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[PMID]: 28717111 [Au] Autor: Watanabe H; Honda Y; Deguchi J; Yamada T; Bando K [Ad] Endereço: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd. [Ti] Título: Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes. [So] Source: J Toxicol Sci;42(4):519-527, 2017. [Is] ISSN: 1880-3989 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a ß-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery. [Mh] Termos MeSH primário: Cálcio/metabolismo Cardiotônicos/toxicidade Células-Tronco Pluripotentes Induzidas/citologia Miócitos Cardíacos/metabolismo Testes de Toxicidade/métodos [Mh] Termos MeSH secundário: Arritmias Cardíacas/induzido quimicamente Astemizol/toxicidade Bloqueadores dos Canais de Cálcio/toxicidade Diferenciação Celular Células Cultivadas Digoxina/toxicidade Relação Dose-Resposta a Droga Descoberta de Drogas Fluoroquinolonas/toxicidade Isoproterenol/toxicidade Contração Miocárdica/efeitos dos fármacos Propranolol/toxicidade Verapamil/toxicidade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium Channel Blockers); 0 (Cardiotonic Agents); 0 (Fluoroquinolones); 73K4184T59 (Digoxin); 7HU6337315 (Astemizole); 9Y8NXQ24VQ (Propranolol); CJ0O37KU29 (Verapamil); L628TT009W (Isoproterenol); SY7Q814VUP (Calcium); U188XYD42P (moxifloxacin) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171005 [Lr] Data última revisão: 171005 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170719 [St] Status: MEDLINE [do] DOI: 10.2131/jts.42.519

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[PMID]: 28418693 [Au] Autor: Styczynska-Soczka K; Zechini L; Zografos L [Ad] Endereço: Parkure Ltd. , Edinburgh, United Kingdom . [Ti] Título: Validating the Predicted Effect of Astemizole and Ketoconazole Using a Drosophila Model of Parkinson's Disease. [So] Source: Assay Drug Dev Technol;15(3):106-112, 2017 Apr. [Is] ISSN: 1557-8127 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically. In this work, we utilize a transgenic Drosophila model of Parkinson's disease, made by expressing human alpha-synuclein in the Drosophila brain, to validate two repurposed compounds: astemizole and ketoconazole. Both have been computationally predicted to have an ameliorative effect on Parkinson's disease, but neither had been tested using an in vivo model of the disease. After treating the flies in parallel, results showed that both drugs rescue the motor phenotype that is developed by the Drosophila model with age, but only ketoconazole treatment reversed the increased dopaminergic neuron death also observed in these models, which is a hallmark of Parkinson's disease. In addition to validating the predicted improvement in Parkinson's disease symptoms for both drugs and revealing the potential neuroprotective activity of ketoconazole, these results highlight the value of Drosophila models of Parkinson's disease as key tools in the context of in vivo drug discovery, drug repurposing, and prioritization of hits, especially when coupled with computational predictions. [Mh] Termos MeSH primário: Astemizol/administração & dosagem Modelos Animais de Doenças Drosophila/efeitos dos fármacos Drosophila/fisiologia Cetoconazol/administração & dosagem Avaliação de Resultados (Cuidados de Saúde)/métodos Doença de Parkinson/tratamento farmacológico [Mh] Termos MeSH secundário: Animais Relação Dose-Resposta a Droga Reposicionamento de Medicamentos/métodos Seres Humanos Prognóstico Especificidade da Espécie Resultado do Tratamento [Pt] Tipo de publicação: EVALUATION STUDIES; JOURNAL ARTICLE; VALIDATION STUDIES [Nm] Nome de substância: 7HU6337315 (Astemizole); R9400W927I (Ketoconazole) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170419 [St] Status: MEDLINE [do] DOI: 10.1089/adt.2017.776

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[PMID]: 28259991 [Au] Autor: Horst CH; Titze-de-Almeida R; Titze-de-Almeida SS [Ad] Endereço: Technology for Gene Therapy Laboratory, Central Institute of Sciences, Faculty of Agronomy and Veterinary Medicine, University of Brasília, Brasília 70910­900, Brazil. [Ti] Título: The involvement of Eag1 potassium channels and miR-34a in rotenone-induced death of dopaminergic SH-SY5Y cells. [So] Source: Mol Med Rep;15(4):1479-1488, 2017 Apr. [Is] ISSN: 1791-3004 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: The loss of dopaminergic neurons and the resultant motor impairment are hallmarks of Parkinson's disease. The SH­SY5Y cell line is a model of dopaminergic neurons, and allows for the study of dopaminergic neuronal injury. Previous studies have revealed changes in Ether à go­go 1 (Eag1) potassium channel expression during p53-induced SH­SY5Y apoptosis, and the regulatory involvement of microRNA­34a (miR­34a) was demonstrated. In the present study, the involvement of Eag1 and miR­34a in rotenone­induced SH­SY5Y cell injury was investigated. Rotenone is a neurotoxin, which is often used to generate models of Parkinson's disease, since it causes the death of nigrostriatal neurons by inducing intracellular aggregation of alpha synuclein and ubiquitin. In the present study, rotenone resulted in a dose­dependent decrease in cell viability, as revealed by 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide (MTT) and trypan blue cell counting assays. In addition, Eag1 was demonstrated to be constitutively expressed by SH­SY5Y cells, and involved in cell viability. Suppression of Eag1 with astemizole resulted in a dose­dependent decrease in cell viability, as revealed by MTT assay. Astemizole also enhanced the severity of rotenone­induced injury in SH­SY5Y cells. RNA interference against Eag1, using synthetic small interfering RNAs (siRNAs), corroborated this finding, as siRNAs potentiated rotenone­induced injury. Eag1­targeted siRNAs (kv10.1­3 or EAG1hum_287) resulted in a statistically significant 16.4­23.5% increase in vulnerability to rotenone. An increased number of apoptotic nuclei were observed in cells transfected with EAG1hum_287. Notably, this siRNA intensified rotenone­induced apoptosis, as revealed by an increase in caspase 3/7 activity. Conversely, a miR­34a inhibitor was demonstrated to exert neuroprotective effects. The viability of cells exposed to rotenone for 24 or 48 h and treated with miR­34a inhibitor was restored by 8.4­8.8%. In conclusion, Eag1 potassium channels and miR­34a are involved in the response to rotenone-induced injury in SH­SY5Y cells. The neuroprotective effect of mir­34a inhibitors merits further investigations in animal models of Parkinson's disease. [Mh] Termos MeSH primário: Neurônios Dopaminérgicos/citologia Neurônios Dopaminérgicos/metabolismo Canais de Potássio Éter-A-Go-Go/metabolismo MicroRNAs/metabolismo [Mh] Termos MeSH secundário: Astemizol/farmacologia Morte Celular/efeitos dos fármacos Linhagem Celular Tumoral Sobrevivência Celular/efeitos dos fármacos Neurônios Dopaminérgicos/efeitos dos fármacos Inativação Gênica/efeitos dos fármacos Seres Humanos Imuno-Histoquímica MicroRNAs/genética RNA Interferente Pequeno/metabolismo Rotenona/farmacologia Transfecção [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ether-A-Go-Go Potassium Channels); 0 (KCNH1 protein, human); 0 (MIRN34 microRNA, human); 0 (MicroRNAs); 0 (RNA, Small Interfering); 03L9OT429T (Rotenone); 7HU6337315 (Astemizole) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170619 [Lr] Data última revisão: 170619 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170306 [St] Status: MEDLINE [do] DOI: 10.3892/mmr.2017.6191

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[PMID]: 27333030 [Au] Autor: Ellegaard AM; Dehlendorff C; Vind AC; Anand A; Cederkvist L; Petersen NHT; Nylandsted J; Stenvang J; Mellemgaard A; Østerlind K; Friis S; Jäättelä M [Ad] Endereço: Cell Death & Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark. [Ti] Título: Repurposing Cationic Amphiphilic Antihistamines for Cancer Treatment. [So] Source: EBioMedicine;9:130-139, 2016 Jul. [Is] ISSN: 2352-3964 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug (CAD) library for cytotoxicity against NSCLC cells and identified several CAD antihistamines as inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamine use on mortality of patients diagnosed with non-localized cancer in Denmark between 1995 and 2011. The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non-CAD antihistamines and adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizole showed a similar significant association with reduced mortality as loratadine among patients with any non-localized cancer, and ebastine use showed a similar tendency. The association between CAD antihistamine use and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy. [Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico Antagonistas dos Receptores Histamínicos/uso terapêutico Neoplasias Pulmonares/tratamento farmacológico [Mh] Termos MeSH secundário: Células A549 Adulto Apoptose/efeitos dos fármacos Astemizol/farmacologia Astemizol/uso terapêutico Western Blotting Carcinoma Pulmonar de Células não Pequenas/mortalidade Cátions/química Linhagem Celular Tumoral Estudos de Coortes Dinamarca Reposicionamento de Medicamentos Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos Antagonistas dos Receptores Histamínicos/farmacologia Seres Humanos Loratadina/farmacologia Loratadina/uso terapêutico Neoplasias Pulmonares/mortalidade Lisossomos/metabolismo Modelos de Riscos Proporcionais Sistema de Registros Taxa de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cations); 0 (Histamine Antagonists); 7AJO3BO7QN (Loratadine); 7HU6337315 (Astemizole) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160623 [St] Status: MEDLINE

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[PMID]: 27262902 [Au] Autor: Izumi-Nakaseko H; Nakamura Y; Cao X; Wada T; Ando K; Sugiyama A [Ad] Endereço: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. [Ti] Título: Possibility as an anti-cancer drug of astemizole: Evaluation of arrhythmogenicity by the chronic atrioventricular block canine model. [So] Source: J Pharmacol Sci;131(2):150-3, 2016 Jun. [Is] ISSN: 1347-8648 [Cp] País de publicação: Japan [La] Idioma: eng [Ab] Resumo: Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug. [Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos Astemizol/efeitos adversos Torsades de Pointes/induzido quimicamente [Mh] Termos MeSH secundário: Animais Bloqueio Atrioventricular Modelos Animais de Doenças Cães Feminino Masculino [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 7HU6337315 (Astemizole) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170504 [Lr] Data última revisão: 170504 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160606 [St] Status: MEDLINE

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[PMID]: 26899760 [Au] Autor: Uehara S; Uno Y; Inoue T; Okamoto E; Sasaki E; Yamazaki H [Ad] Endereço: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan . [Ti] Título: Marmoset cytochrome P450 2J2 mainly expressed in small intestines and livers effectively metabolizes human P450 2J2 probe substrates, astemizole and terfenadine. [So] Source: Xenobiotica;46(11):977-85, 2016 Nov. [Is] ISSN: 1366-5928 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: 1. Common marmoset (Callithrix jacchus), a New World Monkey, has potential to be a useful animal model in preclinical studies. However, drug metabolizing properties have not been fully understood due to insufficient information on cytochrome P450 (P450), major drug metabolizing enzymes. 2. Marmoset P450 2J2 cDNA was isolated from marmoset livers. The deduced amino acid sequence showed a high-sequence identity (91%) with cynomolgus monkey and human P450 2J2 enzymes. A phylogenetic tree revealed that marmoset P450 2J2 was evolutionarily closer to cynomolgus monkey and human P450 2J2 enzymes, than P450 2J forms in pigs, rabbits, rats or mice. 3. Marmoset P450 2J2 mRNA was abundantly expressed in the small intestine and liver, and to a lesser extent in the brain, lung and kidney. Immunoblot analysis also showed expression of marmoset P450 2J2 protein in the small intestine and liver. 4. Enzyme assays using marmoset P450 2J2 protein heterologously expressed in Escherichia coli indicated that marmoset P450 2J2 effectively catalyzed astemizole O-demethylation and terfenadine t-butyl hydroxylation, similar to human and cynomolgus monkey P450 2J2 enzymes. 5. These results suggest the functional characteristics of P450 2J2 enzymes are similar among marmosets, cynomolgus monkeys and humans. [Mh] Termos MeSH primário: Astemizol/metabolismo Sistema Enzimático do Citocromo P-450/metabolismo Antagonistas dos Receptores Histamínicos H1 não Sedativos/metabolismo Macaca fascicularis/metabolismo Terfenadina/metabolismo [Mh] Termos MeSH secundário: Animais Seres Humanos Intestino Delgado/metabolismo Fígado/metabolismo Camundongos Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Histamine H1 Antagonists, Non-Sedating); 7BA5G9Y06Q (Terfenadine); 7HU6337315 (Astemizole); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (arachidonate epoxygenase) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170209 [Lr] Data última revisão: 170209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160223 [St] Status: MEDLINE [do] DOI: 10.3109/00498254.2016.1146366

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[PMID]: 26878482 [Au] Autor: Kim JY; Choi YS; Lee BK; Lee DW [Ad] Endereço: Graduate School of Mechanical Engineering, Chonnam National University, Gwangju 500757, Republic of Korea. [Ti] Título: Surface-patterned SU-8 cantilever arrays for preliminary screening of cardiac toxicity. [So] Source: Biosens Bioelectron;80:456-462, 2016 Jun 15. [Is] ISSN: 1873-4235 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Arrays of a µgrooved SU-8 cantilever were utilized to analyze changes in the contraction force and beating frequency of cardiomyocytes in vitro. The longitudinally patterned µgrooves facilitates alignment of cardiomyocytes on top of the SU-8 cantilever, which increases the contraction force of cardiomyocytes by a factor of about 2.5. The bending displacement of the SU-8 cantilever was precisely measured in nanoscale using a laser-based measurement system combined with a motorized xyz stage. The cantilever displacement due to contraction of the cardiomyocytes showed the maximum on day 8 after their cultivation. Following preliminary experiments, Isoproterenol, Verapamil, and Astemizole were used to investigate the effect of drug toxicity on the physiology of cardiomyocytes. The experimental results indicated that 1 µM of Isoproterenol treatment increased contraction force and beating frequencies of cardiomyocytes by 30% and 200%, respectively, whereas 500 nM of Verapamil treatment decreased contraction force and beating frequencies of cardiomyocytes by 56% and 42%, respectively. A concentration of less than 5 nM of the hERG channel suppression drug Astemizole did not change the contraction forces in the displacement but slightly decreased the beating frequencies. However, irregular or abnormal heartbeats were observed at Astemizole concentrations of 5 nM and higher. We experimentally conformed that the proposed SU-8 cantilever arrays combined with the laser-based measurement systems has the great potential for a high-throughput drug toxicity screening system in future. [Mh] Termos MeSH primário: Técnicas Biossensoriais Cardiotoxicidade Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos Miócitos Cardíacos/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Astemizol/efeitos adversos Células Cultivadas Compostos de Epóxi/administração & dosagem Compostos de Epóxi/química Seres Humanos Isoproterenol/efeitos adversos Lasers Contração Muscular/efeitos dos fármacos Polímeros/administração & dosagem Polímeros/química Ratos Verapamil/efeitos adversos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Epoxy Compounds); 0 (Polymers); 0 (SU-8 compound); 7HU6337315 (Astemizole); CJ0O37KU29 (Verapamil); L628TT009W (Isoproterenol) [Em] Mês de entrada: 1611 [Cu] Atualização por classe: 170924 [Lr] Data última revisão: 170924 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160216 [St] Status: MEDLINE

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[PMID]: 26739061 [Au] Autor: Jakhar R; Paul S; Bhardwaj M; Kang SC [Ad] Endereço: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea. [Ti] Título: Astemizole-Histamine induces Beclin-1-independent autophagy by targeting p53-dependent crosstalk between autophagy and apoptosis. [So] Source: Cancer Lett;372(1):89-100, 2016 Mar 01. [Is] ISSN: 1872-7980 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: Apoptosis and autophagy are genetically regulated, evolutionarily conserved processes that can jointly seal cancer cell fates, and numerous death stimuli are capable of activating either pathway. Although crosstalk between apoptosis and autophagy is quite complex and sometimes contradictory, it remains a key factor determining the outcomes of death-related pathologies such as cancer. In the present study, exposure of MCF-7 breast cancer cells to HIS and the H1 receptor antagonist AST both alone and together with HIS (AST-HIS) led to generation of intracellular ROS, which induced massive cellular vacuolization through dilation of the ER and mitochondria. Consequently, apoptosis by Bax translocation, cytochrome c release, and caspase activation were triggered. In addition, AST-HIS caused ER stress-induced autophagy in MCF-7 cells, as evidenced by an increased LC3-II/LC3-I ratio, with surprisingly no changes in Beclin-1 expression. Non-canonical autophagy was induced via p53 phosphorylation, which increased p53-p62 interactions to enhance Beclin-1-independent autophagy as evidenced by immunocytochemistry and immunoprecipitation. In the absence of Beclin-1, enhanced autophagy further activated apoptosis through caspase induction. In conclusion, these findings indicate that AST-HIS-induced apoptosis and autophagy can be regulated by ROS-mediated signaling pathways. [Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia Proteínas Reguladoras de Apoptose/metabolismo Apoptose/efeitos dos fármacos Astemizol/farmacologia Autofagia/efeitos dos fármacos Neoplasias da Mama/tratamento farmacológico Antagonistas dos Receptores Histamínicos H1 não Sedativos/farmacologia Histamina/farmacologia Proteínas de Membrana/metabolismo Proteína Supressora de Tumor p53/metabolismo [Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo Proteínas Reguladoras de Apoptose/genética Beclina-1 Neoplasias da Mama/genética Neoplasias da Mama/metabolismo Neoplasias da Mama/patologia Caspases/metabolismo Estresse do Retículo Endoplasmático/efeitos dos fármacos Feminino Seres Humanos Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo Células MCF-7 Proteínas de Membrana/genética Proteínas Associadas aos Microtúbulos/metabolismo Estresse Oxidativo/efeitos dos fármacos Fosforilação Interferência de RNA Espécies Reativas de Oxigênio/metabolismo Proteína Sequestossoma-1 Transdução de Sinais/efeitos dos fármacos Transfecção Proteína Supressora de Tumor p53/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Apoptosis Regulatory Proteins); 0 (BECN1 protein, human); 0 (Beclin-1); 0 (Histamine H1 Antagonists, Non-Sedating); 0 (MAP1LC3A protein, human); 0 (Membrane Proteins); 0 (Microtubule-Associated Proteins); 0 (Reactive Oxygen Species); 0 (SQSTM1 protein, human); 0 (Sequestosome-1 Protein); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 0 (light chain 3, human); 7HU6337315 (Astemizole); 820484N8I3 (Histamine); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 3.4.22.- (Caspases) [Em] Mês de entrada: 1607 [Cu] Atualização por classe: 161126 [Lr] Data última revisão: 161126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160108 [St] Status: MEDLINE

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[PMID]: 26506361 [Au] Autor: Fan YQ; Li PH; Chao YX; Chen H; Du N; He QX; Liu KC [Ad] Endereço: Key Lab of Marine Bioactive Substances, First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, China. fanyaqin.826@163.com. [Ti] Título: Alkaloids with Cardiovascular Effects from the Marine-Derived Fungus Penicillium expansum Y32. [So] Source: Mar Drugs;13(10):6489-504, 2015 Oct 22. [Is] ISSN: 1660-3397 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5-7, and 9-12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their structures including the absolute configurations were elucidated by spectroscopic and Mosher's and Marfey's methods, along with quantum electronic circular dichroism (ECD) calculations. Each of the compounds was evaluated for cardiovascular effects in a live zebrafish model. All of the compounds showed a significant mitigative effect on bradycardia caused by astemizole (ASM) in the heart rate experiments. Compounds 4-6 and 8-12 exhibited potent vasculogenetic activity in vasculogenesis experiments. This is the first study to report that these types of compounds show cardiovascular effects in zebrafish. The results suggest that these compounds could be promising candidates for cardiovascular disease lead compounds. [Mh] Termos MeSH primário: Alcaloides/farmacologia Bradicardia/tratamento farmacológico Fármacos Cardiovasculares/farmacologia Penicillium/metabolismo [Mh] Termos MeSH secundário: Alcaloides/química Alcaloides/isolamento & purificação Animais Astemizol/farmacologia Fármacos Cardiovasculares/química Fármacos Cardiovasculares/isolamento & purificação Dicroísmo Circular Frequência Cardíaca/efeitos dos fármacos Neovascularização Fisiológica/efeitos dos fármacos Metabolismo Secundário Peixe-Zebra [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Alkaloids); 0 (Cardiovascular Agents); 7HU6337315 (Astemizole) [Em] Mês de entrada: 1607 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151028 [St] Status: MEDLINE [do] DOI: 10.3390/md13106489

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[PMID]: 26209360 [Au] Autor: Jeon YJ; Kim JS; Hwang GH; Wu Z; Han HJ; Park SH; Chang W; Kim LK; Lee YM; Liu KH; Lee MY [Ad] Endereço: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea. [Ti] Título: Inhibition of cytochrome P450 2J2 by tanshinone IIA induces apoptotic cell death in hepatocellular carcinoma HepG2 cells. [So] Source: Eur J Pharmacol;764:480-8, 2015 Oct 05. [Is] ISSN: 1879-0712 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Cytochrome P450 2J2 (CYP2J2) is highly expressed in human tumors and carcinoma cell lines, and has been implicated in the pathogenesis of human cancers. The aim of this study was to identify a compound that could inhibit the activity of CYP2J2, and to examine its anticancer activity. To identify CYP2J2 inhibitors, 10 terpenoids obtained from plants were screened using astemizole as a CYP2J2 probe substrate in human liver microsomes (HLMs). Of these, tanshinone IIA dose-dependently and non-competitively inhibited CYP2J2-mediated astemizole O-demethylation activity. Tanshinone IIA significantly decreased viability of human hepatoma HepG2 cells and SiHa cervical cancer cells; however, it was not cytotoxic against mouse hepatocytes. Furthermore, treatment of cells with tanshinone IIA significantly increased apoptotic cell death rate, as shown by the increase in Annexin V-stained cell populations, Bcl-2 associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio, and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage in HepG2 cells. Furthermore, the results of this study showed that tanshinone IIA significantly decreased HepG2 cell-based tumor growth in nude mice in a dose-dependent manner. On the other hand, the tanshinone IIA-induced apoptotic cell death rate was significantly attenuated by enhanced up-regulation of CYP2J2 expression. Thus, our data strongly suggest that tanshinone IIA exerts its anticancer effect by inhibiting CYP2J2 activity. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Carcinoma Hepatocelular/tratamento farmacológico Inibidores das Enzimas do Citocromo P-450/farmacologia Sistema Enzimático do Citocromo P-450/metabolismo Diterpenos Abietanos/farmacologia Neoplasias Hepáticas/tratamento farmacológico [Mh] Termos MeSH secundário: Animais Proteínas Reguladoras de Apoptose/metabolismo Astemizol/metabolismo Carcinoma Hepatocelular/enzimologia Carcinoma Hepatocelular/genética Carcinoma Hepatocelular/patologia Sobrevivência Celular/efeitos dos fármacos Sistema Enzimático do Citocromo P-450/genética Remoção de Radical Alquila Relação Dose-Resposta a Droga Feminino Células Hep G2 Seres Humanos Neoplasias Hepáticas/enzimologia Neoplasias Hepáticas/genética Neoplasias Hepáticas/patologia Camundongos Camundongos Endogâmicos BALB C Camundongos Nus Especificidade da Espécie Fatores de Tempo Transfecção Carga Tumoral/efeitos dos fármacos Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Apoptosis Regulatory Proteins); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Diterpenes, Abietane); 03UUH3J385 (tanshinone); 7HU6337315 (Astemizole); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (arachidonate epoxygenase) [Em] Mês de entrada: 1607 [Cu] Atualização por classe: 151009 [Lr] Data última revisão: 151009 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150726 [St] Status: MEDLINE

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