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[PMID]:28890318
[Au] Autor:von Tesmar A; Hoffmann M; Pippel J; Fayad AA; Dausend-Werner S; Bauer A; Blankenfeldt W; Müller R
[Ad] Endereço:Department of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI) and Institute for Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany; German Center for Infection Research (DZIF
[Ti] Título:Total Biosynthesis of the Pyrrolo[4,2]benzodiazepine Scaffold Tomaymycin on an In Vitro Reconstituted NRPS System.
[So] Source:Cell Chem Biol;24(10):1216-1227.e8, 2017 Oct 19.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vitro reconstitution and biochemical analysis of natural product biosynthetic pathways remains a challenging endeavor, especially if megaenzymes of the nonribosomal peptide synthetase (NRPS) type are involved. In theory, all biosynthetic steps may be deciphered using mass spectrometry (MS)-based analyses of both the carrier protein-coupled intermediates and the free intermediates. We here report the "total biosynthesis" of the pyrrolo[4,2]benzodiazepine scaffold tomaymycin using an in vitro reconstituted NRPS system. Proteoforms were analyzed by liquid chromatography (LC)-MS to decipher every step of the biosynthesis on its respective megasynthetase with up to 170 kDa in size. To the best of our knowledge, this is the first report of a comprehensive analysis of virtually all chemical steps involved in the biosynthesis of nonribosomally synthesized natural products. The study includes experiments to determine substrate specificities of the corresponding A-domains in competition assays by analyzing the adenylation step as well as the transfer to the respective carrier protein domain.
[Mh] Termos MeSH primário: Benzodiazepinas/química
Peptídeo Sintases/metabolismo
Pirróis/química
[Mh] Termos MeSH secundário: Benzodiazepinonas/química
Benzodiazepinonas/metabolismo
Modelos Moleculares
Peptídeo Sintases/química
Domínios Proteicos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzodiazepinones); 0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 12794-10-4 (Benzodiazepines); 35050-55-6 (tomaymycin); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE


  2 / 4215 MEDLINE  
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[PMID]:28782580
[Au] Autor:Richter LHJ; Maurer HH; Meyer MR
[Ad] Endereço:Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany.
[Ti] Título:New psychoactive substances: Studies on the metabolism of XLR-11, AB-PINACA, FUB-PB-22, 4-methoxy-α-PVP, 25-I-NBOMe, and meclonazepam using human liver preparations in comparison to primary human hepatocytes, and human urine.
[So] Source:Toxicol Lett;280:142-150, 2017 Oct 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:New psychoactive substances (NPS) are an increasing problem in clinical and forensic toxicology. The knowledge of their metabolism is important for toxicological risk assessment and for developing toxicological urine screenings. Considering the huge numbers of NPS annually appearing on the market, metabolism studies should be realized in a fast, simple, cost efficient, and reliable way. Primary human hepatocytes (PHH) were recommended to be the gold standard for in vitro metabolism studies as they are expected to contain natural enzyme clusters, co-substrates, and drug transporters. In addition, they were already successfully used for metabolism studies of NPS. However, they also have disadvantages such as high costs and limited applicability without special equipment. The aims of the present study were therefore first to investigate exemplarily the phase I and phase II metabolism of six NPS (XLR-11, AB-PINACA, FUB-PB-22, 4-methoxy-α-PVP, 25-I-NBOMe, and meclonazepam) from different drug classes using pooled human S9 fraction (pS9) or pooled human liver microsomes combined with cytosol (pHLM/pHLC) after addition of the co-substrates for the main metabolic phase I and II reactions. Second to compare results to published data generated using primary human hepatocytes and human urine samples. Results of the incubations with pS9 or pHLM/pHLC were comparable in number and abundance of metabolites. Formation of metabolites, particularly after multi-step reactions needed a longer incubation time. However, incubations using human liver preparations resulted in a lower number of total detected metabolites compared to PHH, but they were still able to allow the identification of the main human urinary excretion products. Human liver preparations and particularly the pooled S9 fraction could be shown to be a sufficient and more cost-efficient alternative in context of metabolism studies also for developing toxicological urine screenings. It might be recommended to use the slightly cheaper pS9 fraction instead of a pHLM/pHLC combination. As formation of some metabolites needed a long incubation time, two sampling points at 60 and 360min should be recommended.
[Mh] Termos MeSH primário: Psicotrópicos/metabolismo
[Mh] Termos MeSH secundário: Benzodiazepinonas/química
Benzodiazepinonas/metabolismo
Butirofenonas/química
Butirofenonas/metabolismo
Canabinoides/química
Canabinoides/metabolismo
Hepatócitos/metabolismo
Seres Humanos
Indazóis/química
Indazóis/metabolismo
Indóis/química
Indóis/metabolismo
Fígado/enzimologia
Fígado/metabolismo
Microssomos Hepáticos/metabolismo
Estrutura Molecular
Fenetilaminas/química
Fenetilaminas/metabolismo
Psicotrópicos/química
Pirrolidinas/química
Pirrolidinas/metabolismo
Quinolinas/química
Quinolinas/metabolismo
Valina/análogos & derivados
Valina/química
Valina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2,5-dimethoxy-N-benzylphenethylamine); 0 (4-methoxy-alpha-pyrrolidinovalerophenone); 0 (Benzodiazepinones); 0 (Butyrophenones); 0 (Cannabinoids); 0 (FUB-PB-22 compound); 0 (Indazoles); 0 (Indoles); 0 (N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide); 0 (Phenethylamines); 0 (Psychotropic Drugs); 0 (Pyrrolidines); 0 (Quinolines); HG18B9YRS7 (Valine); L2M8B977ZE (XLR-11); RN43209SMA (meclonazepam)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE


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[PMID]:28739697
[Au] Autor:Shiomi Y; Yoshimura M; Kuki K; Hori Y; Tanaka T
[Ad] Endereço:Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Kumagaya, Japan yoshihiro-shiomi@zeria.co.jp.
[Ti] Título:Z-360 Suppresses Tumor Growth in MIA PaCa-2-bearing Mice Inhibition of Gastrin-induced Anti-Apoptotic Effects.
[So] Source:Anticancer Res;37(8):4127-4137, 2017 08.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model. MATERIALS AND METHODS: The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity. RESULTS: In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited apoptosis in vitro and Z-360 dose-dependently abrogated this effect. CONCLUSION: These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Benzodiazepinonas/administração & dosagem
Neoplasias Pancreáticas/tratamento farmacológico
Receptor de Colecistocinina B/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Desoxicitidina/administração & dosagem
Desoxicitidina/análogos & derivados
Endopeptidases/administração & dosagem
Gastrinas/administração & dosagem
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteínas Inibidoras de Apoptose/biossíntese
Camundongos
Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Receptor de Colecistocinina B/antagonistas & inibidores
Receptor de Colecistocinina B/biossíntese
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/biossíntese
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BIRC5 protein, human); 0 (Benzodiazepinones); 0 (Gastrins); 0 (Inhibitor of Apoptosis Proteins); 0 (MCL1 protein, human); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Receptor, Cholecystokinin B); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 0 (Z-360); 0W860991D6 (Deoxycytidine); 60748-06-3 (gastrin 17); B76N6SBZ8R (gemcitabine); EC 3.4.- (Endopeptidases); EC 3.4.99.- (gastrinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28645478
[Au] Autor:Musman J; Paradis S; Panel M; Pons S; Barau C; Caccia C; Leoni V; Ghaleh B; Morin D
[Ad] Endereço:INSERM U955, équipe 03, Créteil, France; Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, Créteil, France. Electronic address: julien.musman@inserm.fr.
[Ti] Título:A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction during myocardial ischemia-reperfusion in hypercholesterolemic rats.
[So] Source:Biochem Pharmacol;142:87-95, 2017 Oct 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A major cause of cell death during myocardial ischemia-reperfusion is mitochondrial dysfunction. We previously showed that the reperfusion of an ischemic myocardium was associated with an accumulation of cholesterol into mitochondria and a concomitant strong generation of auto-oxidized oxysterols. The inhibition of mitochondrial accumulation of cholesterol abolished the formation of oxysterols and prevented mitochondrial injury at reperfusion. The aim of this study was to investigate the impact of hypercholesterolemia on sterol and oxysterol accumulation in rat cardiac cytosols and mitochondria and to analyse the effect of the translocator protein ligand 4'-chlorodiazepam on this accumulation and mitochondrial function. Hypercholesterolemic ZDF fa/fa rats or normocholesterolemic lean rats were submitted to 30min of coronary artery occlusion followed by 15min reperfusion where cardiac cytosols and mitochondria were isolated. Hypercholesterolemia increased the cellular cardiac concentrations of cholesterol, cholesterol precursors and oxysterols both in cytosol and mitochondria in non-ischemic conditions. It also amplified the accumulation of all these compounds in cardiac cells and the alteration of mitochondrial function with ischemia-reperfusion. Administration of 4'-chlorodiazepam to ZDF fa/fa rats had no effect on the enhancement of sterols and oxysterols observed in the cytosols but inhibited cholesterol transfer to the mitochondria. It also alleviated the mitochondrial accumulation of all the investigated sterols and oxysterols. This was associated with a restoration of oxidative phosphorylation and a prevention of mitochondrial transition pore opening. The inhibition of cholesterol accumulation with TSPO ligands represents an interesting strategy to protect the mitochondria during ischemia-reperfusion in hypercholesterolemic conditions.
[Mh] Termos MeSH primário: Benzodiazepinonas/farmacologia
Proteínas de Transporte/metabolismo
Hipercolesterolemia/metabolismo
Mitocôndrias Cardíacas/metabolismo
Traumatismo por Reperfusão Miocárdica/prevenção & controle
Receptores de GABA-A/metabolismo
Esteróis/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzodiazepinonas/uso terapêutico
Citosol/metabolismo
Hipercolesterolemia/complicações
Ligantes
Masculino
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Traumatismo por Reperfusão Miocárdica/etiologia
Traumatismo por Reperfusão Miocárdica/metabolismo
Fosforilação Oxidativa
Ratos Zucker
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzodiazepinones); 0 (Carrier Proteins); 0 (Ligands); 0 (Mitochondrial Membrane Transport Proteins); 0 (Receptors, GABA-A); 0 (Sterols); 0 (mitochondrial permeability transition pore); 141440-82-6 (Tspo protein, rat); 2QW0IK1742 (4'-chlorodiazepam)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE


  5 / 4215 MEDLINE  
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[PMID]:28634650
[Au] Autor:Ueno M; Li CP; Ikeda M; Ishii H; Mizuno N; Yamaguchi T; Ioka T; Oh DY; Ichikawa W; Okusaka T; Matsuyama Y; Arai D; Chen LT; Park YS; Furuse J
[Ad] Endereço:Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama-shi, Kanagawa, 241-8515, Japan. uenom@kcch.jp.
[Ti] Título:A randomized phase II study of gemcitabine plus Z-360, a CCK2 receptor-selective antagonist, in patients with metastatic pancreatic cancer as compared with gemcitabine plus placebo.
[So] Source:Cancer Chemother Pharmacol;80(2):307-315, 2017 Aug.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We investigated the efficacy and safety of 60, 120, or 240 mg of Z-360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer. METHODS: Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m gemcitabine for each cycle and Z-360 tablets of 60 mg (GZ 60 mg group), 120, 240 mg or placebo tablets (Gem group) orally twice daily. The primary endpoint was overall survival (OS). RESULTS: The median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated. CONCLUSIONS: In this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Neoplasias Pancreáticas/tratamento farmacológico
Receptor de Colecistocinina B/antagonistas & inibidores
[Mh] Termos MeSH secundário: Administração Oral
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Benzodiazepinonas/administração & dosagem
Desoxicitidina/administração & dosagem
Desoxicitidina/análogos & derivados
Relação Dose-Resposta a Droga
Método Duplo-Cego
Feminino
Seres Humanos
Masculino
Meia-Idade
Metástase Neoplásica
Neoplasias Pancreáticas/patologia
Taxa de Sobrevida
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Benzodiazepinones); 0 (Receptor, Cholecystokinin B); 0 (Z-360); 0W860991D6 (Deoxycytidine); B76N6SBZ8R (gemcitabine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-017-3351-4


  6 / 4215 MEDLINE  
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[PMID]:28442392
[Au] Autor:Arbo BD; Hoppe JB; Rodrigues K; Garcia-Segura LM; Salbego CG; Ribeiro MF
[Ad] Endereço:Laboratório de Interação Neuro-Humoral - Department of Physiology - ICBS - Universidade Federal do Rio Grande do Sul (UFRGS), Rua Sarmento Leite, 500, 90050-170, Porto Alegre, RS, Brazil. Electronic address: brunoarbo@gmail.com.
[Ti] Título:4'-Chlorodiazepam is neuroprotective against amyloid-beta in organotypic hippocampal cultures.
[So] Source:J Steroid Biochem Mol Biol;171:281-287, 2017 Jul.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The translocator protein (TSPO) is an outer mitochondrial membrane protein involved in the transport of cholesterol into the mitochondria, which is the first step for the synthesis of steroid hormones, as well as in the regulation of mitochondrial permeability transition pore opening and apoptosis. Studies have shown that the activation of TSPO may promote neuroprotective actions in experimental models of neurodegeneration and brain injury. In a previous study, our group showed that 4'-chlorodiazepam (4'-CD), a TSPO ligand, was neuroprotective against amyloid-beta (Aß) in SHSY-5Y neuroblastoma cells. The aim of this study was to evaluate if 4'-CD was also neuroprotective against Aß in organotypic hippocampal cultures and to identify its mechanisms of action. Aß decreased the cell viability of organotypic hippocampal cultures, while 4'-CD had a neuroprotective effect when administered at 100nM and 1000nM. The neuroprotective effects of 4'-CD against Aß were associated with an increased expression of superoxide dismutase (SOD). No differences were found in the expression of catalase, glial fibrillary acidic protein, Akt and procaspase-3. In summary, our results show that 4'-CD is neuroprotective against Aß by a mechanism involving the modulation of SOD protein expression.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/antagonistas & inibidores
Apoptose/efeitos dos fármacos
Benzodiazepinonas/farmacologia
Hipocampo/efeitos dos fármacos
Proteínas do Tecido Nervoso/antagonistas & inibidores
Neurônios/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
[Mh] Termos MeSH secundário: Peptídeos beta-Amiloides/metabolismo
Animais
Antioxidantes/farmacologia
Biomarcadores/metabolismo
Proteínas de Transporte/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Hipocampo/metabolismo
Ligantes
Masculino
Proteínas do Tecido Nervoso/agonistas
Proteínas do Tecido Nervoso/metabolismo
Neurônios/metabolismo
Nootrópicos/farmacologia
Concentração Osmolar
Estresse Oxidativo/efeitos dos fármacos
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/metabolismo
Ratos Wistar
Receptores de GABA-A/metabolismo
Superóxido Dismutase-1/química
Superóxido Dismutase-1/metabolismo
Técnicas de Cultura de Tecidos
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Antioxidants); 0 (Benzodiazepinones); 0 (Biomarkers); 0 (Carrier Proteins); 0 (Ligands); 0 (Nerve Tissue Proteins); 0 (Neuroprotective Agents); 0 (Nootropic Agents); 0 (Peptide Fragments); 0 (Receptors, GABA-A); 0 (amyloid beta-protein (1-42)); 141440-82-6 (Tspo protein, rat); 2QW0IK1742 (4'-chlorodiazepam); EC 1.15.1.1 (Sod1 protein, rat); EC 1.15.1.1 (Superoxide Dismutase-1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE


  7 / 4215 MEDLINE  
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[PMID]:28388054
[Au] Autor:Pegoli A; She X; Wifling D; Hübner H; Bernhardt G; Gmeiner P; Keller M
[Ad] Endereço:Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
[Ti] Título:Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M Muscarinic Acetylcholine Receptor.
[So] Source:J Med Chem;60(8):3314-3334, 2017 Apr 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increasingly applied to muscarinic receptors (MRs). In this article, we present the synthesis and characterization of a M R subtype-preferring radiolabeled dibenzodiazepinone-type antagonist ([ H]UNSW-MK259, [ H]19) and its homodimeric analogue [ H]UR-AP060 ([ H]33). Saturation binding studies at the M R, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and the dimeric compound bind to the orthosteric binding site (apparent K : 0.87 and 0.31 nM, respectively). Various binding studies with [ H]19 and [ H]33 at the M R, for instance, saturation binding experiments in the presence of the allosteric MR modulators W84 (8) or LY2119620 (9) (Schild-like analysis) suggested a competitive mechanism between the allosteric modulator and the dibenzodiazepinone derivatives, and thus a dualsteric binding mode of both 19 and 33. This was consistent with the results of M R MD simulations (≥2 µs) performed with 19 and 33.
[Mh] Termos MeSH primário: Benzodiazepinonas/metabolismo
Antagonistas Muscarínicos/farmacologia
Radioisótopos/química
Receptor Muscarínico M2/antagonistas & inibidores
[Mh] Termos MeSH secundário: Sítios de Ligação
Simulação de Dinâmica Molecular
Receptor Muscarínico M2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzodiazepinones); 0 (Muscarinic Antagonists); 0 (Radioisotopes); 0 (Receptor, Muscarinic M2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01892


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[PMID]:28259934
[Au] Autor:Liu Z; Liu J; Zhao L; Geng H; Ma J; Zhang Z; Yu D; Zhong C
[Ad] Endereço:Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China.
[Ti] Título:Curcumin reverses benzidine-induced epithelial-mesenchymal transition via suppression of ERK5/AP-1 in SV-40 immortalized human urothelial cells.
[So] Source:Int J Oncol;50(4):1321-1329, 2017 Apr.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Overexposure to benzidine has been manifested as an important cause of bladder cancer. However, the molecular mechanism of benzidine-induced malignancy is still insufficiently interpreted. Epithelial-mesenchymal transition (EMT) is a crucial pathophysiological process in embryonic development as well as initiation and development of epithelium-originated malignant tumors. The role of extracellular regulated protein kinase 5 (ERK5) in benzidine-meditated bladder cancer development has not been explored. In the present study, we explored the role of ERK5/AP-1 pathway in benzidine-induced EMT in human normal urothelial cells and the intervention effect of curcumin on bezidine-induced EMT. We found that benzidine-induced EMT in SV-40 immortalized human urothelial cells (SV-HUC-1) at low concentrations. We detected that ERK5/AP-1 pathway was notably activated. Specific ERK5 inhibitor, XMD8-92 was applied to determine the role of ERK5 in benzidine-induced EMT. Results indicated that XMD8-92 reversed the EMT process. Furthermore, curcumin effectively attenuated benzidine-induced urocystic EMT by suppressing ERK5/AP-1 pathway. In conclusion, the present study revealed the positive role of ERK5/AP-1 in benzidine-provoked urocystic EMT and the curcumin promising use in bladder cancer prevention and intervention via ERK5/AP-1 pathway.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzidinas/toxicidade
Curcumina/farmacologia
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Proteína Quinase 7 Ativada por Mitógeno/metabolismo
Fator de Transcrição AP-1/metabolismo
Neoplasias da Bexiga Urinária/prevenção & controle
[Mh] Termos MeSH secundário: Benzodiazepinonas/farmacologia
Carcinogênese/efeitos dos fármacos
Células Cultivadas
Seres Humanos
Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Proteínas Quinases/metabolismo
Bexiga Urinária
Neoplasias da Bexiga Urinária/induzido quimicamente
Urotélio/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzidines); 0 (Benzodiazepinones); 0 (Protein Kinase Inhibitors); 0 (Transcription Factor AP-1); 0 (XMD 8-92); 2X02101HVF (benzidine); EC 2.7.- (Protein Kinases); EC 2.7.11.24 (MAPK7 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170306
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2017.3887


  9 / 4215 MEDLINE  
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[PMID]:27943591
[Au] Autor:Qin Q; Zhi LT; Li XT; Yue ZY; Li GZ; Zhang H
[Ad] Endereço:Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
[Ti] Título:Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission.
[So] Source:CNS Neurosci Ther;23(2):162-173, 2017 Feb.
[Is] ISSN:1755-5949
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission. AIMS: To address this gap in knowledge, we examined the effects of three types of LRRK2 inhibitors (LRRK2-IN-1, GSK2578215A, and GNE-7915) on dopamine (DA) release in the dorsal striatum using fast-scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta (SNpc) using patch clamp in mouse brain slices. RESULTS: We found that LRRK2-IN-1 at a concentration higher than 1 µM causes off-target effects and decreases DA release, whereas GSK2578215A and GNE-7915 do not. All three inhibitors at 1 µM have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclinical LRRK2 mouse models (i.e., BAC transgenic hG2019S and hR1441G) and demonstrated that GNE-7915 enhances DA release and synaptic vesicle mobilization/recycling. CONCLUSION: GNE-7915 can be validated for further therapeutic development for PD.
[Mh] Termos MeSH primário: Corpo Estriado/citologia
Dopamina/metabolismo
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo
Doença de Parkinson/patologia
Substância Negra/citologia
[Mh] Termos MeSH secundário: Aminopiridinas/farmacologia
Animais
Benzamidas/farmacologia
Benzodiazepinonas/farmacologia
Fenômenos Biofísicos/efeitos dos fármacos
Fenômenos Biofísicos/genética
Corpo Estriado/efeitos dos fármacos
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Estimulação Elétrica
Técnicas In Vitro
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética
Masculino
Camundongos
Camundongos Transgênicos
Morfolinas/farmacologia
Mutação/genética
Doença de Parkinson/tratamento farmacológico
Doença de Parkinson/genética
Técnicas de Patch-Clamp
Pirimidinas/farmacologia
Substância Negra/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone); 0 (Aminopyridines); 0 (Benzamides); 0 (Benzodiazepinones); 0 (GSK2578215A); 0 (LRRK2-IN1); 0 (Morpholines); 0 (Pyrimidines); EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE
[do] DOI:10.1111/cns.12660


  10 / 4215 MEDLINE  
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[PMID]:27932068
[Au] Autor:Rudin CM; Pietanza MC; Bauer TM; Ready N; Morgensztern D; Glisson BS; Byers LA; Johnson ML; Burris HA; Robert F; Han TH; Bheddah S; Theiss N; Watson S; Mathur D; Vennapusa B; Zayed H; Lally S; Strickland DK; Govindan R; Dylla SJ; Peng SL; Spigel DR; SCRX16-001 investigators
[Ad] Endereço:Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudinc@mskcc.org.
[Ti] Título:Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.
[So] Source:Lancet Oncol;18(1):42-51, 2017 Jan.
[Is] ISSN:1474-5488
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS: We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS: Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION: Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING: Stemcentrx Inc.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Antineoplásicos/uso terapêutico
Benzodiazepinonas/uso terapêutico
Carcinoma de Células Grandes/tratamento farmacológico
Carcinoma Neuroendócrino/tratamento farmacológico
Imunoconjugados/uso terapêutico
Peptídeos e Proteínas de Sinalização Intracelular/imunologia
Neoplasias Pulmonares/tratamento farmacológico
Proteínas de Membrana/imunologia
Recidiva Local de Neoplasia/tratamento farmacológico
Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Carcinoma de Células Grandes/imunologia
Carcinoma de Células Grandes/patologia
Carcinoma Neuroendócrino/imunologia
Carcinoma Neuroendócrino/patologia
Relação Dose-Resposta a Droga
Feminino
Seguimentos
Seres Humanos
Imunoconjugados/farmacologia
Neoplasias Pulmonares/imunologia
Neoplasias Pulmonares/patologia
Masculino
Dose Máxima Tolerável
Meia-Idade
Recidiva Local de Neoplasia/imunologia
Recidiva Local de Neoplasia/patologia
Estadiamento de Neoplasias
Prognóstico
Carcinoma de Pequenas Células do Pulmão/imunologia
Carcinoma de Pequenas Células do Pulmão/patologia
Taxa de Sobrevida
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents); 0 (Benzodiazepinones); 0 (DLL3 protein, human); 0 (Immunoconjugates); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (rovalpituzumab tesirine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170624
[Lr] Data última revisão:
170624
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE



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