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1.
Mol Nutr Food Res ; 63(22): e1900659, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483556

RESUMO

SCOPE: The goal of this work is to identify circulating biomarkers of habitual coffee intake using a metabolomic approach, and to investigate their associations with coffee intake in four European countries. METHODS AND RESULTS: Untargeted mass spectrometry-based metabolic profiling is performed on serum samples from 451 participants of the European Prospective Investigation on Cancer and Nutrition (EPIC) originating from France, Germany, Greece, and Italy. Eleven coffee metabolites are found to be associated with self-reported habitual coffee intake, including eight more strongly correlated (r = 0.25-0.51, p < 10E-07 ). Trigonelline shows the highest correlation, followed by caffeine, two caffeine metabolites (paraxanthine and 5-Acetylamino-6-amino-3-methyluracil), quinic acid, and three compounds derived from coffee roasting (cyclo(prolyl-valyl), cyclo(isoleucyl-prolyl), cyclo(leucyl-prolyl), and pyrocatechol sulfate). Differences in the magnitude of correlations are observed between countries, with trigonelline most highly correlated with coffee intake in France and Germany, quinic acid in Greece, and cyclo(isoleucyl-prolyl) in Italy. CONCLUSION: Several biomarkers of habitual coffee intake are identified. No unique biomarker is found to be optimal for all tested populations. Instead, optimal biomarkers are shown to depend on the population and on the type of coffee consumed. These biomarkers should help to further explore the role of coffee in disease risk.

2.
Int J Cancer ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506954

RESUMO

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992-2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00-1.26), with no detected heterogeneity across countries (phomogeneity = 0.42). This risk increased linearly with duration of use (ptrend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97-1.43), which was heterogeneous across countries (phomogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.

3.
Redox Biol ; 2: 323-32, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24563850

RESUMO

Free radicals originate from both exogenous environmental sources and as by-products of the respiratory chain and cellular oxygen metabolism. Sustained accumulation of free radicals, beyond a physiological level, induces oxidative stress that is harmful for the cellular homeodynamics as it promotes the oxidative damage and stochastic modification of all cellular biomolecules including proteins. In relation to proteome stability and maintenance, the increased concentration of oxidants disrupts the functionality of cellular protein machines resulting eventually in proteotoxic stress and the deregulation of the proteostasis (homeostasis of the proteome) network (PN). PN curates the proteome in the various cellular compartments and the extracellular milieu by modulating protein synthesis and protein machines assembly, protein recycling and stress responses, as well as refolding or degradation of damaged proteins. Molecular chaperones are key players of the PN since they facilitate folding of nascent polypeptides, as well as holding, folding, and/or degradation of unfolded, misfolded, or non-native proteins. Therefore, the expression and the activity of the molecular chaperones are tightly regulated at both the transcriptional and post-translational level at organismal states of increased oxidative and, consequently, proteotoxic stress, including ageing and various age-related diseases (e.g. degenerative diseases and cancer). In the current review we present a synopsis of the various classes of intra- and extracellular chaperones, the effects of oxidants on cellular homeodynamics and diseases and the redox regulation of chaperones.


Assuntos
Chaperonas Moleculares/fisiologia , Estresse Oxidativo/fisiologia , Proteínas/metabolismo , Animais , Transporte de Elétrons , Retículo Endoplasmático/metabolismo , Radicais Livres/metabolismo , Proteínas de Choque Térmico/fisiologia , Homeostase , Humanos , Modelos Biológicos , Oxidantes/metabolismo , Oxirredução , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Proteoma , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Mol Cancer Res ; 7(12): 1902-19, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19934273

RESUMO

p57(KIP2) is an imprinted gene located at the chromosomal locus 11p15.5. It is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family, which includes additionally p21(CIP1/WAF1) and p27(KIP1). It is the least studied CIP/KIP member and has a unique role in embryogenesis. p57(KIP2) regulates the cell cycle, although novel functions have been attributed to this protein including cytoskeletal organization. Molecular analysis of animal models and patients with Beckwith-Wiedemann Syndrome have shown its nodal implication in the pathogenesis of this syndrome. p57(KIP2) is frequently down-regulated in many common human malignancies through several mechanisms, denoting its anti-oncogenic function. This review is a thorough analysis of data available on p57(KIP2), in relation to p21(CIP1/WAF1) and p27(KIP1), on gene and protein structure, its transcriptional and translational regulation, and its role in human physiology and pathology, focusing on cancer development.


Assuntos
Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Animais , Inibidor de Quinase Dependente de Ciclina p57/química , Inibidor de Quinase Dependente de Ciclina p57/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
Am J Pathol ; 175(1): 376-91, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19541929

RESUMO

Osteosarcoma is the most common primary bone cancer. Mutations of the RB gene represent the most frequent molecular defect in this malignancy. A major consequence of this alteration is that the activity of the key cell cycle regulator E2F1 is unleashed from the inhibitory effects of pRb. Studies in animal models and in human cancers have shown that deregulated E2F1 overexpression possesses either "oncogenic" or "oncosuppressor" properties, depending on the cellular context. To address this issue in osteosarcomas, we examined the status of E2F1 relative to cell proliferation and apoptosis in a clinical setting of human primary osteosarcomas and in E2F1-inducible osteosarcoma cell line models that are wild-type and deficient for p53. Collectively, our data demonstrated that high E2F1 levels exerted a growth-suppressing effect that relied on the integrity of the DNA damage response network. Surprisingly, induction of p73, an established E2F1 target, was also DNA damage response-dependent. Furthermore, a global proteome analysis associated with bioinformatics revealed novel E2F1-regulated genes and potential E2F1-driven signaling networks that could provide useful targets in challenging this aggressive neoplasm by innovative therapies.


Assuntos
Neoplasias Ósseas/metabolismo , Fator de Transcrição E2F1/metabolismo , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/fisiologia , Western Blotting , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Proliferação de Células , Criança , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição E2F1/genética , Eletroforese em Gel Bidimensional , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Osteossarcoma/genética , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/deficiência , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
6.
Cancer Genomics Proteomics ; 5(1): 63-78, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18359981

RESUMO

The human osteosarcoma U2OS cell line is one of the first generated cell lines and is used in various areas of biomedical research. Knowledge of its protein expression is limited and no comprehensive study on the proteome of this cell line has been reported to date. Proteomics technology was used in order to analyse the proteins of the U2OS cell line. Total protein extracts were separated by two-dimensional gel electrophoresis (2-DE) and analysed by matrix-assisted laser desorption ionisation-mass spectrometry (MALDI-MS) and MALDI--MS-MS following in-gel digestion with trypsin and, finally, protein identification was carried out by peptide mass fingerprint (PMF) and post source decay (PSD), respectively. Approximately 3,000 spots were excised from two 2-DE gels and were analysed, resulting in the identification of 237 different gene products. The majority of the identified proteins were enzymes, regulatory proteins and RNA-associated proteins, while leukocyte markers and oncogenes were also present. Our findings include 11 protooncogenes (FKBP4, SRC8, PSD10, FUBP1, PARK7, NPM, PDIA1, OXRP, SET, TCTP and GRP75) related to the cancerous state of the U2OS cell line. The U2OS 2-DE database provides the basis for future protein studies.


Assuntos
Neoplasias Ósseas/química , Proteínas de Neoplasias/análise , Osteossarcoma/química , Proteoma/química , Adolescente , Linhagem Celular Tumoral , Bases de Dados de Proteínas , Eletroforese em Gel Bidimensional , Feminino , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
7.
Nature ; 444(7119): 633-7, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17136093

RESUMO

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.


Assuntos
Transformação Celular Neoplásica/genética , Senescência Celular/genética , Dano ao DNA , Oncogenes , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular , Ciclina E/genética , Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , DNA , Replicação do DNA , Genes mos , Humanos , Camundongos , Invasividade Neoplásica/genética , Proteínas Nucleares/genética , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia
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