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  1 / 122577 MEDLINE  
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[PMID]:29370193
[Au] Autor:Kalita D; Holm DG; LaBarbera DV; Petrash JM; Jayanty SS
[Ad] Endereço:San Luis Valley Research Center, Department of Horticulture and Landscape Architecture, Colorado State University, Center, United States of America.
[Ti] Título:Inhibition of α-glucosidase, α-amylase, and aldose reductase by potato polyphenolic compounds.
[So] Source:PLoS One;13(1):e0191025, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diabetes mellitus is a chronic disease that is becoming a serious global health problem. Diabetes has been considered to be one of the major risks of cataract and retinopathy. Synthetic and natural product inhibitors of carbohydrate degrading enzymes are able to reduce type 2 diabetes and its complications. For a long time, potatoes have been portrayed as unhealthy for diabetic patients by some nutritionist due to their high starch content. However, purple and red potato cultivars have received considerable attention from consumers because they have high levels of polyphenolic compounds that have potent antioxidant activities. In this study, we screened the total phenolics (TP) and total anthocyanins (TA) and analyzed the phenolic and anthocyanin compounds in selected potato cultivars and advanced selections with distinct flesh colors (purple, red, yellow and white). Purple and red potato cultivars had higher levels of TP and TA than tubers with other flesh colors. Chlorogenic acid is the predominant phenolic acid, and major anthocyanin is composed of the derivatives of petunidin, peonidin, malvidin and pelargonidin. We tested the potential inhibitory effect of potato extracts on the activities of α-amylase and α-glucosidase, which were targeted to develop antidiabetic therapeutic agents. We also measured inhibitory effect of potato extracts on aldose reductase (AR) which is a key enzyme that has been a major drug target for the development of therapies to treat diabetic complications. Purple flesh tubers extract showed the most effective inhibition of α-amylase, α-glucosidase, and aldose reductase with IC50 values 25, 42, and 32 µg/ml, respectively. Kinetic studies showed that anthocyanins are noncompetitive inhibitors of these enzymes, whereas phenolic acids behaved as mixed inhibitors for α-amylase and α-glucosidase and noncompetitive inhibitors for AR. This study supports the development of a positive and healthful image of potatoes, which is an important issue for consumers.
[Mh] Termos MeSH primário: Aldeído Redutase/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Polifenóis/farmacologia
Solanum tuberosum/química
alfa-Amilases/antagonistas & inibidores
alfa-Glucosidases/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antocianinas/análise
Antocianinas/farmacologia
Cromatografia Líquida
Espectrometria de Massas
Polifenóis/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anthocyanins); 0 (Enzyme Inhibitors); 0 (Polyphenols); EC 1.1.1.21 (Aldehyde Reductase); EC 3.2.1.1 (alpha-Amylases); EC 3.2.1.20 (alpha-Glucosidases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191025


  2 / 122577 MEDLINE  
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[PMID]:29268128
[Au] Autor:Jafari B; Ospanov M; Ejaz SA; Yelibayeva N; Khan SU; Amjad ST; Safarov S; Abilov ZA; Turmukhanova MZ; Kalugin SN; Ehlers P; Lecka J; Sévigny J; Iqbal J; Langer P
[Ad] Endereço:Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany.
[Ti] Título:2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study.
[So] Source:Eur J Med Chem;144:116-127, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (P /PP ) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4-thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies.
[Mh] Termos MeSH primário: Fosfatase Alcalina/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Pirimidinonas/química
Pirimidinonas/farmacologia
Tiadiazóis/química
Tiadiazóis/farmacologia
[Mh] Termos MeSH secundário: Fosfatase Alcalina/metabolismo
Inibidores Enzimáticos/síntese química
Halogenação
Seres Humanos
Simulação de Acoplamento Molecular
Pirimidinonas/síntese química
Relação Estrutura-Atividade
Tiadiazóis/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Pyrimidinones); 0 (Thiadiazoles); EC 3.1.3.1 (Alkaline Phosphatase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


  3 / 122577 MEDLINE  
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[PMID]:29247860
[Au] Autor:Schulz-Fincke J; Hau M; Barth J; Robaa D; Willmann D; Kürner A; Haas J; Greve G; Haydn T; Fulda S; Lübbert M; Lüdeke S; Berg T; Sippl W; Schüle R; Jung M
[Ad] Endereço:Institute of Pharmaceutical Sciences, University of Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
[Ti] Título:Structure-activity studies on N-Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation.
[So] Source:Eur J Med Chem;144:52-67, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase-inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N-substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals. Here, we show that N-substituted 2-PCPA derivatives without a basic function or even a polar group are still potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture. Yet, these lipophilic inhibitors also block the structurally related monoamine oxidases (MAO-A and MAO-B), which may be of interest for the treatment of neurodegenerative disorders, but this property is undesired for applications in cancer treatment. The introduction of a polar, non-basic function led to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells. Cellular target engagement is shown via a Cellular Thermal Shift Assay (CETSA) for LSD1.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Histona Desmetilases/antagonistas & inibidores
Tranilcipromina/análogos & derivados
Tranilcipromina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Histona Desmetilases/metabolismo
Seres Humanos
Leucemia/tratamento farmacológico
Leucemia/metabolismo
Leucemia/patologia
Camundongos
Modelos Moleculares
Inibidores da Monoaminoxidase/química
Inibidores da Monoaminoxidase/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Monoamine Oxidase Inhibitors); 3E3V44J4Z9 (Tranylcypromine); EC 1.14.11.- (Histone Demethylases); EC 1.5.- (KDM1A protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  4 / 122577 MEDLINE  
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[PMID]:29247859
[Au] Autor:Zhao S; Li K; Jin Y; Lin J
[Ad] Endereço:Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
[Ti] Título:Synthesis and biological evaluation of novel 1-(aryl-aldehyde-oxime)uracil derivatives as a new class of thymidine phosphorylase inhibitors.
[So] Source:Eur J Med Chem;144:41-51, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC values ranging between 0.12 ± 0.05 and 7.2 ± 1.4 µM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC is from 10.7 to 39.9 µM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Timidina Fosforilase/antagonistas & inibidores
Uracila/análogos & derivados
Uracila/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/síntese química
Inibidores da Angiogênese/química
Inibidores da Angiogênese/farmacologia
Inibidores Enzimáticos/síntese química
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Concentração Inibidora 50
Modelos Moleculares
Oximas/síntese química
Oximas/química
Oximas/farmacologia
Relação Estrutura-Atividade
Timidina Fosforilase/metabolismo
Uracila/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Enzyme Inhibitors); 0 (Oximes); 56HH86ZVCT (Uracil); EC 2.4.2.4 (Thymidine Phosphorylase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  5 / 122577 MEDLINE  
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[PMID]:29216900
[Au] Autor:Ribas L; Vanezis K; Imués MA; Piferrer F
[Ad] Endereço:Institut de Ciències del Mar, Consejo Superior de Investigaciones Científicas (CSIC), Passeig Marítim, 37-45, 08003, Barcelona, Spain.
[Ti] Título:Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads.
[So] Source:Epigenetics Chromatin;10(1):59, 2017 12 08.
[Is] ISSN:1756-8935
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The role of epigenetic modifications such as DNA methylation during vertebrate sexual development is far from being clear. Using the zebrafish model, we tested the effects of one of the most common DNA methyltransferase (dnmt) inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), which is approved for the treatment of acute myeloid leukaemia and is under active investigation for the treatment of solid tumours. Several dose-response experiments were carried out during two periods, including not only the very first days of development (0-6 days post-fertilization, dpf), as done in previous studies, but also, and as a novelty, the period of gonadal development (10-30 dpf). RESULTS: Early treatment with 5-aza-dC altered embryonic development, delayed hatching and increased teratology and mortality, as expected. The most striking result, however, was an increase in the number of females, suggesting that alterations induced by 5-aza-dC treatment can affect sexual development as well. Results were confirmed when treatment coincided with gonadal development. In addition, we also found that the adult gonadal transcriptome of 5-aza-dC-exposed females included significant changes in the expression of key reproduction-related genes (e.g. cyp11a1, esr2b and figla), and that several pro-female-related pathways such as the Fanconi anaemia or the Wnt signalling pathways were downregulated. Furthermore, an overall inhibition of genes implicated in epigenetic regulatory mechanisms (e.g. dnmt1, dicer, cbx4) was also observed. CONCLUSIONS: Taken together, our results indicate that treatment with a DNA methylation inhibitor can also alter the sexual development in zebrafish, with permanent alterations of the adult gonadal transcriptome, at least in females. Our results show the importance of DNA methylation for proper control of sexual development, open new avenues for the potential control of sex ratios in fish (aquaculture, population control) and call attention to possibly hidden long-term effects of dnmt therapy when used, for example, in the treatment of prepuberal children affected by some types of cancer.
[Mh] Termos MeSH primário: Metilases de Modificação do DNA/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Feminização/induzido quimicamente
Ovário/efeitos dos fármacos
Peixe-Zebra/embriologia
[Mh] Termos MeSH secundário: Animais
Azacitidina/análogos & derivados
Azacitidina/farmacologia
Relação Dose-Resposta a Droga
Feminino
Masculino
Ovário/metabolismo
Razão de Masculinidade
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 776B62CQ27 (decitabine); EC 2.1.1.- (DNA Modification Methylases); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180310
[Lr] Data última revisão:
180310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1186/s13072-017-0168-7


  6 / 122577 MEDLINE  
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[PMID]:28463568
[Au] Autor:Salinas G; Gao W; Wang Y; Bonilla M; Yu L; Novikov A; Virginio VG; Ferreira HB; Vieites M; Gladyshev VN; Gambino D; Dai S
[Ad] Endereço:1 Worm Biology Lab, Institut Pasteur de Montevideo , Montevideo, Uruguay .
[Ti] Título:The Enzymatic and Structural Basis for Inhibition of Echinococcus granulosus Thioredoxin Glutathione Reductase by Gold(I).
[So] Source:Antioxid Redox Signal;27(18):1491-1504, 2017 Dec 20.
[Is] ISSN:1557-7716
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: New drugs are needed to treat flatworm infections that cause severe human diseases such as schistosomiasis. The unique flatworm enzyme thioredoxin glutathione reductase (TGR), structurally different from the human enzyme, is a key drug target. Structural studies of the flatworm Echinococcus granulosus TGR, free and complexed with Au -MPO, a novel gold inhibitor, together with inhibition assays were performed. RESULTS: Au -MPO is a potent TGR inhibitor that achieves 75% inhibition at a 1:1 TGR:Au ratio and efficiently kills E. granulosus in vitro. The structures revealed salient insights: (i) unique monomer-monomer interactions, (ii) distinct binding sites for thioredoxin and the glutaredoxin (Grx) domain, (iii) a single glutathione disulfide reduction site in the Grx domain, (iv) rotation of the Grx domain toward the Sec-containing redox active site, and (v) a single gold atom bound to Cys and Cys in the Au -TGR complex. Structural modeling suggests that these residues are involved in the stabilization of the Sec-containing C-terminus. Consistently, Cys→Ser mutations in these residues decreased TGR activities. Mass spectroscopy confirmed these cysteines are the primary binding site. INNOVATION: The identification of a primary site for gold binding and the structural model provide a basis for gold compound optimization through scaffold adjustments. CONCLUSIONS: The structural study revealed that TGR functions are achieved not only through a mobile Sec-containing redox center but also by rotation of the Grx domain and distinct binding sites for Grx domain and thioredoxin. The conserved Cys and Cys residues targeted by gold assist catalysis through stabilization of the Sec-containing redox center. Antioxid. Redox Signal. 27, 1491-1504.
[Mh] Termos MeSH primário: Echinococcus granulosus/enzimologia
Complexos Multienzimáticos/química
Complexos Multienzimáticos/metabolismo
NADH NADPH Oxirredutases/química
NADH NADPH Oxirredutases/metabolismo
Compostos Organoáuricos/farmacologia
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/efeitos dos fármacos
Cisteína/metabolismo
Echinococcus granulosus/química
Echinococcus granulosus/genética
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacocinética
Glutarredoxinas/metabolismo
Proteínas de Helminto/química
Proteínas de Helminto/genética
Proteínas de Helminto/metabolismo
Modelos Moleculares
Complexos Multienzimáticos/genética
Mutação
NADH NADPH Oxirredutases/genética
Compostos Organoáuricos/química
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Glutaredoxins); 0 (Helminth Proteins); 0 (Multienzyme Complexes); 0 (Organogold Compounds); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.4.- (thioredoxin glutathione reductase); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1089/ars.2016.6816


  7 / 122577 MEDLINE  
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[PMID]:29458547
[Au] Autor:Growcott EJ; Bamba D; Galarneau JR; Leonard VHJ; Schul W; Stein D; Osborne CS
[Ad] Endereço:1​Novartis Institutes for Biomedical Research, Infectious Disease, Emeryville, CA, USA.
[Ti] Título:The effect of P38 MAP kinase inhibition in a mouse model of influenza.
[So] Source:J Med Microbiol;67(3):452-462, 2018 Mar.
[Is] ISSN:1473-5644
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Influenza viruses are a common cause of human respiratory infections, resulting in epidemics of high morbidity and mortality. We investigated the effect of a novel mitogen-activated protein kinase (MAPK) inhibitor in vitro and in a murine influenza model to further explore whether p38 MAPK inhibition could reduce viral replication. METHODS: In vitro, the antiviral effect of p38 MAPK inhibitor BCT194 was evaluated in differentiated human bronchial epithelial cells (HBECs); in vivo, female BALB/c mice were infected intranasally with 150 pfu of influenza H1N1 A/Puerto Rico/8/34 and treated with BCT197 (a closely related p38 MAPK inhibitor with an IC50 value of<1 µM, currently in clinical testing), dexamethasone or oseltamivir (Tamiflu) starting 24 h post infection. Body weight, bronchoalveolar lavage cells, cytokines, total protein and lactate dehydrogenase as well as serum cytokines were measured; a subset of animals was evaluated histopathologically.Results/Key findings. p38MAP kinase inhibition with BCT194 had no impact on influenza replication in HBECs. When examining BCT197 in vivo, and comparing to vehicle-treated animals, reduced weight loss, improvement in survival and lack of impaired viral control was observed at BCT197 concentrations relevant to those being used in clinical trials of acute exacerbations of chronic obstructive pulmonary disease; at higher concentrations of BCT197 these effects were reduced. CONCLUSIONS: Compared to vehicle treatment, BCT197 (administered at a clinically relevant concentration) improved outcomes in a mouse model of influenza. This is encouraging given that the use of innate inflammatory pathway inhibitors may raise concerns of negative effects on infection regulation.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Inibidores Enzimáticos/farmacologia
Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos
Infecções por Orthomyxoviridae/virologia
Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antivirais/administração & dosagem
Antivirais/uso terapêutico
Brônquios/citologia
Linhagem Celular
Citocinas/sangue
Dexametasona/uso terapêutico
Modelos Animais de Doenças
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/uso terapêutico
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/virologia
Feminino
Seres Humanos
Vírus da Influenza A Subtipo H1N1/fisiologia
Influenza Humana/tratamento farmacológico
Influenza Humana/virologia
Camundongos
Camundongos Endogâmicos BALB C
Infecções por Orthomyxoviridae/tratamento farmacológico
Oseltamivir/uso terapêutico
Resultado do Tratamento
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Cytokines); 0 (Enzyme Inhibitors); 20O93L6F9H (Oseltamivir); 7S5I7G3JQL (Dexamethasone); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[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:180221
[St] Status:MEDLINE
[do] DOI:10.1099/jmm.0.000684


  8 / 122577 MEDLINE  
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[PMID]:29177308
[Au] Autor:Fang K; Wu S; Dong G; Wu Y; Chen S; Liu J; Wang W; Sheng C
[Ad] Endereço:School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China. wwang@unm.edu.
[Ti] Título:Discovery of IDO1 and DNA dual targeting antitumor agents.
[So] Source:Org Biomol Chem;15(47):9992-9995, 2017 Dec 06.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The development of small molecules for cancer immunotherapy is highly challenging and indoleamine 2,3-dioxygenase 1 (IDO1) represents a promising target. Inspired by the synergistic effects between IDO1 inhibitors and traditional antitumor chemotherapeutics, the first orally active dual IDO1 and DNA targeting agents were designed by the pharmacophore fusion strategy. The bifunctional hybrids exhibited enhanced IDO1 enzyme inhibitory activity and in vitro cytotoxicity as compared to IDO1 inhibitor 1-methyl-tryptophan and DNA alkylating agent melphalan. In a murine LLC tumor model, the dual targeting agents demonstrated excellent antitumor efficacy, highlighting the advantages of this novel design strategy to improve the efficacy of small molecule cancer immunotherapy.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA de Neoplasias/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores
Melfalan/farmacologia
Triptofano/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Descoberta de Drogas
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Imunoterapia
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
Melfalan/síntese química
Melfalan/química
Camundongos
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Relação Estrutura-Atividade
Triptofano/síntese química
Triptofano/química
Triptofano/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-methyltryptophan); 0 (Antineoplastic Agents); 0 (DNA, Neoplasm); 0 (Enzyme Inhibitors); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (indoleamine 2,3-dioxygenase 1, human); 8DUH1N11BX (Tryptophan); Q41OR9510P (Melphalan)
[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:171128
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob02529g


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[PMID]:29295999
[Au] Autor:Han S; Ren Y; He W; Liu H; Zhi Z; Zhu X; Yang T; Rong Y; Ma B; Purwin TJ; Ouyang Z; Li C; Wang X; Wang X; Yang H; Zheng Y; Aplin AE; Liu J; Shao Y
[Ad] Endereço:Frontier Institute of Science and Technology, and Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
[Ti] Título:ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.
[So] Source:Nat Commun;9(1):28, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica/genética
Melanoma/genética
Mutação
Proteínas Proto-Oncogênicas B-raf/genética
Fatores de Transcrição SOXE/genética
Neoplasias Cutâneas/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Inibidores Enzimáticos/farmacologia
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Indóis/farmacologia
Melanoma/tratamento farmacológico
Melanoma/metabolismo
Camundongos Endogâmicos BALB C
Camundongos Nus
Fosforilação
Proteínas Proto-Oncogênicas B-raf/metabolismo
Interferência de RNA
Receptor ErbB-3/genética
Receptor ErbB-3/metabolismo
Fatores de Transcrição SOXE/metabolismo
Neoplasias Cutâneas/tratamento farmacológico
Neoplasias Cutâneas/metabolismo
Sulfonamidas/farmacologia
Sumoilação
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (FOXD3 protein, human); 0 (Forkhead Transcription Factors); 0 (Indoles); 0 (SOX10 protein, human); 0 (SOXE Transcription Factors); 0 (Sulfonamides); 207SMY3FQT (vemurafenib); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, ErbB-3); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02354-x


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[PMID]:29302025
[Au] Autor:Guéant JL; Chéry C; Oussalah A; Nadaf J; Coelho D; Josse T; Flayac J; Robert A; Koscinski I; Gastin I; Filhine-Tresarrieu P; Pupavac M; Brebner A; Watkins D; Pastinen T; Montpetit A; Hariri F; Tregouët D; Raby BA; Chung WK; Morange PE; Froese DS; Baumgartner MR; Benoist JF; Ficicioglu C; Marchand V; Motorin Y; Bonnemains C; Feillet F; Majewski J; Rosenblatt DS
[Ad] Endereço:INSERM, UMR_S954 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy), 54505, Nancy, France. jean-louis.gueant@univ-lorraine.fr.
[Ti] Título:APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.
[So] Source:Nat Commun;9(1):67, 2018 01 04.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.
[Mh] Termos MeSH primário: Proteínas de Transporte/genética
Epistasia Genética
Erros Inatos do Metabolismo/genética
Mutação
Peroxirredoxinas/genética
Vitamina B 12/metabolismo
[Mh] Termos MeSH secundário: Alelos
Azacitidina/farmacologia
Sequência de Bases
Inibidores Enzimáticos/farmacologia
Saúde da Família
Feminino
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Heterozigoto
Seres Humanos
Masculino
Erros Inatos do Metabolismo/metabolismo
Linhagem
Sequenciamento Completo do Genoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Enzyme Inhibitors); 0 (MMACHC protein, human); EC 1.11.1.15 (PRDX1 protein, human); EC 1.11.1.15 (Peroxiredoxins); M801H13NRU (Azacitidine); P6YC3EG204 (Vitamin B 12)
[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:180106
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02306-5



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