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[PMID]: 29182018 [Au] Autor: Amin SA; Adhikari N; Jha T [Ad] Endereço: Natural Science Laboratory, Department of Pharmaceutical Technology, Division of Medicinal & Pharmaceutical Chemistry, PO Box 17020, Jadavpur University, Kolkata 700032, West Bengal, India. [Ti] Título: Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery. [So] Source: Future Med Chem;9(18):2211-2237, 2017 12. [Is] ISSN: 1756-8927 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The pan-histone deacetylase (HDAC) inhibitors comprise a fish-like structural orientation where hydrophobic aryl- and zinc-binding groups act as head and tail, respectively of a fish. The linker moiety correlates the body of the fish linking head and tail groups. Despite these pan-HDAC inhibitors, selective HDAC-8 inhibitors are still in demand as a safe remedy. HDAC-8 is involved in invasion and metastasis in cancer. This review deals with the rationale behind HDAC-8 inhibitory activity and selectivity along with detailed structure-activity relationships of diverse hydroxamate-based HDAC-8 inhibitors. HDAC-8 inhibitory potency may be increased by modifying the fish-like pharmacophoric features of such type of pan-HDAC inhibitors. This review may provide a preliminary basis to design and optimize new lead molecules with higher HDAC-8 inhibitory activity. This work may surely enlighten in providing useful information in the field of target-specific anticancer therapy. [Mh] Termos MeSH primário: Antineoplásicos/química Inibidores de Histona Desacetilases/química Ácidos Hidroxâmicos/química Proteínas Repressoras/antagonistas & inibidores [Mh] Termos MeSH secundário: Animais Antineoplásicos/uso terapêutico Sítios de Ligação Desenho de Drogas Inibidores de Histona Desacetilases/uso terapêutico Histona Desacetilases/metabolismo Seres Humanos Ácidos Hidroxâmicos/uso terapêutico Simulação de Acoplamento Molecular Neoplasias/tratamento farmacológico Neoplasias/patologia Proteínas Repressoras/metabolismo Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (Repressor Proteins); EC 3.5.1.98 (HDAC8 protein, human); EC 3.5.1.98 (Histone Deacetylases) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180308 [Lr] Data última revisão: 180308 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171129 [St] Status: MEDLINE [do] DOI: 10.4155/fmc-2017-0130

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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]: 28463020 [Au] Autor: Saini M; Selokar NL; Agrawal H; Singla SK; Chauhan MS; Manik RS; Palta P [Ad] Endereço: Embryo Biotechnology Laboratory, Animal Biotechnology Centre, ICAR-National Dairy Research Institute , Karnal, India . [Ti] Título: Treatment of Donor Cells and Reconstructed Embryos with a Combination of Trichostatin-A and 5-aza-2'-Deoxycytidine Improves the Developmental Competence and Quality of Buffalo Embryos Produced by Handmade Cloning and Alters Their Epigenetic Status and Gene Expression. [So] Source: Cell Reprogram;19(3):208-215, 2017 Jun. [Is] ISSN: 2152-4998 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The application of cloning technology on a large scale is limited by very low offspring rate primarily due to aberrant or incomplete epigenetic reprogramming. Trichostatin A (TSA), a histone deacetylase inhibitor, and 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferases, are widely used for altering the epigenetic status of cloned embryos. We optimized the doses of these epigenetic modifiers for production of buffalo embryos by handmade cloning and examined whether combined treatment with these epigenetic modifiers offered any advantage over treatment with the individual epigenetic modifier. Irrespective of whether donor cells or reconstructed embryos or both were treated with 50 nM TSA +7.5 nM 5-aza-dC, (1) the blastocyst rate was significantly higher (71.6 ± 3.5, 68.3 ± 2.6, and 71.8 ± 2.4, respectively, vs. 43.1 ± 3.4 for controls, p < 0.05); (2) the apoptotic index was lower (5.4 ± 1.1, 9.5 ± 1.0, and 7.4 ± 1.3, respectively, vs. 19.5 ± 2.1 for controls, p < 0.05) and was similar to that of in vitro fertilization blastocysts (6.0 ± 0.8); (3) the global level of H3K18ac was higher (p < 0.01) and that of H3K27me3 lower (p < 0.05) than in controls and was similar among all treatment groups; and (4) the expression level of epigenetic-(HDAC1, DNMT1, and DNMT3a), pluripotency-(OCT4 and NANOG), and development-related (FGF4) genes, but not that of SOX2 and CDX2, was similar among all treatment groups. These results demonstrate that similar levels of beneficial effects can be obtained following treatment of either donor cells or reconstructed embryos or both with the combination of TSA +5-aza-dC. Therefore, there is no advantage in treating both donor cells and reconstructed embryos when the combination of TSA and 5-aza-dC is used. [Mh] Termos MeSH primário: Azacitidina/análogos & derivados Búfalos Clonagem de Organismos/métodos Embrião de Mamíferos/metabolismo Epigênese Genética/efeitos dos fármacos Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos Ácidos Hidroxâmicos/farmacologia [Mh] Termos MeSH secundário: Animais Azacitidina/farmacologia Búfalos/embriologia Búfalos/genética Embrião de Mamíferos/citologia Feminino Masculino [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Hydroxamic Acids); 3X2S926L3Z (trichostatin A); 776B62CQ27 (decitabine); M801H13NRU (Azacitidine) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180301 [Lr] Data última revisão: 180301 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1089/cell.2016.0061

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[PMID]: 29288941 [Au] Autor: Ling Y; Guo J; Yang Q; Zhu P; Miao J; Gao W; Peng Y; Yang J; Xu K; Xiong B; Liu G; Tao J; Luo L; Zhu Q; Zhang Y [Ad] Endereço: School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China. [Ti] Título: Development of novel ß-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells. [So] Source: Eur J Med Chem;144:398-409, 2018 Jan 20. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: A series of novel ß-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these ß-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC values of 0.53-1.56 µM, which was considerably more potent than harmine (IC = 46.7-55.3 µM) and also three-to ten-fold lower than that of SAHA (IC = 4.48-6.26 µM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and α-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Carbolinas/farmacologia Inibidores de Histona Desacetilases/farmacologia Histona Desacetilases/metabolismo Ácidos Hidroxâmicos/farmacologia [Mh] Termos MeSH secundário: Antineoplásicos/síntese química Antineoplásicos/química Carbolinas/química Pontos de Checagem do Ciclo Celular/efeitos dos fármacos Proliferação Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Ensaios de Seleção de Medicamentos Antitumorais Inibidores de Histona Desacetilases/síntese química Inibidores de Histona Desacetilases/química Seres Humanos Ácidos Hidroxâmicos/síntese química Ácidos Hidroxâmicos/química Estrutura Molecular Relação Estrutura-Atividade Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Carbolines); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 94HMA1I78O (norharman); EC 3.5.1.98 (Histone Deacetylases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171231 [St] Status: MEDLINE

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[PMID]: 29227512 [Au] Autor: Anumanthan G; Sharma A; Waggoner M; Hamm CW; Gupta S; Hesemann NP; Mohan RR [Ti] Título: Efficacy and Safety Comparison Between Suberoylanilide Hydroxamic Acid and Mitomycin C in Reducing the Risk of Corneal Haze After PRK Treatment In Vivo. [So] Source: J Refract Surg;33(12):834-839, 2017 Dec 01. [Is] ISSN: 1081-597X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PURPOSE: This study compared the efficacy and safety of suberoylanilide hydroxamic acid (SAHA) and mitomycin C (MMC) up to 4 months in the prevention of corneal haze induced by photorefractive keratectomy (PRK) in rabbits in vivo. METHODS: Corneal haze in rabbits was produced with -9.00 diopter PRK. A single application of SAHA (25 µM) or MMC (0.02%) was applied topically immediately after PRK. Effects of the two drugs were analyzed by slit-lamp microscope, specular microscope, TUNEL assay, and immunofluorescence. RESULTS: Single topical adjunct use of SAHA (25 µM) or MMC (0.02%) after PRK attenuated more than 95% corneal haze and myofibroblast formation (P < .001). SAHA did not reduce keratocyte density, cause keratocyte apoptosis, or increase immune cell infiltration compared to MMC (P < .01 or .001). Furthermore, SAHA dosing did not compromise corneal endothelial phenotype, density, or function in rabbit eyes, whereas MMC application did (P < .01 or .001). CONCLUSIONS: SAHA and MMC significantly decreased corneal haze after PRK in rabbits in vivo. SAHA exhibited significantly reduced short- and long-term damage to the corneal endothelium compared to MMC in rabbits. SAHA is an effective and potentially safer alternative to MMC for the prevention of corneal haze after PRK. Clinical trials are warranted. [J Refract Surg. 2017;33(12):834-839.]. [Mh] Termos MeSH primário: Alquilantes/uso terapêutico Opacidade da Córnea/prevenção & controle Modelos Animais de Doenças Inibidores de Histona Desacetilases/uso terapêutico Ácidos Hidroxâmicos/uso terapêutico Mitomicina/uso terapêutico Ceratectomia Fotorrefrativa/efeitos adversos [Mh] Termos MeSH secundário: Alquilantes/efeitos adversos Animais Apoptose Córnea/cirurgia Opacidade da Córnea/etiologia Técnica Indireta de Fluorescência para Anticorpo Inibidores de Histona Desacetilases/efeitos adversos Ácidos Hidroxâmicos/efeitos adversos Marcação In Situ das Extremidades Cortadas Mitomicina/efeitos adversos Coelhos Lâmpada de Fenda Resultado do Tratamento [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Alkylating Agents); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 50SG953SK6 (Mitomycin); 58IFB293JI (vorinostat) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171212 [St] Status: MEDLINE [do] DOI: 10.3928/1081597X-20170921-02

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[PMID]: 29233468 [Au] Autor: Li Q; Ding C; Meng T; Lu W; Liu W; Hao H; Cao L [Ad] Endereço: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China. [Ti] Título: Butyrate suppresses motility of colorectal cancer cells via deactivating Akt/ERK signaling in histone deacetylase dependent manner. [So] Source: J Pharmacol Sci;135(4):148-155, 2017 Dec. [Is] ISSN: 1347-8648 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: Butyrate is a typical short chain fatty acid produced by gut microbiota of which the dysmetabolism has been consistently associated with colorectal diseases. However, whether butyrate affects metastatic colorectal cancer is not clear. In this study we investigated in vitro the effect of butyrate on motility, a significant metastatic factor of colorectal cancer cells and explored the potential mechanism. By using wound healing and transwell-based invasion models, we demonstrated that pretreatment of butyrate significantly inhibited motility of HCT116, HT29, LOVO and HCT8 cells, this activity was further attributed to deactivation of Akt1 and ERK1/2. Suberanilohydroxamic acid (SAHA), another HDAC inhibitor, mimicked the inhibitory effect of butyrate on cell motility and deactivation of Akt/ERK. Furthermore, by silencing of HDAC3 with siRNA, we confirmed dependence of butyrate's effect on HDAC3, the similar reduced cell motility observed under HDAC3 silencing also indicates the significance of HDAC itself in cell motility. In conclusion, we confirmed the HDAC3-relied activity of butyrate on inhibiting motility of colorectal cancer cells via deactivating Akt/ERK signaling. Our data indicate that modulating butyrate metabolism is an effective therapeutic strategy of metastatic colorectal cancer; and HDAC3 might be a novel target for management of colorectal cancer metastasis. [Mh] Termos MeSH primário: Butiratos/farmacologia Movimento Celular/efeitos dos fármacos Neoplasias Colorretais/tratamento farmacológico Neoplasias Colorretais/patologia Histona Desacetilases/metabolismo Sistema de Sinalização das MAP Quinases/efeitos dos fármacos [Mh] Termos MeSH secundário: Butiratos/metabolismo Butiratos/uso terapêutico Linhagem Celular Tumoral Inibidores de Histona Desacetilases Histona Desacetilases/fisiologia Seres Humanos Ácidos Hidroxâmicos/farmacologia Terapia de Alvo Molecular Metástase Neoplásica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Butyrates); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 58IFB293JI (vorinostat); EC 3.5.1.98 (Histone Deacetylases); EC 3.5.1.98 (histone deacetylase 3) [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: 171214 [St] Status: MEDLINE

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[PMID]: 29233643 [Au] Autor: Wood M; Rymarchyk S; Zheng S; Cen Y [Ad] Endereço: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 261 Mountain View Drive, Colchester, VT 05446, USA. [Ti] Título: Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6. [So] Source: Arch Biochem Biophys;638:8-17, 2018 01 15. [Is] ISSN: 1096-0384 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: SIRT6 is an epigenetic modification enzyme that regulates gene transcription through its deacetylase activity. In addition to histone protein, SIRT6 also modify other proteins and enzymes, some of which are central players in metabolic reprogramming and aging process. Therefore, SIRT6 has emerged as a therapeutic target for the treatment of metabolic disorder and age-related diseases. Here, we report that SIRT6 deacetylates lysine 382 of p53 in short synthetic peptide sequence and in full length p53. Further studies showed that the deacetylation of H3K9Ac and p53K382Ac are insensitive to nicotinamide inhibition, but are sensitive to trichostatin A (TSA) inhibition. Detailed kinetic analysis revealed that TSA competes with the peptide substrate for inhibition, and this inhibition is unique to SIRT6 in the sirtuin family. Taken together, this study not only suggests potential roles of SIRT6 in regulating apoptosis and stress resistance via direct deacetylation of p53, but also provides lead compound for the development of potent and selective SIRT6 inhibitors. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Histonas Ácidos Hidroxâmicos/farmacologia Sirtuínas Proteína Supressora de Tumor p53 [Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos Células HEK293 Histonas/química Histonas/metabolismo Seres Humanos Peptídeos/química Peptídeos/farmacologia Sirtuínas/química Sirtuínas/metabolismo Proteína Supressora de Tumor p53/química Proteína Supressora de Tumor p53/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Histones); 0 (Hydroxamic Acids); 0 (Peptides); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 3X2S926L3Z (trichostatin A); EC 3.5.1.- (SIRT6 protein, human); EC 3.5.1.- (Sirtuins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180214 [Lr] Data última revisão: 180214 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171214 [St] Status: MEDLINE

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[PMID]: 29195073 [Au] Autor: Topper MJ; Vaz M; Chiappinelli KB; DeStefano Shields CE; Niknafs N; Yen RC; Wenzel A; Hicks J; Ballew M; Stone M; Tran PT; Zahnow CA; Hellmann MD; Anagnostou V; Strissel PL; Strick R; Velculescu VE; Baylin SB [Ad] Endereço: Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA; The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. [Ti] Título: Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. [So] Source: Cell;171(6):1284-1300.e21, 2017 Nov 30. [Is] ISSN: 1097-4172 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/ß-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC. [Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/terapia Quimioterapia Combinada Neoplasias Pulmonares/terapia Evasão Tumoral/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Apresentação do Antígeno/efeitos dos fármacos Antineoplásicos/uso terapêutico Azacitidina/uso terapêutico Carcinoma Pulmonar de Células não Pequenas/genética Carcinoma Pulmonar de Células não Pequenas/imunologia Linhagem Celular Tumoral Inibidores de Histona Desacetilases/uso terapêutico Ácidos Hidroxâmicos/uso terapêutico Imunoterapia Neoplasias Pulmonares/genética Neoplasias Pulmonares/imunologia Camundongos Linfócitos T/imunologia Transcriptoma Microambiente Tumoral [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); M801H13NRU (Azacitidine); Z02132R2QQ (givinostat hydrochloride) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180214 [Lr] Data última revisão: 180214 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171202 [St] Status: MEDLINE

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[PMID]: 28468311 [Au] Autor: Lu CY; Chang YC; Hua CH; Chuang C; Huang SH; Kung SH; Hour MJ; Lin CW [Ad] Endereço: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan. cylu0424@gmail.com. [Ti] Título: Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis. [So] Source: Int J Mol Sci;18(5), 2017 May 01. [Is] ISSN: 1422-0067 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Japanese encephalitis virus (JEV), a neurotropic flavivirus, annually causes over 30,000 Japanese Encephalitis (JE) cases in East and Southeast Asia. Histone deacetylases (HDACs) modulate lysine acetylation of histones and non-histone proteins, regulating many processes including inflammation and antiviral immune response. This study investigated antiviral activity of pan- and selective-HDAC inhibitors as host-targeting agents against JEV. Among HDAC inhibitors, selective HDAC6 inhibitors (tubastatin-A (TBSA) and tubacin) concentration-dependently inhibited JEV-induced cytopathic effect and apoptosis, as well as reduced virus yield in human cerebellar medulloblastoma cells. The 50% inhibitory concentration (IC50) values of virus yield was 0.26 µM for tubacin and 1.75 µM for TBSA, respectively. Tubacin (IC50 of 1.52 µM), but not TBSA, meaningfully blocked the production of intracellular infectious virus particles. In time-of-addition assays, the greatest potency of antiviral activity was observed in the mode of pre-treatment with tubacin (IC50 of 1.89 µM) compared to simultaneous (IC50 of 4.88 µM) and post-treatment (IC50 of 2.05 µM) modes. Interestingly, tubacin induced the hyperacetylation of a HDAC6 substrate Hsp90 and reduced the interaction of Hsp90 with JEV NS5 protein. Novobiocin, an Hsp90 inhibitor, diminished the NS5 protein amount and virus replication in JEV-infected cells. Meantime, tubacin suppressed the NS5 expression and antisense RNA genome synthesis in infected cells. Tubacin-induced Hsp90 hyperacetylation was suggested to influence the NS5 activity in JEV replication. Therefore, tubacin had a high potential of a host-targeting agent against JEV, exhibiting preventive and therapeutic activities against JEV infection. [Mh] Termos MeSH primário: Anilidas/farmacologia Antivirais/farmacologia Vírus da Encefalite Japonesa (Subgrupo)/fisiologia Inibidores de Histona Desacetilases/farmacologia Ácidos Hidroxâmicos/farmacologia Replicação Viral/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Linhagem Celular Linhagem Celular Tumoral Cricetinae Cricetulus Vírus da Encefalite Japonesa (Subgrupo)/efeitos dos fármacos Proteínas de Choque Térmico HSP90/metabolismo Desacetilase 6 de Histona/antagonistas & inibidores Seres Humanos RNA Viral/metabolismo Proteínas não Estruturais Virais/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anilides); 0 (Antiviral Agents); 0 (HSP90 Heat-Shock Proteins); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (RNA, Viral); 0 (Viral Nonstructural Proteins); 02C2G1D30D (tubacin); EC 3.5.1.98 (HDAC6 protein, human); EC 3.5.1.98 (Histone Deacetylase 6) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180202 [Lr] Data última revisão: 180202 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE

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[PMID]: 28448670 [Au] Autor: Futakuchi A; Inoue T; Fujimoto T; Kuroda U; Inoue-Mochita M; Takahashi E; Ohira S; Tanihara H [Ad] Endereço: Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. [Ti] Título: Molecular Mechanisms Underlying the Filtration Bleb-Maintaining Effects of Suberoylanilide Hydroxamic Acid (SAHA). [So] Source: Invest Ophthalmol Vis Sci;58(4):2421-2429, 2017 04 01. [Is] ISSN: 1552-5783 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Purpose: Suberoylanilide hydroxamic acid (SAHA) has been shown to support the maintenance of experimental filtration blebs in animal models. This study was performed to investigate the molecular mechanisms underlying the bleb-maintaining effects of SAHA in modulating wound healing activities of conjunctival fibroblasts. Methods: Human conjunctival fibroblasts (HConFs) were pretreated with SAHA before treatment with TGF-ß2. Microarray-based screening was used to investigate the gene expression profiles. Gene ontology (GO) analysis was conducted to categorize the gene functions. The expression of TGF-ß-induced signaling molecules, α-smooth muscle actin, and extracellular matrix (ECM) proteins were evaluated by Western blot analyses. Multiplex immunoassay was performed to evaluate supernatant cytokine concentrations. Tube formation assay was used to evaluate angiogenesis using human umbilical vein endothelial cells. Results: GO analysis showed that SAHA, in the presence of TGF-ß2, induced changes in expression of genes involved in the TGF-ß receptor signaling pathway, cell proliferation, extracellular matrix organization, inflammatory responses, and angiogenesis. Subsequent in vitro experiments showed that SAHA partly inhibited the phosphorylation of Smad2, Smad3, and Akt. SAHA pretreatment potently suppressed TGF-ß2-driven cell proliferation, myofibroblast differentiation, contraction, ECM production, and angiogenic cytokine expression. The supernatant of HConFs treated with SAHA inhibited tube formation. Conclusions: SAHA has been shown to suppress angiogenesis and activation of conjunctival fibroblasts partly via inhibition of Smad and non-Smad TGF-ß signaling. This in vitro study provides new evidence for the molecular basis of the potential bleb-maintaining effects of SAHA, a novel candidate drug in modulating scar formation after glaucoma filtration surgery. [Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia Túnica Conjuntiva/efeitos dos fármacos Fibroblastos/efeitos dos fármacos Inibidores de Histona Desacetilases/farmacocinética Ácidos Hidroxâmicos/farmacologia [Mh] Termos MeSH secundário: Vesícula/metabolismo Movimento Celular/efeitos dos fármacos Proliferação Celular/efeitos dos fármacos Células Cultivadas Colágeno Tipo I/metabolismo Túnica Conjuntiva/citologia Citocinas/metabolismo Proteínas da Matriz Extracelular/metabolismo Fibroblastos/metabolismo Cirurgia Filtrante Perfilação da Expressão Gênica Seres Humanos Receptores de Fatores de Crescimento Transformadores beta/metabolismo Transdução de Sinais/efeitos dos fármacos Proteínas Smad/metabolismo Análise Serial de Tecidos Fator de Crescimento Transformador beta2/farmacologia Cicatrização/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Angiogenesis Inhibitors); 0 (Collagen Type I); 0 (Cytokines); 0 (Extracellular Matrix Proteins); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (Receptors, Transforming Growth Factor beta); 0 (Smad Proteins); 0 (Transforming Growth Factor beta2); 58IFB293JI (vorinostat) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 180118 [Lr] Data última revisão: 180118 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1167/iovs.16-21403

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