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  1 / 2793 MEDLINE  
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[PMID]:28759224
[Au] Autor:Nedelcovych MT; Tenora L; Kim BH; Kelschenbach J; Chao W; Hadas E; Jancarík A; Prchalová E; Zimmermann SC; Dash RP; Gadiano AJ; Garrett C; Furtmüller G; Oh B; Brandacher G; Alt J; Majer P; Volsky DJ; Rais R; Slusher BS
[Ti] Título:N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders.
[So] Source:J Med Chem;60(16):7186-7198, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
[Mh] Termos MeSH primário: Aminocaproatos/farmacologia
Compostos Azo/farmacologia
Diazo-Oxo-Norleucina/farmacologia
Transtornos Neurocognitivos/tratamento farmacológico
Nootrópicos/farmacologia
Pró-Fármacos/farmacologia
[Mh] Termos MeSH secundário: Aminocaproatos/administração & dosagem
Aminocaproatos/síntese química
Animais
Compostos Azo/administração & dosagem
Compostos Azo/síntese química
Sangue/metabolismo
Encéfalo/metabolismo
Diazo-Oxo-Norleucina/administração & dosagem
Estabilidade de Medicamentos
Feminino
Ácido Glutâmico/metabolismo
Glutaminase/antagonistas & inibidores
Infecções por HIV/complicações
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Transtornos Neurocognitivos/etiologia
Nootrópicos/administração & dosagem
Nootrópicos/síntese química
Pró-Fármacos/administração & dosagem
Pró-Fármacos/síntese química
Suínos
Carga Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Azo Compounds); 0 (Nootropic Agents); 0 (Prodrugs); 0 (isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate); 03J0H273KZ (Diazooxonorleucine); 3KX376GY7L (Glutamic Acid); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00966


  2 / 2793 MEDLINE  
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[PMID]:27417712
[Au] Autor:Piotrovskiy LB; Litasova EV; Dumpis MA; Nikolaev DN; Yakovleva EE; Dravolina OA; Bespalov AY
[Ad] Endereço:Institute of Experimental Medicine, St. Petersburg, Russia. levon-piotrovsky@yandex.ru.
[Ti] Título:Enhanced brain penetration of hexamethonium in complexes with derivatives of fullerene C60.
[So] Source:Dokl Biochem Biophys;468(1):173-5, 2016 May.
[Is] ISSN:1608-3091
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:The present report describes development of hexamethonium complexes based on fullerene C60. Hexamethonium has a limited penetration into CNS and therefore can antagonize central effects of nicotine only when given at high doses. In the present studies conducted in laboratory rodents, intraperitoneal administration of hexamethonium-fullerene complexes blocked effects of nicotine (convulsions and locomotor stimulation). When compared to equimolar doses of hexamethonium, complexes of hexamethonium with derivatives of fullerene C60 were 40 times more potent indicating an enhanced ability to interact with central nicotine receptors. Thus, fullerene C60 derivatives should be explored further as potential carrier systems for polar drug delivery into CNS.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Fulerenos/farmacocinética
Compostos de Hexametônio/farmacocinética
Antagonistas Nicotínicos/farmacocinética
[Mh] Termos MeSH secundário: Aminocaproatos/química
Animais
Anticonvulsivantes/química
Anticonvulsivantes/farmacocinética
Encéfalo/metabolismo
Relação Dose-Resposta a Droga
Fulerenos/administração & dosagem
Fulerenos/química
Compostos de Hexametônio/administração & dosagem
Compostos de Hexametônio/química
Locomoção/efeitos dos fármacos
Masculino
Camundongos
Nicotina
Antagonistas Nicotínicos/administração & dosagem
Antagonistas Nicotínicos/química
Ratos Wistar
Convulsões/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Anticonvulsants); 0 (Fullerenes); 0 (Hexamethonium Compounds); 0 (Nicotinic Antagonists); 6M3C89ZY6R (Nicotine); NP9U26B839 (fullerene C60)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160716
[St] Status:MEDLINE
[do] DOI:10.1134/S1607672916030030


  3 / 2793 MEDLINE  
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[PMID]:26784681
[Au] Autor:Fenner AM; Engene N; Spadafora C; Gerwick WH; Balunas MJ
[Ad] Endereço:Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States.
[Ti] Título:Medusamide A, a Panamanian Cyanobacterial Depsipeptide with Multiple ß-Amino Acids.
[So] Source:Org Lett;18(3):352-5, 2016 Feb 05.
[Is] ISSN:1523-7052
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:From a collection of marine cyanobacteria made in the Coiba National Park along the Pacific coast of the Republic of Panama a novel cyclic depsipeptide, given the trivial name medusamide A, has been isolated and fully characterized. Medusamide A contains four contiguous ß-amino acid (2R,3R)-3-amino-2-methylhexanoic acid (Amha) residues. This is the first report of multiple Amha residues and contiguous ß-amino acid residues within a single cyclic peptide-type natural product. Stereochemical assignment of the Amha residues was completed following the synthesis of reference standards for this ß-amino acid and the subsequent derivatization with Marfey's reagent and LC-MS analysis.
[Mh] Termos MeSH primário: Cianobactérias/química
Depsipeptídeos/isolamento & purificação
[Mh] Termos MeSH secundário: Aminocaproatos/química
Depsipeptídeos/química
Depsipeptídeos/farmacologia
Estrutura Molecular
Ressonância Magnética Nuclear Biomolecular
Panamá
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Depsipeptides); 0 (medusamide A); 73322-75-5 (2-amino-5-methyl-5-hexenoic acid)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160120
[St] Status:MEDLINE
[do] DOI:10.1021/acs.orglett.5b03110


  4 / 2793 MEDLINE  
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[PMID]:26415531
[Au] Autor:Cho JS; Oh YJ; Kim OS; Na S
[Ad] Endereço:Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
[Ti] Título:The effects of arginase inhibitor on lung oxidative stress and inflammation caused by pneumoperitoneum in rats.
[So] Source:BMC Anesthesiol;15:129, 2015 Sep 28.
[Is] ISSN:1471-2253
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pneumoperitoneum-induced oxidative stress and organ injury are known to be associated with nitric oxide (NO) inactivation. Because arginase competes with NO synthase (NOS) for a common substrate, L-arginine, arginase inhibition may increase NO bioavailability. Therefore, we evaluated the ability of the arginase inhibitor, 2 (S)-amino-6-boronohexanoic acid (ABH), to attenuate pneumoperitoneum-induced decrease of NO bioavailability and lung injury. METHODS: Thirty rats were randomly divided into the following groups: 1) the PP-ABH group received a subcutaneous injection of ABH (5 mg/kg) 1 h before induction of pneumoperitoneum (insufflation to intraperitoneal pressure of 15 mmHg for 60 min); 2) the PP group received saline by subcutaneous injection 1 h before induction of pneumoperitoneum; and 3) the control group received saline by subcutaneous injection before a sham procedure with no gas insufflation. After desufflation, blood was collected to determine levels of plasma nitrite, NOS, inflammatory cytokines, and malondialdehyde, a marker of oxidative stress. Lung tissue was obtained for histological evaluation. RESULTS: We found that plasma nitrite levels were lower in the PP group and higher in the PP-ABH group, compared with controls (P <0.01 and P <0.05, respectively). In the PP group, endothelial NOS activity was decreased and inducible NOS activity was increased compared with the PP-ABH and control groups. Malondialdehyde levels increased 3-fold in the PP group and 2-fold in the PP-ABH group compared with controls. Tumor necrosis factor-α, interleukin-6, and interleukin-1ß levels were elevated in the PP group compared to the control group, but the increase in cytokine production was attenuated or blocked in the PP-ABH group. Lung injury scores were 4.8-fold higher in the PP group and 2-fold higher in the PP-ABH group compared with controls (P <0.001 and P <0.01, respectively). DISCUSSION: Pneumoperitoneum decreases NO bioavailability and increases the inflammation cytokines, resulting in organ injuries. Inhibition of arginase activity could maintain NO bioavailability by attenuating pneumoperitoneum-induced changes in NOS activity. In addition, arginase inhibition attenuated the oxidative stress and inflammation and decreased the severity of lung injury caused by pneumoperitoneum. CONCLUSIONS: By increasing NO bioavailability and suppressing oxidative stress and inflammation, pretreatment with an arginase inhibitor may protect against lung injury caused by pneumoperitoneum.
[Mh] Termos MeSH primário: Aminocaproatos/farmacologia
Arginase/antagonistas & inibidores
Compostos de Boro/farmacologia
Inflamação/prevenção & controle
Estresse Oxidativo/efeitos dos fármacos
Pneumoperitônio/complicações
[Mh] Termos MeSH secundário: Aminocaproatos/administração & dosagem
Animais
Compostos de Boro/administração & dosagem
Citocinas/metabolismo
Modelos Animais de Doenças
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/farmacologia
Inflamação/etiologia
Injeções Subcutâneas
Lesão Pulmonar/etiologia
Lesão Pulmonar/prevenção & controle
Masculino
Malondialdeído/metabolismo
Óxido Nítrico/metabolismo
Pneumoperitônio/tratamento farmacológico
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-6-boronohexanoic acid); 0 (Aminocaproates); 0 (Boron Compounds); 0 (Cytokines); 0 (Enzyme Inhibitors); 31C4KY9ESH (Nitric Oxide); 4Y8F71G49Q (Malondialdehyde); EC 3.5.3.1 (Arginase)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170923
[Lr] Data última revisão:
170923
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150930
[St] Status:MEDLINE
[do] DOI:10.1186/s12871-015-0112-y


  5 / 2793 MEDLINE  
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[PMID]:26029848
[Au] Autor:De Oliveira DM; Law RH; Ly D; Cook SM; Quek AJ; McArthur JD; Whisstock JC; Sanderson-Smith ML
[Ad] Endereço:†Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong 2522, Australia.
[Ti] Título:Preferential Acquisition and Activation of Plasminogen Glycoform II by PAM Positive Group A Streptococcal Isolates.
[So] Source:Biochemistry;54(25):3960-8, 2015 Jun 30.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Plasminogen (Plg) circulates in the host as two predominant glycoforms. Glycoform I Plg (GI-Plg) contains glycosylation sites at Asn289 and Thr346, whereas glycoform II Plg (GII-Plg) is exclusively glycosylated at Thr346. Surface plasmon resonance experiments demonstrated that Plg binding group A streptococcal M protein (PAM) exhibits comparative equal affinity for GI- and GII-Plg in the "closed" conformation (for GII-Plg, KD = 27.4 nM; for GI-Plg, KD = 37.0 nM). When Plg was in the "open" conformation, PAM exhibited an 11-fold increase in affinity for GII-Plg (KD = 2.8 nM) compared with that for GI-Plg (KD = 33.2 nM). The interaction of PAM with Plg is believed to be mediated by lysine binding sites within kringle (KR) 2 of Plg. PAM-GI-Plg interactions were fully inhibited with 100 mM lysine analogue ε-aminocaproic acid (εACA), whereas PAM-GII-Plg interactions were shown to be weakened but not inhibited in the presence of 400 mM εACA. In contrast, binding to the KR1-3 domains of GII-Plg (angiostatin) by PAM was completely inhibited in the presence 5 mM εACA. Along with PAM, emm pattern D GAS isolates express a phenotypically distinct SK variant (type 2b SK) that requires Plg ligands such as PAM to activate Plg. Type 2b SK was able to generate an active site and activate GII-Plg at a rate significantly higher than that of GI-Plg when bound to PAM. Taken together, these data suggest that GAS selectively recruits and activates GII-Plg. Furthermore, we propose that the interaction between PAM and Plg may be partially mediated by a secondary binding site outside of KR2, affected by glycosylation at Asn289.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Plasminogênio/metabolismo
Infecções Estreptocócicas/enzimologia
Streptococcus pyogenes/metabolismo
[Mh] Termos MeSH secundário: Aminocaproatos/química
Aminocaproatos/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Sítios de Ligação
Ativação Enzimática
Glicosilação
Seres Humanos
Kringles
Plasminogênio/química
Plasminogênio/genética
Ligação Proteica
Conformação Proteica
Infecções Estreptocócicas/genética
Infecções Estreptocócicas/microbiologia
Streptococcus pyogenes/química
Streptococcus pyogenes/genética
Streptococcus pyogenes/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Bacterial Proteins); 9001-91-6 (Plasminogen)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:150630
[Lr] Data última revisão:
150630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150602
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.5b00130


  6 / 2793 MEDLINE  
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Alves, Claudio Nahum
PubMed Central Texto completo
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[PMID]:25889635
[Au] Autor:Honarparvar B; Pawar SA; Alves CN; Lameira J; Maguire GE; Silva JR; Govender T; Kruger HG
[Ad] Endereço:Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4041, South Africa. honarparvar@ukzn.ac.za.
[Ti] Título:Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study.
[So] Source:J Biomed Sci;22:15, 2015 Feb 18.
[Is] ISSN:1423-0127
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values of less than 1.00 µM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides. RESULTS: The PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC50 = 0.076 µM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC50 = 0.850 µM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆Gsolv) were also considered. CONCLUSIONS: A general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC50 data.
[Mh] Termos MeSH primário: Aminocaproatos/farmacologia
Infecções por HIV/tratamento farmacológico
Inibidores da Protease de HIV/farmacologia
HIV-1/efeitos dos fármacos
Lactamas/farmacologia
Lactonas/farmacologia
[Mh] Termos MeSH secundário: Peptídeos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aminocaproates); 0 (HIV Protease Inhibitors); 0 (Lactams); 0 (Lactones); 0 (Peptides); 62023-30-7 (3-amino-2-hydroxy-5-methylhexanoic acid)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150419
[St] Status:MEDLINE
[do] DOI:10.1186/s12929-015-0115-5


  7 / 2793 MEDLINE  
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[PMID]:25595650
[Au] Autor:Grasemann H; Dhaliwal R; Ivanovska J; Kantores C; McNamara PJ; Scott JA; Belik J; Jankov RP
[Ad] Endereço:Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; hartmut.grasemann@sickkids.ca.
[Ti] Título:Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.
[So] Source:Am J Physiol Lung Cell Mol Physiol;308(6):L503-10, 2015 Mar 15.
[Is] ISSN:1522-1504
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension.
[Mh] Termos MeSH primário: Aminocaproatos/farmacologia
Antibióticos Antineoplásicos/efeitos adversos
Arginase/antagonistas & inibidores
Bleomicina/efeitos adversos
Compostos de Boro/farmacologia
Colágeno/metabolismo
Hipertensão Pulmonar
Pulmão/enzimologia
Remodelação Vascular/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antibióticos Antineoplásicos/farmacologia
Arginase/metabolismo
Arginina/metabolismo
Bleomicina/farmacologia
Displasia Broncopulmonar/induzido quimicamente
Displasia Broncopulmonar/enzimologia
Displasia Broncopulmonar/patologia
Displasia Broncopulmonar/prevenção & controle
Modelos Animais de Doenças
Hipertensão Pulmonar/induzido quimicamente
Hipertensão Pulmonar/enzimologia
Hipertensão Pulmonar/patologia
Hipertensão Pulmonar/prevenção & controle
Pulmão/patologia
Lesão Pulmonar/induzido quimicamente
Lesão Pulmonar/enzimologia
Lesão Pulmonar/patologia
Lesão Pulmonar/prevenção & controle
Óxido Nítrico/metabolismo
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-6-boronohexanoic acid); 0 (Aminocaproates); 0 (Antibiotics, Antineoplastic); 0 (Boron Compounds); 11056-06-7 (Bleomycin); 31C4KY9ESH (Nitric Oxide); 9007-34-5 (Collagen); 94ZLA3W45F (Arginine); EC 3.5.3.1 (Arginase)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:150316
[Lr] Data última revisão:
150316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150118
[St] Status:MEDLINE
[do] DOI:10.1152/ajplung.00328.2014


  8 / 2793 MEDLINE  
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[PMID]:25707105
[Au] Autor:Esikova TZ; Akatova EV; Taran SA
[Ti] Título:[Bacteria that degrade low-molecular linear epsilon-caprolactam olygomers].
[So] Source:Prikl Biokhim Mikrobiol;50(5):481-9, 2014 Sep-Oct.
[Is] ISSN:0555-1099
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Five bacterial strains with the unique ability to utilize low-molecular linear caprolactam olygomers (nylon olygomers) were isolated from soil samples contaminated with industrial wastes of epsilon-caprolactam. Based on the properties studied and also on the analysis of 16S rRNA gene nucleotide sequences, the strains BS2,BS3, BS9, BS38, and BS57 were classified to the general Arthrobacter, Brevibacterium, Microbacteriun, Gulosibacter, and Achromobacter, respectively. All of the strains also utilized 6-aminohexanoic and adipic acids, which are intermidiates of the epsilon-caprolactam catabolism. This indirectly points to the fact that degradation of olygomers in these bacteria occurs via the monomer degradation pathway. The BS9 and BS57 strains utilized only olygomers of the epsilon-caprolactam, while BS2, BS3, and BS38 also degraded epsilon-caprolactam and its homologs, enantolactam and caprylolactam, which differentiates the latter from the previously known degraders of olygomers and suggests the presence in these strains of enzymes with lactam hydrolase activity, in addition to 6-aminohexanoate-dimer hydrolase.
[Mh] Termos MeSH primário: Achromobacter/metabolismo
Amidoidrolases/metabolismo
Arthrobacter/metabolismo
Proteínas de Bactérias/metabolismo
Brevibacterium/metabolismo
Caprolactama/metabolismo
DNA Bacteriano/genética
[Mh] Termos MeSH secundário: Achromobacter/genética
Achromobacter/crescimento & desenvolvimento
Adipatos/metabolismo
Aminocaproatos/metabolismo
Arthrobacter/genética
Arthrobacter/crescimento & desenvolvimento
Biodegradação Ambiental
Brevibacterium/genética
Brevibacterium/crescimento & desenvolvimento
Seres Humanos
Resíduos Industriais
RNA Ribossômico 16S/genética
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adipates); 0 (Aminocaproates); 0 (Bacterial Proteins); 0 (DNA, Bacterial); 0 (Industrial Waste); 0 (RNA, Ribosomal, 16S); 6879X594Z8 (Caprolactam); EC 3.5.- (Amidohydrolases); EC 3.5.1.46 (6-aminohexanoate-dimer hydrolase)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:150224
[Lr] Data última revisão:
150224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150225
[St] Status:MEDLINE


  9 / 2793 MEDLINE  
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[PMID]:25159818
[Au] Autor:Soragni E; Miao W; Iudicello M; Jacoby D; De Mercanti S; Clerico M; Longo F; Piga A; Ku S; Campau E; Du J; Penalver P; Rai M; Madara JC; Nazor K; O'Connor M; Maximov A; Loring JF; Pandolfo M; Durelli L; Gottesfeld JM; Rusche JR
[Ad] Endereço:Departments of Cell and Molecular Biology, Scripps Research Institute, La Jolla, CA.
[Ti] Título:Epigenetic therapy for Friedreich ataxia.
[So] Source:Ann Neurol;76(4):489-508, 2014 Oct.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. METHODS: We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. RESULTS: In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. INTERPRETATION: Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.
[Mh] Termos MeSH primário: Ataxia de Friedreich/tratamento farmacológico
Ataxia de Friedreich/genética
Regulação da Expressão Gênica/efeitos dos fármacos
Inibidores de Histona Desacetilases/uso terapêutico
Proteínas de Ligação ao Ferro/genética
[Mh] Termos MeSH secundário: Administração Oral
Adolescente
Adulto
Aminocaproatos/farmacologia
Aminocaproatos/uso terapêutico
Área Sob a Curva
Benzamidas/farmacologia
Benzamidas/uso terapêutico
Diferenciação Celular/efeitos dos fármacos
Diferenciação Celular/genética
Linhagem Celular Transformada
Imunoprecipitação da Cromatina
Estudos de Coortes
Estudos Transversais
Metilação de DNA/efeitos dos fármacos
Metilação de DNA/genética
Relação Dose-Resposta a Droga
Método Duplo-Cego
Feminino
Ataxia de Friedreich/patologia
Regulação da Expressão Gênica/genética
Seres Humanos
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/metabolismo
Masculino
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/fisiologia
Meia-Idade
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Neurônios/efeitos dos fármacos
Células-Tronco Pluripotentes
Expansão das Repetições de Trinucleotídeos/genética
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Benzamides); 0 (Histone Deacetylase Inhibitors); 0 (Iron-Binding Proteins); 0 (Nerve Tissue Proteins); 0 (frataxin); 17V14R89EU (RG2833)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140828
[St] Status:MEDLINE
[do] DOI:10.1002/ana.24260


  10 / 2793 MEDLINE  
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[PMID]:25125482
[Au] Autor:Suzuki C; Tsuji AB; Kato K; Kikuchi T; Sudo H; Okada M; Sugyo A; Zhang MR; Arano Y; Saga T
[Ad] Endereço:Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
[Ti] Título:Preclinical characterization of 5-amino-4-oxo-[6-11C]hexanoic acid as an imaging probe to estimate protoporphyrin IX accumulation induced by exogenous aminolevulinic acid.
[So] Source:J Nucl Med;55(10):1671-7, 2014 Oct.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Preoperative noninvasive imaging to estimate the quantity and spatial distribution of protoporphyrin IX (PpIX) accumulation in tumors induced by 5-aminolevulinic acid (ALA) administration is expected to improve the efficacy of ALA-based fluorescence-guided resection and photo- and sonodynamic therapies. PpIX synthesis from exogenous ALA has been reported to be regulated by ALA influx or ALA dehydratase (ALAD) activity, which catalyzes the first step of the synthesis. In this study, we characterized the properties of a (11)C-labeled ALA analog, 5-amino-4-oxo-[6-(11)C]hexanoic acid ((11)C-MALA), as a PET tracer to estimate PpIX accumulation. METHODS: In vitro uptake of (11)C-MALA and (3)H-ALA was determined in 5 tumor cell lines after 10-min incubation with each tracer at 37°C. The expression levels of ALAD were determined by Western blot analysis. In vivo distribution and dynamic PET studies were conducted in tumor-bearing mice. In vitro and in vivo accumulation of ALA-induced PpIX was determined by measuring fluorescence in extracts of cells or tumors. RESULTS: In vitro uptake of (11)C-MALA in 5 tumor cell lines was correlated with ALAD expression levels and PpIX accumulation. In vivo biodistribution and dynamic PET studies showed that (11)C-MALA was rapidly incorporated into tumors, and the tumor-to-muscle ratio of (11)C-MALA at 1 min after injection was significantly correlated with that of (3)H-ALA. (11)C-MALA in tumors was continuously decreased thereafter, and the elimination rate of (11)C-MALA from AsPC-1 tumors with the highest ALAD expression level was slower than from other tumors with lower expression levels. These results suggest that the influx and intracellular retention of (11)C-MALA reflect ALA influx and ALAD expression levels, respectively. Tumor accumulation of (11)C-MALA at 60 min after injection was strongly correlated with PpIX accumulation in tumor tissues. CONCLUSION: (11)C-MALA PET has the potential to noninvasively estimate the quantitative and spatial accumulation of exogenous ALA-induced PpIX.
[Mh] Termos MeSH primário: Aminocaproatos/química
Ácido Aminolevulínico/química
Neoplasias/diagnóstico por imagem
Protoporfirinas/química
[Mh] Termos MeSH secundário: Aminocaproatos/farmacocinética
Animais
Linhagem Celular Tumoral
Seres Humanos
Camundongos
Transplante de Neoplasias
Neoplasias/tratamento farmacológico
Tomografia por Emissão de Pósitrons/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Protoporphyrins); 78524-74-0 (4-keto-5-amino-6-hydroxyhexanoic acid); 88755TAZ87 (Aminolevulinic Acid); C2K325S808 (protoporphyrin IX)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140816
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.114.145086



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