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[PMID]: 23010496 [Au] Autor: Ungerstedt J; Du Y; Zhang H; Nair D; Holmgren A [Ad] Endereço: Hematology and Regenerative Medicine Center, Institute for Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden. [Ti] Título: In vivo redox state of human thioredoxin and redox shift by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). [So] Source: Free Radic Biol Med;53(11):2002-7, 2012 Dec 1. [Is] ISSN: 1873-4596 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The cytosolic thioredoxin (Trx1) system is essential for maintaining a reduced intracellular environment, via reduced Trx1 acting as a general protein disulfide reductase. Trx1 is implicated in cell signaling such as proliferation, DNA synthesis, enzyme activation, cell cycle regulation, transcription, gene activation, and prevention of apoptosis. Human Trx1 contains the active-site cysteines, Cys32 and Cys35, and three additional structural cysteines, Cys62, Cys69, and Cys73, that regulate Trx1 structure and activity via a second disulfide formation, S-glutathionylation or S-nitrosylation. The present study uses an electrophoretic redox Western blot method to analyze the oxidation state of Trx1 in vivo separating the protein-changed isoform following alkylation with iodoacetic acid in 8M urea. Treatment with the histone deacetylase inhibitor SAHA increased Trx1 inhibitor thioredoxin interacting protein (Txnip) levels, decreased Trx1 activity, and switched the Trx1 oxidation state toward a more oxidized one, as a result of complex formation with Trx1, and increased reactive oxygen species (ROS). SAHA is currently in clinical trials for cancer treatment, and one possible mechanism for its anticancer effect is via effects on the Trx1 system. Determining the exact oxidation state of human cytosolic Trx1 may be useful in developing and evaluating cancer drugs and antioxidant agents. [Mh] Termos MeSH primário: Inibidores de Histona Desacetilases/farmacologia Ácidos Hidroxâmicos/farmacologia Tiorredoxinas/metabolismo [Mh] Termos MeSH secundário: Proteínas de Transporte/metabolismo Sobrevivência Celular/efeitos de drogas Células HeLa Humanos Oxirredução [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Carrier Proteins); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (TXNIP protein, human); 149647-78-9 (vorinostat); 52500-60-4 (Thioredoxins) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121127 [St] Status: MEDLINE

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[PMID]: 22817680 [Au] Autor: Gao Q; Wang X; Xu H; Xu Y; Ling J; Zhang D; Gao S; Liu X [Ad] Endereço: Animal Infectious Disease Laboratory, Ministry of Education Key Lab for Avian Preventive Medicine, College of Veterinary Medicine, Yangzhou University, Jiangsu, People's Republic of China. [Ti] Título: Roles of iron acquisition systems in virulence of extraintestinal pathogenic Escherichia coli: salmochelin and aerobactin contribute more to virulence than heme in a chicken infection model. [So] Source: BMC Microbiol;12:143, 2012. [Is] ISSN: 1471-2180 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Avian pathogenic Escherichia coli (APEC) and uropathogenic E. coli (UPEC) are the two main subsets of extraintestinal pathogenic E. coli (ExPEC). Both types have multiple iron acquisition systems, including heme and siderophores. Although iron transport systems involved in the pathogenesis of APEC or UPEC have been documented individually in corresponding animal models, the contribution of these systems during simultaneous APEC and UPEC infection is not well described. To determine the contribution of each individual iron acquisition system to the virulence of APEC and UPEC, isogenic mutants affecting iron uptake in APEC E058 and UPEC U17 were constructed and compared in a chicken challenge model. RESULTS: Salmochelin-defective mutants E058ΔiroD and U17ΔiroD showed significantly decreased pathogenicity compared to the wild-type strains. Aerobactin defective mutants E058ΔiucD and U17ΔiucD demonstrated reduced colonization in several internal organs, whereas the heme defective mutants E058ΔchuT and U17ΔchuT colonized internal organs to the same extent as their wild-type strains. The triple mutant ΔchuTΔiroDΔiucD in both E058 and U17 showed decreased pathogenicity compared to each of the single mutants. The histopathological lesions in visceral organs of birds challenged with the wild-type strains were more severe than those from birds challenged with ΔiroD, ΔiucD or the triple mutants. Conversely, chickens inoculated with the ΔchuT mutants had lesions comparable to those in chickens inoculated with the wild-type strains. However, no significant differences were observed between the mutants and the wild-type strains in resistance to serum, cellular invasion and intracellular survival in HD-11, and growth in iron-rich or iron-restricted medium. CONCLUSIONS: Results indicated that APEC and UPEC utilize similar iron acquisition mechanisms in chickens. Both salmochelin and aerobactin systems appeared to be important in APEC and UPEC virulence, while salmochelin contributed more to the virulence. Heme bounded by ChuT in the periplasm appeared to be redundant in this model, indicating that other periplasmic binding proteins likely contributed to the observed no phenotype for the heme uptake mutant. No differences were observed between the mutants and their wild-type parents in other phenotypic traits, suggesting that other virulence mechanisms compensate for the effect of the mutations. [Mh] Termos MeSH primário: Enterobactina/análogos & derivados Infecções por Escherichia coli/microbiologia Infecções por Escherichia coli/patologia Escherichia coli/patogenicidade Glucosídeos/metabolismo Ácidos Hidroxâmicos/metabolismo Ferro/metabolismo Fatores de Virulência/metabolismo [Mh] Termos MeSH secundário: Estruturas Animais/patologia Animais Galinhas Modelos Animais de Doenças Enterobactina/metabolismo Escherichia coli/genética Deleção de Genes Heme/metabolismo Histocitoquímica Microscopia Fatores de Virulência/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Glucosides); 0 (Hydroxamic Acids); 0 (Virulence Factors); 0 (salmochelin S4); 14875-96-8 (Heme); 26198-65-2 (aerobactin); 28384-96-5 (Enterobactin); 7439-89-6 (Iron) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121115 [St] Status: MEDLINE [do] DOI: 10.1186/1471-2180-12-143

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[PMID]: 22785124 [Au] Autor: Oh HJ; Lee TH; Lee JH; Lee BC [Ad] Endereço: Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul, Korea. [Ti] Título: Trichostatin a improves preimplantation development of bovine cloned embryos and alters expression of epigenetic and pluripotency genes in cloned blastocysts. [So] Source: J Vet Med Sci;74(11):1409-15, 2012 Nov. [Is] ISSN: 1347-7439 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: We investigated the effects of exposure time and concentration of trichostatin A (TSA) on in vitro development and quality of bovine SCNT embryos. At multiple time points, the relative expression of genes related to pluripotency and reprogramming was analyzed in order to assess the quality of preimplantation embryos cultured in media with TSA using real-time PCR. Development into blastocysts was higher in 100 nM TSA than in controls (35.96 vs. 28.30%, P<0.05). Study of 100 nM TSA exposure time showed development into blastocysts was higher during both short-term and long-term exposure than in controls (36.17 and 34.04 vs. 23.45%), but there was no significant difference between TSA groups. Nanog expression in blastocysts after long-term TSA exposure was similar to that in IVF blastocysts and greater than in controls and short-term exposed embryos. The Oct4 levels in the short-term exposure group were similar to those of IVF blastocysts, while Oct4 expression in long-term exposed embryos was significantly higher than in other groups. Measurement of DNMT1 and HDAC1 in blastocysts showed a similar expression profile among IVF and TSA groups regardless of treatment duration. In conclusion, this study suggests that TSA treatment after SCNT in bovine embryos can improve in vitro development of embryos by increasing the blastocysts formation and positive reprogramming of the reconstructed embryo genome caused by downregulation of DNA methylation and up-regulation of pluripotency. [Mh] Termos MeSH primário: Blastocisto/metabolismo Clonagem de Organismos/veterinária Desenvolvimento Embrionário/efeitos de drogas Epigênese Genética/efeitos de drogas Regulação da Expressão Gênica no Desenvolvimento/efeitos de drogas Ácidos Hidroxâmicos/farmacologia Técnicas de Transferência Nuclear/veterinária [Mh] Termos MeSH secundário: Animais Bovinos Metilação de DNA/efeitos de drogas Relação Dose-Resposta a Droga Epigênese Genética/genética Proteínas de Homeodomínio/metabolismo Ácidos Hidroxâmicos/administração & dosagem Fator 3 de Transcrição de Octâmero/metabolismo Reação em Cadeia da Polimerase em Tempo Real/veterinária Fatores de Tempo [Pt] Tipo de publicação: IN VITRO; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Homeodomain Proteins); 0 (Hydroxamic Acids); 0 (Octamer Transcription Factor-3); 3X2S926L3Z (trichostatin A) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121204 [St] Status: MEDLINE

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[PMID]: 22981498 [Au] Autor: Duvic M; Dummer R; Becker JC; Poulalhon N; Ortiz Romero P; Grazia Bernengo M; Lebbé C; Assaf C; Squier M; Williams D; Marshood M; Tai F; Prince HM [Ad] Endereço: MD Anderson Cancer Center, Houston, TX, USA. mduvic@mdanderson.org [Ti] Título: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. [So] Source: Eur J Cancer;49(2):386-94, 2013 Jan. [Is] ISSN: 1879-0852 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Patients with CTCL subtypes mycosis fungoides and Sézary syndrome who received ⩾2 prior systemic therapy regimens received panobinostat (20mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ⩾25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir. RESULTS: Seventy-nine bexarotene-exposed and 60 bexarotene-naïve patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the bexarotene-exposed and -naïve groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the bexarotene-exposed and -naïve groups, respectively. The median duration of response was 5.6 months in the bexarotene-exposed patients and was not reached at data cutoff in the bexarotene-naïve patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable. CONCLUSION: Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in bexarotene-exposed and -naïve CTCL patients. ClinicalTrials.gov Identifier: NCT00425555. [Mh] Termos MeSH primário: Anticarcinógenos/administração & dosagem Antineoplásicos/uso terapêutico Ácidos Hidroxâmicos/uso terapêutico Indóis/uso terapêutico Micose Fungoide/quimioterapia Síndrome de Sézary/quimioterapia Neoplasias Cutâneas/quimioterapia Tetra-Hidronaftalenos/administração & dosagem [Mh] Termos MeSH secundário: Antineoplásicos/efeitos adversos Progressão da Doença Sobrevivência Livre de Doença Feminino Inibidores de Histona Desacetilases/efeitos adversos Inibidores de Histona Desacetilases/uso terapêutico Humanos Ácidos Hidroxâmicos/efeitos adversos Indóis/efeitos adversos Masculino Meia-Idade Micose Fungoide/patologia Síndrome de Sézary/patologia Neoplasias Cutâneas/patologia [Pt] Tipo de publicação: CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anticarcinogenic Agents); 0 (Antineoplastic Agents); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (Indoles); 0 (Tetrahydronaphthalenes); 0 (bexarotene); 0 (panobinostat) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130109 [Cl] Clinical Trial: ClinicalTrial [St] Status: MEDLINE

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[PMID]: 23297421 [Au] Autor: Webster SJ; Waite SL; Cookson VJ; Warren A; Khan R; Gandhi SV; Europe-Finner GN; Chapman NR [Ad] Endereço: Academic Unit of Reproductive and Developmental Medicine, Department of Human Metabolism, University of Sheffield, Level 4, Jessop Wing, Tree Root Walk, Sheffield S10 2SF, United Kingdom. [Ti] Título: Regulation of GTP-binding protein (Gαs) expression in human myometrial cells: a role for tumor necrosis factor in modulating Gαs promoter acetylation by transcriptional complexes. [So] Source: J Biol Chem;288(9):6704-16, 2013 Mar 1. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The onset of parturition is associated with a number of proinflammatory mediators that are themselves regulated by the nuclear factor κB (NF-κB) family of transcription factors. In this context, we previously reported that the RelA NF-κB subunit represses transcription and mRNA expression of the proquiescent Gαs gene in human myometrial cells following stimulation with the proinflammatory cytokine TNF. In the present study, we initially defined the functional consequence of this on myometrial contractility. Here we show that, contrary to our initial expectations, TNF did not induce myometrial contractility but did inhibit the relaxation produced by the histone deacetylase inhibitor trichostatin A, an effect that in turn was abolished by the NF-κB inhibitor N(4)-[2-(4-phenoxyphenyl)ethyl]-4,6-quinazolinediamine. This result suggested a role for TNF in regulating Gαs expression via activating NF-κB and modifying histone acetylation associated with the promoter region of the gene. In this context, we show that the -837 to -618 region of the endogenous Gαs promoter is occupied by cAMP-response element-binding protein (CREB), Egr-1, and Sp1 transcription factors and that CREB-binding protein (CBP) transcriptional complexes form within this region where they induce histone acetylation, resulting in increased Gαs expression. TNF, acting via NF-κB, did not change the levels of CREB, Sp1, or Egr-1 binding to the Gαs promoter, but it induced a significant reduction in the level of CBP. This was associated with increased levels of histone deacetylase-1 and surprisingly an increase in H4K8 acetylation. The latter is discussed herein. [Mh] Termos MeSH primário: Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo Regulação da Expressão Gênica/fisiologia Complexos Multiproteicos/metabolismo Proteínas Musculares/metabolismo Miométrio/metabolismo Elementos de Resposta/fisiologia Fatores de Transcrição/metabolismo Fator de Necrose Tumoral alfa/farmacologia [Mh] Termos MeSH secundário: Acetilação/efeitos de drogas Adolescente Adulto Células Cultivadas Feminino Subunidades alfa de Proteínas de Ligação ao GTP/genética Histona Desacetilase 1/genética Histona Desacetilase 1/metabolismo Inibidores de Histona Desacetilases/farmacologia Histonas/genética Histonas/metabolismo Humanos Ácidos Hidroxâmicos/farmacologia Complexos Multiproteicos/genética Proteínas Musculares/genética Miométrio/citologia Fator de Transcrição RelA/genética Fator de Transcrição RelA/metabolismo Fatores de Transcrição/genética Fator de Necrose Tumoral alfa/metabolismo Contração Uterina/efeitos de drogas Contração Uterina/fisiologia [Pt] Tipo de publicação: CLINICAL TRIAL; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (GTP-Binding Protein alpha Subunits); 0 (Histone Deacetylase Inhibitors); 0 (Histones); 0 (Hydroxamic Acids); 0 (Multiprotein Complexes); 0 (Muscle Proteins); 0 (RELA protein, human); 0 (Transcription Factor RelA); 0 (Transcription Factors); 0 (Tumor Necrosis Factor-alpha); 3X2S926L3Z (trichostatin A); EC 3.5.1.98 (HDAC1 protein, human); EC 3.5.1.98 (Histone Deacetylase 1) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130304 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M112.440602

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[PMID]: 22960696 [Au] Autor: Calugi C; Trabocchi A; Lalli C; Guarna A [Ad] Endereço: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy. [Ti] Título: D-proline-based peptidomimetic inhibitors of anthrax lethal factor. [So] Source: Eur J Med Chem;56:96-107, 2012 Oct. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: In this work we reported the generation of d-proline-derived hydroxamic acids as inhibitors of anthrax lethal factor (LF), taking advantage of a pyrrolidine ring as the central scaffold and a hydroxamate group as the Zn(2+) chelating agent. The introduction of two hydrophobic groups addressing the S1' subsite and a long substrate-binding groove was conceived by overlapping the bioactive conformations of two reported LF inhibitors. Micromolar affinity of compound 38 suggested cis-3-substituted-1-sulfonamido-d-proline hydroxamic acids as a promising class of peptidomimetic inhibitors for developing novel LF inhibitors. [Mh] Termos MeSH primário: Toxinas Bacterianas/antagonistas & inibidores Ácidos Hidroxâmicos/farmacologia Peptidomiméticos/farmacologia Prolina/farmacologia [Mh] Termos MeSH secundário: Antígenos de Bactérias Ácidos Hidroxâmicos/síntese química Ácidos Hidroxâmicos/química Modelos Moleculares Peptidomiméticos/síntese química Peptidomiméticos/química Prolina/síntese química Prolina/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antigens, Bacterial); 0 (Bacterial Toxins); 0 (Hydroxamic Acids); 0 (Peptidomimetics); 0 (anthrax toxin); 147-85-3 (Proline) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121022 [St] Status: MEDLINE

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[PMID]: 22825043 [Au] Autor: Qiao F; Su X; Qiu X; Qian D; Peng X; Chen H; Zhao Z; Fan H [Ad] Endereço: Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Institute of Life Science, and Department of Genetics and Developmental Biology, Medical School of Southeast University, Nanjing 210009, PR China. [Ti] Título: Enforced expression of RASAL1 suppresses cell proliferation and the transformation ability of gastric cancer cells. [So] Source: Oncol Rep;28(4):1475-81, 2012 Oct. [Is] ISSN: 1791-2431 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: RAS protein activator like 1 (RASAL1) is a member of the RAS GTPase-activating protein (GAP) family, and it is an important molecule in the regulation of RAS activation. In the present study, we investigated the role of RASAL1 in gastric carcinogenesis. Decreased expression pattern of RASAL1 in gastric cancer tissues and cell lines was found in protein and RNA levels, although there was no statistically significant relationship between RASAL1 and clinicopathological features. Restored expression of RASAL1 induced by DNA methylation inhibitor 5-aza-2'-deoxycytidine (5'-AZA) and HDAC inhibitor trichostatin A (TSA) implied that RASAL1 expression is regulated by epigenetic mechanisms. The biological role of RASAL1 in gastric carcinogenesis was determined by in vitro tumorigenicity assays. Overexpression of RASAL1 showed suppression of cell proliferation due to cell apoptosis. Subsequently, enforced expression of RASAL1 repressed significantly the gastric cancer cell transformation ability. These findings demonstrated that decreased RASAL1 expression is a characteristic of gastric cancer and regulated by epigenetic mechanisms. RASAL1 may be a functional tumor suppressor involved in gastric cancer. This study provides novel insights into the biological role of RASAL1 in gastric carcinogenesis. [Mh] Termos MeSH primário: Proteínas Ativadoras de GTPase/genética Neoplasias Gástricas/genética Neoplasias Gástricas/patologia [Mh] Termos MeSH secundário: Idoso Azacitidina/análogos & derivados Azacitidina/farmacologia Linhagem Celular Tumoral Movimento Celular/genética Proliferação de Células/efeitos de drogas Metilação de DNA/efeitos de drogas Relação Dose-Resposta a Droga Epigênese Genética Infecções por Vírus Epstein-Barr/genética Feminino Proteínas Ativadoras de GTPase/metabolismo Regulação Neoplásica da Expressão Gênica Infecções por Helicobacter/genética Inibidores de Histona Desacetilases/farmacologia Humanos Ácidos Hidroxâmicos/farmacologia Masculino Meia-Idade Neoplasias Gástricas/quimioterapia Neoplasias Gástricas/metabolismo Neoplasias Gástricas/microbiologia Neoplasias Gástricas/virologia Proteínas Ativadoras de ras GTPase/genética Proteínas Ativadoras de ras GTPase/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (GTPase-Activating Proteins); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (RASAL1 protein, human); 0 (ras GTPase-Activating Proteins); 2353-33-5 (decitabine); 320-67-2 (Azacitidine); 3X2S926L3Z (trichostatin A) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120912 [St] Status: MEDLINE [do] DOI: 10.3892/or.2012.1920

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[PMID]: 23094795 [Au] Autor: Librizzi M; Longo A; Chiarelli R; Amin J; Spencer J; Luparello C [Ad] Endereço: Dipartimento STEMBIO, Edificio 16, Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy. [Ti] Título: Cytotoxic effects of Jay Amin hydroxamic acid (JAHA), a ferrocene-based class I histone deacetylase inhibitor, on triple-negative MDA-MB231 breast cancer cells. [So] Source: Chem Res Toxicol;25(11):2608-16, 2012 Nov 19. [Is] ISSN: 1520-5010 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives may be obtained by three-dimensional manipulation of SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA [ Spencer , et al. ( 2011 ) ACS Med. Chem. Lett. 2 , 358 - 362 ]. These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple-negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC(50) of 8.45 µM at 72 h of treatment. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G(2)/M transition and in an early reactive oxygen species production followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short- (5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi. Although caution must be exercised in extrapolation of in vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of "aggressive" breast carcinoma, thus prompting us to get more insight into the molecular basis of its antibreast cancer activity. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Compostos Ferrosos/química Compostos Ferrosos/farmacologia Inibidores de Histona Desacetilases/farmacologia Ácidos Hidroxâmicos/farmacologia [Mh] Termos MeSH secundário: Antineoplásicos/síntese química Antineoplásicos/química Apoptose/efeitos de drogas Ciclo Celular/efeitos de drogas Sobrevivência Celular/efeitos de drogas Relação Dose-Resposta a Droga Ensaios de Seleção de Medicamentos Antitumorais Compostos Ferrosos/síntese química Inibidores de Histona Desacetilases/síntese química Inibidores de Histona Desacetilases/química Humanos Ácidos Hidroxâmicos/síntese química Ácidos Hidroxâmicos/química Potencial da Membrana Mitocondrial/efeitos de drogas Estrutura Molecular Espécies de Oxigênio Reativas/metabolismo Relação Estrutura-Atividade Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Ferrous Compounds); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (Reactive Oxygen Species); 0 (jay amin hydroxamic acid); U96PKG90JQ (ferrocene) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121120 [St] Status: MEDLINE [do] DOI: 10.1021/tx300376h

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[PMID]: 23152903 [Au] Autor: Liu W; Fan LX; Zhou X; Sweeney WE; Avner ED; Li X [Ad] Endereço: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America. [Ti] Título: HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. [So] Source: PLoS One;7(11):e49418, 2012. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We present for the first time that histone deacetylase 6 (HDAC6) regulates EGFR degradation and trafficking along microtubules in Pkd1 mutant renal epithelial cells. HDAC6, the microtubule-associated α-tubulin deacetylase, demonstrates increased expression and activity in Pkd1 mutant mouse embryonic kidney cells. Targeting HDAC6 with a general HDAC inhibitor, trichostatin (TSA), or a specific HDAC6 inhibitor, tubacin, increased the acetylation of α-tubulin and downregulated the expression of EGFR in Pkd1 mutant renal epithelial cells. HDAC6 was co-localized with EGF induced endocytic EGFR and endosomes, respectively. Inhibition of the activity of HDAC6 accelerated the trafficking of EGFR from early endosomes to late endosomes along the microtubules. Without EGF stimulation EGFR was randomly distributed while after stimulation with EGF for 30 min, EGFR was accumulated around α-tubulin labeled microtubule bundles. These data suggested that the Pkd1 mutation induced upregulation of HDAC6 might act to slow the trafficking of EGFR from early endosomes to late endosomes along the microtubules for degradation through deacetylating α-tubulin. In addition, inhibition of HDAC activity decreased the phosphorylation of ERK1/2, the downstream target of EGFR axis, and normalized EGFR localization from apical to basolateral in Pkd1 knockout mouse kidneys. Thus, targeting HDAC6 to downregulate EGFR activity may provide a potential therapeutic approach to treat polycystic kidney disease. [Mh] Termos MeSH primário: Endocitose Células Epiteliais/citologia Histona Desacetilases/metabolismo Rim/citologia Proteólise Receptor do Fator de Crescimento Epidérmico/metabolismo [Mh] Termos MeSH secundário: Anilidas/farmacologia Animais Endocitose/efeitos de drogas Endossomos/efeitos de drogas Endossomos/metabolismo Fator de Crescimento Epidérmico/farmacologia Células Epiteliais/efeitos de drogas Células Epiteliais/enzimologia MAP Quinases Reguladas por Sinal Extracelular/metabolismo Células HEK293 Inibidores de Histona Desacetilases/farmacologia Humanos Ácidos Hidroxâmicos/farmacologia Lisossomos/efeitos de drogas Lisossomos/metabolismo Camundongos Microtúbulos/efeitos de drogas Microtúbulos/metabolismo Nocodazol/farmacologia Fosforilação/efeitos de drogas Transporte Proteico/efeitos de drogas Proteólise/efeitos de drogas RNA Interferente Pequeno/metabolismo Canais de Cátion TRPP/genética Tubulina (Proteína)/metabolismo Regulação para Cima/efeitos de drogas [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anilides); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (RNA, Small Interfering); 0 (TRPP Cation Channels); 0 (Tubulin); 0 (polycystic kidney disease 1 protein); 0 (tubacin); 31430-18-9 (Nocodazole); 3X2S926L3Z (trichostatin A); 62229-50-9 (Epidermal Growth Factor); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.5.1.98 (HDAC6 protein, human); EC 3.5.1.98 (Hdac6 protein, mouse); EC 3.5.1.98 (Histone Deacetylases) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121115 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0049418

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[PMID]: 23510467 [Au] Autor: Poplineau M; Doliwa C; Schnekenburger M; Antonicelli F; Diederich M; Trussardi-Régnier A; Dufer J [Ad] Endereço: Unité MEDyC, URCA-CNRS FRE 3481, SFR Cap-Santé, Faculté de Pharmacie, Université de Reims, Reims, France. [Ti] Título: Epigenetically induced changes in nuclear textural patterns and gelatinase expression in human fibrosarcoma cells. [So] Source: Cell Prolif;46(2):127-36, 2013 Apr. [Is] ISSN: 1365-2184 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Chromatin texture patterns of tumour cell nuclei can serve as cancer biomarkers, either to define diagnostic classifications or to obtain relevant prognostic information, in a large number of human tumours. Epigenetic mechanisms, mainly DNA methylation and histone post-translational modification, have been shown to influence chromatin packing states, and therefore nuclear texture. The aim of this study was to analyse effects of these two mechanisms on chromatin texture, and also on correlation with gelatinase expression, in human fibrosarcoma tumour cells. MATERIALS AND METHODS: We investigated effects of DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-azadC) and histone deacetylase inhibitor trichostatin A (TSA) on nuclear textural characteristics of human HT1080 fibrosarcoma cells, evaluated by image cytometry, and expression of gelatinases MMP-2 and MMP-9, two metalloproteinases implicated in cancer progression and metastasis. RESULTS: 5-azadC induced significant variation in chromatin higher order organization, particularly chromatin decondensation, associated with reduction in global DNA methylation, concomitantly with increase in MMP-9, and to a lesser extent, MMP-2 expression. TSA alone did not have any effect on HT1080 cells, but exhibited differential activity when added to cells treated with 5-azadC. When treated with both drugs, nuclei had higher texture abnormalities. In this setting, reduction in MMP-9 expression was observed, whereas MMP-2 expression remained unaffected. CONCLUSIONS: These data show that hypomethylating drug 5-azadC and histone deacetylase inhibitor TSA were able to induce modulation of higher order chromatin organization and gelatinase expression in human HT1080 fibrosarcoma cells. [Mh] Termos MeSH primário: Núcleo Celular/genética Epigênese Genética Regulação Enzimológica da Expressão Gênica Regulação Neoplásica da Expressão Gênica Metaloproteinase 2 da Matriz/metabolismo Metaloproteinase 9 da Matriz/metabolismo [Mh] Termos MeSH secundário: Azacitidina/análogos & derivados Azacitidina/farmacologia Linhagem Celular Tumoral Núcleo Celular/efeitos de drogas Núcleo Celular/enzimologia Cromatina/genética Cromatina/metabolismo Montagem e Desmontagem da Cromatina/efeitos de drogas Metilação de DNA Progressão da Doença Fibrossarcoma/enzimologia Fibrossarcoma/patologia Inibidores de Histona Desacetilases/farmacologia Histonas/genética Histonas/metabolismo Humanos Ácidos Hidroxâmicos/farmacologia Citometria por Imagem Metaloproteinase 2 da Matriz/genética Metaloproteinase 9 da Matriz/genética Inibidores de Metaloproteinases de Matriz/farmacologia Metástase Neoplásica/genética Metástase Neoplásica/patologia Proteínas de Neoplasias/genética Proteínas de Neoplasias/metabolismo Marcadores Biológicos de Tumor/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Chromatin); 0 (Histone Deacetylase Inhibitors); 0 (Histones); 0 (Hydroxamic Acids); 0 (Matrix Metalloproteinase Inhibitors); 0 (Neoplasm Proteins); 0 (Tumor Markers, Biological); 2353-33-5 (decitabine); 320-67-2 (Azacitidine); 3X2S926L3Z (trichostatin A); EC 3.4.24.24 (MMP2 protein, human); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9) [Em] Mês de entrada: 1305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130320 [St] Status: MEDLINE [do] DOI: 10.1111/cpr.12021

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