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Pesquisa : D02.455.426.559.389.657.120 [Categoria DeCS]
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[PMID]:28931042
[Au] Autor:Ayyagari VN; Diaz-Sylvester PL; Hsieh TJ; Brard L
[Ad] Endereço:Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL, United States of America.
[Ti] Título:Evaluation of the cytotoxicity of the Bithionol-paclitaxel combination in a panel of human ovarian cancer cell lines.
[So] Source:PLoS One;12(9):e0185111, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previously, Bithionol (BT) was shown to enhance the chemosensitivity of ovarian cancer cell lines to cisplatin treatment. In the present study, we focused on the anti-tumor potential of the BT-paclitaxel combination when added to a panel of ovarian cancer cell lines. This in vitro study aimed to 1) determine the optimum schedule for combination of BT and paclitaxel and 2) assess the nature and mechanism(s) underlying BT-paclitaxel interactions. The cytotoxic effects of both drugs either alone or in combination were assessed by presto-blue cell viability assay using six human ovarian cancer cell lines. Inhibitory concentrations to achieve 50% cell death (IC50) were determined for BT and paclitaxel in each cell line. Changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27 were determined via immunoblot. Luminescent and colorimetric assays were used to determine caspases 3/7 and autotaxin (ATX) activity. Cellular reactive oxygen species (ROS) were measured by flow cytometry. Our results show that the efficacy of the BT-paclitaxel combination depends upon the concentrations and sequence of addition of paclitaxel and BT. Pretreatment with BT followed by paclitaxel resulted in antagonistic interactions whereas synergistic interactions were observed when both drugs were added simultaneously or when cells were pretreated with paclitaxel followed by BT. Synergistic interactions between BT and paclitaxel were attributed to increased ROS generation and enhanced apoptosis. Decreased expression of pro-survival factors (XIAP, bcl-2, bcl-xL) and increased expression of pro-apoptotic factors (caspases 3/7, PARP cleavage) was observed. Additionally, increased expression of key cell cycle regulators p21 and p27 was observed. These results show that BT and paclitaxel interacted synergistically at most drug ratios which, however, was highly dependent on the sequence of the addition of drugs. Our results suggest that BT-paclitaxel combination therapy may be effective in sensitizing ovarian cancer cells to paclitaxel treatment, thus mitigating some of the toxic effects associated with high doses of paclitaxel.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Neoplasias Ovarianas/tratamento farmacológico
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Bitionol/administração & dosagem
Ciclo Celular/efeitos dos fármacos
Ciclo Celular/fisiologia
Linhagem Celular Tumoral
Cisplatino/farmacologia
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Seres Humanos
Concentração Inibidora 50
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Paclitaxel/administração & dosagem
Diester Fosfórico Hidrolases/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); AMT77LS62O (Bithionol); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase); P88XT4IS4D (Paclitaxel); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185111


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[PMID]:28918317
[Au] Autor:Zheng W; Park JA; Abd El-Aty AM; Kim SK; Cho SH; Choi JM; Yi H; Cho SM; El-Banna HA; Shim JH; Chang BJ; Wang J; Kim JS; Shin HC
[Ad] Endereço:Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
[Ti] Título:Bithionol residue analysis in animal-derived food products by an effective and rugged extraction method coupled with liquid chromatography-tandem mass spectrometry.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1064:100-108, 2017 Oct 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Herein, we developed a simple analytical procedure for the quantitation of bithionol residues in animal-derived food products such as porcine muscle, eggs, milk, eel, flatfish, and shrimp using a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction method coupled with liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI /MS-MS). Samples were extracted with 0.1% solution of formic acid in acetonitrile and the extract was purified using a C18 sorbent. Separation was performed on a Waters XBridge™ C18 reversed-phase analytical column using 0.1% solution of formic acid/acetonitrile as the mobile phase. Six-point matrix-matched calibration indicated good linearity, with the calculated coefficients of determination (R ) being≥0.9813. Intra- and inter-day recoveries (determined at spiking levels equivalent to 1×and 2×the limit of quantitation (0.25µg/kg)) ranged between 80.0 and 94.0%, with the corresponding relative standard deviations (RSDs) being≤8.2%. The developed experimental protocol was applied to different samples purchased from local markets in Seoul, which were tested negative for bithionol residues. In conclusion, the proposed method proved to be versatile and precise, being ideally suited for the routine detection of bithionol residues in animal-derived food products with various protein and fat contents.
[Mh] Termos MeSH primário: Bitionol/análise
Cromatografia Líquida/métodos
Resíduos de Drogas/análise
Contaminação de Alimentos/análise
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Animais
Bitionol/química
Bitionol/isolamento & purificação
Fracionamento Químico/métodos
Resíduos de Drogas/química
Resíduos de Drogas/isolamento & purificação
Ovos/análise
Limite de Detecção
Modelos Lineares
Leite/química
Reprodutibilidade dos Testes
Alimentos Marinhos/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
AMT77LS62O (Bithionol)
[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:170918
[St] Status:MEDLINE


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[PMID]:28086831
[Au] Autor:Ayyagari VN; Hsieh TJ; Diaz-Sylvester PL; Brard L
[Ad] Endereço:Division of Gynecologic Oncology; Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL, USA.
[Ti] Título:Evaluation of the cytotoxicity of the Bithionol - cisplatin combination in a panel of human ovarian cancer cell lines.
[So] Source:BMC Cancer;17(1):49, 2017 01 13.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Combination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments. In this in vitro study, we evaluated the antitumor efficacy of cisplatin in combination with Bithionol (BT) against a panel of ovarian cancer cell lines with special focus on cisplatin-sensitive and cisplatin-resistant cell lines. The primary objectives of this study are to determine the nature of the interactions between BT and cisplatin and to understand the mechanism(s) of action of BT-cisplatin combination. METHODS: The cytotoxic effects of drugs either alone or in combination were evaluated using presto-blue assay. Cellular reactive oxygen species were measured by flow cytometry. Immunoblot analysis was carried out to investigate changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27. Luminescent and colorimetric assays were used to test caspases 3/7 and ATX activity. RESULTS: The efficacy of the BT-cisplatin combination depends upon the cell type and concentrations of cisplatin and BT. In cisplatin-sensitive cell lines, BT and cisplatin were mostly antagonistic except when used at low concentrations, where synergy was observed. In contrast, in cisplatin-resistant cells, BT-cisplatin combination treatment displayed synergistic effects at most of the drug ratios/concentrations. Our results further revealed that the synergistic interaction was linked to increased reactive oxygen species generation and apoptosis. Enhanced apoptosis was correlated with loss of pro-survival factors (XIAP, bcl-2, bcl-xL), expression of pro-apoptotic markers (caspases 3/7, PARP cleavage) and enhanced cell cycle regulators p21 and p27. CONCLUSION: In cisplatin-resistant cell lines, BT potentiated cisplatin-induced cytotoxicity at most drug ratios via enhanced ROS generation and modulation of key regulators of apoptosis. Low doses of BT and cisplatin enhanced efficiency of cisplatin treatment in all the ovarian cancer cell lines tested. Our results suggest that novel combinations such as BT and cisplatin might be an attractive therapeutic approach to enhance ovarian cancer chemosensitivity. Combining low doses of cisplatin with subtherapeutic doses of BT can ultimately lead to the development of an innovative combination therapy to reduce/prevent the side effects normally occurring when high doses of cisplatin are administered.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Bitionol/farmacologia
Cisplatino/farmacologia
Neoplasias Ovarianas/tratamento farmacológico
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Biomarcadores Tumorais/metabolismo
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Feminino
Seres Humanos
Neoplasias Ovarianas/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Reactive Oxygen Species); AMT77LS62O (Bithionol); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170115
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-016-3034-2


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[PMID]:27545877
[Au] Autor:Fleming MR; Brown MR; Kronengold J; Zhang Y; Jenkins DP; Barcia G; Nabbout R; Bausch AE; Ruth P; Lukowski R; Navaratnam DS; Kaczmarek LK
[Ad] Endereço:Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.
[Ti] Título:Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex.
[So] Source:Cell Rep;16(9):2281-8, 2016 Aug 30.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human mutations in the cytoplasmic C-terminal domain of Slack sodium-activated potassium (KNa) channels result in childhood epilepsy with severe intellectual disability. Slack currents can be increased by pharmacological activators or by phosphorylation of a Slack C-terminal residue by protein kinase C. Using an optical biosensor assay, we find that Slack channel stimulation in neurons or transfected cells produces loss of mass near the plasma membrane. Slack mutants associated with intellectual disability fail to trigger any change in mass. The loss of mass results from the dissociation of the protein phosphatase 1 (PP1) targeting protein, Phactr-1, from the channel. Phactr1 dissociation is specific to wild-type Slack channels and is not observed when related potassium channels are stimulated. Our findings suggest that Slack channels are coupled to cytoplasmic signaling pathways and that dysregulation of this coupling may trigger the aberrant intellectual development associated with specific childhood epilepsies.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Proteína do X Frágil de Retardo Mental/genética
Proteínas dos Microfilamentos/genética
Proteínas do Tecido Nervoso/genética
Neurônios/metabolismo
Canais de Potássio/genética
Transdução de Sinais
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores
Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Técnicas Biossensoriais
Bitionol/farmacologia
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Membrana Celular/efeitos dos fármacos
Córtex Cerebral/citologia
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/metabolismo
Proteína do X Frágil de Retardo Mental/antagonistas & inibidores
Proteína do X Frágil de Retardo Mental/metabolismo
Regulação da Expressão Gênica
Células HEK293
Seres Humanos
Transporte de Íons/efeitos dos fármacos
Camundongos
Camundongos Knockout
Proteínas dos Microfilamentos/antagonistas & inibidores
Proteínas dos Microfilamentos/metabolismo
Mutação
Proteínas do Tecido Nervoso/agonistas
Proteínas do Tecido Nervoso/metabolismo
Neurônios/citologia
Neurônios/efeitos dos fármacos
Técnicas de Patch-Clamp
Fosforilação
Canais de Potássio/agonistas
Canais de Potássio/metabolismo
Cultura Primária de Células
Ligação Proteica
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Tiazolidinas/farmacologia
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (CYFIP1 protein, human); 0 (FMR1 protein, human); 0 (KCNT1 protein, human); 0 (Microfilament Proteins); 0 (Nerve Tissue Proteins); 0 (Phactr-1 protein, human); 0 (Potassium Channels); 0 (RNA, Small Interfering); 0 (Thiazolidines); 139135-51-6 (Fragile X Mental Retardation Protein); AMT77LS62O (Bithionol); LW7U308U7U (latrunculin B)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE


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[PMID]:27486194
[Au] Autor:Park YD; Sun W; Salas A; Antia A; Carvajal C; Wang A; Xu X; Meng Z; Zhou M; Tawa GJ; Dehdashti J; Zheng W; Henderson CM; Zelazny AM; Williamson PR
[Ad] Endereço:Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
[Ti] Título:Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening.
[So] Source:MBio;7(4), 2016 Aug 02.
[Is] ISSN:2150-7511
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. IMPORTANCE: Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its growth. The present study utilized a recently identified fungicidal agent, bithionol, to identify potential fungicidal drug targets that can be used in developing modern fungicidal agents. A combined protein and genetic analysis approach was used to identify a class of enzymes, dehydrogenases, that the fungus uses to maintain homeostasis with regard to sugar nutrients. Similarities in the drug target site were found that resulted in simultaneous inhibition and killing of the fungus by bithionol. These studies thus identify a common, multitarget site for antifungal development.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Bitionol/farmacologia
Cryptococcus neoformans/efeitos dos fármacos
Cryptococcus neoformans/enzimologia
Oxirredutases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Citosol/química
Compensação de Dosagem (Genética)
Simulação de Acoplamento Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); AMT77LS62O (Bithionol); EC 1.- (Oxidoreductases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160804
[St] Status:MEDLINE


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[PMID]:27174683
[Au] Autor:Wang K; Guo X; Guo B; Li W; Zhang M; Li Y
[Ad] Endereço:Laboratory of Advanced Optoelectronic Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China.
[Ti] Título:Broad Bandgap D-A Copolymer Based on Bithiazole Acceptor Unit for Application in High-Performance Polymer Solar Cells with Lower Fullerene Content.
[So] Source:Macromol Rapid Commun;37(13):1066-73, 2016 Jul.
[Is] ISSN:1521-3927
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:A new broad bandgap and 2D-conjugated D-A copolymer, PBDTBTz-T, based on bithienyl-benzodithiophene donor unit and bithiazole (BTz) acceptor unit, is designed and synthesized for the application as donor material in polymer solar cells (PSCs). The polymer possesses highly coplanar and crystalline structure with a higher hole mobility and lower HOMO energy level which is beneficial to achieve higher open circuit voltage (Voc ) of the PSCs with the polymer as donor. The PSCs based on PBDTBTz-T:PC71 BM blend film with a lower PC71 BM content of 40% demonstrate a power conversion efficiency (PCE) of 6.09% with a relatively higher Voc of 0.92 V. These results indicate that the lower HOMO energy level of the BTz-based D-A copolymer is beneficial to a high Voc of the PSCs. The polymer, with highly coplanar and crystalline structure, can effectively reduce the content of fullerene acceptor in the active layer and can enhance the absorption and PCE of the PSCs.
[Mh] Termos MeSH primário: Bitionol/química
Fulerenos/química
Polímeros/química
Energia Solar
[Mh] Termos MeSH secundário: Estrutura Molecular
Tiofenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fullerenes); 0 (Polymers); 0 (Thiophenes); AMT77LS62O (Bithionol)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170328
[Lr] Data última revisão:
170328
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160514
[St] Status:MEDLINE
[do] DOI:10.1002/marc.201600115


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[PMID]:26961873
[Au] Autor:Kleinboelting S; Ramos-Espiritu L; Buck H; Colis L; van den Heuvel J; Glickman JF; Levin LR; Buck J; Steegborn C
[Ad] Endereço:From the Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
[Ti] Título:Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site.
[So] Source:J Biol Chem;291(18):9776-84, 2016 Apr 29.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (ACs) and one soluble AC (sAC). Despite similarities in their catalytic domains, these ACs differ in regulation. Transmembrane ACs respond to G proteins, whereas sAC is uniquely activated by bicarbonate. Via bicarbonate regulation, sAC acts as a physiological sensor for pH/bicarbonate/CO2, and it has been implicated as a therapeutic target, e.g. for diabetes, glaucoma, and a male contraceptive. Here we identify the bisphenols bithionol and hexachlorophene as potent, sAC-specific inhibitors. Inhibition appears mostly non-competitive with the substrate ATP, indicating that they act via an allosteric site. To analyze the interaction details, we solved a crystal structure of an sAC·bithionol complex. The structure reveals that the compounds are selective for sAC because they bind to the sAC-specific, allosteric binding site for the physiological activator bicarbonate. Structural comparison of the bithionol complex with apo-sAC and other sAC·ligand complexes along with mutagenesis experiments reveals an allosteric mechanism of inhibition; the compound induces rearrangements of substrate binding residues and of Arg(176), a trigger between the active site and allosteric site. Our results thus provide 1) novel insights into the communication between allosteric regulatory and active sites, 2) a novel mechanism for sAC inhibition, and 3) pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. These studies provide support for the future development of sAC-modulating drugs.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/química
Adenilil Ciclases/química
Bicarbonatos/química
Bitionol/química
[Mh] Termos MeSH secundário: Regulação Alostérica
Domínio Catalítico
Cristalografia por Raios X
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bicarbonates); 8L70Q75FXE (Adenosine Triphosphate); AMT77LS62O (Bithionol); EC 4.6.1.1 (ADCY10 protein, human); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170429
[Lr] Data última revisão:
170429
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160311
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.708255


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[PMID]:25173807
[Au] Autor:Eleuteri S; Di Giovanni S; Rockenstein E; Mante M; Adame A; Trejo M; Wrasidlo W; Wu F; Fraering PC; Masliah E; Lashuel HA
[Ad] Endereço:Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) CH-1015 Lausanne, Switzerland; Department of Neurosciences, School of Medicine, University of California at San Diego, La Joll
[Ti] Título:Novel therapeutic strategy for neurodegeneration by blocking Aß seeding mediated aggregation in models of Alzheimer's disease.
[So] Source:Neurobiol Dis;74:144-57, 2015 Feb.
[Is] ISSN:1095-953X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aß accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aß nucleated polymerization is essential for Aß fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aß seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aß seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aß-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aß42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aß seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/fisiopatologia
Peptídeos beta-Amiloides/efeitos dos fármacos
Degeneração Neural/tratamento farmacológico
Degeneração Neural/fisiopatologia
Fármacos Neuroprotetores/farmacologia
Fragmentos de Peptídeos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Doença de Alzheimer/patologia
Peptídeos beta-Amiloides/toxicidade
Precursor de Proteína beta-Amiloide/genética
Precursor de Proteína beta-Amiloide/metabolismo
Animais
Bitionol/farmacocinética
Bitionol/farmacologia
Células Cultivadas
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/patologia
Córtex Cerebral/fisiopatologia
Modelos Animais de Doenças
Avaliação Pré-Clínica de Medicamentos
Feminino
Gliose/tratamento farmacológico
Gliose/patologia
Gliose/fisiopatologia
Hexaclorofeno/farmacocinética
Hexaclorofeno/farmacologia
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Mitoxantrona/farmacocinética
Mitoxantrona/farmacologia
Degeneração Neural/patologia
Neurônios/efeitos dos fármacos
Neurônios/patologia
Neurônios/fisiologia
Fármacos Neuroprotetores/farmacocinética
Fragmentos de Peptídeos/toxicidade
Placa Amiloide/tratamento farmacológico
Placa Amiloide/patologia
Placa Amiloide/fisiopatologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (APP protein, human); 0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Neuroprotective Agents); 0 (Peptide Fragments); 0 (amyloid beta-protein (1-42)); AMT77LS62O (Bithionol); BZ114NVM5P (Mitoxantrone); IWW5FV6NK2 (Hexachlorophene)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140901
[St] Status:MEDLINE


  9 / 142 MEDLINE  
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[PMID]:24495391
[Au] Autor:Ayyagari VN; Brard L
[Ti] Título:Bithionol inhibits ovarian cancer cell growth in vitro - studies on mechanism(s) of action.
[So] Source:BMC Cancer;14:61, 2014 Feb 04.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Drug resistance is a cause of ovarian cancer recurrence and low overall survival rates. There is a need for more effective treatment approaches because the development of new drug is expensive and time consuming. Alternatively, the concept of 'drug repurposing' is promising. We focused on Bithionol (BT), a clinically approved anti-parasitic drug as an anti-ovarian cancer drug. BT has previously been shown to inhibit solid tumor growth in several preclinical cancer models. A better understanding of the anti-tumor effects and mechanism(s) of action of BT in ovarian cancer cells is essential for further exploring its therapeutic potential against ovarian cancer. METHODS: The cytotoxic effects of BT against a panel of ovarian cancer cell lines were determined by Presto Blue cell viability assay. Markers of apoptosis such as caspases 3/7, cPARP induction, nuclear condensation and mitochondrial transmembrane depolarization were assessed using microscopic, FACS and immunoblotting methods. Mechanism(s) of action of BT such as cell cycle arrest, reactive oxygen species (ROS) generation, autotaxin (ATX) inhibition and effects on MAPK and NF-kB signalling were determined by FACS analysis, immunoblotting and colorimetric methods. RESULTS: BT caused dose dependent cytotoxicity against all ovarian cancer cell lines tested with IC50 values ranging from 19 µM - 60 µM. Cisplatin-resistant variants of A2780 and IGROV-1 have shown almost similar IC50 values compared to their sensitive counterparts. Apoptotic cell death was shown by expression of caspases 3/7, cPARP, loss of mitochondrial potential, nuclear condensation, and up-regulation of p38 and reduced expression of pAkt, pNF-κB, pIκBα, XIAP, bcl-2 and bcl-xl. BT treatment resulted in cell cycle arrest at G1/M phase and increased ROS generation. Treatment with ascorbic acid resulted in partial restoration of cell viability. In addition, dose and time dependent inhibition of ATX was observed. CONCLUSIONS: BT exhibits cytotoxic effects on various ovarian cancer cell lines regardless of their sensitivities to cisplatin. Cell death appears to be via caspases mediated apoptosis. The mechanisms of action appear to be partly via cell cycle arrest, ROS generation and inhibition of ATX. The present study provides preclinical data suggesting a potential therapeutic role for BT against recurrent ovarian cancer.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Bitionol/farmacologia
Proliferação Celular/efeitos dos fármacos
Neoplasias Ovarianas/patologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Proteínas Reguladoras de Apoptose/metabolismo
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Cisplatino/farmacologia
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Concentração Inibidora 50
Potencial da Membrana Mitocondrial/efeitos dos fármacos
NF-kappa B/metabolismo
Neoplasias Ovarianas/metabolismo
Diester Fosfórico Hidrolases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Apoptosis Regulatory Proteins); 0 (NF-kappa B); 0 (Reactive Oxygen Species); AMT77LS62O (Bithionol); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1409
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140206
[St] Status:MEDLINE
[do] DOI:10.1186/1471-2407-14-61


  10 / 142 MEDLINE  
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[PMID]:23990907
[Au] Autor:Sun W; Park YD; Sugui JA; Fothergill A; Southall N; Shinn P; McKew JC; Kwon-Chung KJ; Zheng W; Williamson PR
[Ad] Endereço:National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.
[Ti] Título:Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.
[So] Source:PLoS One;8(8):e70506, 2013.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Ascomicetos/efeitos dos fármacos
Avaliação Pré-Clínica de Medicamentos/métodos
Reposicionamento de Medicamentos/métodos
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/química
Anfotericina B/química
Antifúngicos/química
Bitionol/química
Linhagem Celular Tumoral
Floxuridina/química
Seres Humanos
Hifas/efeitos dos fármacos
Sepse/tratamento farmacológico
Esporos Fúngicos/efeitos dos fármacos
Tacrolimo/química
Triazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Triazoles); 039LU44I5M (Floxuridine); 6TK1G07BHZ (posaconazole); 7XU7A7DROE (Amphotericin B); 8L70Q75FXE (Adenosine Triphosphate); AMT77LS62O (Bithionol); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1404
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130831
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0070506



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