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[PMID]:29339161
[Au] Autor:El Nagar S; Zindy F; Moens C; Martin L; Plassard D; Roussel MF; Lamonerie T; Billon N
[Ad] Endereço:Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France.
[Ti] Título:A new genetically engineered mouse model of choroid plexus carcinoma.
[So] Source:Biochem Biophys Res Commun;496(2):568-574, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Choroid plexus carcinomas (CPCs) are highly malignant brain tumours predominantly found in children and associated to poor prognosis. Improved therapy for these cancers would benefit from the generation of animal models. Here we have created a novel mouse CPC model by expressing a stabilised form of c-Myc (MycT58A) and inactivating Trp53 in the choroid plexus of newborn mice. This induced aberrant proliferation of choroid plexus epithelial cells, leading to aggressive tumour development and death within 150 days. Choroid plexus tumours occurred with a complete penetrance in all brain ventricles, with prevalence in the lateral and fourth ventricles. Histological and cellular analysis indicated that these tumours were CPCs resembling their human counterparts. Comparison of gene expression profiles of CPCs and non-neoplastic tissues revealed profound alterations in cell cycle regulation and DNA damage responses, suggesting that dysregulation of cell division and DNA checkpoint pathways may represent key vulnerabilities. This novel animal model of CPC provides an invaluable tool to elucidate the mechanism of CPC formation and to develop successful therapies against this devastating paediatric cancer.
[Mh] Termos MeSH primário: Carcinoma/genética
Carcinoma/patologia
Neoplasias do Plexo Corióideo/genética
Neoplasias do Plexo Corióideo/patologia
Plexo Corióideo/patologia
Proteínas Proto-Oncogênicas c-myc/genética
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Animais
Carcinogênese/genética
Carcinogênese/patologia
Proliferação Celular
Dano ao DNA
Modelos Animais de Doenças
Seres Humanos
Camundongos
Camundongos Transgênicos
Mutação
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Proto-Oncogene Proteins c-myc); 0 (Tumor Suppressor Protein p53)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE


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[PMID]:29309426
[Au] Autor:McDonald JS; McDonald RJ; Ekins JB; Tin AS; Costes S; Hudson TM; Schroeder DJ; Kallmes K; Kaufmann SH; Young PM; Lu A; Kadirvel R; Kallmes DF
[Ad] Endereço:Department of Radiology, College of Medicine, Mayo Clinic, Rochester, MN, United States of America.
[Ti] Título:Gadolinium-enhanced cardiac MR exams of human subjects are associated with significant increases in the DNA repair marker 53BP1, but not the damage marker γH2AX.
[So] Source:PLoS One;13(1):e0190890, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Magnetic resonance imaging is considered low risk, yet recent studies have raised a concern of potential damage to DNA in peripheral blood leukocytes. This prospective Institutional Review Board-approved study examined potential double-strand DNA damage by analyzing changes in the DNA damage and repair markers γH2AX and 53BP1 in patients who underwent a 1.5 T gadolinium-enhanced cardiac magnetic resonance (MR) exam. Sixty patients were enrolled (median age 55 years, 39 males). Patients with history of malignancy or who were receiving chemotherapy, radiation therapy, or steroids were excluded. MR sequence data were recorded and blood samples obtained immediately before and after MR exposure. An automated immunofluorescence assay quantified γH2AX or 53BP1 foci number in isolated peripheral blood mononuclear cells. Changes in foci number were analyzed using the Wilcoxon signed-rank test. Clinical and MR procedural characteristics were compared between patients who had a >10% increase in γH2AX or 53BP1 foci numbers and patients who did not. The number of γH2AX foci did not significantly change following cardiac MR (median foci per cell pre-MR = 0.11, post-MR = 0.11, p = .90), but the number of 53BP1 foci significantly increased following MR (median foci per cell pre-MR = 0.46, post-MR = 0.54, p = .0140). Clinical and MR characteristics did not differ significantly between patients who had at least a 10% increase in foci per cell and those who did not. We conclude that MR exposure leads to a small (median 25%) increase in 53BP1 foci, however the clinical relevance of this increase is unknown and may be attributable to normal variation instead of MR exposure.
[Mh] Termos MeSH primário: Biomarcadores/metabolismo
Dano ao DNA
Reparo do DNA
Gadolínio/administração & dosagem
Coração/diagnóstico por imagem
Histonas/metabolismo
Imagem por Ressonância Magnética/métodos
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Feminino
Seres Humanos
Masculino
Meia-Idade
Estudos Prospectivos
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (H2AFX protein, human); 0 (Histones); 0 (TP53BP1 protein, human); 0 (Tumor Suppressor p53-Binding Protein 1); AU0V1LM3JT (Gadolinium)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190890


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[PMID]:29274491
[Au] Autor:Srivastava P; Singh K; Verma M; Sivakumar S; Patra AK
[Ad] Endereço:Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India.
[Ti] Título:Photoactive platinum(II) complexes of nonsteroidal anti-inflammatory drug naproxen: Interaction with biological targets, antioxidant activity and cytotoxicity.
[So] Source:Eur J Med Chem;144:243-254, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The effect on the therapeutic efficacy of Pt(II) complexes on combining non-steroidal anti-inflammatory drugs (NSAIDs) is an attractive strategy to circumvent chronic inflammation mediated by cancer and metastasis. Two square-planar platinum(II) complexes: [Pt(dach)(nap)Cl] (1) and [Pt(dach)(nap) ] (2), where dach = (1R,2R)-dichloro(cyclohexane-1,2-diamine) and NSAID drug naproxen (nap), have been designed for studying their biological activity. The naproxen bound to the Pt(II) centre get released upon photoirradiation with low-power UV-A light as confirmed by the significant enhancement in emission intensities of the complexes. The compounds were evaluated for their photophysical properties, photostability, reactivity with 5'-guanosine monophophosphate (5'-GMP), interactions with CT-DNA and BSA, antioxidant activity and reactive oxygen species mediated photo-induced DNA damage properties. ESI-MS studies demonstrated the formation of bis-adduct with 5'-GMP and the formation of Pt -DNA crosslinks by gel electrophoretic mobility shift assay and ITC studies. The interaction of the complexes 1 and 2 with the CT-DNA exhibits potential binding affinity (K âˆ¼ 10 M , K ∼ 10 M ), implying intercalation to CT-DNA through planar naphthyl ring of the complexes. Both the complexes also exhibit strong binding affinity towards BSA (K ∼ 10 M ). The complexes exhibit efficient DNA damage activity on irradiation at 365 nm via formation of singlet oxygen ( O ) and hydroxyl radical ( OH) under physiological conditions. Both the complexes were cytotoxic in dark and exhibit significant enhancement of cytotoxicity upon photo-exposure against HeLa and HepG2 cancer cells giving IC values ranging from 8 to 12 µM for 1 and 2. The cellular internalization data showed cytosolic and nuclear localization of the complexes in the HeLa cells.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/química
Antineoplásicos/química
Antioxidantes/química
Naproxeno/análogos & derivados
Compostos Organoplatínicos/química
[Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/farmacologia
Antineoplásicos/farmacologia
Antioxidantes/farmacologia
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos da radiação
Dano ao DNA/efeitos dos fármacos
Dano ao DNA/efeitos da radiação
Células HeLa
Células Hep G2
Seres Humanos
Naproxeno/farmacologia
Neoplasias/tratamento farmacológico
Neoplasias/genética
Compostos Organoplatínicos/farmacologia
Fármacos Fotossensibilizantes/química
Fármacos Fotossensibilizantes/farmacologia
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Antineoplastic Agents); 0 (Antioxidants); 0 (Organoplatinum Compounds); 0 (Photosensitizing Agents); 57Y76R9ATQ (Naproxen)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE


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[PMID]:28467092
[Au] Autor:Wu M; Ye H; Shao C; Zheng X; Li Q; Wang L; Zhao M; Lu G; Chen B; Zhang J; Wang Y; Wang G; Hao H
[Ad] Endereço:Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines and ‡School of Pharmacy, China Pharmaceutical University , Tongjiaxiang #24, Nanjing 210009, China.
[Ti] Título:Metabolomics-Proteomics Combined Approach Identifies Differential Metabolism-Associated Molecular Events between Senescence and Apoptosis.
[So] Source:J Proteome Res;16(6):2250-2261, 2017 Jun 02.
[Is] ISSN:1535-3907
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Apoptosis and senescence are two types of cell fates in response to chemotherapy. Besides canonical pathways that mediate cell fates, cancer cell metabolism has been revealed as a crucial factor affecting cell fate decisions and thus represents a new target for antitumor therapy. Therefore, a comprehensive description of metabolic pathways underlying cell senescence and apoptosis in response to chemotherapy is highly demanded for therapeutic exploitation of both processes. Herein we employed a metabolomics-proteomics combined approach to identify metabolism-associated molecular events that mediate cellular responses to senescence and apoptosis using doxorubicin-treated human breast cancer cells MCF7 as models. Such biomics approach revealed that tricarboxylic acid cycle, pentose phosphate pathway, and nucleotide synthesis pathways were significantly upregulated in the senescent model, whereas fatty acid synthesis was reduced. In apoptotic cells, an overall reduced activity of major metabolic pathways was observed except for the arginine and proline pathway. Combinatorially, these data show the utility of biomics in exploring biochemical mechanism-based differences between apoptosis and senescence and reveal an unprecedented finding of the metabolic events that were induced for survival by facilitating ROS elimination and DNA damage repair in senescent cells, while they were downregulated in apoptotic cells when DNA damage was irreparable.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Senescência Celular/efeitos dos fármacos
Redes e Vias Metabólicas/efeitos dos fármacos
Metabolômica/métodos
Proteômica/métodos
[Mh] Termos MeSH secundário: Ciclo do Ácido Cítrico
Dano ao DNA
Doxorrubicina/farmacologia
Doxorrubicina/uso terapêutico
Ácidos Graxos/biossíntese
Seres Humanos
Células MCF-7
Nucleotídeos/biossíntese
Via de Pentose Fosfato
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Nucleotides); 0 (Reactive Oxygen Species); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jproteome.7b00111


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[PMID]:28456783
[Au] Autor:Cai S; Li Y; Bai JY; Zhang ZQ; Wang Y; Qiao YB; Zhou XZ; Yang B; Tian Y; Cao C
[Ad] Endereço:Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
[Ti] Título:Gαi3 nuclear translocation causes irradiation resistance in human glioma cells.
[So] Source:Oncotarget;8(21):35061-35068, 2017 May 23.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have previously shown that Gαi3 is elevated in human glioma, mediating Akt activation and cancer cell proliferation. Here, we imply that Gαi3 could also be important for irradiation resistance. In A172 human glioma cells, Gαi3 knockdown (by targeted shRNAs) or dominant-negative mutation significantly potentiated irradiation-induced cell apoptosis. Reversely, forced over-expression of wild-type or constitutively-active Gαi3 inhibited irradiation-induced A172 cell apoptosis. Irradiation in A172 cells induced Gαi3 translocation to cell nuclei and association with local protein DNA-dependent protein kinase (DNA-PK) catalytic subunit. This association was important for DNA damage repair. Gαi3 knockdown, depletion (using Gαi3 knockout MEFs) or dominant-negative mutation potentiated irradiation-induced DNA damages. On the other hand, expression of the constitutively-active Gαi3 in A172 cells inhibited DNA damage by irradiation. Together, these results indicate a novel function of Gαi3 in irradiation-resistance in human glioma cells.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Glioma/metabolismo
Tolerância a Radiação
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/genética
Neoplasias Encefálicas/radioterapia
Linhagem Celular Tumoral
Núcleo Celular/metabolismo
Dano ao DNA
Proteína Quinase Ativada por DNA/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética
Regulação Neoplásica da Expressão Gênica/efeitos da radiação
Glioma/genética
Glioma/radioterapia
Seres Humanos
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 3.6.5.1 (GNAI3 protein, human); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.17043


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[PMID]:28453388
[Au] Autor:Ayars M; Eshleman J; Goggins M
[Ad] Endereço:a Department of Pathology , The Johns Hopkins University School of Medicine , Baltimore , MD, USA.
[Ti] Título:Susceptibility of ATM-deficient pancreatic cancer cells to radiation.
[So] Source:Cell Cycle;16(10):991-998, 2017 May 19.
[Is] ISSN:1551-4005
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ataxia telangiectasia mutated (ATM) is inactivated in a significant minority of pancreatic ductal adenocarcinomas and may be predictor of treatment response. We determined if ATM deficiency renders pancreatic cancer cells more sensitive to fractionated radiation or commonly used chemotherapeutics. ATM expression was knocked down in three pancreatic cancer cell lines using ATM-targeting shRNA. Isogenic cell lines were tested for sensitivity to several chemotherapeutic agents and radiation. DNA repair kinetics were analyzed in irradiated cells using the comet assay. We find that while rendering pancreatic cancer cells ATM-deficient did not significantly change their sensitivity to several chemotherapeutics, it did render them exquisitely sensitized to radiation. Pancreatic cancer ATM status may help predict response to radiotherapy.
[Mh] Termos MeSH primário: Adenocarcinoma/radioterapia
Proteínas Mutadas de Ataxia Telangiectasia/genética
Carcinoma Ductal Pancreático/radioterapia
Tolerância a Radiação/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/genética
Adenocarcinoma/patologia
Carcinoma Ductal Pancreático/genética
Carcinoma Ductal Pancreático/patologia
Linhagem Celular Tumoral
Quebras de DNA de Cadeia Dupla
Dano ao DNA/efeitos da radiação
Reparo do DNA/efeitos da radiação
Regulação Neoplásica da Expressão Gênica/efeitos da radiação
Seres Humanos
Fosforilação/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.1 (ATM protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1080/15384101.2017.1312236


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[PMID]:28954371
[Au] Autor:Ajima MNO; Pandey PK; Kumar K; Poojary N
[Ad] Endereço:Department of Fisheries and Aquaculture Technology, Federal University of Technology, Owerri, Nigeria. Electronic address: malajimo@gmail.com.
[Ti] Título:Alteration in DNA structure, molecular responses and Na -K -ATPase activities in the gill of Nile tilapia, Oreochromis niloticus (Linnaeus, 1758) in response to sub-lethal verapamil.
[So] Source:Ecotoxicol Environ Saf;147:809-816, 2018 Jan.
[Is] ISSN:1090-2414
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The ecotoxicological consequences of residues from pharmaceutical drugs on aquatic biota have necessitated the development of sensitive and reliable techniques to assess the impact of these xenobiotics on aquatic organisms. This study investigated the alteration in DNA structure, molecular responses and the activities of Na -K -ATPase and antioxidant enzymes in the gill of Nile tilapia, Oreochromis niloticus, exposed to long-term effects at the concentrations (0.14, 0.28 and 0.57mgL ) of verapamil in static renewal system for 15, 30, 45 and 60 days. Evaluation of DNA structure, using single cell gel electrophoresis, revealed certain degree of DNA damages in the gill in a time and concentration-dependent relationship. Transcription of mRNA of superoxide dismutase (sod), catalase (cat) and heat shock protein (hsp70) genes in the gill of the fish showed the genes were up-regulated. Na -K -ATPase activity was inhibited in a concentration and time dependent manner. The indices of oxidative stress biomarkers (lipid peroxidation and carbonyl protein) as well as superoxide dismutase, glutathione peroxidase, glutathione-S-transferase were elevated in the treated fish in comparison to the control. Further, the level of reduced glutathione and catalase activity were inhibited at 0.28mgL after day 30. Long-term exposure to sub-lethal concentration of verapamil can cause DNA damages, molecular effects and oxidative stress in O. niloticus. The biomarkers analysed can be used as early warning signals in environmental biomonitoring and assessment of drug contamination in aquatic ecosystem.
[Mh] Termos MeSH primário: Ciclídeos/metabolismo
Dano ao DNA
Brânquias/efeitos dos fármacos
ATPase Trocadora de Sódio-Potássio/metabolismo
Verapamil/toxicidade
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Antioxidantes/metabolismo
Biomarcadores/metabolismo
Ciclídeos/genética
Relação Dose-Resposta a Droga
Monitoramento Ambiental/métodos
Brânquias/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Verapamil/metabolismo
Poluentes Químicos da Água/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Biomarkers); 0 (Water Pollutants, Chemical); CJ0O37KU29 (Verapamil); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE


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[PMID]:28458064
[Au] Autor:Nagel ZD; Engelward BP; Brenner DJ; Begley TJ; Sobol RW; Bielas JH; Stambrook PJ; Wei Q; Hu JJ; Terry MB; Dilworth C; McAllister KA; Reinlib L; Worth L; Shaughnessy DT
[Ad] Endereço:Department of Environmental Health, Harvard School of Public Health, Boston, MA, 02115, USA.
[Ti] Título:Towards precision prevention: Technologies for identifying healthy individuals with high risk of disease.
[So] Source:Mutat Res;800-802:14-28, 2017 08.
[Is] ISSN:1873-135X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The rise of advanced technologies for characterizing human populations at the molecular level, from sequence to function, is shifting disease prevention paradigms toward personalized strategies. Because minimization of adverse outcomes is a key driver for treatment decisions for diseased populations, developing personalized therapy strategies represent an important dimension of both precision medicine and personalized prevention. In this commentary, we highlight recently developed enabling technologies in the field of DNA damage, DNA repair, and mutagenesis. We propose that omics approaches and functional assays can be integrated into population studies that fuse basic, translational and clinical research with commercial expertise in order to accelerate personalized prevention and treatment of cancer and other diseases linked to aberrant responses to DNA damage. This collaborative approach is generally applicable to efforts to develop data-driven, individualized prevention and treatment strategies for other diseases. We also recommend strategies for maximizing the use of biological samples for epidemiological studies, and for applying emerging technologies to clinical applications.
[Mh] Termos MeSH primário: Neoplasias/diagnóstico
Neoplasias/prevenção & controle
Medicina de Precisão
[Mh] Termos MeSH secundário: Dano ao DNA
Reparo do DNA
Seres Humanos
Mutagênese
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29362359
[Au] Autor:Naumann M; Pal A; Goswami A; Lojewski X; Japtok J; Vehlow A; Naujock M; Günther R; Jin M; Stanslowsky N; Reinhardt P; Sterneckert J; Frickenhaus M; Pan-Montojo F; Storkebaum E; Poser I; Freischmidt A; Weishaupt JH; Holzmann K; Troost D; Ludolph AC; Boeckers TM; Liebau S; Petri S; Cordes N; Hyman AA; Wegner F; Grill SW; Weis J; Storch A; Hermann A
[Ad] Endereço:Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany.
[Ti] Título:Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation.
[So] Source:Nat Commun;9(1):335, 2018 01 23.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/metabolismo
Dano ao DNA
Neurônios Motores/metabolismo
Mutação
Agregação Patológica de Proteínas/metabolismo
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/genética
Idoso
Idoso de 80 Anos ou mais
Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/patologia
Diferenciação Celular
Núcleo Celular/metabolismo
Citoplasma/metabolismo
Feminino
Expressão Gênica
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/patologia
Masculino
Meia-Idade
Neurônios Motores/patologia
Sinais de Localização Nuclear/genética
Sinais de Localização Nuclear/metabolismo
Poli(ADP-Ribose) Polimerase-1/genética
Poli(ADP-Ribose) Polimerase-1/metabolismo
Agregação Patológica de Proteínas/genética
Agregação Patológica de Proteínas/patologia
Proteína FUS de Ligação a RNA/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nuclear Localization Signals); 0 (RNA-Binding Protein FUS); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02299-1


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[PMID]:29378162
[Au] Autor:Vila L; García-Rodríguez A; Cortés C; Velázquez A; Xamena N; Sampayo-Reyes A; Marcos R; Hernández A
[Ad] Endereço:Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
[Ti] Título:Effects of cerium oxide nanoparticles on differentiated/undifferentiated human intestinal Caco-2 cells.
[So] Source:Chem Biol Interact;283:38-46, 2018 Mar 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Since ingestion constitute one of the main routes of nanoparticles (NPs) exposure, intestinal cells seems to be a suitable choice to evaluate their potential harmful effects. Caco-2 cells, derived from a human colon adenocarcinoma, have the ability to differentiate forming consistent cell monolayer structures. For these reasons Caco-2 cells, both in their undifferentiated or differentiated state, are extendedly used. We have used well-structured monolayers of differentiated Caco-2 cells, as a model of intestinal barrier, to evaluate potential harmful effects associated to CeO NPs exposure via ingestion. Different parameters such as cell toxicity, monolayer integrity and permeability, cell internalization, translocation through the monolayer, and induction of DNA damage were evaluated. No toxic effects of CeO NPs were observed, independently of the differentiated state of the Caco-2 cells. In the same way, no effects on the monolayer integrity/permeability were observed. Although important cell uptake was demonstrated in undifferentiated cells (by using confocal microscopy), CeO NPs remained mostly attached to the apical membrane in the differentiated cells. In spite of this apparent lack of uptake in differentiated cells, translocation of CeO NPs to the basolateral chamber was observed by using confocal microscopy. Finally no genotoxic effects were observed when the comet assay was used, although decreases in the levels of oxidized bases were observed, supporting the antioxidant role of CeO NPs.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Cério/química
Nanopartículas Metálicas/toxicidade
[Mh] Termos MeSH secundário: Células CACO-2
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Permeabilidade da Membrana Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Dano ao DNA/efeitos dos fármacos
Seres Humanos
Intestinos/citologia
Intestinos/metabolismo
Nanopartículas Metálicas/química
Microscopia Confocal
Tamanho da Partícula
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
30K4522N6T (Cerium); 619G5K328Y (ceric oxide)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180130
[St] Status:MEDLINE



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