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[PMID]: 29267500 [Au] Autor: Vieira E; Maia HS; Monteiro CB; Carvalho LM; Tonon T; Vanz AP; Schwartz IVD; Ribeiro MG [Ad] Endereço: Agência Nacional de Saúde Suplementar, Rio de Janeiro, RJ, Brasil. [Ti] Título: Quality of life and adherence to treatment in early-treated Brazilian phenylketonuria pediatric patients. [So] Source: Braz J Med Biol Res;51(2):e6709, 2017 Dec 11. [Is] ISSN: 1414-431X [Cp] País de publicação: Brazil [La] Idioma: eng [Ab] Resumo: Early dietary treatment of phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, results in normal cognitive development. Although health-related quality of life (HRQoL) of PKU patients has been reported as unaffected in high-income countries, there are scarce data concerning HRQoL and adherence to treatment of PKU children and adolescents from Brazil. The present study compared HRQoL scores in core dimensions of Brazilian early-treated PKU pediatric patients with those of a reference population, and explored possible relationships between adherence to treatment and HRQoL. Early-treated PKU pediatric patient HRQoL was evaluated by self- and parent-proxy reports of the Pediatric Quality of Life Inventory (PedsQL) core scales. Adherence to treatment was evaluated by median Phe levels and percentage of results within the therapeutic target range in two periods. Means for total and core scales scores of PedsQL self- and parent proxy-reports of PKU patients were significantly lower than their respective means for controls. Adequacy of median Phe concentrations and the mean percentage of values in the target range fell substantially from the first year of life to the last year of this study. There was no significant difference in mean total and core scale scores for self- and parent proxy-reports between patients with adequate and those with inadequate median Phe concentrations. The harmful consequences for intellectual capacity caused by poor adherence to dietary treatment could explain the observed decrease in all HRQoL scales, especially in school functioning. Healthcare system and financial difficulties may also have influenced negatively all HRQoL dimensions. [Mh] Termos MeSH primário: Fenilcetonúrias/dietoterapia Qualidade de Vida Cooperação e Adesão ao Tratamento/estatística & dados numéricos [Mh] Termos MeSH secundário: Adolescente Fatores Etários Análise de Variância Brasil Criança Feminino Seres Humanos Testes de Inteligência Modelos Lineares Masculino Pais Fenilalanina/sangue Fenilcetonúrias/psicologia Procurador Qualidade de Vida/psicologia Prevenção Secundária Autorrelato Fatores Socioeconômicos Fatores de Tempo Cooperação e Adesão ao Tratamento/psicologia Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 47E5O17Y3R (Phenylalanine) [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: 171222 [St] Status: MEDLINE

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[PMID]: 29339755 [Au] Autor: Rout SK; Friedmann MP; Riek R; Greenwald J [Ad] Endereço: Laboratory of Physical Chemistry, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland. [Ti] Título: A prebiotic template-directed peptide synthesis based on amyloids. [So] Source: Nat Commun;9(1):234, 2018 01 16. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The prebiotic replication of information-coding molecules is a central problem concerning life's origins. Here, we report that amyloids composed of short peptides can direct the sequence-selective, regioselective and stereoselective condensation of amino acids. The addition of activated DL-arginine and DL-phenylalanine to the peptide RFRFR-NH in the presence of the complementary template peptide Ac-FEFEFEFE-NH yields the isotactic product FRFRFRFR-NH , 1 of 64 possible triple addition products, under conditions in which the absence of template yields only single and double additions of mixed stereochemistry. The templating mechanism appears to be general in that a different amyloid formed by (Orn)V(Orn)V(Orn)V(Orn)V-NH and Ac-VDVDVDVDV-NH is regioselective and stereoselective for N-terminal, L-amino-acid addition while the ornithine-valine peptide alone yields predominantly sidechain condensation products with little stereoselectivity. Furthermore, the templating reaction is stable over a wide range of pH (5.6-8.6), salt concentration (0-4 M NaCl), and temperature (25-90 °C), making the amyloid an attractive model for a prebiotic peptide replicating system. [Mh] Termos MeSH primário: Aminoácidos/química Amiloide/química Técnicas de Química Sintética/métodos Peptídeos/química [Mh] Termos MeSH secundário: Sequência de Aminoácidos Aminoácidos/genética Aminoácidos/metabolismo Amiloide/metabolismo Amiloide/ultraestrutura Arginina/química Arginina/genética Arginina/metabolismo Concentração de Íons de Hidrogênio Microscopia Eletrônica Origem da Vida Biossíntese Peptídica/genética Peptídeos/genética Peptídeos/metabolismo Fenilalanina/química Fenilalanina/genética Fenilalanina/metabolismo Cloreto de Sódio/química Estereoisomerismo Temperatura Ambiente Moldes Genéticos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amino Acids); 0 (Amyloid); 0 (Peptides); 451W47IQ8X (Sodium Chloride); 47E5O17Y3R (Phenylalanine); 94ZLA3W45F (Arginine) [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: 180118 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-017-02742-3

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[PMID]: 29360847 [Au] Autor: Sutanto EN; Scaffidi A; Garratt LW; Looi K; Foo CJ; Tessari MA; Janssen RA; Fischer DF; Stick SM; Kicic A; AREST CF [Ad] Endereço: Telethon Kids Institute, the University of Western Australia, Nedlands, Western Australia, Australia. [Ti] Título: Assessment of p.Phe508del-CFTR functional restoration in pediatric primary cystic fibrosis airway epithelial cells. [So] Source: PLoS One;13(1):e0191618, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can reduce function of the CFTR ion channel activity and impair cellular chloride secretion. The gold standard method to assess CFTR function of ion transport using the Ussing chamber requires a high number of airway epithelial cells grown at air-liquid interface, limiting the application of this method for high throughput screening of potential therapeutic compounds in primary airway epithelial cells (pAECs) featuring less common CFTR mutations. This study assessed an alternative approach, using a small scale halide assay that can be adapted for a personalized high throughput setting to analyze CFTR function of pAEC. METHODS: Pediatric pAECs derived from children with CF (pAECCF) were established and expanded as monolayer cultures, before seeding into 96-well plates for the halide assay. Cells were then transduced with an adenoviral construct containing yellow fluorescent protein (eYFP) reporter gene, alone or in combination with either wild-type CFTR (WT-CFTR) or p.Phe508del CFTR. Four days post transduction, cells were stimulated with forskolin and genistein, and assessed for quenching of the eYFP signal following injection of iodide solution into the assay media. RESULTS: Data showed that pAECCF can express eYFP at high efficiency following transduction with the eYFP construct. The halide assay was able to discriminate functional restoration of CFTR in pAECCF treated with either WT-CFTR construct or the positive controls syntaxin 8 and B-cell receptor-associated protein 31 shRNAs. SIGNIFICANCE: The current study demonstrates that the halide assay can be adapted for pediatric pAECCF to evaluate restoration of CFTR function. With the ongoing development of small molecules to modulate the folding and/or activity of various mutated CFTR proteins, this halide assay presents a small-scale personalized screening platform that could assess therapeutic potential of molecules across a broad range of CFTR mutations. [Mh] Termos MeSH primário: Brônquios/metabolismo Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia Fibrose Cística/fisiopatologia Fenilalanina/química Traqueia/metabolismo [Mh] Termos MeSH secundário: Adenoviridae/genética Brônquios/citologia Células Cultivadas Criança Fibrose Cística/patologia Regulador de Condutância Transmembrana em Fibrose Cística/química Regulador de Condutância Transmembrana em Fibrose Cística/genética Células Epiteliais/metabolismo Vetores Genéticos Seres Humanos Transporte Proteico Traqueia/citologia Transdução Genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 47E5O17Y3R (Phenylalanine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180124 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191618

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[PMID]: 29336152 [Au] Autor: Fu B; Xu T; Cui Z; Ng HL; Wang K; Li J; Li QX [Ad] Endereço: Beijing Key Laboratory of Biodiversity and Organic Farming, College of Resources and Environmental Sciences, China Agricultural University , 2 Yuanmingyuan West Road, Beijing 100193, China. [Ti] Título: Mutation of Phenylalanine-223 to Leucine Enhances Transformation of Benzo[a]pyrene by Ring-Hydroxylating Dioxygenase of Sphingobium sp. FB3 by increasing Accessibility of the Catalytic Site. [So] Source: J Agric Food Chem;66(5):1206-1213, 2018 Feb 07. [Is] ISSN: 1520-5118 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Burning of agricultural biomass generates polycyclic aromatic hydrocarbons (PAHs) including the carcinogen benzo[a]pyrene, of which the catabolism is primarily initiated by a ring-hydroxylating dioxygenase (RHD). This study explores catalytic site accessibility and its role in preferential catabolism of some PAHs over others. The genes flnA1f, flnA2f, flnA3, and flnA4, encoding the oxygenase α and ß subunits, ferredoxin, and ferredoxin reductase, respectively, of the RHD enzyme complex (FlnA) were cloned from Sphingobium sp. FB3 and coexpressed in E. coli BL21. The FlnA effectively transformed fluoranthene but not benzo[a]pyrene. Substitution of the bulky phenylalanine-223 by leucine reduces the steric constraint in the substrate entrance to make the catalytic site of FlnA more accessible to large substrates, as visualized by 3D modeling, and allows the FlnA mutant to efficiently transform benzo[a]pyrene. Accessibility of the catalytic site to PAHs is a mechanism of RHD substrate specificity. The results shed light on why some PAHs are more recalcitrant than others. [Mh] Termos MeSH primário: Benzo(a)pireno/metabolismo Domínio Catalítico/fisiologia Dioxigenases/metabolismo Leucina/genética Mutação Fenilalanina/genética [Mh] Termos MeSH secundário: Biodegradação Ambiental Clonagem Molecular Dioxigenases/genética Escherichia coli/genética Fluorenos/metabolismo Expressão Gênica Hidroxilação Leucina/química Fenilalanina/química Hidrocarbonetos Aromáticos Policíclicos/metabolismo Proteobactérias/enzimologia Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Fluorenes); 0 (Polycyclic Aromatic Hydrocarbons); 3417WMA06D (Benzo(a)pyrene); 360UOL779Z (fluoranthene); 47E5O17Y3R (Phenylalanine); EC 1.13.11.- (Dioxygenases); GMW67QNF9C (Leucine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180117 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jafc.7b05018

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[PMID]: 29181548 [Au] Autor: Senín A; Fernández-Rodríguez C; Bellosillo B; Camacho L; Longarón R; Angona A; Besses C; Álvarez-Larrán A [Ad] Endereço: Hematology Department, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universidad Autónoma de Barcelona, Passeig Marítim 25-29, 08003, Barcelona, Spain. [Ti] Título: Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up. [So] Source: Ann Hematol;97(3):443-451, 2018 Mar. [Is] ISSN: 1432-0584 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1-6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6-57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4-49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation. [Mh] Termos MeSH primário: Transformação Celular Neoplásica/genética Janus Quinase 2/genética Mutação de Sentido Incorreto Policitemia Vera/genética Trombocitemia Essencial/genética [Mh] Termos MeSH secundário: Adulto Idoso Idoso de 80 Anos ou mais Alelos Substituição de Aminoácidos Análise Citogenética Progressão da Doença Feminino Seguimentos Frequência do Gene Seres Humanos Masculino Meia-Idade Fenilalanina/genética Policitemia Vera/patologia Trombocitemia Essencial/patologia Valina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 47E5O17Y3R (Phenylalanine); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2); HG18B9YRS7 (Valine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171129 [St] Status: MEDLINE [do] DOI: 10.1007/s00277-017-3193-5

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[PMID]: 29224335 [Au] Autor: Hidalgo FJ; Navarro JL; Zamora R [Ad] Endereço: Instituto de la Grasa, Consejo Superior de Investigaciones Científicas , Carretera de Utrera km 1, Campus Universitario - Edificio 46, 41013-Seville, Spain. [Ti] Título: Structure-Activity Relationship (SAR) of Phenolics for 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Formation in Phenylalanine/Creatinine Reaction Mixtures Including (or Not) Oxygen and Lipid Hydroperoxides. [So] Source: J Agric Food Chem;66(1):255-264, 2018 Jan 10. [Is] ISSN: 1520-5118 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Phenolics can act as either promoters or inhibitors in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation. In an attempt to clarify the structure-activity relationship (SAR) of phenolics for this reaction, the formation of PhIP in mixtures of phenylalanine, creatinine, 13-hydroperoxide of linoleic acid (LOOH) or 4-oxo-2-nonenal, and a wide array of phenolics was studied in the presence and in the absence of oxygen. The obtained results suggested that those phenolics having a high carbonyl scavenging ability inhibited the formation of PhIP. On the other hand, those phenolics that mainly acted as free radical scavengers and, therefore, were easily converted into quinones promoted the formation of PhIP. Phenolics of the first type were m-diphenols and 1,3,5-triphenols. Phenolics of the second type were o- and p-diphenols. Other phenolics, like 1,2,3- and 1,2,4-triphenols, exhibited a behavior either as carbonyl scavengers or as free radical scavengers depending on ring substitutions. Among the studied derivatives, the presence of a carboxylic or a methoxyl group at certain positions inhibited their behavior as carbonyl scavengers and, therefore, promoted the formation of PhIP. A procedure to classify phenolics as either carbonyl or free radical scavengers is proposed. [Mh] Termos MeSH primário: Creatinina/química Imidazóis/química Peróxidos Lipídicos/química Oxigênio/química Fenóis/química Fenilalanina/química [Mh] Termos MeSH secundário: Estrutura Molecular Oxirredução Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Imidazoles); 0 (Lipid Peroxides); 0 (Phenols); 47E5O17Y3R (Phenylalanine); 909C6UN66T (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine); AYI8EX34EU (Creatinine); S88TT14065 (Oxygen) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180205 [Lr] Data última revisão: 180205 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171212 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jafc.7b04859

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[PMID]: 28456080 [Au] Autor: Tang C; Nie D; Tang G; Gao S; Liu S; Wen F; Tang X [Ad] Endereço: Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application PET-CT Center and Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-Se [Ti] Título: Radiosynthesis and biological evaluation of N-(2-[ F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine as a PET tracer for oncologic imaging. [So] Source: Nucl Med Biol;50:39-46, 2017 Jul. [Is] ISSN: 1872-9614 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Several C and F labeled 3,4-dihydroxy-l-phenylalanine (l-DOPA) analogues have been used for neurologic and oncologic diseases, especially for brain tumors and neuroendocrine tumors PET imaging. However, F-labeled N-substituted l-DOPA analogues have not been reported so far. In the current study, radiosynthesis and biological evaluation of a new F-labeled l-DOPA analogue, N-(2-[ F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine ([ F]FPDOPA) for tumor PET imaging are performed. METHODS: The synthesis of [ F]FPDOPA was via a two-step reaction sequence from 4-nitrophenyl-2-[ F]fluoropropionate ([ F]NFP). The biodistribution of [ F]FPDOPA was determined in normal Kunming mice. In vitro competitive inhibition and protein incorporation experiments were performed with SPC-A-1 lung adenocarcinoma cell lines. PET/CT studies of [ F]FPDOPA were conducted in C6 rat glioma and SPC-A-1 human lung adenocarcinoma and H460 human large cell lung cancer-bearing nude mice. RESULTS: [ F]FPDOPA was prepared with a decay-corrected radiochemical yield of 28±5% and a specific activity of 50±15GBq/µmol (n=10) within 125min. In vitro cell experiments showed that [ F]FPDOPA uptake in SPC-A-1 cells was primarily transported through Na -independent system L, with Na -dependent system B and system ASC partly involved in it. Biodistribution data in mice showed that renal-bladder route was the main excretory system of [ F]FPDOPA. PET imaging demonstrated intense accumulation of [ F]FPDOPA in several tumor xenografts, with (8.50±0.40)%ID/g in C6 glioma, (6.30±0.12)%ID/g in SPC-A-1 lung adenocarcinoma, and (6.50±0.10)%ID/g in H460 large cell lung cancer, respectively. CONCLUSION: A novel N-substituted F-labeled L-DOPA analogue [ F]FPDOPA is synthesized and evaluated in vitro and in vivo. The results support that [ F]FPDOPA seems to be a potential PET tracer for tumor imaging, especially be a better potential PET tracer than [ F]fluoro-2-deoxy-d-glucose ([ F]FDG) for brain tumor imaging. [Mh] Termos MeSH primário: Neoplasias/diagnóstico por imagem Fenilalanina/análogos & derivados Fenilalanina/síntese química Fenilalanina/farmacocinética Tomografia por Emissão de Pósitrons [Mh] Termos MeSH secundário: Animais Linhagem Celular Tumoral Técnicas de Química Sintética Estabilidade de Medicamentos Seres Humanos Camundongos Neoplasias/metabolismo Fenilalanina/química Traçadores Radioativos Radioquímica Ratos Distribuição Tecidual [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Radioactive Tracers); 47E5O17Y3R (Phenylalanine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180126 [Lr] Data última revisão: 180126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 28845687 [Au] Autor: Swain RP; Subudhi BB [Ad] Endereço: a Drug Development and Analysis Laboratory, School of Pharmaceutical Sciences , Siksha O Anusandhan University , Bhubaneswar , India. [Ti] Título: Effect of semicrystalline polymers on self-emulsifying solid dispersions of nateglinide: in vitro and in vivo evaluation. [So] Source: Drug Dev Ind Pharm;44(1):56-65, 2018 Jan. [Is] ISSN: 1520-5762 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: This study was undertaken to improve solubility and bioavailability of nateglinide by preparation of stable self-emulsifying solid dispersions (SESDs). The influence of semicrystalline polymers (poloxamer 407, gelucire 50/13) and method of preparation on dissolution behavior, in vivo performance and stability of nateglinide SESDs were investigated. After optimization, SESDs were prepared at 1:5 weight ratio of nateglinide and polymer individually. All the SESDs were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Aqueous solubility of nateglinide was enhanced by 91.82-fold. The SESDs (poloxamer 407-based solid dispersions) achieved rapid and complete drug release (∼100% within 45 min) at pH 2. The improved dissolution appeared to be well correlated with the enhanced bioavailability of nateglinide in rabbits. After oral administration of SESDs (poloxamer 407-based solid dispersions), C and AUC of nateglinide were increased by ∼2.92 and 1.77-folds, respectively, signifying the effectiveness of solid dispersions to improve the bioavailability of nateglinide. Stability during storage was established to show prevention of recrystallization. In conclusion, SESDs with poloxamer 407 in solvent method appeared to be an economic and promising technique to improve the dissolution, bioavailability, and stability of nateglinide. [Mh] Termos MeSH primário: Cicloexanos/química Portadores de Fármacos/química Emulsões/farmacocinética Fenilalanina/análogos & derivados Poloxâmero/química Polímeros/química Espectroscopia de Infravermelho com Transformada de Fourier/métodos [Mh] Termos MeSH secundário: Administração Oral Animais Disponibilidade Biológica Varredura Diferencial de Calorimetria Liberação Controlada de Fármacos Emulsões/química Fenilalanina/química Coelhos Solubilidade Difração de Raios X [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclohexanes); 0 (Drug Carriers); 0 (Emulsions); 0 (Polymers); 106392-12-5 (Poloxamer); 41X3PWK4O2 (nateglinide); 47E5O17Y3R (Phenylalanine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180111 [Lr] Data última revisão: 180111 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170829 [St] Status: MEDLINE [do] DOI: 10.1080/03639045.2017.1371739

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[PMID]: 29202403 [Au] Autor: Guo Y; Zhao Y; Wang G; Chen Y; Jiang Y; Ouyang L; Liu B [Ad] Endereço: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. [Ti] Título: Design, synthesis and structure-activity relationship of a focused library of ß-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer. [So] Source: Eur J Med Chem;143:402-418, 2018 Jan 01. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca /calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a ß-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity. After several rounds of kinase and anti-proliferative activity screening, we discovered an eEF2K inhibitor (21l) with best eEF2K enzymatic activity (IC of 5.5 µM) and anti-proliferative activity (MDA-MB-231 cells, IC of 12.6 µM, MDA-MB-436 cells, IC of 19.8 µM). Moreover, we found that 21l could induce cell death via the apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. Subsequently, we evaluated its anti-tumor activity and apoptosis-inducing mechanisms in vivo. These results suggested that 21l inhibited tumor growth by apoptosis in the xenograft mouse model of breast cancer (MDA-MB-231 and MDA-MB-436). Collectively, our results demonstrate a novel small-molecule inhibitor targeting eEF2K with mechanism of apoptosis and a therapeutic potential in breast cancer. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Neoplasias da Mama/tratamento farmacológico Quinase do Fator 2 de Elongação/antagonistas & inibidores Fenilalanina/farmacologia Inibidores de Proteínas Quinases/farmacologia Bibliotecas de Moléculas Pequenas/farmacologia [Mh] Termos MeSH secundário: Animais Antineoplásicos/síntese química Antineoplásicos/química Neoplasias da Mama/metabolismo Neoplasias da Mama/patologia Proliferação Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Desenho de Drogas Ensaios de Seleção de Medicamentos Antitumorais Quinase do Fator 2 de Elongação/metabolismo Feminino Seres Humanos Neoplasias Mamárias Experimentais/tratamento farmacológico Neoplasias Mamárias Experimentais/metabolismo Neoplasias Mamárias Experimentais/patologia Camundongos Estrutura Molecular Fenilalanina/síntese química Fenilalanina/química Inibidores de Proteínas Quinases/síntese química Inibidores de Proteínas Quinases/química Bibliotecas de Moléculas Pequenas/síntese química Bibliotecas de Moléculas Pequenas/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Small Molecule Libraries); 47E5O17Y3R (Phenylalanine); EC 2.7.1.17 (EEF2K protein, human); EC 2.7.11.20 (Elongation Factor 2 Kinase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180101 [Lr] Data última revisão: 180101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 28742327 [Au] Autor: Song SJ; Lee S; Ryu KS; Choi JS [Ad] Endereço: Department of Biochemistry, College of Natural Sciences, Chungnam National University , 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea. [Ti] Título: Amphiphilic Peptide Nanorods Based on Oligo-Phenylalanine as a Biocompatible Drug Carrier. [So] Source: Bioconjug Chem;28(9):2266-2276, 2017 09 20. [Is] ISSN: 1520-4812 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Peptide nanostructure has been widely explored for drug-delivery systems in recent studies. Peptides possess comparatively lower cytotoxicity and are more efficient than polymeric carriers. Here, we propose a peptide nanorod system, composed of an amphiphilic oligo-peptide RH F (Arg-His -Phe ), as a drug-delivery carrier. Arginine is an essential amino acid in typical cell-penetration peptides, and histidine induces endo- and lysosomal escape because of its proton sponge effect. Phenylalanine is introduced to provide rich hydrophobicity for stable self-assembly and drug encapsulation. The self-assembled structure of RH F showed nanorod-shaped morphology, positive surface charge, and retained formation in water for 35 days. RH F , labeled with Nile Red, showed high cellar uptake and accumulation in both cytoplasm and nucleus. The RH F nanorods demonstrated negligible cytotoxicity, as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and hemolysis assays. To confirm the efficiency of drug delivery, curcumin was encapsulated in the RH F nanorod system (RH F -Cur). RH F -Cur showed high encapsulation efficiency (24.63%) under the conditions of 200 µM curcumin. The RH F -Cur retained nanoscale size and positive surface charge, similar to those of the empty RH F nanorods. RH F -Cur displayed a robust anticancer effect in HeLa and A549 cells, and inhibited the proliferation of cancer cells in a zebrafish model. These results indicate that the RH F nanorods may be a promising candidate for a safe and effective drug-delivery system. [Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem Curcumina/administração & dosagem Portadores de Fármacos/química Nanotubos/química Oligopeptídeos/química Fenilalanina/análogos & derivados Tensoativos/química [Mh] Termos MeSH secundário: Animais Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Materiais Biocompatíveis/química Materiais Biocompatíveis/metabolismo Materiais Biocompatíveis/toxicidade Linhagem Celular Tumoral Curcumina/farmacologia Portadores de Fármacos/metabolismo Portadores de Fármacos/toxicidade Células HeLa Hemólise/efeitos dos fármacos Seres Humanos Nanotubos/ultraestrutura Neoplasias/tratamento farmacológico Oligopeptídeos/metabolismo Oligopeptídeos/toxicidade Fenilalanina/metabolismo Fenilalanina/toxicidade Tensoativos/metabolismo Tensoativos/toxicidade Peixe-Zebra [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Biocompatible Materials); 0 (Drug Carriers); 0 (Oligopeptides); 0 (Surface-Active Agents); 47E5O17Y3R (Phenylalanine); IT942ZTH98 (Curcumin) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171219 [Lr] Data última revisão: 171219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170726 [St] Status: MEDLINE [do] DOI: 10.1021/acs.bioconjchem.7b00247

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