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  1 / 3996 MEDLINE  
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[PMID]:29202397
[Au] Autor:Xie R; Li Y; Tang P; Yuan Q
[Ad] Endereço:Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
[Ti] Título:Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
[So] Source:Eur J Med Chem;143:320-333, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC values of as low as 0.54-2.49 µM compared with CS055 (2.28∼ >26 µM) and MS275 (0.47-6.74 µM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Inibidores de Histona Desacetilases/farmacologia
Histona Desacetilases/metabolismo
Tiocarbamatos/farmacologia
ortoaminobenzoatos/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores de Histona Desacetilases/síntese química
Inibidores de Histona Desacetilases/química
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Relação Estrutura-Atividade
Tiocarbamatos/química
ortoaminobenzoatos/síntese química
ortoaminobenzoatos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Histone Deacetylase Inhibitors); 0 (Thiocarbamates); 0 (ortho-Aminobenzoates); EC 3.5.1.98 (Histone Deacetylases); Q1M2WEK6VA (anthranilamide)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


  2 / 3996 MEDLINE  
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[PMID]:28868930
[Au] Autor:Laskar S; Sánchez-Sánchez L; López-Ortiz M; López-Muñoz H; Escobar-Sánchez ML; Sánchez AT; Regla I
[Ad] Endereço:a Lab. de Síntesis de Fármacos, Laboratorio 9 UMIEZ, Facultad de Estudios Superiores Zaragoza , Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
[Ti] Título:Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis.
[So] Source:J Enzyme Inhib Med Chem;32(1):1129-1135, 2017 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Compostos Azabicíclicos/farmacologia
Tiocarbamatos/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Compostos Azabicíclicos/síntese química
Compostos Azabicíclicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Relação Estrutura-Atividade
Tiocarbamatos/síntese química
Tiocarbamatos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Azabicyclo Compounds); 0 (Thiocarbamates)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1363197


  3 / 3996 MEDLINE  
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[PMID]:28766952
[Au] Autor:Nocentini A; Vullo D; Del Prete S; Osman SM; Alasmary FAS; AlOthman Z; Capasso C; Carta F; Gratteri P; Supuran CT
[Ad] Endereço:a Department Neurofarba - Pharmaceutical and Nutraceutical Section , University of Firenze , Firenze , Italy.
[Ti] Título:Inhibition of the ß-carbonic anhydrase from the dandruff-producing fungus Malassezia globosa with monothiocarbamates.
[So] Source:J Enzyme Inhib Med Chem;32(1):1064-1070, 2017 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of monothiocarbamates (MTCs) was investigated for the inhibition of the ß-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa, MgCA. These MTCs incorporate various scaffolds, among which aliphatic amine with 1-4 carbons atom in their molecule, morpholine, piperazine, as well as phenethylamine and benzylamine derivatives. All the reported MTCs displayed a better efficacy in inhibiting MgCA compared to the clinically used sulphonamide drug acetazolamide (K of 74 µM), with K s spanning between 1.85 and 18.9 µM. The homology model of the enzyme previously reported by us was used to rationalize the results by docking some of these MTCs within the fungal CA active site. This study might be useful to enrich the knowledge of the MgCA inhibition profile, eliciting novel ideas pertaining the design of modulators with potential efficacy in combatting dandruff or other fungal infections.
[Mh] Termos MeSH primário: Inibidores da Anidrase Carbônica/farmacologia
Anidrases Carbônicas/metabolismo
Malassezia/química
Tiocarbamatos/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Anidrase Carbônica/química
Inibidores da Anidrase Carbônica/isolamento & purificação
Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Tiocarbamatos/química
Tiocarbamatos/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carbonic Anhydrase Inhibitors); 0 (Thiocarbamates); EC 4.2.1.1 (Carbonic Anhydrases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1355307


  4 / 3996 MEDLINE  
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[PMID]:28733145
[Au] Autor:Liu X; Wang CN; Qiu CY; Song W; Wang LF; Liu B
[Ad] Endereço:Department of Vascular Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
[Ti] Título:Adipocytes promote nicotine-induced injury of endothelial cells via the NF-κB pathway.
[So] Source:Exp Cell Res;359(1):251-256, 2017 Oct 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cigarette smoking is one of the most important risk factors of atherosclerosis, which can induce endothelial injury. Meanwhile, adipocytes are the main cell type of perivascular adipose tissue (PVAT), the largest endocrine and paracrine organ and direct anatomical connection to adventitia, which may play a key role in the injury of endothelial cells. We used nicotine to induce dysfunctional HUVECs and adipocytes. In addition, we used a novel model to co-culture HUVECs and adipocytes in vitro by the transwell co-culture system to determine the effect of adipocytes on endothelial injury. Cell apoptosis was detected by Annexin V-FITC. Genes and proteins involved in the nuclear factor kappa B (NF-κB) signaling pathway were detected by qRT-PCR and western blot analysis, respectively. We also investigated the nuclear translocation of NF-κB p65 using immunofluorescence staining. Our results showed that nicotine dose-dependently induces the apoptosis of HUVECs and adipocytes and is associated with increased IKKß and NF-κB p65 expression and with IkBα degradation. Meanwhile through the co-culture system, adipocytes promoted the expression of IKKß and NF-κB p65, as well as the translocation of NF-κB p65, and they accelerated the degradation of IkBα, resulting in increased apoptosis of HUVECs compared with that of the single cultured system. In conclusion, adipocytes could promote endothelial injury via the NF-κB pathway. Moreover, the NF-κB pathway plays pivotal roles in nicotine-induced vascular injury.
[Mh] Termos MeSH primário: Adipócitos/metabolismo
Adipócitos/patologia
Células Endoteliais/patologia
NF-kappa B/metabolismo
Nicotina/efeitos adversos
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos/efeitos dos fármacos
Animais
Apoptose/efeitos dos fármacos
Apoptose/genética
Diferenciação Celular/efeitos dos fármacos
Técnicas de Cocultura
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/metabolismo
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Células Endoteliais da Veia Umbilical Humana/metabolismo
Quinase I-kappa B/metabolismo
Camundongos
NF-kappa B/antagonistas & inibidores
Prolina/análogos & derivados
Prolina/farmacologia
Regiões Promotoras Genéticas/genética
Proteólise/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Tiocarbamatos/farmacologia
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NF-kappa B); 0 (Thiocarbamates); 135467-92-4 (prolinedithiocarbamate); 6M3C89ZY6R (Nicotine); 9DLQ4CIU6V (Proline); EC 2.7.11.10 (I-kappa B Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE


  5 / 3996 MEDLINE  
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[PMID]:28719912
[Au] Autor:Li S; Liu X; Lei J; Yang J; Tian P; Gao Y
[Ad] Endereço:Department of Nephropathy, Xi'an, China.
[Ti] Título:Crocin Protects Podocytes Against Oxidative Stress and Inflammation Induced by High Glucose Through Inhibition of NF-κB.
[So] Source:Cell Physiol Biochem;42(4):1481-1492, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Diabetic nephropathy (DN) is a microangiopathic disease characterized by excessive urinary albumin excretion, which occurs in 30% of patients with diabetes mellitus. It is the second leading cause of end-stage renal diseases in China. Nuclear factor-kappa B (NF-κB) is reported to be closely correlated with the inflammation underlying diabetes-associated renal damage. Crocin, a plant-derived compound, has antioxidant properties that may inhibit NF-κB. METHODS: In the present study, we used a conditionally immortalized mouse podocyte cell line to explore whether crocin could effectively block albuminuria. Cells were incubated with 15 or 25 mM D-glucose to mimic diabetic conditions. The expression of Wilms tumor 1 (WT-1) and synaptopodin was evaluated to identify differentiated podocytes, and the expression of nephrin, podocin, and CD2ap was measured as markers of slit diaphragms, the main structures within the glomerular filtration barrier. RESULTS: The high-glucose conditions led to reduced nephrin, podocin, and CD2ap expression, which was prevented by pretreatment with crocin. The oxidative stress and pro-inflammatory response of podocytes associated with DN induced by high glucose were also reduced by crocin pretreatment. Phosphorylated IκBα (p-IκBα) expression induced by high glucose was also significantly decreased by crocin pretreatment. Moreover, pyrrolidine dithiocarbamate, a NF-κB inhibitor, pyrrolidine dithio carbamate, augmented the protective effects of crocin. CONCLUSION: Our results demonstrate a protective role of crocin against damage to podocytes and slit diaphragms under high-glucose conditions via inhibition of NF-κB. This study presents a potential therapy for DN and contributes to the understanding of the mechanism underlying DN.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Carotenoides/farmacologia
Glucose/antagonistas & inibidores
NF-kappa B/genética
Podócitos/efeitos dos fármacos
Pirrolidinas/farmacologia
Tiocarbamatos/farmacologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Linhagem Celular Transformada
Proteínas do Citoesqueleto/genética
Proteínas do Citoesqueleto/metabolismo
Combinação de Medicamentos
Sinergismo Farmacológico
Regulação da Expressão Gênica
Glucose/toxicidade
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Proteínas dos Microfilamentos/genética
Proteínas dos Microfilamentos/metabolismo
Inibidor de NF-kappaB alfa/genética
Inibidor de NF-kappaB alfa/metabolismo
NF-kappa B/antagonistas & inibidores
NF-kappa B/metabolismo
Estresse Oxidativo
Podócitos/citologia
Podócitos/metabolismo
Transdução de Sinais
Proteínas WT1/genética
Proteínas WT1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antioxidants); 0 (CD2-associated protein); 0 (Cytoskeletal Proteins); 0 (Drug Combinations); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (Microfilament Proteins); 0 (NF-kappa B); 0 (NPHS2 protein); 0 (Pyrrolidines); 0 (Synpo protein, mouse); 0 (Thiocarbamates); 0 (WT1 Proteins); 0 (nephrin); 139874-52-5 (NF-KappaB Inhibitor alpha); 25769-03-3 (pyrrolidine dithiocarbamic acid); 36-88-4 (Carotenoids); 877GWI46C2 (crocin); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1159/000479212


  6 / 3996 MEDLINE  
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[PMID]:28715444
[Au] Autor:Lu CW; Lin Y; Lei YP; Wang L; He ZM; Xiong Y
[Ad] Endereço:Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, P. R. China.
[Ti] Título:Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity.
[So] Source:PLoS One;12(7):e0179908, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Endothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been involved in diabetic endothelial dysfunction. This study was to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on impairment of endothelium-dependent vasodilatation in diabetic rats and its potential mechanism. METHODS: Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (60mg/kg), and PDTC (10mg/kg) was given in drinking water for 8 weeks. Blood glucose and serum ADMA concentrations were measured in experimental rats. Recombinant adenovirus encoding human DDAH2 gene were constructed and ex vivo transferred to isolated rat aortas. The maximal relaxation (Emax) and half maximal effective concentration (EC50) of aortic rings response to accumulative concentrations of acetylcholine and vascular DDAH activity were examined before and after gene transfection. RESULTS: Diabetic rats displayed significant elevations of blood glucose and serum ADMA levels compared to control group (P<0.01). Vascular DDAH activity and endothelium-dependent relaxation of aortas were inhibited, as expressed by the decreased Emax and increased EC50 in diabetic rats compared to control rats (P<0.01). Treatment with PDTC not only decreased blood glucose and serum ADMA concentration (P<0.01) but also restored vascular DDAH activity and endothelium-dependent relaxation, evidenced by the higher Emax and lower EC50 in PDTC-treated diabetic rats compared to untreated diabetic rats (P<0.01). Similar restoration of Emax, EC50 and DDAH activity were observed in diabetic aortas after DDAH2-gene transfection. CONCLUSIONS: These results indicate that PDTC could ameliorate impairment of endothelium-dependent relaxation in diabetic rats. The underlying mechanisms might be related to preservation of vascular DDAH activity and consequent reduction of endogenous ADMA in endothelium via its antioxidant action. This study highlights the therapeutic potential of PDTC in impaired vasodilation and provides a new strategy for treatment of diabetic cardiovascular complications.
[Mh] Termos MeSH primário: Amidoidrolases/metabolismo
Aorta Torácica/efeitos dos fármacos
Aorta Torácica/fisiopatologia
Diabetes Mellitus Experimental/enzimologia
Diabetes Mellitus Experimental/fisiopatologia
Endotélio Vascular/efeitos dos fármacos
Pirrolidinas/farmacologia
Tiocarbamatos/farmacologia
[Mh] Termos MeSH secundário: Animais
Arginina/análogos & derivados
Arginina/metabolismo
Glicemia/metabolismo
Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Experimental/metabolismo
Endotélio Vascular/fisiopatologia
Células HEK293
Seres Humanos
Óxido Nítrico/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Pirrolidinas/uso terapêutico
Ratos
Tiocarbamatos/uso terapêutico
Vasodilatação/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Pyrrolidines); 0 (Thiocarbamates); 0 (dimethylarginine); 25769-03-3 (pyrrolidine dithiocarbamic acid); 31C4KY9ESH (Nitric Oxide); 94ZLA3W45F (Arginine); EC 3.5.- (Amidohydrolases); EC 3.5.3.18 (dimethylargininase)
[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:170718
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179908


  7 / 3996 MEDLINE  
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[PMID]:28712932
[Au] Autor:Lee EH; Kim SS; Seo SR
[Ad] Endereço:Department of Molecular Bioscience, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea.
[Ti] Título:Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction.
[So] Source:Biochem Pharmacol;143:107-117, 2017 Nov 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC-mediated inhibitory effect on NF-κB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Citocinas/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/biossíntese
Proteínas Musculares/biossíntese
NF-kappa B/metabolismo
Pirrolidinas/farmacologia
Tiocarbamatos/farmacologia
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/metabolismo
Imunoprecipitação da Cromatina
Citocinas/sangue
Citocinas/imunologia
Células HEK293
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Camundongos
Camundongos Knockout
Proteínas Musculares/genética
NF-kappa B/imunologia
Transdução de Sinais
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Cytokines); 0 (DSCR1 protein, mouse); 0 (Intracellular Signaling Peptides and Proteins); 0 (Muscle Proteins); 0 (NF-kappa B); 0 (Pyrrolidines); 0 (RCAN1 protein, human); 0 (Thiocarbamates); 25769-03-3 (pyrrolidine dithiocarbamic acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


  8 / 3996 MEDLINE  
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[PMID]:28712788
[Au] Autor:Zhao X; Liu M; Li J; Yin S; Wu Y; Wang A
[Ad] Endereço:School of Veterinary Medicine, Yangzhou University, Yangzhou 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, PR China.
[Ti] Título:Antimalarial agent artesunate protects Concanavalin A-induced autoimmune hepatitis in mice by inhibiting inflammatory responses.
[So] Source:Chem Biol Interact;274:116-123, 2017 Aug 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The anti-malarial drug artesunate (ARS) has been shown to possess anti-inflammatory activity. Its effect on autoimmune hepatitis remains unclear. Concanavalin A (Con A)-induced hepatitis was used in this study to reveal the potential action of ARS and the related mechanism. Mice were pretreated with ARS followed by Con A challenge. Con A caused obvious hepatic injury with higher levels of liver enzymes, elevated pro-inflammatory cytokines and activation of nuclear factor-κB (NF-κB) and mitogen activated protein kinase (MAPK) signaling pathways. However, ARS pretreatment notably inhibited Con A-induced liver injury with remarkable reduction of liver enzymes, and dramatically suppressed the expression of inflammatory cytokines including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and IL-17, and increased anti-inflammatory cytokines IL-10. In line with cytokines, the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (p38), nuclear factor-κBα (IκBα) and NF-κB p65 was also significantly inhibited by ARS pretreatment. As a contrast, the specific inhibitor of NF-κB pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as ARS on phosphorylation of p65 and IκBα, and serum levels of aminotransferases. Taken together, these data highlight that ARS has facilitating to make a better understanding of ARS against acute autoimmune hepatitis, and indicating a promising therapy candidate for autoimmune hepatitis.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Artemisininas/farmacologia
Hepatite Autoimune/prevenção & controle
Substâncias Protetoras/farmacologia
[Mh] Termos MeSH secundário: Animais
Concanavalina A/toxicidade
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Hepatite Autoimune/etiologia
Interleucina-17/análise
Interleucina-6/análise
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Fígado/efeitos dos fármacos
Fígado/metabolismo
Fígado/patologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Inibidor de NF-kappaB alfa/metabolismo
NF-kappa B/antagonistas & inibidores
NF-kappa B/metabolismo
Fosforilação/efeitos dos fármacos
Pirrolidinas/farmacologia
Transdução de Sinais/efeitos dos fármacos
Tiocarbamatos/farmacologia
Fator de Necrose Tumoral alfa/análise
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Artemisinins); 0 (Interleukin-17); 0 (Interleukin-6); 0 (NF-kappa B); 0 (Protective Agents); 0 (Pyrrolidines); 0 (Thiocarbamates); 0 (Tumor Necrosis Factor-alpha); 11028-71-0 (Concanavalin A); 139874-52-5 (NF-KappaB Inhibitor alpha); 25769-03-3 (pyrrolidine dithiocarbamic acid); 60W3249T9M (artesunate); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


  9 / 3996 MEDLINE  
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[PMID]:28692063
[Au] Autor:Karimy JK; Zhang J; Kurland DB; Theriault BC; Duran D; Stokum JA; Furey CG; Zhou X; Mansuri MS; Montejo J; Vera A; DiLuna ML; Delpire E; Alper SL; Gunel M; Gerzanich V; Medzhitov R; Simard JM; Kahle KT
[Ad] Endereço:Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
[Ti] Título:Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.
[So] Source:Nat Med;23(8):997-1003, 2017 Aug.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.
[Mh] Termos MeSH primário: Hemorragia Cerebral/imunologia
Líquido Cefalorraquidiano/secreção
Plexo Corióideo/secreção
Hidrocefalia/imunologia
NF-kappa B/imunologia
Receptor 4 Toll-Like/imunologia
[Mh] Termos MeSH secundário: Acetazolamida/farmacologia
Animais
Antioxidantes/farmacologia
Western Blotting
Bumetanida/farmacologia
Hemorragia Cerebral/complicações
Ventrículos Cerebrais
Plexo Corióideo/efeitos dos fármacos
Plexo Corióideo/imunologia
Diuréticos/farmacologia
Técnicas de Silenciamento de Genes
Técnicas de Inativação de Genes
Hidrocefalia/etiologia
Hidrocefalia/metabolismo
Immunoblotting
Imuno-Histoquímica
Imunoprecipitação
Inflamação
Prolina/análogos & derivados
Prolina/farmacologia
Proteínas Serina-Treonina Quinases/metabolismo
Ratos
Ratos Wistar
Salicilanilidas/farmacologia
Membro 2 da Família 12 de Carreador de Soluto/metabolismo
Sulfonamidas/farmacologia
Tiocarbamatos/farmacologia
Receptor 4 Toll-Like/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Diuretics); 0 (NF-kappa B); 0 (Salicylanilides); 0 (Slc12a2 protein, mouse); 0 (Solute Carrier Family 12, Member 2); 0 (Sulfonamides); 0 (Thiocarbamates); 0 (Tlr4 protein, rat); 0 (Toll-Like Receptor 4); 0 (ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate); 0Y2S3XUQ5H (Bumetanide); 135467-92-4 (prolinedithiocarbamate); 9DLQ4CIU6V (Proline); EC 2.7.1.- (Stk39 protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EUL532EI54 (closantel); O3FX965V0I (Acetazolamide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4361


  10 / 3996 MEDLINE  
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[PMID]:28651154
[Au] Autor:Tomasello MF; Nardon C; Lanza V; Di Natale G; Pettenuzzo N; Salmaso S; Milardi D; Caliceti P; Pappalardo G; Fregona D
[Ad] Endereço:IBB-CNR, Istituto di Biostrutture e Bioimmagini, Sede Secondaria di Catania, Via Paolo Gaifami, 18 - 95126, Catania, Italy.
[Ti] Título:New comprehensive studies of a gold(III) Dithiocarbamate complex with proven anticancer properties: Aqueous dissolution with cyclodextrins, pharmacokinetics and upstream inhibition of the ubiquitin-proteasome pathway.
[So] Source:Eur J Med Chem;138:115-127, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The gold(III)-dithiocarbamate complex AuL12 (dibromo [ethyl-N-(dithiocarboxy-kS,kS')-N-methylglycinate] gold(III)), is endowed with promising in vitro/in vivo antitumor activity and toxicological profile. Here, we report our recent strategies to improve its water solubility and stability under physiological conditions along with our efforts for unravelling its tangled mechanism of action. We used three types of α-cyclodextrins (CDs), namely ß-CD, Me-ß-CD and HP-ß-CD to prepare aqueous solutions of AuL12. The ability of these natural oligosaccharide carriers to enhance water solubility of hydrophobic compounds, allowed drug stability of AuL12 to be investigated. Moreover, pharmacokinetic experiments were first carried out for a gold(III) coordination compound, after i.v. injection of the nanoformulation AuL12/HP-ß-CD to female mice. The gold content in the blood samples was detected at scheduled times by AAS (atomic absorption spectrometry) analysis, highlighting a fast biodistribution with a t of few minutes and a slow escretion (t of 14.3 h). The in vitro cytotoxic activity of AuL12 was compared with the AuL12/HP-ß-CD mixture against a panel of three human tumor cell lines (i.e., HeLa, KB and MCF7). Concerning the mechanism of action, we previously reported the proteasome-inhibitory activity of some our gold(III)-based compounds. In this work, we moved from the proteasome target to upstream of the important ubiquitin-proteasome pathway, testing the effects of AuL12 on the polyubiquitination reactions involving the Ub-activating (E1) and -conjugating (E2) enzymes.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Ciclodextrinas/química
Ouro/farmacologia
Complexo de Endopeptidases do Proteassoma/metabolismo
Tiocarbamatos/farmacologia
Ubiquitina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Ouro/química
Seres Humanos
Camundongos
Camundongos Endogâmicos BALB C
Estrutura Molecular
Solubilidade
Relação Estrutura-Atividade
Tiocarbamatos/química
Distribuição Tecidual
Células Tumorais Cultivadas
Ubiquitina/metabolismo
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cyclodextrins); 0 (Thiocarbamates); 0 (Ubiquitin); 059QF0KO0R (Water); 7440-57-5 (Gold); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE



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