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Pesquisa : D02.241.223.268.070 [Categoria DeCS]
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[PMID]:28870898
[Au] Autor:Kuban-Jankowska A; Sahu KK; Gorska-Ponikowska M; Tuszynski JA; Wozniak M
[Ad] Endereço:Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland alicjakuban@gumed.edu.pl.
[Ti] Título:Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2.
[So] Source:Anticancer Res;37(9):4799-4806, 2017 09.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO). MATERIALS AND METHODS: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2. RESULTS: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity. CONCLUSION: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.
[Mh] Termos MeSH primário: Ácido Aurintricarboxílico/farmacologia
Neoplasias da Mama/enzimologia
Desferroxamina/farmacologia
Quelantes de Ferro/farmacologia
Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores
Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Ácido Aurintricarboxílico/química
Sítios de Ligação
Neoplasias da Mama/patologia
Catalase/metabolismo
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Desferroxamina/química
Feminino
Seres Humanos
Concentração Inibidora 50
Células MCF-7
Simulação de Acoplamento Molecular
Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Iron Chelating Agents); 4431-00-9 (Aurintricarboxylic Acid); EC 1.11.1.6 (Catalase); EC 3.1.3.48 (PTPN1 protein, human); EC 3.1.3.48 (PTPN11 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11); J06Y7MXW4D (Deferoxamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


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[PMID]:28182739
[Au] Autor:Cervia LD; Chang CC; Wang L; Yuan F
[Ad] Endereço:Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
[Ti] Título:Distinct effects of endosomal escape and inhibition of endosomal trafficking on gene delivery via electrotransfection.
[So] Source:PLoS One;12(2):e0171699, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A recent theory suggests that endocytosis is involved in uptake and intracellular transport of electrotransfected plasmid DNA (pDNA). The goal of the current study was to understand if approaches used previously to improve endocytosis of gene delivery vectors could be applied to enhancing electrotransfection efficiency (eTE). Results from the study showed that photochemically induced endosomal escape, which could increase poly-L-lysine (PLL)-mediated gene delivery, decreased eTE. The decrease could not be blocked by treatment of cells with endonuclease inhibitors (aurintricarboxylic acid and zinc ion) or antioxidants (L-glutamine and ascorbic acid). Chemical treatment of cells with an endosomal trafficking inhibitor that blocks endosome progression, bafilomycin A1, resulted in a significant decrease in eTE. However, treatment of cells with lysosomotropic agents (chloroquine and ammonium chloride) had little effects on eTE. These data suggested that endosomes played important roles in protecting and intracellular trafficking of electrotransfected pDNA.
[Mh] Termos MeSH primário: Eletricidade
Endocitose/efeitos dos fármacos
Endossomos/efeitos dos fármacos
Técnicas de Transferência de Genes
Macrolídeos/farmacologia
Transfecção/métodos
[Mh] Termos MeSH secundário: Animais
Antioxidantes/farmacologia
Ácido Aurintricarboxílico/farmacologia
Transporte Biológico/efeitos dos fármacos
Células COS
Cercopithecus aethiops
Endocitose/fisiologia
Endossomos/metabolismo
Terapia Genética/métodos
Células HCT116
Células HEK293
Seres Humanos
Polilisina/química
Polilisina/farmacologia
Zinco/farmacologia
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Macrolides); 25104-18-1 (Polylysine); 4431-00-9 (Aurintricarboxylic Acid); 88899-55-2 (bafilomycin A1); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0171699


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[PMID]:28103571
[Au] Autor:Roos A; Dhruv HD; Mathews IT; Inge LJ; Tuncali S; Hartman LK; Chow D; Millard N; Yin HH; Kloss J; Loftus JC; Winkles JA; Berens ME; Tran NL
[Ad] Endereço:Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
[Ti] Título:Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells.
[So] Source:Oncotarget;8(7):12234-12246, 2017 Feb 14.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The survival of patients diagnosed with glioblastoma (GBM), the most deadly form of brain cancer, is compromised by the proclivity for local invasion into the surrounding normal brain, which prevents complete surgical resection and contributes to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) superfamily, can stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. To discover small molecule inhibitors that disrupt the TWEAK-Fn14 signaling axis, we utilized a cell-based drug-screening assay using HEK293 cells engineered to express both Fn14 and a NF-κB-driven firefly luciferase reporter protein. Focusing on the LOPAC1280 library of 1280 pharmacologically active compounds, we identified aurintricarboxylic acid (ATA) as an agent that suppressed TWEAK-Fn14-NF-κB dependent signaling, but not TNFα-TNFR-NF-κB driven signaling. We demonstrated that ATA repressed TWEAK-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or Fn14 expression. In addition, ATA treatment enhanced glioma cell sensitivity to both the chemotherapeutic agent temozolomide (TMZ) and radiation-induced cell death. In summary, this work reports a repurposed use of a small molecule inhibitor that targets the TWEAK-Fn14 signaling axis, which could potentially be developed as a new therapeutic agent for treatment of GBM patients.
[Mh] Termos MeSH primário: Ácido Aurintricarboxílico/farmacologia
Neoplasias Encefálicas/tratamento farmacológico
Glioblastoma/tratamento farmacológico
Receptores do Fator de Necrose Tumoral/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fatores de Necrose Tumoral/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos Alquilantes/farmacologia
Ácido Aurintricarboxílico/química
Neoplasias Encefálicas/genética
Neoplasias Encefálicas/metabolismo
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Movimento Celular/genética
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Sobrevivência Celular/efeitos da radiação
Citocina TWEAK
Dacarbazina/análogos & derivados
Dacarbazina/farmacologia
Sinergismo Farmacológico
Glioblastoma/genética
Glioblastoma/metabolismo
Células HEK293
Seres Humanos
Estimativa de Kaplan-Meier
Camundongos Nus
Estrutura Molecular
Interferência de RNA
Receptores do Fator de Necrose Tumoral/genética
Transdução de Sinais/genética
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Receptor de TWEAK
Fatores de Necrose Tumoral/genética
Ensaios Antitumorais Modelo de Xenoenxerto/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Cytokine TWEAK); 0 (Receptors, Tumor Necrosis Factor); 0 (Small Molecule Libraries); 0 (TNFRSF12A protein, human); 0 (TNFSF12 protein, human); 0 (TWEAK Receptor); 0 (Tnfrsf12a protein, mouse); 0 (Tumor Necrosis Factors); 4431-00-9 (Aurintricarboxylic Acid); 7GR28W0FJI (Dacarbazine); YF1K15M17Y (temozolomide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170120
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14685


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[PMID]:27562597
[Au] Autor:Kuban-Jankowska A; Sahu KK; Gorska M; Niedzialkowski P; Tuszynski JA; Ossowski T; Wozniak M
[Ad] Endereço:Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland. alicjakuban@gumed.edu.pl.
[Ti] Título:Aurintricarboxylic acid structure modifications lead to reduction of inhibitory properties against virulence factor YopH and higher cytotoxicity.
[So] Source:World J Microbiol Biotechnol;32(10):163, 2016 Oct.
[Is] ISSN:1573-0972
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Yersinia sp. bacteria owe their viability and pathogenic virulence to the YopH factor, which is a highly active bacterial protein tyrosine phosphatase. Inhibition of YopH phosphatase results in the lack of Yersinia sp. pathogenicity. We have previously described that aurintricarboxylic acid inhibits the activity of YopH at nanomolar concentrations and represents a unique mechanism of YopH inactivation due to a redox process. This work is a continuation of our previous studies. Here we show that modifications of the structure of aurintricarboxylic acid reduce the ability to inactivate YopH and lead to higher cytotoxicity. In the present paper we examine the inhibitory properties of aurintricarboxylic acid analogues, such as eriochrome cyanine R (ECR) and pararosaniline. Computational docking studies we report here indicate that ATA analogues are not precluded to bind in the YopH active site and in all obtained binding conformations ECR and pararosaniline bind to YopH active site. The free binding energy calculations show that ECR has a stronger binding affinity to YopH than pararosaniline, which was confirmed by experimental YopH enzymatic activity studies. We found that ATA analogues can reversibly reduce the enzymatic activity of YopH, but possess weaker inhibitory properties than ATA. The ATA analogues induced inactivation of YopH is probably due to oxidative mechanism, as pretreatment with catalase prevents from inhibition. We also found that ATA analogues significantly decrease the viability of macrophage cells, especially pararosaniline, while ATA reveals only slight effect on cell viability.
[Mh] Termos MeSH primário: Ácido Aurintricarboxílico/análogos & derivados
Proteínas da Membrana Bacteriana Externa/química
Benzenossulfonatos/química
Proteínas Tirosina Fosfatases/química
Corantes de Rosanilina/química
Toluidinas/química
Yersinia/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Ácido Aurintricarboxílico/química
Ácido Aurintricarboxílico/farmacologia
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores
Benzenossulfonatos/farmacologia
Domínio Catalítico/efeitos dos fármacos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Camundongos
Modelos Moleculares
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Estrutura Molecular
Ligação Proteica
Proteínas Tirosina Fosfatases/antagonistas & inibidores
Corantes de Rosanilina/farmacologia
Toluidinas/farmacologia
Yersinia/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Outer Membrane Proteins); 0 (Benzenesulfonates); 0 (Rosaniline Dyes); 0 (Toluidines); 20N4C0M8NM (pararosaniline); 3564-18-9 (solochrome cyanine R); 4431-00-9 (Aurintricarboxylic Acid); EC 3.1.3.48 (Protein Tyrosine Phosphatases); EC 3.1.3.48 (yopH protein, Yersinia)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170321
[Lr] Data última revisão:
170321
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160827
[St] Status:MEDLINE
[do] DOI:10.1007/s11274-016-2123-3


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[PMID]:27020607
[Au] Autor:Mohamed TM; Abou-Leisa R; Stafford N; Maqsood A; Zi M; Prehar S; Baudoin-Stanley F; Wang X; Neyses L; Cartwright EJ; Oceandy D
[Ad] Endereço:Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
[Ti] Título:The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy.
[So] Source:Nat Commun;7:11074, 2016 Mar 29.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The heart responds to pathological overload through myocyte hypertrophy. Here we show that this response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4). Pmca4 deletion in mice, both systemically and specifically in fibroblasts, reduces the hypertrophic response to pressure overload; however, knocking out Pmca4 specifically in cardiomyocytes does not produce this effect. Mechanistically, cardiac fibroblasts lacking PMCA4 produce higher levels of secreted frizzled related protein 2 (sFRP2), which inhibits the hypertrophic response in neighbouring cardiomyocytes. Furthermore, we show that treatment with the PMCA4 inhibitor aurintricarboxylic acid (ATA) inhibits and reverses cardiac hypertrophy induced by pressure overload in mice. Our results reveal that PMCA4 regulates the development of cardiac hypertrophy and provide proof of principle for a therapeutic approach to treat this condition.
[Mh] Termos MeSH primário: ATPases Transportadoras de Cálcio/metabolismo
Cardiomegalia/patologia
Membrana Celular/enzimologia
Fibroblastos/metabolismo
Miocárdio/patologia
Miócitos Cardíacos/patologia
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Aorta/patologia
Ácido Aurintricarboxílico/farmacologia
ATPases Transportadoras de Cálcio/antagonistas & inibidores
ATPases Transportadoras de Cálcio/deficiência
Cardiomegalia/complicações
Membrana Celular/efeitos dos fármacos
Constrição Patológica
Meios de Cultivo Condicionados/farmacologia
Modelos Animais de Doenças
Fibroblastos/efeitos dos fármacos
Deleção de Genes
Proteínas de Membrana/metabolismo
Camundongos Knockout
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/metabolismo
Pressão
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Culture Media, Conditioned); 0 (Membrane Proteins); 0 (Sfrp2 protein, mouse); 4431-00-9 (Aurintricarboxylic Acid); EC 3.6.3.8 (Calcium-Transporting ATPases); EC 3.6.3.8 (PMCA4 protein, mouse)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160330
[St] Status:MEDLINE
[do] DOI:10.1038/ncomms11074


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[PMID]:26377038
[Au] Autor:Kotera N; Poyer F; Granzhan A; Teulade-Fichou MP
[Ad] Endereço:CNRS UMR9187/INSERM U1196 "Chemistry, Modelling and Imaging for Biology", Centre de Recherche, Institut Curie, 91405 Orsay, France. anton.granzhan@curie.fr.
[Ti] Título:Efficient inhibition of human AP endonuclease 1 (APE1) via substrate masking by abasic site-binding macrocyclic ligands.
[So] Source:Chem Commun (Camb);51(88):15948-51, 2015 Nov 14.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Bis-naphthalene macrocycles, which bind with high affinity and selectivity to abasic sites in DNA, efficiently inhibit their cleavage by APE1 (IC50 = 55-60 nM in the kinetic assay with a model THF substrate). These results demonstrate that substrate masking by non-covalent abasic-site ligands is an efficient strategy for inhibition of APE1.
[Mh] Termos MeSH primário: DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Substâncias Intercalantes/química
Substâncias Intercalantes/farmacologia
Ligantes
Compostos Macrocíclicos/química
Compostos Macrocíclicos/farmacologia
Naftalenos/química
Naftalenos/farmacologia
[Mh] Termos MeSH secundário: Animais
Ácido Aurintricarboxílico/farmacologia
Bovinos
DNA/química
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo
Etídio/farmacologia
Seres Humanos
Indóis/farmacologia
Cinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-nitro-1H-indole-2-carboxylic acid); 0 (Enzyme Inhibitors); 0 (Indoles); 0 (Intercalating Agents); 0 (Ligands); 0 (Macrocyclic Compounds); 0 (Naphthalenes); 4431-00-9 (Aurintricarboxylic Acid); 9007-49-2 (DNA); 91080-16-9 (calf thymus DNA); EC 4.2.99.18 (APEX1 protein, human); EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase); EN464416SI (Ethidium)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151022
[Lr] Data última revisão:
151022
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150918
[St] Status:MEDLINE
[do] DOI:10.1039/c5cc06084b


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[PMID]:26286963
[Au] Autor:Kuban-Jankowska A; Sahu KK; Niedzialkowski P; Gorska M; Tuszynski JA; Ossowski T; Wozniak M
[Ad] Endereço:Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
[Ti] Título:Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor of Yersinia pestis.
[So] Source:Oncotarget;6(21):18364-73, 2015 Jul 30.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:YopH is a bacterial protein tyrosine phosphatase, which is essential for the viability and pathogenic virulence of the plague-causing Yersinia sp. bacteria. Inactivation of YopH activity would lead to the loss of bacterial pathogenicity. We have studied the inhibitory properties of aurintricarboxylic acid (ATA) against YopH phosphatase and found that at nanomolar concentrations ATA reversibly decreases the activity of YopH. Computational docking studies indicated that in all binding poses ATA binds in the YopH active site. Molecular dynamics simulations showed that in the predicted binding pose, ATA binds to the essential Cys403 and Arg409 residues in the active site and has a stronger binding affinity than the natural substrate (pTyr). The cyclic voltammetry experiments suggest that ATA reacts remarkably strongly with molecular oxygen. Additionally, the electrochemical reduction of ATA in the presence of a negative potential from -2.0 to 2.5 V generates a current signal, which is observed for hydrogen peroxide. Here we showed that ATA indicates a unique mechanism of YopH inactivation due to a redox process. We proposed that the potent inhibitory properties of ATA are a result of its strong binding in the YopH active site and in situ generation of hydrogen peroxide near catalytic cysteine residue.
[Mh] Termos MeSH primário: Ácido Aurintricarboxílico/química
Proteínas da Membrana Bacteriana Externa/química
Proteínas Tirosina Fosfatases/química
Fatores de Virulência/química
[Mh] Termos MeSH secundário: Algoritmos
Ácido Aurintricarboxílico/metabolismo
Ácido Aurintricarboxílico/farmacologia
Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores
Proteínas da Membrana Bacteriana Externa/metabolismo
Seres Humanos
Cinética
Conformação Molecular
Simulação de Dinâmica Molecular
Estrutura Molecular
Oxirredução
Peste/microbiologia
Ligação Proteica
Estrutura Terciária de Proteína
Proteínas Tirosina Fosfatases/antagonistas & inibidores
Proteínas Tirosina Fosfatases/metabolismo
Virulência
Fatores de Virulência/antagonistas & inibidores
Fatores de Virulência/metabolismo
Yersinia pestis/metabolismo
Yersinia pestis/patogenicidade
Yersinia pestis/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Outer Membrane Proteins); 0 (Virulence Factors); 4431-00-9 (Aurintricarboxylic Acid); EC 3.1.3.48 (Protein Tyrosine Phosphatases); EC 3.1.3.48 (yopH protein, Yersinia)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170412
[Lr] Data última revisão:
170412
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150820
[St] Status:MEDLINE


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[PMID]:26248865
[Au] Autor:Lee M; Wathier M; Love JA; McGeer E; McGeer PL
[Ad] Endereço:Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
[Ti] Título:Inhibition of aberrant complement activation by a dimer of acetylsalicylic acid.
[So] Source:Neurobiol Aging;36(10):2748-56, 2015 Oct.
[Is] ISSN:1558-1497
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We here report synthesis for the first time of the acetyl salicylic acid dimer 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS). DAS inhibits aberrant complement activation by selectively blocking factor D of the alternative complement pathway and C9 of the membrane attack complex. We have previously identified aurin tricarboxylic and its oligomers as promising agents in this regard. DAS is much more potent, inhibiting erythrocyte hemolysis by complement-activated serum with an IC50 in the 100-170 nanomolar range. There are numerous conditions where self-damage from the complement system has been implicated in the pathology, including such chronic degenerative diseases of aging as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and age-related macular degeneration. Consequently, there is a high priority for the discovery and development of agents that can successfully treat such conditions. DAS holds considerable promise for being such an agent.
[Mh] Termos MeSH primário: Aspirina/análogos & derivados
Compostos Benzidrílicos/farmacologia
Ativação do Complemento/efeitos dos fármacos
Fator D do Complemento/antagonistas & inibidores
[Mh] Termos MeSH secundário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/etiologia
Animais
Aspirina/síntese química
Aspirina/farmacologia
Ácido Aurintricarboxílico
Compostos Benzidrílicos/síntese química
Gatos
Células Cultivadas
Complemento C6/antagonistas & inibidores
Complexo de Ataque à Membrana do Sistema Complemento
Via Alternativa do Complemento
Cães
Relação Dose-Resposta a Droga
Descoberta de Drogas
Eritrócitos/efeitos dos fármacos
Hemólise/efeitos dos fármacos
Seres Humanos
Degeneração Macular/tratamento farmacológico
Degeneração Macular/etiologia
Terapia de Alvo Molecular
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,5'-methylenebis(2-acetoxybenzoic acid)); 0 (Benzhydryl Compounds); 0 (Complement C6); 0 (Complement Membrane Attack Complex); 4431-00-9 (Aurintricarboxylic Acid); EC 3.4.21.46 (Complement Factor D); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:150908
[Lr] Data última revisão:
150908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150808
[St] Status:MEDLINE


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[PMID]:26104676
[Au] Autor:Zhao T; Gao J; Van J; To E; Wang A; Cao S; Cui JZ; Guo JP; Lee M; McGeer PL; Matsubara JA
[Ad] Endereço:Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, V5Z 3N9, BC, Canada. sixi@ualberta.ca.
[Ti] Título:Age-related increases in amyloid beta and membrane attack complex: evidence of inflammasome activation in the rodent eye.
[So] Source:J Neuroinflammation;12:121, 2015 Jun 24.
[Is] ISSN:1742-2094
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The membrane attack complex (MAC) is a key player in the pathogenesis of age-related macular degeneration (AMD) and is a putative activator of the NLRP3 inflammasome. Amyloid beta (Aß), a component of drusen deposits, has also been implicated in inflammasome activation by our work and those of others. However, the interactions of MAC and Aß are still poorly understood, especially their roles in aging and retinal degenerative pathologies. Since inflammasome activation may represent a key cellular pathway underlying age-related chronic inflammation in the eye, the purpose of this study is to identify the effects associated with MAC and inflammasome activation in the retinal pigment epithelium (RPE)/choroid and to evaluate the therapeutic merits of MAC suppression. METHODS: Adult Long-Evans rats were divided into treatment and control groups. Treatment groups received oral aurin tricarboxylic acid complex (ATAC), a MAC inhibitor, in drinking-water, and control groups received drinking-water alone (No ATAC). Groups were sacrificed at 7.5 or 11.5 months, after approximately 40 days of ATAC treatment. To study age-related changes of Aß and MAC in RPE/choroid, naive animals were sacrificed at 2.5, 7.5, and 11.5 months. Eye tissues underwent immunohistochemistry and western blot analysis for MAC, Aß, NF-κB activation, as well as cleaved caspase-1 and IL-18. Vitreal samples were collected and assessed by multiplex assays for secreted levels of IL-18 and IL-1ß. Statistical analyses were performed, and significance level was set at p ≤ 0.05. RESULTS: In vivo studies demonstrated an age-dependent increase in MAC, Aß, and NF-κB activation in the RPE/choroid. Systemic ATAC resulted in a prominent reduction in MAC formation and a concomitant reduction in inflammasome activation measured by cleaved caspase-1 and secreted levels of IL-18 and IL-1ß, but not in NF-κB activation. In vitro studies demonstrated Aß-induced MAC formation on RPE cells. CONCLUSIONS: Age-dependent increases in Aß and MAC are present in the rodent outer retina. Our results suggest that suppressing MAC formation and subsequent inflammasome activation in the RPE/choroid may reduce chronic low-grade inflammation associated with IL-18 and IL-1ß in the outer retina.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Peptídeos beta-Amiloides/metabolismo
Proteínas de Transporte/metabolismo
Corioide/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Inflamassomos/metabolismo
Retina/metabolismo
[Mh] Termos MeSH secundário: Animais
Ácido Aurintricarboxílico/farmacologia
Corioide/efeitos dos fármacos
Modelos Animais de Doenças
Interleucina-18/metabolismo
Interleucina-1beta/metabolismo
Degeneração Macular/metabolismo
NF-kappa B/metabolismo
Proteína 3 que Contém Domínio de Pirina da Família NLR
Ratos
Ratos Long-Evans
Retina/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Carrier Proteins); 0 (Complement Membrane Attack Complex); 0 (Inflammasomes); 0 (Interleukin-18); 0 (Interleukin-1beta); 0 (NF-kappa B); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (Nlrp3 protein, rat); 4431-00-9 (Aurintricarboxylic Acid)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150625
[St] Status:MEDLINE
[do] DOI:10.1186/s12974-015-0337-1


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[PMID]:25477506
[Au] Autor:Davis AL; Qiao S; Lesson JL; Rojo de la Vega M; Park SL; Seanez CM; Gokhale V; Cabello CM; Wondrak GT
[Ad] Endereço:From the Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724.
[Ti] Título:The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells.
[So] Source:J Biol Chem;290(3):1623-38, 2015 Jan 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Here, we describe the identification of a novel drug-like heat shock response inducer for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. Screening a focused library of compounds containing redox-directed electrophilic pharmacophores employing the Stress & Toxicity PathwayFinder(TM) PCR Array technology as a discovery tool, a drug-like triphenylmethane-derivative (aurin; 4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one) was identified as an experimental cell stress modulator that causes (i) heat shock factor transcriptional activation, (ii) up-regulation of heat shock response gene expression (HSPA6, HSPA1A, DNAJB4, HMOX1), (iii) early unfolded protein response signaling (phospho-PERK, phospho-eIF2α, CHOP (CCAAT/enhancer-binding protein homologous protein)), (iv) proteasome impairment with increased protein-ubiquitination, and (v) oxidative stress with glutathione depletion. Fluorescence polarization-based experiments revealed that aurin displays activity as a geldanamycin-competitive Hsp90α-antagonist, a finding further substantiated by molecular docking and ATPase inhibition analysis. Aurin exposure caused caspase-dependent cell death in a panel of human malignant melanoma cells (A375, G361, LOX-IMVI) but not in non-malignant human skin cells (Hs27 fibroblasts, HaCaT keratinocytes, primary melanocytes) undergoing the aurin-induced heat shock response without impairment of viability. Aurin-induced melanoma cell apoptosis depends on Noxa up-regulation as confirmed by siRNA rescue experiments demonstrating that siPMAIP1-based target down-regulation suppresses aurin-induced cell death. Taken together, our data suggest feasibility of apoptotic elimination of malignant melanoma cells using the quinone methide-derived heat shock response inducer aurin.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Apoptose
Ácido Aurintricarboxílico/análogos & derivados
Proteínas de Choque Térmico/metabolismo
Melanoma/tratamento farmacológico
Neoplasias Cutâneas/tratamento farmacológico
[Mh] Termos MeSH secundário: Ácido Aurintricarboxílico/química
Linhagem Celular Tumoral
Sobrevivência Celular
Ensaios de Seleção de Medicamentos Antitumorais
Citometria de Fluxo
Glutationa/metabolismo
Resposta ao Choque Térmico/genética
Seres Humanos
Indolquinonas/química
Concentração Inibidora 50
Queratinócitos/efeitos dos fármacos
Melanócitos/efeitos dos fármacos
Potencial da Membrana Mitocondrial
Modelos Moleculares
Estresse Oxidativo
Reação em Cadeia da Polimerase
RNA Interferente Pequeno/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Heat-Shock Proteins); 0 (Indolequinones); 0 (NOXA1 protein, human); 0 (RNA, Small Interfering); 138230-21-4 (quinone methide); 4431-00-9 (Aurintricarboxylic Acid); 85N4AK3JAU (aurin); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141206
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.592626



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