causing LMP and complex SGC-7901 cell death. This mechanism suggests a promising novel treatment for human cancer.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Membranas Intracelulares/efeitos dos fármacos
Lisossomos/metabolismo
Multimerização Proteica/efeitos dos fármacos
Pironas/farmacologia
Tubulina (Proteína)/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Caspases/metabolismo
Morte Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Seres Humanos
Microtúbulos/química
Microtúbulos/metabolismo
Óxido Nítrico/biossíntese
Permeabilidade
Fosforilação
Estatmina/metabolismo
Tubulina (Proteína)/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyrones); 0 (STMN1 protein, human); 0 (Stathmin); 0 (Tubulin); 31C4KY9ESH (Nitric Oxide); EC 3.4.22.- (Caspases); SSJ18CG55E (hispidin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15935


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[PMID]:29291446
[Au] Autor:Stefanski T; Mikstacka R; Kurczab R; Dutkiewicz Z; Kucinska M; Murias M; Zielinska-Przyjemska M; Cichocki M; Teubert A; Kaczmarek M; Hogendorf A; Sobiak S
[Ad] Endereço:Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland. Electronic address: tstefanski@ump.edu.pl.
[Ti] Título:Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents.
[So] Source:Eur J Med Chem;144:797-816, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC values of 0.86, 1.05, and 0.85 µM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Microtúbulos/efeitos dos fármacos
Estilbenos/farmacologia
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Ciclo Celular/efeitos dos fármacos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Técnicas de Química Combinatória
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Polimerização/efeitos dos fármacos
Estilbenos/síntese química
Estilbenos/química
Relação Estrutura-Atividade
Tubulina (Proteína)/metabolismo
Moduladores de Tubulina/síntese química
Moduladores de Tubulina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Stilbenes); 0 (Tubulin); 0 (Tubulin Modulators); I5590ES2QZ (fosbretabulin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180102
[St] Status:MEDLINE


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[PMID]:27770501
[Au] Autor:Neumann S; Chassefeyre R; Campbell GE; Encalada SE
[Ad] Endereço:Department of Molecular and Experimental Medicine, Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California.
[Ti] Título:KymoAnalyzer: a software tool for the quantitative analysis of intracellular transport in neurons.
[So] Source:Traffic;18(1):71-88, 2017 01.
[Is] ISSN:1600-0854
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In axons, proper localization of proteins, vesicles, organelles, and other cargoes is accomplished by the highly regulated coordination of kinesins and dyneins, molecular motors that bind to cargoes and translocate them along microtubule (MT) tracks. Impairment of axonal transport is implicated in the pathogenesis of multiple neurodegenerative disorders including Alzheimer's and Huntington's diseases. To understand how MT-based cargo motility is regulated and to delineate its role in neurodegeneration, it is critical to analyze the detailed dynamics of moving cargoes inside axons. Here, we present KymoAnalyzer, a software tool that facilitates the robust analysis of axonal transport from time-lapse live-imaging sequences. KymoAnalyzer is an open-source software that automatically classifies particle trajectories and systematically calculates velocities, run lengths, pauses, and a wealth of other parameters that are characteristic of motor-based transport. We anticipate that laboratories will easily use this package to unveil previously uncovered intracellular transport details of individually-moving cargoes inside neurons.
[Mh] Termos MeSH primário: Neurônios/metabolismo
Neurônios/fisiologia
[Mh] Termos MeSH secundário: Animais
Transporte Axonal/fisiologia
Axônios/metabolismo
Axônios/fisiologia
Dineínas/metabolismo
Cinesina/metabolismo
Microtúbulos/metabolismo
Microtúbulos/fisiologia
Doenças Neurodegenerativas/metabolismo
Doenças Neurodegenerativas/fisiopatologia
Organelas/metabolismo
Organelas/fisiologia
Software
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.6.4.2 (Dyneins); EC 3.6.4.4 (Kinesin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1111/tra.12456


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[PMID]:28453723
[Au] Autor:Blanca Ramírez M; Lara Ordóñez AJ; Fdez E; Madero-Pérez J; Gonnelli A; Drouyer M; Chartier-Harlin MC; Taymans JM; Bubacco L; Greggio E; Hilfiker S
[Ad] Endereço:Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain.
[Ti] Título:GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2.
[So] Source:Hum Mol Genet;26(14):2747-2767, 2017 07 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the most common cause of familial Parkinson's disease (PD), and sequence variants modify risk for sporadic PD. Previous studies indicate that LRRK2 interacts with microtubules (MTs) and alters MT-mediated vesicular transport processes. However, the molecular determinants within LRRK2 required for such interactions have remained unknown. Here, we report that most pathogenic LRRK2 mutants cause relocalization of LRRK2 to filamentous structures which colocalize with a subset of MTs, and an identical relocalization is seen upon pharmacological LRRK2 kinase inhibition. The pronounced colocalization with MTs does not correlate with alterations in LRRK2 kinase activity, but rather with increased GTP binding. Synthetic mutations which impair GTP binding, as well as LRRK2 GTP-binding inhibitors profoundly interfere with the abnormal localization of both pathogenic mutant as well as kinase-inhibited LRRK2. Conversely, addition of a non-hydrolyzable GTP analog to permeabilized cells enhances the association of pathogenic or kinase-inhibited LRRK2 with MTs. Our data elucidate the mechanism underlying the increased MT association of select pathogenic LRRK2 mutants or of pharmacologically kinase-inhibited LRRK2, with implications for downstream MT-mediated transport events.
[Mh] Termos MeSH primário: Guanosina Trifosfato/metabolismo
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo
Doença de Parkinson/metabolismo
[Mh] Termos MeSH secundário: GTP Fosfo-Hidrolases/metabolismo
Proteínas de Ligação ao GTP/genética
Proteínas de Ligação ao GTP/metabolismo
Variação Genética
Guanosina Trifosfato/genética
Células HEK293
Seres Humanos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética
Microtúbulos/genética
Microtúbulos/metabolismo
Mutação
Doença de Parkinson/genética
Fosforilação
Inibidores de Proteínas Quinases/farmacologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 86-01-1 (Guanosine Triphosphate); EC 2.7.11.1 (LRRK2 protein, human); EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.1.- (GTP-Binding Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx161


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[PMID]:29395083
[Au] Autor:Yamagishi Y; Oya K; Matsuura A; Abe H
[Ad] Endereço:Department of Nanobiology, Graduate School of Advanced Integration Science, Chiba University, Chiba 263-8522, Japan. Electronic address: afha3649@chiba-u.jp.
[Ti] Título:Use of CK-548 and CK-869 as Arp2/3 complex inhibitors directly suppresses microtubule assembly both in vitro and in vivo.
[So] Source:Biochem Biophys Res Commun;496(3):834-839, 2018 02 12.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Two types of Arp2/3 complex inhibitors, CK-666/636 and CK-548/869, are commonly used to study Arp2/3 complex-dependent actin assembly both in vitro and in vivo. However, we found that CK-548 and CK-869 directly suppress microtubule (MT) assembly independent of the actin cytoskeleton. Treatment of cultured mammalian cells with 50 µM CK-869 dramatically decreased MT networks and, instead, accumulated tubulin at the cell periphery, as did nocodazole that inhibits MT assembly. An in vitro MT-sedimentation assay revealed that CK-548 and CK-869 significantly suppressed MT polymerization. In budding yeast, although CK-548 and CK-869 are reported to lack binding abilities in the yeast Arp3, CK-548 treatment decreased cytoplasmic MT at several tens of micromolar concentrations. In addition, we found that the effects of CK-548 and CK-869 on MT assembly varied according to species. We propose that CK-548 and CK-869 are not suitable for studying the cytoskeleton in living cells.
[Mh] Termos MeSH primário: Complexo 2-3 de Proteínas Relacionadas à Actina/antagonistas & inibidores
Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo
Microtúbulos/fisiologia
Compostos Organosselênicos/administração & dosagem
Compostos de Organossilício/administração & dosagem
Tiazóis/administração & dosagem
Tubulina (Proteína)/metabolismo
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Drosophila melanogaster/metabolismo
Fibroblastos/efeitos dos fármacos
Fibroblastos/fisiologia
Gálio
Índio
Camundongos
Microtúbulos/efeitos dos fármacos
Células NIH 3T3
Ratos
Saccharomyces cerevisiae/metabolismo
Especificidade da Espécie
Moduladores de Tubulina
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Actin-Related Protein 2-3 Complex); 0 (CK-0993548); 0 (CK-869); 0 (In(0.3)Ga(0.7)N); 0 (Organoselenium Compounds); 0 (Organosilicon Compounds); 0 (Thiazoles); 0 (Tubulin); 0 (Tubulin Modulators); 045A6V3VFX (Indium); CH46OC8YV4 (Gallium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180204
[St] Status:MEDLINE


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[PMID]:29198720
[Au] Autor:Luscan R; Mechaussier S; Paul A; Tian G; Gérard X; Defoort-Dellhemmes S; Loundon N; Audo I; Bonnin S; LeGargasson JF; Dumont J; Goudin N; Garfa-Traoré M; Bras M; Pouliet A; Bessières B; Boddaert N; Sahel JA; Lyonnet S; Kaplan J; Cowan NJ; Rozet JM; Marlin S; Perrault I
[Ad] Endereço:Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
[Ti] Título:Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
[So] Source:Am J Hum Genet;101(6):1006-1012, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in ß-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the ß-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αß-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αß-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.
[Mh] Termos MeSH primário: Amaurose Congênita de Leber/genética
Microtúbulos/genética
Tubulina (Proteína)/genética
[Mh] Termos MeSH secundário: Adulto
Sítios de Ligação/genética
Células Cultivadas
Criança
Análise Mutacional de DNA
Feminino
Seres Humanos
Masculino
Microtúbulos/metabolismo
Meia-Idade
Mutação de Sentido Incorreto/genética
Células Fotorreceptoras/metabolismo
Tubulina (Proteína)/metabolismo
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tubulin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


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[PMID]:28467385
[Au] Autor:Field JJ; Northcote PT; Paterson I; Altmann KH; Díaz JF; Miller JH
[Ad] Endereço:Centre for Biodiscovery and Schools, Victoria University of Wellington, PO Box 600, Wellington 6140, New Zealand. jessica.field.nz@gmail.com.
[Ti] Título:Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration.
[So] Source:Int J Mol Sci;18(5), 2017 May 03.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Zampanolide, first discovered in a sponge extract in 1996 and later identified as a microtubule-stabilizing agent in 2009, is a covalent binding secondary metabolite with potent, low nanomolar activity in mammalian cells. Zampanolide was not susceptible to single amino acid mutations at the taxoid site of ß-tubulin in human ovarian cancer 1A9 cells, despite evidence that it selectively binds to the taxoid site. As expected, it did not synergize with other taxoid site microtubule-stabilizing agents (paclitaxel, ixabepilone, discodermolide), but surprisingly also did not synergize in 1A9 cells with laulimalide/peloruside binding site agents either. Efforts to generate a zampanolide-resistant cell line were unsuccessful. Using a standard wound scratch assay in cell culture, it was an effective inhibitor of migration of human umbilical vein endothelial cells (HUVEC) and fibroblast cells (D551). These properties of covalent binding, the ability to inhibit cell growth in paclitaxel and epothilone resistant cells, and the ability to inhibit cell migration suggest that it would be of interest to investigate zampanolide in preclinical animal models to determine if it is effective in vivo at preventing tumor growth and metastasis.
[Mh] Termos MeSH primário: Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Macrolídeos/farmacologia
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Linhagem Celular Tumoral
Feminino
Fibroblastos/efeitos dos fármacos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Seres Humanos
Lactonas/farmacologia
Microtúbulos/metabolismo
Taxoides/metabolismo
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Lactones); 0 (Macrolides); 0 (Taxoids); 0 (Tubulin); 0 (Tubulin Modulators); 0 (laulimalide); 0 (peloruside A); 0 (zampanolide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  10 / 28215 MEDLINE  
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[PMID]:29220790
[Au] Autor:Romagnoli R; Kimatrai Salvador M; Schiaffino Ortega S; Baraldi PG; Oliva P; Baraldi S; Lopez-Cara LC; Brancale A; Ferla S; Hamel E; Balzarini J; Liekens S; Mattiuzzo E; Basso G; Viola G
[Ad] Endereço:Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
[Ti] Título:2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.
[So] Source:Eur J Med Chem;143:683-698, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC values ranging from 0.13 to 0.84 µM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC value of 140 nM, inhibited tubulin polymerization with an IC value of 1.2 µM, similar to that of CA-4 (IC : 1.1 µM), and induced apoptosis in HeLa cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Microtúbulos/efeitos dos fármacos
Tiofenos/farmacologia
Moduladores de Tubulina/farmacologia
Tubulina (Proteína)/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos
Modelos Moleculares
Estrutura Molecular
Polimerização/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Relação Estrutura-Atividade
Tiofenos/síntese química
Tiofenos/química
Moduladores de Tubulina/síntese química
Moduladores de Tubulina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Reactive Oxygen Species); 0 (Thiophenes); 0 (Tubulin); 0 (Tubulin Modulators)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE



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