Base de dados : MEDLINE
Pesquisa : D02.241.081.901 [Categoria DeCS]
Referências encontradas : 763 [refinar]
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[PMID]:28827149
[Au] Autor:Tarhonskaya H; Nowak RP; Johansson C; Szykowska A; Tumber A; Hancock RL; Lang P; Flashman E; Oppermann U; Schofield CJ; Kawamura A
[Ad] Endereço:Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom.
[Ti] Título:Studies on the Interaction of the Histone Demethylase KDM5B with Tricarboxylic Acid Cycle Intermediates.
[So] Source:J Mol Biol;429(19):2895-2906, 2017 Sep 15.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Methylation of lysine-4 of histone H3 (H3K4me ) is an important regulatory factor in eukaryotic transcription. Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. Altered levels of tricarboxylic acid (TCA) cycle intermediates and the associated metabolites D- and L-2-hydroxyglutarate (2HG) can cause changes in chromatin methylation status. We report comprehensive biochemical, structural and cellular studies on the interaction of TCA cycle intermediates with KDM5B, which is a current medicinal chemistry target for cancer. The tested TCA intermediates were poor or moderate KDM5B inhibitors, except for oxaloacetate and succinate, which were shown to compete for binding with 2OG. D- and L-2HG were moderate inhibitors at levels that might be relevant in cancer cells bearing isocitrate dehydrogenase mutations. Crystallographic analyses with succinate, fumarate, L-malate, oxaloacetate, pyruvate and D- and L-2HG support the kinetic studies showing competition with 2OG. An unexpected binding mode for oxaloacetate was observed in which it coordinates the active site metal via its C-4 carboxylate rather than the C-1 carboxylate/C-2 keto groups. Studies employing immunofluorescence antibody-based assays reveal no changes in H3K4me levels in cells ectopically overexpressing KDM5B in response to dosing with TCA cycle metabolite pro-drug esters, suggesting that the high levels of cellular 2OG may preclude inhibition. The combined results reveal the potential for KDM5B inhibition by TCA cycle intermediates, but suggest that in cells, such inhibition will normally be effectively competed by 2OG.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/metabolismo
Glutaratos/metabolismo
Histona Desmetilases com o Domínio Jumonji/química
Histona Desmetilases com o Domínio Jumonji/metabolismo
Proteínas Nucleares/química
Proteínas Nucleares/metabolismo
Proteínas Repressoras/química
Proteínas Repressoras/metabolismo
Ácidos Tricarboxílicos/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Cinética
Modelos Moleculares
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Glutarates); 0 (Nuclear Proteins); 0 (Repressor Proteins); 0 (Tricarboxylic Acids); 2889-31-8 (alpha-hydroxyglutarate); EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases); EC 1.14.11.- (KDM5B protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE


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[PMID]:28064043
[Au] Autor:Wang H; Han H; Ma Z
[Ad] Endereço:Department of Chemistry, Capital Normal University, Beijing 100048, China.
[Ti] Título:Conductive hydrogel composed of 1,3,5-benzenetricarboxylic acid and Fe used as enhanced electrochemical immunosensing substrate for tumor biomarker.
[So] Source:Bioelectrochemistry;114:48-53, 2017 Apr.
[Is] ISSN:1878-562X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In this work, a new conductive hydrogel was prepared by a simple cross-linking coordination method using 1,3,5-benzenetricarboxylic acid as the ligand and Fe as the metal ion. The hydrogel film was formed on a glassy carbon electrode (GCE) by a drop coating method, which can dramatically facilitate the transport of electrons. A sensitive label-free electrochemical immunosensor was fabricated following electrodeposition of gold nanoparticles (AuNPs) on a hydrogel film and immobilization of an antibody. Neuron-specific enolase (NSE), a lung cancer biomarker, was used as the model analyte to be detected. The proposed immunosensor exhibited a wide linear detection range of 1pgmL to 200ngmL and a limit of detection of 0.26pgmL (the ratio of signal to noise (S/N)=3). Moreover, the detection of NSE in human serum samples showed satisfactory accuracy compared with the data determined by enzyme-linked immunosorbent assay (ELISA), indicating good analytical performance of the immunoassay.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/análise
Técnicas Biossensoriais/métodos
Condutividade Elétrica
Hidrogel de Polietilenoglicol-Dimetacrilato/química
Imunoensaio/métodos
Ácidos Tricarboxílicos/química
[Mh] Termos MeSH secundário: Biomarcadores Tumorais/química
Técnicas Biossensoriais/instrumentação
Eletroquímica
Ouro/química
Seres Humanos
Imunoensaio/instrumentação
Limite de Detecção
Nanopartículas Metálicas/química
Fosfopiruvato Hidratase/análise
Fosfopiruvato Hidratase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Tricarboxylic Acids); 25852-47-5 (Hydrogel, Polyethylene Glycol Dimethacrylate); 7440-57-5 (Gold); EC 4.2.1.11 (Phosphopyruvate Hydratase); OU36OO5MTN (trimesic acid)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:27831491
[Au] Autor:Shimizu T; Yin L; Yoshida A; Yokooji Y; Hachisuka SI; Sato T; Tomita T; Nishida H; Atomi H; Kuzuyama T; Nishiyama M
[Ad] Endereço:Biotechnology Research Center, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
[Ti] Título:Structure and function of an ancestral-type ß-decarboxylating dehydrogenase from Thermococcus kodakarensis.
[So] Source:Biochem J;474(1):105-122, 2017 Jan 01.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ß-Decarboxylating dehydrogenases, which are involved in central metabolism, are considered to have diverged from a common ancestor with broad substrate specificity. In a molecular phylogenetic analysis of 183 ß-decarboxylating dehydrogenase homologs from 84 species, TK0280 from Thermococcus kodakarensis was selected as a candidate for an ancestral-type ß-decarboxylating dehydrogenase. The biochemical characterization of recombinant TK0280 revealed that the enzyme exhibited dehydrogenase activities toward homoisocitrate, isocitrate, and 3-isopropylmalate, which correspond to key reactions involved in the lysine biosynthetic pathway, tricarboxylic acid cycle, and leucine biosynthetic pathway, respectively. In T. kodakarensis, the growth characteristics of the KUW1 host strain and a TK0280 deletion strain suggested that TK0280 is involved in lysine biosynthesis in this archaeon. On the other hand, gene complementation analyses using Thermus thermophilus as a host revealed that TK0280 functions as both an isocitrate dehydrogenase and homoisocitrate dehydrogenase in this organism, but not as a 3-isopropylmalate dehydrogenase, most probably reflecting its low catalytic efficiency toward 3-isopropylmalate. A crystallographic study on TK0280 binding each substrate indicated that Thr71 and Ser80 played important roles in the recognition of homoisocitrate and isocitrate while the hydrophobic region consisting of Ile82 and Leu83 was responsible for the recognition of 3-isopropylmalate. These analyses also suggested the importance of a water-mediated hydrogen bond network for the stabilization of the ß3-α4 loop, including the Thr71 residue, with respect to the promiscuity of the substrate specificity of TK0280.
[Mh] Termos MeSH primário: Proteínas Arqueais
Oxirredutases
Thermococcus
[Mh] Termos MeSH secundário: Proteínas Arqueais/química
Proteínas Arqueais/genética
Proteínas Arqueais/metabolismo
Domínio Catalítico
Teste de Complementação Genética
Isocitratos/química
Isocitratos/metabolismo
Lisina/biossíntese
Lisina/química
Lisina/genética
Malatos/química
Malatos/metabolismo
Oxirredutases/química
Oxirredutases/genética
Oxirredutases/metabolismo
Estrutura Secundária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Relação Estrutura-Atividade
Especificidade por Substrato
Thermococcus/enzimologia
Thermococcus/genética
Thermus thermophilus/enzimologia
Thermus thermophilus/genética
Ácidos Tricarboxílicos/química
Ácidos Tricarboxílicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); 0 (Isocitrates); 0 (Malates); 0 (Recombinant Proteins); 0 (Tricarboxylic Acids); 0 (homoisocitric acid); 320-77-4 (isocitric acid); 921-28-8 (beta-isopropylmalate); EC 1.- (Oxidoreductases); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161111
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20160699


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[PMID]:27697650
[Au] Autor:Sun K; Li L; Yu X; Liu L; Meng Q; Wang F; Zhang R
[Ad] Endereço:Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Hubei University, Wuhan 430062, China.
[Ti] Título:Functionalization of mixed ligand metal-organic frameworks as the transport vehicles for drugs.
[So] Source:J Colloid Interface Sci;486:128-135, 2017 Jan 15.
[Is] ISSN:1095-7103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We reported the design and synthesis of mixed ligands Cu-metal organic frameworks (MOFs), MOFs-2 and MOFs-3, and their application as the transport vehicles for the delivery of Ibuprofen (IBU) and doxorubicin hydrochloride (DOX). The unique MOFs with mixed ligands, 1,3,5-benzene tricarboxylate (BTC) and isophthalic acid (IPA), were easily prepared by hydro-thermal method, and their structures were well characterized by XRD, FTIR, and SEM imaging analysis. Single ligand MOFs with BTC or IPA only were also prepared and characterized as the control group. The biocompatibility of synthesized MOFs towards human cells, HEK 293A was evaluated by MTT assay. To demonstrate the practical applications of the prepared MOFs as the transport vehicles for drugs, the capability of loading and controlled release of IBU and DOX by MOFs-1, MOFs-2, MOFs-3, and MOFs-4 were then examined. In addition, the drug delivery efficiency of various MOFs with different ligands was investigated.
[Mh] Termos MeSH primário: Cobre/química
Portadores de Fármacos
Compostos Organometálicos/síntese química
Água/química
[Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/química
Anti-Inflamatórios não Esteroides/farmacologia
Antibióticos Antineoplásicos/química
Antibióticos Antineoplásicos/farmacologia
Sobrevivência Celular/efeitos dos fármacos
Doxorrubicina/química
Doxorrubicina/farmacologia
Composição de Medicamentos
Liberação Controlada de Fármacos
Células HEK293
Temperatura Alta
Seres Humanos
Concentração de Íons de Hidrogênio
Ibuprofeno/química
Ibuprofeno/farmacologia
Cinética
Ácidos Ftálicos/química
Ácidos Tricarboxílicos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Antibiotics, Antineoplastic); 0 (Drug Carriers); 0 (Organometallic Compounds); 0 (Phthalic Acids); 0 (Tricarboxylic Acids); 059QF0KO0R (Water); 121-91-5 (isophthalate); 789U1901C5 (Copper); 80168379AG (Doxorubicin); OU36OO5MTN (trimesic acid); WK2XYI10QM (Ibuprofen)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170917
[Lr] Data última revisão:
170917
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE


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[PMID]:27601325
[Au] Autor:Takahashi K; Tomita T; Kuzuyama T; Nishiyama M
[Ad] Endereço:Biotechnology Research Center, The University of Tokyo, Japan.
[Ti] Título:Determinants of dual substrate specificity revealed by the crystal structure of homoisocitrate dehydrogenase from Thermus thermophilus in complex with homoisocitrate·Mg(2+)·NADH.
[So] Source:Biochem Biophys Res Commun;478(4):1688-93, 2016 09 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HICDH (Homoisocitrate dehydrogenase) is a member of the ß-decarboxylating dehydrogenase family that catalyzes the conversion of homoisocitrate to α-ketoadipate using NAD(+) as a coenzyme, which is the fourth reaction involved in lysine biosynthesis through the α-aminoadipate pathway. Although typical HICDHs from fungi and yeast exhibit strict substrate specificities toward homoisocitrate (HIC), HICDH from a thermophilic bacterium Thermus thermophilus (TtHICDH) catalyzes the reactions using both HIC and isocitrate (IC) as substrates at similar efficiencies. We herein determined the crystal structure of the quaternary complex of TtHICDH with HIC, NADH, and Mg(2+) ion at a resolution of 2.5 Å. The structure revealed that the distal carboxyl group of HIC was recognized by the side chains of Ser72 and Arg85 from one subunit, and Asn173 from another subunit of a dimer unit. Model structures were constructed for TtHICDH in complex with IC and also for HICDH from Saccharomyces cerevisiae (ScHICDH) in complex with HIC. TtHICDH recognized the distal carboxyl group of IC by Arg85 in the model. In ScHICDH, the distal carboxyl group of HIC was recognized by the side chains of Ser98 and Ser108 from one subunit and Asn208 from another subunit of a dimer unit. By contrast, in ScHICDH, which lacks an Arg residue at the position corresponding to Arg85 in TtHICDH, these residues may not interact with the distal carboxyl group of shorter IC. These results provide a molecular basis for the differences in substrate specificities between TtHICDH and ScHICDH.
[Mh] Termos MeSH primário: Oxirredutases do Álcool/metabolismo
Proteínas de Bactérias/metabolismo
Magnésio/metabolismo
NAD/metabolismo
Thermus thermophilus/enzimologia
Ácidos Tricarboxílicos/metabolismo
[Mh] Termos MeSH secundário: Oxirredutases do Álcool/química
Oxirredutases do Álcool/genética
Sequência de Aminoácidos
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Sítios de Ligação/genética
Biocatálise
Cristalização
Cristalografia por Raios X
Ligações de Hidrogênio
Cinética
Magnésio/química
Modelos Moleculares
NAD/química
Ligação Proteica
Domínios Proteicos
Multimerização Proteica
Estrutura Quaternária de Proteína
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/química
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Homologia de Sequência de Aminoácidos
Especificidade da Espécie
Eletricidade Estática
Especificidade por Substrato
Thermus thermophilus/genética
Ácidos Tricarboxílicos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Saccharomyces cerevisiae Proteins); 0 (Tricarboxylic Acids); 0 (homoisocitric acid); 0U46U6E8UK (NAD); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.1.87 (homoisocitrate dehydrogenase); I38ZP9992A (Magnesium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171127
[Lr] Data última revisão:
171127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160908
[St] Status:MEDLINE


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[PMID]:27600687
[Au] Autor:Jantas D; Greda A; Golda S; Korostynski M; Lason W
[Ad] Endereço:Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Kraków, Poland. Electronic address: jantas@if-pan.krakow.pl.
[Ti] Título:The neuroprotective effects of orthosteric agonists of group II and III mGluRs in primary neuronal cell cultures are dependent on developmental stage.
[So] Source:Neuropharmacology;111:195-211, 2016 Dec.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Activation of metabotropic glutamate receptors (mGluRs) modulates neuronal excitability. Here, we evaluated the neuroprotective potential of four structurally diverse activators of group II and III mGluRs: an orthosteric agonist of group II (LY354740), an orthosteric agonist of group III (ACPT-I), an allosteric agonist of mGluR7 (AMN082) and a positive allosteric modulator (PAM) of mGluR4 (VU0361737). Neurotoxicity was induced by the pro-apoptotic agents: staurosporine (St) and doxorubicin (Dox) or the excitotoxic factor glutamate (Glu). The effects were analyzed in primary hippocampal (HIP) and cerebellar granule cell (CGC) cultures at two developmental stages, at 7 and 12 days in vitro (DIV). The data reveal a general neuroprotective effect of group II and III mGluR activators against the St- and Glu- but not Dox-induced cell damage. We found that neuroprotective effects of group II and III mGluR orthosteric agonists (LY354740 and ACPT-I) were higher at 12 DIV when compared to 7 DIV cells. In contrast, the efficiency of allosteric mGluR agents (AMN082 and VU0361737) did not differ between 7 and 12 DIV in both, St and Glu models of neuronal cell damage. Interestingly, the protective effects of activators of group II and III mGluRs were blocked by relevant antagonists only against Glu-induced neurotoxicity. Moreover, the observed neuroprotective action of group II and III mGluR activators in the St model was associated with a decreased number of PI-positive cells and no alterations in the caspase-3 activity. Finally, we showed that MAPK/ERK pathway activation was potentially involved in the mechanism of ACPT-I- and AMN082-induced neuroprotection against the St-evoked cellular damage. Our comparative study demonstrated the developmental stage-dependent neuroprotective effect of orthosteric group II and III mGluR agonists. In comparison to allosteric modulators, orthosteric compounds may provide more specific tools for suppression of neuronal cell loss associated with various chronic neurodegenerative conditions. Our results also suggest that the inhibition of intracellular pathways mediating necrotic, rather than apoptotic cascades, may be involved in neuroprotective effects of activators of group II and III mGluRs.
[Mh] Termos MeSH primário: Compostos de Anilina/administração & dosagem
Compostos Benzidrílicos/administração & dosagem
Compostos Bicíclicos com Pontes/administração & dosagem
Morte Celular/efeitos dos fármacos
Ciclopentanos/administração & dosagem
Neurônios/efeitos dos fármacos
Fármacos Neuroprotetores/administração & dosagem
Ácidos Picolínicos/administração & dosagem
Receptores de Glutamato Metabotrópico/agonistas
Ácidos Tricarboxílicos/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Células Cultivadas
Cerebelo/efeitos dos fármacos
Doxorrubicina/toxicidade
Ácido Glutâmico/toxicidade
Hipocampo/efeitos dos fármacos
Camundongos
Cultura Primária de Células
Estaurosporina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-aminocyclopentane-1,2,4-tricarboxylic acid); 0 (Aniline Compounds); 0 (Benzhydryl Compounds); 0 (Bridged Bicyclo Compounds); 0 (Cyclopentanes); 0 (N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride); 0 (N-(4-chloro-3-methoxyphenyl)-2-picolinamide); 0 (Neuroprotective Agents); 0 (Picolinic Acids); 0 (Receptors, Metabotropic Glutamate); 0 (Tricarboxylic Acids); 0 (metabotropic glutamate receptor 4); 0 (metabotropic glutamate receptor 7); 3KX376GY7L (Glutamic Acid); 80168379AG (Doxorubicin); H88EPA0A3N (Staurosporine); ONU5A67T2S (eglumetad)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160908
[St] Status:MEDLINE


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[PMID]:27552427
[Au] Autor:Teodoro FS; Ramos SNDC; Elias MMC; Mageste AB; Ferreira GMD; da Silva LHM; Gil LF; Gurgel LVA
[Ad] Endereço:Grupo de Físico-Química Orgânica, Departamento de Química, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, s/n°, Bauxita, 35400-000 Ouro Preto, Minas Gerais, Brazil.
[Ti] Título:Synthesis and application of a new carboxylated cellulose derivative. Part I: Removal of Co(2+), Cu(2+) and Ni(2+) from monocomponent spiked aqueous solution.
[So] Source:J Colloid Interface Sci;483:185-200, 2016 Dec 01.
[Is] ISSN:1095-7103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A new carboxylated cellulose derivative (CTA) was prepared from the esterification of cellulose with 1,2,4-Benzenetricarboxylic anhydride. CTA was characterized by percent weight gain (pwg), amount of carboxylic acid groups (nCOOH), elemental analysis, FTIR, TGA, solid-state (13)C NMR, X-ray diffraction (DRX), specific surface area, pore size distribution, SEM and EDX. The best CTA synthesis condition yielded a pwg and nCOOH of 94.5% and 6.81mmolg(-1), respectively. CTA was used as an adsorbent material to remove Co(2+), Cu(2+) and Ni(2+) from monocomponent spiked aqueous solution. Adsorption studies were developed as a function of the solution pH, contact time and initial adsorbate concentration. Langmuir model better fitted the experimental adsorption data and the maximum adsorption capacities estimated by this model were 0.749, 1.487 and 1.001mmolg(-1) for Co(2+), Cu(2+) and Ni(2+), respectively. The adsorption mechanism was investigated by using isothermal titration calorimetry. The values of ΔadsH° were in the range from 5.36 to 8.09kJmol(-1), suggesting that the mechanism controlling the phenomenon is physisorption. Desorption and re-adsorption studies were also performed. Desorption and re-adsorption efficiencies were closer to 100%, allowing the recovery of both metal ions and CTA adsorbent.
[Mh] Termos MeSH primário: Celulose/síntese química
Cobalto/isolamento & purificação
Cobre/isolamento & purificação
Níquel/isolamento & purificação
Poluentes Químicos da Água/isolamento & purificação
[Mh] Termos MeSH secundário: Adsorção
Anidridos/química
Cátions Bivalentes
Celulose/análogos & derivados
Concentração de Íons de Hidrogênio
Cinética
Termodinâmica
Ácidos Tricarboxílicos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anhydrides); 0 (Cations, Divalent); 0 (Tricarboxylic Acids); 0 (Water Pollutants, Chemical); 3G0H8C9362 (Cobalt); 789U1901C5 (Copper); 7OV03QG267 (Nickel); 9004-34-6 (Cellulose); OU36OO5MTN (trimesic acid)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160824
[St] Status:MEDLINE


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[PMID]:27521256
[Au] Autor:Morgenstern J; Busch M; Baumann P; Hubbuch J
[Ad] Endereço:Institute of Process Engineering in Life Sciences, Section IV: Molecular Separation Engineering, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany. Electronic address: Josefine.Morgenstern@kit.edu.
[Ti] Título:Quantification of PEGylated proteases with varying degree of conjugation in mixtures: An analytical protocol combining protein precipitation and capillary gel electrophoresis.
[So] Source:J Chromatogr A;1462:153-64, 2016 Sep 02.
[Is] ISSN:1873-3778
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:PEGylation, i.e. the covalent attachment of chemically activated polyethylene glycol (PEG) to proteins, is a technique commonly used in biopharmaceutical industry to improve protein stability, pharmacokinetics and resistance to proteolytic degradation. Therefore, PEGylation represents a valuable strategy to reduce autocatalysis of biopharmaceutical relevant proteases during production, purification and storage. In case of non-specific random conjugation the existence of more than one accessible binding site results in conjugates which vary in position and number of attached PEG molecules. These conjugates may differ considerably in their physicochemical properties. Optimizing the reaction conditions with respect to the degree of PEGylation (number of linked PEG molecules) using high-throughput screening (HTS) technologies requires a fast and reliable analytical method which allows stopping the reaction at defined times. In this study an analytical protocol for PEGylated proteases is proposed combining preservation of sample composition by trichloroacetic acid (TCA) precipitation with high-throughput capillary gel electrophoresis (HT-CGE). The well-studied protein hen egg-white lysozyme served as a model system for validating the newly developed analytical protocol for 10kDa mPEG-aldehyde conjugates. PEGamer species were purified by chromatographic separation for calibrating the HT-CGE system. In a case study, the serine protease Savinase(®) which is highly sensitive to autocatalysis was randomly modified with 5kDa and 10kDa mPEG-aldehyde and analyzed. Using the presented TCA protocol baseline separation between PEGamer species was achieved allowing for the analysis of heterogeneous PEGamer mixtures while preventing protease autocatalysis.
[Mh] Termos MeSH primário: Precipitação Química
Eletroforese Capilar/métodos
Muramidase/análise
Muramidase/química
Polietilenoglicóis/química
Proteínas/análise
Proteínas/química
[Mh] Termos MeSH secundário: Animais
Biocatálise
Galinhas
Feminino
Serina Endopeptidases/química
Serina Endopeptidases/metabolismo
Ácidos Tricarboxílicos
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Proteins); 0 (Tricarboxylic Acids); 30IQX730WE (Polyethylene Glycols); 9004-74-4 (monomethoxypolyethylene glycol); EC 3.2.1.- (hen egg lysozyme); EC 3.2.1.17 (Muramidase); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.62 (microbial serine proteinases)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170111
[Lr] Data última revisão:
170111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160814
[St] Status:MEDLINE


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[PMID]:27520505
[Au] Autor:Lanterna C; Musumeci A; Raccosta L; Corna G; Moresco M; Maggioni D; Fontana R; Doglioni C; Bordignon C; Traversari C; Russo V
[Ad] Endereço:Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
[Ti] Título:The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice.
[So] Source:Cancer Immunol Immunother;65(11):1303-1315, 2016 Nov.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function. We show that zaragozic acids inhibit the in vivo growth of the RMA lymphoma and the Lewis lung carcinoma (LLC) without inducing side effects. Tumor growth inhibition requires an intact immune system, as immunodeficient tumor-bearing mice do not respond to zaragozic acid treatment. Of note, the effect of zaragozic acids is accompanied by a marked reduction in the LXR target genes Abcg1, Mertk, Scd1 and Srebp-1c in the tumor microenvironment. On the other hand, zoledronate, which blocks also isoprenoid formation, did not control the LLC tumor growth. Finally, we show that zaragozic acids potentiate the antitumor effects of active and adoptive immunotherapy, significantly prolonging the overall survival of tumor-bearing mice treated with the combo zaragozic acids and TAA-loaded DCs. This study identifies zaragozic acids as new antitumor compounds exploitable for the treatment of cancer patients.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico
Carcinoma Pulmonar de Lewis/terapia
Células Dendríticas/imunologia
Imunoterapia Adotiva/métodos
Linfoma de Células T/terapia
Ácidos Tricarboxílicos/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Carcinoma Pulmonar de Lewis/imunologia
Colesterol/metabolismo
Terapia Combinada
Células Dendríticas/transplante
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Linfoma de Células T/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos NOD
Camundongos SCID
Oxisteróis/metabolismo
Evasão Tumoral
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Oxysterols); 0 (Tricarboxylic Acids); 1117HVX02L (squalestatin 1); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160814
[St] Status:MEDLINE


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[PMID]:27225895
[Au] Autor:Rondini EA; Duniec-Dmuchowski Z; Cukovic D; Dombkowski AA; Kocarek TA
[Ad] Endereço:Institute of Environmental Health Sciences (E.A.R., Z.D.-D., T.A.K.), and Department of Pediatrics, Division of Clinical Pharmacology and Toxicology (D.C., A.A.D.), Wayne State University, Detroit, Michigan.
[Ti] Título:Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes.
[So] Source:J Pharmacol Exp Ther;358(2):216-29, 2016 Aug.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P < 0.05, ≥1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARα agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway.
[Mh] Termos MeSH primário: Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Colesterol/biossíntese
Regulação da Expressão Gênica/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Pravastatina/farmacologia
Terpenos/metabolismo
Ácidos Tricarboxílicos/farmacologia
[Mh] Termos MeSH secundário: Animais
Sinergismo Farmacológico
Feminino
Masculino
Camundongos
Ratos
Homologia de Sequência do Ácido Nucleico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Terpenes); 0 (Tricarboxylic Acids); 1117HVX02L (squalestatin 1); 97C5T2UQ7J (Cholesterol); KXO2KT9N0G (Pravastatin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160527
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.233312



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