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[PMID]:28257497
[Au] Autor:Matthews H; Deakin J; Rajab M; Idris-Usman M; Nirmalan NJ
[Ad] Endereço:Environment and Life sciences, University of Salford, Greater Manchester, United Kingdom.
[Ti] Título:Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations.
[So] Source:PLoS One;12(3):e0173303, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26-32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product.
[Mh] Termos MeSH primário: Antimaláricos/uso terapêutico
Emetina/uso terapêutico
Malária Falciparum/tratamento farmacológico
[Mh] Termos MeSH secundário: Artemisininas/uso terapêutico
Atovaquona/uso terapêutico
Cloroquina/uso terapêutico
Biologia Computacional
Combinação de Medicamentos
Interações Medicamentosas
Sinergismo Farmacológico
Quimioterapia Combinada
Seres Humanos
Malária Falciparum/parasitologia
Plasmodium falciparum/efeitos dos fármacos
Plasmodium falciparum/patogenicidade
Proguanil/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Artemisinins); 0 (Drug Combinations); 0 (atovaquone, proguanil drug combination); 886U3H6UFF (Chloroquine); 9RMU91N5K2 (artemisinine); S61K3P7B2V (Proguanil); X8D5EPO80M (Emetine); Y883P1Z2LT (Atovaquone)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173303


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[PMID]:28055963
[Au] Autor:Aoki T; Shimada K; Sakamoto A; Sugimoto K; Morishita T; Kojima Y; Shimada S; Kato S; Iriyama C; Kuno S; Harada Y; Tomita A; Hayakawa F; Kiyoi H
[Ad] Endereço:Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
[Ti] Título:Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism.
[So] Source:Oncotarget;8(8):13085-13098, 2017 Feb 21.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Emetina/farmacologia
Glicólise/efeitos dos fármacos
Linfoma Difuso de Grandes Células B/tratamento farmacológico
Proteínas Proto-Oncogênicas c-myc/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Mh] Termos MeSH secundário: Animais
Fibroblastos Associados a Câncer/efeitos dos fármacos
Fibroblastos Associados a Câncer/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Técnicas de Cocultura
Rearranjo Gênico/efeitos dos fármacos
Seres Humanos
Immunoblotting
Hibridização in Situ Fluorescente
Linfoma Difuso de Grandes Células B/genética
Linfoma Difuso de Grandes Células B/metabolismo
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Meia-Idade
Inibidores da Síntese de Proteínas/farmacologia
Proteínas Proto-Oncogênicas c-myc/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Synthesis Inhibitors); 0 (Proto-Oncogene Proteins c-myc); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170106
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14393


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[PMID]:27912879
[Au] Autor:Krstin S; Mohamed T; Wang X; Wink M
[Ad] Endereço:Heidelberg University, Institute of Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany. Electronic address: krstin@uni-heidelberg.de.
[Ti] Título:How do the alkaloids emetine and homoharringtonine kill trypanosomes? An insight into their molecular modes of action.
[So] Source:Phytomedicine;23(14):1771-1777, 2016 Dec 15.
[Is] ISSN:1618-095X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although Trypanosoma brucei causes deadly sleeping sickness, the number of the registered medications is rather limited. Some plant alkaloids are potent trypanocidal agents. PURPOSE: In this study, we wanted to elucidate the molecular modes of trypanocidal activity of the alkaloids emetine and homoharringtonine against Trypanosoma brucei brucei. METHODS: We investigated the activity of both alkaloids regarding growth recovery from alkaloid-induced stress. We measured the inhibition of protein biosynthesis using the Click-iT AHA Alexa Fluor 488 Protein Synthesis HCS Assay kit. Reduction of mitochondrial membrane potential and cell cycle arrest were measured by means of flow cytometry. Additionally, we determined spectrophotometrically the inhibition of the trypanosome specific enzyme trypanothione reductase activity and DNA intercalation. RESULTS: Both alkaloids prevented that parasites could resume normal growth after pretreatment with the alkaloids. They inhibited protein biosynthesis in a time- and concentration-dependent manner. In contrast to homoharringtonine, emetine is also a DNA intercalator. Homoharringtonine decreased the mitochondrial membrane potential. Both alkaloids caused cell cycle arrest. Both alkaloids failed to affect trypanothione reductase, a crucial component of the redox system of trypanosomes. CONCLUSION: We assume that both alkaloids are primarily inhibitors of protein biosynthesis in trypanosomes, with DNA intercalation as an additional mechanism for emetine. This is the first study that elucidates the molecular mode of trypanocidal action of emetine and homoharringtonine.
[Mh] Termos MeSH primário: Emetina/farmacologia
Harringtoninas/farmacologia
Extratos Vegetais/farmacologia
Biossíntese de Proteínas/efeitos dos fármacos
Tripanossomicidas/farmacologia
Trypanosoma brucei brucei/efeitos dos fármacos
Tripanossomíase Africana/parasitologia
[Mh] Termos MeSH secundário: Alcaloides/farmacologia
Inibidores da Angiogênese/farmacologia
Inibidores da Angiogênese/uso terapêutico
Animais
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
DNA de Protozoário/metabolismo
Potencial da Membrana Mitocondrial/efeitos dos fármacos
NADH NADPH Oxirredutases/metabolismo
Fitoterapia
Proteínas de Protozoários/metabolismo
Trypanosoma brucei brucei/crescimento & desenvolvimento
Trypanosoma brucei brucei/metabolismo
Tripanossomíase Africana/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Angiogenesis Inhibitors); 0 (DNA, Protozoan); 0 (Harringtonines); 0 (Plant Extracts); 0 (Protozoan Proteins); 0 (Trypanocidal Agents); 6FG8041S5B (homoharringtonine); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.8.1.12 (trypanothione reductase); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161204
[St] Status:MEDLINE


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[PMID]:27336364
[Au] Autor:Mukhopadhyay R; Roy S; Venkatadri R; Su YP; Ye W; Barnaeva E; Mathews Griner L; Southall N; Hu X; Wang AQ; Xu X; Dulcey AE; Marugan JJ; Ferrer M; Arav-Boger R
[Ad] Endereço:Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
[Ti] Título:Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus.
[So] Source:PLoS Pathog;12(6):e1005717, 2016 Jun.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Infection with human cytomegalovirus (HCMV) is a threat for pregnant women and immunocompromised hosts. Although limited drugs are available, development of new agents against HCMV is desired. Through screening of the LOPAC library, we identified emetine as HCMV inhibitor. Additional studies confirmed its anti-HCMV activities in human foreskin fibroblasts: EC50-40±1.72 nM, CC50-8±0.56 µM, and selectivity index of 200. HCMV inhibition occurred after virus entry, but before DNA replication, and resulted in decreased expression of viral proteins. Synergistic virus inhibition was achieved when emetine was combined with ganciclovir. In a mouse CMV (MCMV) model, emetine was well-tolerated, displayed long half-life, preferential distribution to tissues over plasma, and effectively suppressed MCMV. Since the in vitro anti-HCMV activity of emetine decreased significantly in low-density cells, a mechanism involving cell cycle regulation was suspected. HCMV inhibition by emetine depended on ribosomal processing S14 (RPS14) binding to MDM2, leading to disruption of HCMV-induced MDM2-p53 and MDM2-IE2 interactions. Irrespective of cell density, emetine induced RPS14 translocation into the nucleus during infection. In infected high-density cells, MDM2 was available for interaction with RPS14, resulting in disruption of MDM2-p53 interaction. However, in low-density cells the pre-existing interaction of MDM2-p53 could not be disrupted, and RPS14 could not interact with MDM2. In high-density cells the interaction of MDM2-RPS14 resulted in ubiquitination and degradation of RPS14, which was not observed in low-density cells. In infected-only or in non-infected emetine-treated cells, RPS14 failed to translocate into the nucleus, hence could not interact with MDM2, and was not ubiquitinated. HCMV replicated similarly in RPS14 knockdown or control cells, but emetine did not inhibit virus replication in the former cell line. The interaction of MDM2-p53 was maintained in infected RPS14 knockdown cells despite emetine treatment, confirming a unique mechanism by which emetine exploits RPS14 to disrupt MDM2-p53 interaction. Summarized, emetine may represent a promising candidate for HCMV therapy alone or in combination with ganciclovir through a novel host-dependent mechanism.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Infecções por Citomegalovirus
Citomegalovirus/efeitos dos fármacos
Emetina/farmacologia
[Mh] Termos MeSH secundário: Animais
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Modelos Animais de Doenças
Imunofluorescência
Seres Humanos
Immunoblotting
Imunoprecipitação
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Microscopia Confocal
Reação em Cadeia da Polimerase
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160624
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1005717


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[PMID]:27210430
[Au] Autor:Beteck RM; Coertzen D; Smit FJ; Birkholtz LM; Haynes RK; N'Da DD
[Ad] Endereço:Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom 2520, South Africa.
[Ti] Título:Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.
[So] Source:Bioorg Med Chem Lett;26(13):3006-3009, 2016 07 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Decoquinato/análogos & derivados
Decoquinato/farmacologia
Quinolonas/farmacologia
[Mh] Termos MeSH secundário: Antimaláricos/síntese química
Antimaláricos/toxicidade
Artemisininas/farmacologia
Decoquinato/síntese química
Decoquinato/toxicidade
Resistência a Múltiplos Medicamentos
Emetina/farmacologia
Seres Humanos
Concentração Inibidora 50
Plasmodium falciparum/efeitos dos fármacos
Quinolonas/síntese química
Quinolonas/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antimalarials); 0 (Artemisinins); 0 (Quinolones); 0 (ethyl 1-acetyl-6-decoxy-7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate); 534I52PVWH (Decoquinate); 60W3249T9M (artesunate); C7D6T3H22J (artemether); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160524
[St] Status:MEDLINE


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[PMID]:27135308
[Au] Autor:Ciura K; Kowalski P; Nowakowska J; Markuszewski M; Baczek T; Dziomba S
[Ad] Endereço:Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
[Ti] Título:Sweeping of hydrophobic amines under inhomogeneous electric field and low surfactant concentration in micellar electrokinetic chromatography.
[So] Source:Electrophoresis;37(9):1161-5, 2016 05.
[Is] ISSN:1522-2683
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The influence of sample matrix on sample sweeping in MEKC was examined in the presented manuscript. Significant focusing effect was observed for relatively hydrophobic cationic compounds (emetine, strychnine and quinine) using high ionic strength sample matrix (900 mM H3 PO4 /720 mM Tris) which conductivity was about ninefold higher than utilized BGE. Moreover, the results were obtained using BGE composed of comparatively low surfactant concentration (10 mM SDS) and 40 mM H3 PO4 /32 mM Tris buffer solution. About 200 to 300-fold preconcentration of analytes was reached with the presented method. Basing on experimental results and computer simulation using Simul5 software, hypothetical mechanism of observed phenomenon was proposed.
[Mh] Termos MeSH primário: Cromatografia Capilar Eletrocinética Micelar/métodos
Tensoativos/química
[Mh] Termos MeSH secundário: Simulação por Computador
Emetina/análise
Emetina/química
Emetina/isolamento & purificação
Interações Hidrofóbicas e Hidrofílicas
Modelos Químicos
Quinina/análise
Quinina/química
Quinina/isolamento & purificação
Estricnina/análise
Estricnina/química
Estricnina/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Surface-Active Agents); A7V27PHC7A (Quinine); H9Y79VD43J (Strychnine); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171105
[Lr] Data última revisão:
171105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160503
[St] Status:MEDLINE
[do] DOI:10.1002/elps.201500436


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[PMID]:26835873
[Au] Autor:Akinboye ES; Brennen WN; Rosen DM; Bakare O; Denmeade SR
[Ad] Endereço:Department of Oncology, Chemical Therapeutic Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland.
[Ti] Título:Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy.
[So] Source:Prostate;76(8):703-14, 2016 Jun.
[Is] ISSN:1097-0045
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: There is an urgent need to develop new agents for treating metastatic prostate cancer to overcome multiple drug resistance to the current standard targeted cancer therapy. Emetine is a highly cytotoxic natural product protein synthesis inhibitor, which is toxic to all cell types. Its cytotoxicity can be blocked by derivatizing its N-2' position. Thus emetine can be selectively delivered to cancer cells in the region of metastatic cancer as a prodrug that will be activated by an enzyme selectively overexpressed within the metastatic tumor microenvironment. In this work, we convert emetine to a prodrug activatable by the fibroblast activation protein (FAP), a serine protease overexpressed by the carcinoma associated fibroblasts. METHOD: By using an iterative structure-activity relationship strategy, several peptidyl emetine prodrug analogs (1-11) were synthesized by chemical derivatization of emetine at its N-2' position and tested for in-vitro activation by FAP. The lead prodrug 11 is made up of a DPPIV activatable prodrug precursor 10 (Ala-Pro-PABC-Emetine) coupled to FAP substrate (Ala-Ser-Gly-Pro-Ala-Gly-Pro). Activation assays of the prodrugs were performed in purified FAP, DPPIV, FBS, and human serum and were analyzed by LCMS. In vitro cytotoxicity assays of these prodrugs are carried out in prostate (LNCaP, PC3) and breast (MCF7 and MDA-MB-231) cancer cell lines. The prodrugs are also tested in normal immortalized human prostatic epithelial cell line (PrEC). RESULTS: The lead FAP activated emetine prodrug 11 is activated to emetine in tandem by FAP and DPPIV in about 70% conversion within 24 hr. In prostate and breast cancer cell lines treated with prodrug 11, it is found to be equipotent with emetine in the presence of FAP and DPPIV. However, in the PrEC cell line grown in serum free media, prodrug 11 is more than 200-fold less cytotoxic than emetine in the absence of FAP and DPPIV. CONCLUSION: This FAP activated prodrug of cytotoxic agent emetine further shows the crucial role of the N-2' position of emetine in controlling its cytotoxicity. Significantly reduced toxicity observed in the PrEC cell line in the absence of FAP and DPPIV shows that prodrug 11 could be systemically delivered to regions of metastatic prostate cancer or other solid tumor for activation by cancer selective enzymes within the cancer microenvironment, such as FAP that is overexpressed by the carcinoma-associated fibroblasts. The two-step tandem enzymatic activation of prodrug 11 by FAP and DPPIV is a strategy for overcoming steric hindrance.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Dipeptidil Peptidase 4/metabolismo
Desenho de Drogas
Emetina/uso terapêutico
Gelatinases/metabolismo
Proteínas de Membrana/metabolismo
Pró-Fármacos/uso terapêutico
Neoplasias da Próstata/tratamento farmacológico
Serina Endopeptidases/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Masculino
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Membrane Proteins); 0 (Prodrugs); EC 3.4.14.5 (Dipeptidyl Peptidase 4); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.- (fibroblast activation protein alpha); EC 3.4.24.- (Gelatinases); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:160419
[Lr] Data última revisão:
160419
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160203
[St] Status:MEDLINE
[do] DOI:10.1002/pros.23162


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[PMID]:26278973
[Au] Autor:Mayank; Jaitak V
[Ad] Endereço:Centre for Chemical and Pharmaceutical Sciences, Central University of Punjab, Bathinda, PB 151001, India.
[Ti] Título:Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy.
[So] Source:Comput Biol Chem;62:145-54, 2016 06.
[Is] ISSN:1476-928X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cancer is responsible for millions of deaths throughout the world every year. Increased understanding as well as advancements in the therapeutic aspect seems suboptimal to restrict the huge deaths associated with cancer. The major cause responsible for this is high resistance as well as relapse rate associated with cancers. Several evidences indicated that cancer stem cells (CSC) are mainly responsible for the resistance and relapses associated with cancer. Furthermore, agents targeting a single protein seem to have higher chances of resistance than multitargeting drugs. According to the concept of network model, partial inhibition of multiple targets is more productive than single hit agents. Thus, by fusing both the premises that CSC and single hit anticancer drugs, both are responsible for cancer related resistances and screened alkaloids for the search of leads having CSC targeting ability as well as the capability to modulating multiple target proteins. The in silico experimental data indicated that emetine and cortistatin have the ability to modulate hedgehog (Hh) pathway by binding to sonic hedgehog (Hh), smoothened (Smo) and Gli protein, involved in maintenance CSCs. Furthermore, solamargine, solasonine and tylophorine are also seems to be good lead molecules targeting towards CSCs by modulating Hh pathway. Except solamargine and solasonine, other best lead molecules also showed acceptable in silico ADME profile. The predicted lead molecules can be suitably modified to get multitargeting CSC targeting agent to get rid of associate resistances.
[Mh] Termos MeSH primário: Alcaloides/química
Alcaloides/metabolismo
Antineoplásicos/química
Antineoplásicos/metabolismo
Terapia Baseada em Transplante de Células e Tecidos
Proteínas Hedgehog
Simulação de Acoplamento Molecular
[Mh] Termos MeSH secundário: Alcaloides/uso terapêutico
Sistemas de Liberação de Medicamentos
Ensaios de Seleção de Medicamentos Antitumorais
Emetina/química
Emetina/metabolismo
Proteínas Hedgehog/antagonistas & inibidores
Proteínas Hedgehog/química
Seres Humanos
Modelos Moleculares
Neoplasias/terapia
Células-Tronco Neoplásicas
Neuropeptídeos/química
Neuropeptídeos/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alkaloids); 0 (Antineoplastic Agents); 0 (Hedgehog Proteins); 0 (Neuropeptides); 0 (cortistatin); X8D5EPO80M (Emetine)
[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:150818
[St] Status:MEDLINE


  9 / 1238 MEDLINE  
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[PMID]:26253889
[Au] Autor:Cruz Y López OR; Gómez de la Vega E; Cárdenas-Perea ME; Gutiérrez-Dávila A; Tamariz-Cruz OJ
[Ad] Endereço:Departamento de Agentes Biológicos, Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, México. Electronic address: othoncruz@yahoo.com.
[Ti] Título:Human fasciolosis diagnosed in the acute phase: A first clinical report in Mexico.
[Ti] Título:Fasciolosis humana diagnosticada en fase aguda. Primer reporte clínico en México..
[So] Source:Rev Gastroenterol Mex;81(2):111-3, 2016 Apr-Jun.
[Is] ISSN:0375-0906
[Cp] País de publicação:Mexico
[La] Idioma:eng; spa
[Mh] Termos MeSH primário: Fasciola hepatica
Fasciolíase/diagnóstico
[Mh] Termos MeSH secundário: Adulto
Amebicidas/uso terapêutico
Animais
Emetina/análogos & derivados
Emetina/uso terapêutico
Fasciolíase/tratamento farmacológico
Fasciolíase/parasitologia
Contaminação de Alimentos
Seres Humanos
Masculino
México
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amebicides); 7S79QT1T91 (dehydroemetine); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170412
[Lr] Data última revisão:
170412
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150809
[St] Status:MEDLINE


  10 / 1238 MEDLINE  
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[PMID]:25855062
[Au] Autor:Wu W; Zhou HR; Bursian SJ; Link JE; Pestka JJ
[Ad] Endereço:College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, People's Republic of China.
[Ti] Título:Emetic responses to T-2 toxin, HT-2 toxin and emetine correspond to plasma elevations of peptide YY3-36 and 5-hydroxytryptamine.
[So] Source:Arch Toxicol;90(4):997-1007, 2016 Apr.
[Is] ISSN:1432-0738
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Trichothecene mycotoxins are a family of potent translational inhibitors that are associated with foodborne outbreaks of human and animal gastroenteritis in which vomiting is a clinical hallmark. Deoxynivalenol (DON, vomitoxin) and other Type B trichothecenes have been previously demonstrated to cause emesis in the mink (Neovison vison), and this response has been directly linked to secretion of both the satiety hormone peptide YY3-36 (PYY3-36) and neurotransmitter 5-hydroxytryptamine (5-HT). Here, we characterized the emetic responses in the mink to T-2 toxin (T-2) and HT-2 toxin (HT-2), two highly toxic Type A trichothecenes that contaminate cereals, and further compared these effects to those of emetine, a natural alkaloid that is used medicinally and also well known to block translation and cause vomiting. Following intraperitoneal (IP) and oral exposure, all three agents caused vomiting with evident dose-dependent increases in both duration and number of emetic events as well as decreases in latency to emesis. T-2 and HT-2 doses causing emesis in 50 % of treated animals (ED50s) were 0.05 and 0.02 mg/kg BW following IP and oral administration, respectively, whereas the ED50s for emetine were 2.0 and 1.0 mg/kg BW for IP and oral exposure, respectively. Importantly, oral administration of all three toxins elicited marked elevations in plasma concentrations of PYY3-36 and 5-HT that corresponded to emesis. Taken together, the results suggest that T-2 and HT-2 were much more potent than emetine and that emesis induction by all three translational inhibitors co-occurred with increases in circulating levels of PYY3-36 and 5-HT.
[Mh] Termos MeSH primário: Emetina/farmacologia
Fragmentos de Peptídeos/sangue
Peptídeo YY/sangue
Serotonina/sangue
Toxina T-2/análogos & derivados
Toxina T-2/toxicidade
Vômito/induzido quimicamente
[Mh] Termos MeSH secundário: Administração Oral
Animais
Relação Dose-Resposta a Droga
Eméticos/administração & dosagem
Eméticos/farmacologia
Eméticos/toxicidade
Emetina/administração & dosagem
Emetina/toxicidade
Feminino
Vison
Toxina T-2/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Emetics); 0 (Peptide Fragments); 106388-42-5 (Peptide YY); 123583-37-9 (peptide YY (3-36)); 333DO1RDJY (Serotonin); I3FL5NM3MO (T-2 Toxin); NC6C26RM46 (HT-2 toxin); X8D5EPO80M (Emetine)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150410
[St] Status:MEDLINE
[do] DOI:10.1007/s00204-015-1508-7



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