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1. Fish intake is associated with lower cardiovascular risk in a Mediterranean population: Prospective results from the Moli-sani study

Author

Iacoviello, L., Donati, M.B., de Gaetano, G., Vermylen, J., De Paula Carrasco, I., Giampaoli, S., Spagnuolo, A., Assanelli, D., Centritto, V., Spagnuolo, P., Staniscia, D., Zito, F., Bonanni, A., Cerletti, C., De Curtis, A., Di Castelnuovo, A., Lorenzet, R., Mascioli, A., Olivieri, M., Rotilio, D., Bonaccio, M., Costanzo, S., Gianfagna, F., Giacci, M., Padulo, A., Petraroia, D., Magnacca, S., Marracino, F., Spinelli, M., Silvestri, C., dell’Elba, G., Grippi, C., De Lucia, F., Vohnout, B., Persichillo, M., Verna, A., Di Lillo, M., Di Stefano, I., Pampuch, A., Pannichella, A., Vizzarri, A.R., Arcari, A., Barbato, D., Bracone, F., Di Giorgio, C., Panebianco, S., Chiovitti, A., Caccamo, S., Caruso, V., Rago, L., Cugino, D., Ferri, A., Castaldi, C., Mignogna, M., Guszcz, T., di Giuseppe, R., Barisciano, P., Buonaccorsi, L., Centritto, F., Cutrone, A., Fanelli, F., Santimone, I., Sciarretta, A., Sorella, I., Plescia, E., Molinaro, A., Cavone, C., Galuppo, G., D'Angelo, D., Ramacciato, R., and Ruggiero, E.

Published
2017
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8. ZBTB12 DNA methylation is associated with coagulation- and inflammation-related blood cell parameters: findings from the Moli-family cohort

Author

Noro, F., Gianfagna, F., Gialluisi, A., De Curtis, A., Di Castelnuovo, A., Napoleone, E., Cerletti, C., Donati, M. B., de Gaetano, G., Hoylaerts, M. F., Iacoviello, L., Izzi, B., Vohnout, B., Arca, M., Lorenzet, R., di Castelnuovo, A., Costanzo, S., di Giuseppe, R., Cutrone, A., Magnacca, S., Crescente, M., Pampuch, A., Tamburrelli, C., Zurlo, F., and Nanni, L.

Subjects
Male, 0301 basic medicine, Myocardial Infarction, Cohort Studies, Pathogenesis, Blood cell, Leukocyte Count, 0302 clinical medicine, PLATELET, Genetics (clinical), Genetics & Heredity, DNA methylation, Granulocyte counts, White blood cell counts, Whole blood coagulation time, Zinc fingers, Cardiovascular risk, Principal Component Analysis, DNA methylation, TRANSCRIPTIONAL REGULATION, Methylation, Middle Aged, Blood Coagulation Factors, DNA-Binding Proteins, MEDITERRANEAN DIET, Haematopoiesis, Granulocyte counts, Zinc fingers, medicine.anatomical_structure, Oncology, CpG site, MONOCYTES, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Adult, Biology, Granulocyte, REGION, Young Adult, 03 medical and health sciences, ADHERENCE, White blood cell, Cardiovascular risk, White blood cell counts, Whole blood coagulation time, Genetics, medicine, Humans, Blood Coagulation, Molecular Biology, Science & Technology, Tumor Necrosis Factor-alpha, Research, 030104 developmental biology, TISSUE FACTOR, Immunology, CpG Islands, Granulocytes, Transcription Factors, Developmental Biology
Abstract

Background Zinc finger and BTB domain-containing protein 12 (ZBTB12) is a predicted transcription factor with potential role in hematopoietic development. Recent evidence linked low methylation level of ZBTB12 exon1 to myocardial infarction (MI) risk. However, the role of ZBTB12 in the pathogenesis of MI and cardiovascular disease in general is not yet clarified. We investigated the relation between ZBTB12 methylation and several blood parameters related to cardio-cerebrovascular risk in an Italian family-based cohort. Results ZBTB12 methylation was analyzed on white blood cells from the Moli-family cohort using the Sequenom EpiTYPER MassARRAY (Agena). A total of 13 CpG Sequenom units were analyzed in the small CpG island located in the only translated ZBTB12 exon. Principal component analysis (PCA) was performed to identify groups of CpG units with similar methylation estimates. Linear mixed effect regressions showed a positive association between methylation of ZBTB12 Factor 2 (including CpG units 8, 9–10, 16, 21) and TNF-ɑ stimulated procoagulant activity, a measure of procoagulant and inflammatory potential of blood cells. In addition, we also found a negative association between methylation of ZBTB12 Factor 1 (mainly characterized by CpG units 1, 3–4, 5, 11, and 26) and white blood cell and granulocyte counts. An in silico prediction analysis identified granulopoiesis- and hematopoiesis-specific transcription factors to potentially bind DNA sequences encompassing CpG1, CpG3–4, and CpG11. Conclusions ZBTB12 hypomethylation is linked to shorter TNF-ɑ stimulated whole blood coagulation time and increased WBC and granulocyte counts, further elucidating the possible link between ZBTB12 methylation and cardiovascular disease risk. Electronic supplementary material The online version of this article (10.1186/s13148-019-0665-6) contains supplementary material, which is available to authorized users.

Published
2019

9. Variation of PEAR1 DNA methylation influences platelet and leukocyte function

Author

Izzi, B., Gianfagna, F., Yang, W. -Y., Cludts, K., De Curtis, A., Verhamme, P., Di Castelnuovo, A., Cerletti, C., Donati, M. B., De Gaetano, G., Staessen, J. A., Hoylaerts, M. F., Iacoviello, L., Vohnout, B., Arca, M., Lorenzet, R., Costanzo, S., Di Giuseppe, R., Cutrone, A., Magnacca, S., Crescente, M., Pampuch, A., Tamburrelli, C., Napoleone, E., Zurlo, F., and Nanni, L.

Subjects
Adult, Blood Platelets, Male, 0301 basic medicine, medicine.medical_specialty, Population, Receptors, Cell Surface, DNA methylation, leukocyte function, platelet, PEAR1, 030204 cardiovascular system & hematology, Biology, Epigenesis, Genetic, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Leukocytes, Genetics, medicine, Humans, Platelet, Platelet activation, Epigenetics, education, Molecular Biology, Genetics (clinical), epidemiology, public health, epigenetics, platelet aggregation, inflammation, education.field_of_study, Research, Platelet Distribution Width, Methylation, DNA Methylation, Middle Aged, Blood Cell Count, Pedigree, 030104 developmental biology, Endocrinology, Italy, CpG site, Moli-family Investigators, DNA methylation, Female, Developmental Biology
Abstract

BackgroundPlatelet-endothelial aggregation receptor 1 (PEAR-1) is a transmembrane receptor involved in platelet activation and megakaryopoiesis whose expression is driven by DNA methylation.PEAR1variants were associated with differential platelet response to activation and cardiovascular outcomes. We aimed at investigating the link betweenPEAR1methylation and platelet and leukocyte function markers in a family-based population.ResultsWe measuredPEAR1methylation in 605 Moli-family participants with available blood counts, plasma P-selectin and C-reactive protein, whole blood platelet P-selectin, and platelet-leukocyte mixed conjugate measurements. We performed principal component analysis (PCA) to identify groups of highly correlated CpG sites. We used linear mixed regression models (using age, gender, BMI, smoking, alcohol drinking, being a proband for family recruitment, being a member of myocardial infarction (MI) family as fixed effects, and family as a random effect) to evaluate associations betweenPEAR1methylation and phenotypes.PEAR1methylation Factor2, characterized by the previously identified megakaryocyte-specific CpG sites, was inversely associated with platelet-monocyte conjugates, P-selectin, and WBC counts, while positively associated with the platelet distribution width (PDW) and with leukocyte CD11b and L-selectin. Moreover,PEAR1Factor2 methylation was negatively associated with INFLAscore, a low-grade inflammation score. The latter was partially mediated by thePEAR1methylation effect on platelet variables.PEAR1methylation association with WBC measurements and INFLAscore was confirmed in the independent cohort FLEMENGHO.ConclusionsWe report a significant link between epigenetic signatures in a platelet functional gene and inflammation-dependent platelet function variability measured in two independent cohorts.

Published
2019

13. A score of low-grade inflammation and risk of mortality: prospective findings from the Moli-sani study

Author

Bonaccio, M., Di Castelnuovo, A., Pounis, G., De Curtis, A., Costanzo, S., Persichillo, M., Cerletti, C., Donati, M. B., De Gaetano, G., Iacoviello, L., Vermylen, J., Carrasco, I. P., Giampaoli, S., Spagnuolo, A., Assanelli, D., Centritto, V., Spagnuolo, P., Staniscia, D., Zito, F., Bonanni, A., Lorenzet, R., Mascioli, A., Olivieri, M., Rotilio, D., Gianfagna, F., Giacci, M., Padulo, A., Petraroia, D., Marracino, F., Spinelli, M., Silvestri, C., De Lucia, F., Vohnout, B., Coordinator, G., Verna, A., Di Lillo, M., Di Stefano, I., Pannichella, A., Vizzarri, A. R., Pampuch, A., Arcari, A., Barbato, D., Bracone, F., Di Giorgio, C., Magnacca, S., Panebianco, S., Chiovitti, A., Caccamo, S., Caruso, V., Rago, L., Cugino, D., Ferri, A., Castaldi, C., Mignogna, M., Guszcz, T., Di Giuseppe, R., Barisciano, P., Buonaccorsi, L., Centritto, F., Cutrone, A., Fanelli, F., Santimone, I., Sciarretta, A., Sorella, I., Plescia, E., Molinaro, A., Cavone, C., Galuppo, G., D'Angelo, D., Ramacciato, R., and Molise, A. S. R. D.

Subjects
Adult, Male, Risk, 0301 basic medicine, medicine.medical_specialty, Population, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, Cause of Death, Internal medicine, Epidemiology, medicine, Risk of mortality, Humans, Prospective Studies, Risk factor, education, Prospective cohort study, Aged, Cause of death, Aged, 80 and over, Inflammation, education.field_of_study, business.industry, Hazard ratio, Hematology, Middle Aged, Surgery, 030104 developmental biology, Quartile, Female, business, Biomarkers, Follow-Up Studies
Abstract

Low-grade inflammation is associated with an increased risk of chronic degenerative disease, but its relationship with mortality is less well explored. We aimed at evaluating, at a large epidemiological level, the possible association of low-grade inflammation, as measured by a composite score, with overall mortality risk. We conducted a population-based prospective investigation on 20,337 adult subjects free from major hematological disease and acute inflammatory status, randomly recruited from the general population of the Moli-sani study. A low-grade inflammation score was obtained from the sum of 10-tiles of plasmatic (C-reactive protein) and cellular (leukocyte and platelet counts, granulocyte/lymphocyte ratio) biomarkers of low-grade inflammation; higher levels indicated increased low-grade inflammation. Hazard ratios were calculated using multivariable Cox proportional hazard models with 95% confidence intervals. At the end of follow-up (median 7.6 years), 837 all-cause deaths were recorded. As compared to subjects in the lowest quartile of the low-grade inflammation score, those in the highest category had a significantly increased risk in overall mortality (HR=1.44; 1.17-1.77), independently of possible confounders, including the presence of chronic diseases and a number of health-related behaviors. The magnitude of the association of low-grade inflammation with mortality was relatively higher in type 2 diabetic patients (HR=2.90; 1.74-4.84) and in individuals with a history of cardiovascular disease (HR=2.48; 1.50-4.11) as compared to their counterparts who were free from the disease. In conclusion, an elevated degree of low-grade inflammation, as measured by a composite score of inflammatory biomarkers, is an independent risk factor for total mortality in an apparently healthy adult general population.

Published
2016

14. Fish intake is associated with lower cardiovascular risk in a Mediterranean population: Prospective results from the Moli-sani study

Author

Bonaccio, M., primary, Ruggiero, E., additional, Di Castelnuovo, A., additional, Costanzo, S., additional, Persichillo, M., additional, De Curtis, A., additional, Cerletti, C., additional, Donati, M.B., additional, de Gaetano, G., additional, Iacoviello, L., additional, Vermylen, J., additional, De Paula Carrasco, I., additional, Giampaoli, S., additional, Spagnuolo, A., additional, Assanelli, D., additional, Centritto, V., additional, Spagnuolo, P., additional, Staniscia, D., additional, Zito, F., additional, Bonanni, A., additional, Lorenzet, R., additional, Mascioli, A., additional, Olivieri, M., additional, Rotilio, D., additional, Bonaccio, M., additional, Gianfagna, F., additional, Giacci, M., additional, Padulo, A., additional, Petraroia, D., additional, Magnacca, S., additional, Marracino, F., additional, Spinelli, M., additional, Silvestri, C., additional, dell’Elba, G., additional, Grippi, C., additional, De Lucia, F., additional, Vohnout, B., additional, Verna, A., additional, Di Lillo, M., additional, Di Stefano, I., additional, Pampuch, A., additional, Pannichella, A., additional, Vizzarri, A.R., additional, Arcari, A., additional, Barbato, D., additional, Bracone, F., additional, Di Giorgio, C., additional, Panebianco, S., additional, Chiovitti, A., additional, Caccamo, S., additional, Caruso, V., additional, Rago, L., additional, Cugino, D., additional, Ferri, A., additional, Castaldi, C., additional, Mignogna, M., additional, Guszcz, T., additional, di Giuseppe, R., additional, Barisciano, P., additional, Buonaccorsi, L., additional, Centritto, F., additional, Cutrone, A., additional, Fanelli, F., additional, Santimone, I., additional, Sciarretta, A., additional, Sorella, I., additional, Plescia, E., additional, Molinaro, A., additional, Cavone, C., additional, Galuppo, G., additional, D'Angelo, D., additional, and Ramacciato, R., additional

Published
2017
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15. Nutrition knowledge is associated with higher adherence to Mediterranean diet and lower prevalence of obesity. Results from the Moli-sani study

Author

Bonaccio, M, Di Castelnuovo, A, Costanzo, S, De Lucia, F, Olivieri, M, Donati, Mb, de Gaetano, G, Iacoviello, L, Bonanni, A, Giampaoli, S, Vermylen, J, Carrasco Ide, P, Garaci, E, Assanelli, D, Alessandrini, F, Centritto, V, Storti, S, Muti, P, Schünemann, H, Spagnuolo, P, Staniscia, D, Zito, F, Cerletti, C, De Curtis, A, Lorenzet, R, Mascioli, A, Rotilio, D, Arcari, A, Centritto, F, di Giuseppe, R, Gianfagna, F, Giacci, M, Padulo, A, Petraroia, D, Magnacca, S, Marracino, F, Spinelli, M, Silvestri, C, Vallese, C, Cugino, D, de Gaetano, M, Graziano, M, Santimone, Iolanda, Latella, Mc, Quacquaruccio, G, Vohnout, B, Havranova, A, Cutrone, A, Persichillo, M, Verna, A, Di Lillo, M, Di Stefano, I, Pannichella, A, Vizzarri, Ar, Pampuch, A, Barbato, D, Bracone, F, Di Giorgio, C, Panebianco, S, Chiovitti, A, Caccamo, S, Caruso, V, Rago, L, Ferri, A, Castaldi, C, Mignogna, M, Guszcz, T, Barisciano, P, Buonaccorsi, L, Fanelli, F, Santimone, I, Sciarretta, A, Sorella, I, Plescia, E, Molinaro, A, Cavone, C, Galuppo, G, D'Angelo, D, and Ramacciato, R.

Subjects
Gerontology, Adult, Male, Health Knowledge, Attitudes, Practice, Psychology (all), Mediterranean diet, Cross-sectional study, Population, Health Behavior, Mediterranean, Diet, Mediterranean, Cohort Studies, Environmental health, Surveys and Questionnaires, Nutrition knowledge, Odds Ratio, Prevalence, Medicine, Humans, Nutritional Physiological Phenomena, Obesity, education, Socioeconomic status, General Psychology, education.field_of_study, Principal Component Analysis, Practice, Nutrition and Dietetics, business.industry, Health Knowledge, Odds ratio, Feeding Behavior, medicine.disease, Diet, Cross-Sectional Studies, Female, Italy, Attitudes, Cohort, business, Cohort study
Abstract

A Mediterranean dietary pattern has been associated with reducing the risk of cardiovascular and chronic disease. The aim of this study was to evaluate the role of nutrition knowledge in determining possible differences among dietary patterns in a general population from a Mediterranean region. We conducted a cross-sectional study on a subsample of 744 subjects enrolled in the population-based cohort of the Moli-sani Project. A 92-item questionnaire on nutrition knowledge was elaborated, validated and administered. Dietary information were obtained from the EPIC food frequency questionnaire and adherence to a Mediterranean dietary pattern was evaluated both by the a priori Greek Mediterranean diet score and the a posteriori approach obtained by principal component analysis. Nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern. The odds of having higher adherence to a Mediterranean dietary pattern increased with greater nutrition knowledge. The odds ratio of being obese significantly decreased with increasing nutrition knowledge levels. The results showed that nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern and with lower prevalence of obesity in a Southern Italian region with Mediterranean diet tradition independently from education and other socioeconomic factors.

Published
2013

19. Genetic regulation of inflammation-mediated haemostasis activation: a family-based approach

Author

Iacoviello, Licia, Vohnout, B., Gianfagna, Francesco, Di Castelnuovo, A., Nanni, L., Napoleone, E., Crescente, M., De Curtis, A., Cutrone, A., Tamburrelli, C., Zurlo, F., Lorenzet, R., Cerletti, C., Arca, M., de Gaetano, G., and Donati, M. B.

Subjects
Epidemiology, Risk Factors, genetics, Risk Factors, Inflammation Mediators, Blood Coagulation, genetics
Published
2009

27. TISSUE FACTOR GENE TAG-SNPS AND HAPLOTYPES AND THE RISK OF MYOCARDIAL INFARCTION

Author

Quaquaruccio, G., primary, Latella, M., additional, Graziano, M., additional, Di Castelnuovo, A., additional, Lorenzet, R., additional, Napoleone, E., additional, Giannuzzi, P., additional, Gattone, M., additional, Assanelli, D., additional, Novak, N., additional, Trevisan, M., additional, de Gaetano, G., additional, Donati, M.B., additional, and Iacoviello, L., additional

Published
2007
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30. Polymorphisms of the Interleukin-1β Gene Affect the Risk of Myocardial Infarction and Ischemic Stroke at Young Age and the Response of Mononuclear Cells to Stimulation In Vitro

Author

Iacoviello, L., primary, Di Castelnuovo, A., additional, Gattone, M., additional, Pezzini, A., additional, Assanelli, D., additional, Lorenzet, R., additional, Del Zotto, E., additional, Colombo, M., additional, Napoleone, E., additional, Amore, C., additional, D’Orazio, A., additional, Padovani, A., additional, de Gaetano, G., additional, Giannuzzi, P., additional, and Donati, M.B., additional

Published
2005
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37. Direct Induction of tissue factor synthesis by endotoxin in human macrophages from diverse anatomical sites.

Author

Semeraro, N., Blondi, A., Lorenzet, R., Locati, D., Mantovani, A., and Donati, M. B.

Subjects
KILLER cells, MACROPHAGES, ENDOTOXINS, LEUCOCYTES, MONOCYTES, BLOOD plasma, SALMONELLA, FOOD poisoning
Abstract

On exposure to endotoxin and other stimuli, human peripheral-blood mononuclear cells generate a potent procoagulant activity (PCA), identified as tissue factor. Although it is now recognized that the monocytes are the source of PCA, the question whether these cells per se are capable of procoagulant response to endotoxin or require lymphocyte collaboration remains unsettled. We have investigated the capacity of highly purified human macrophages from diverse anatomical sites to generate PCA following endotoxin stimulation. Purified (>99%) monocyte- derived macrophages were obtained by prolonged (3-10 days) in-vitro culture of adherent monocytes using medium supplemented with 50% human serum. Purified (> 99%) peritoneal and milk macrophages were isolated by adherence to plastic. PCA was measured before and after incubation (4 hr at 37°) with endotoxin (Salmonella enreritidis LPS, W or Escherichits coli O111:B4 LPS, W, 1 μg/mI final concentration) using a one-stage clotting assay and/or a two-stage amidolytic assay. Monocyte-derived macrophages had low baseline PCA (14-19 units/105 cells) but, upon exposure to endotoxin, displayed an eight-fold increase in PCA over control. Peritoneal and milk macrophages expressed very low baseline activity (1-5 units/ 105 cells). The latter, however, increased 15-20 times over control following endotoxin stimulation. PCA was identified as tissue factor by biological and immunological criteria. Its generation was completely abolished by cycloheximide. It is concluded that in the human mononuclear phagocyte series the capacity to produce PCA is not restricted to circulating monocytes but is also expressed by macrophages obtained from diverse anatomical sites. These macrophages appear to be autonomous in their procoagulant response to endotoxin. [ABSTRACT FROM AUTHOR]

Published
1983

40. Occurrence of disseminated intravascular coagulation in rat BNML leukaemia despite lack of leucocyte procoagulant activity

Author

Colucci, M., Lorenzet, R., Locati, D., Semeraro, N., and Maria Benedetta Donati

Subjects
Male, Leukemia, Experimental, Rats, Inbred BN, Leukocytes, Animals, Disseminated Intravascular Coagulation, Research Article, Rats
Abstract

Signs of disseminated intravascular clotting were observed during the development of BNML myelomonocytic leukaemia in rats, when the peripheral leucocyte count exceeded 20,000/microliters and more than 50% blasts were present in the circulation. BNML cells, harvested from blood and tested in appropriate systems, were found devoid of any procoagulant activity (PCA) even following prolonged in vitro incubation with endotoxin. Thus, it appears that these rat leukaemic cells share the same inability to express PCA which had been previously described in peripheral blood mononuclear cells from normal rats. Conceivably, in this rat model, leucocyte PCA does not represent a major trigger of intravascular coagulation and blood clotting is initiated by other, mainly plasmatic, pathways.

Published
1983

48. Circulating Tissue Factor Levels and Risk of Stroke: Findings From the EPICOR Study.

Author

Iacoviello L, Di Castelnuovo A, de Curtis A, Agnoli C, Frasca G, Mattiello A, Matullo G, Ricceri F, Sacerdote C, Grioni S, Tumino R, Napoleone E, Lorenzet R, de Gaetano G, Panico S, and Donati MB

Subjects
Adult, Aged, Brain Ischemia blood, Female, Follow-Up Studies, Humans, Intracranial Hemorrhages blood, Italy, Male, Middle Aged, Prospective Studies, Risk Factors, Stroke blood, Thromboplastin metabolism
Abstract

Background and Purpose: Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort., Methods: Using a nested case-cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35-71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method., Results: Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratioIVvsI quartile, 2.01; 95% confidence interval, 1.25-3.23). The association was independent from several potential confounders (odds ratioIVvsI quartile, 1.91; 95% confidence interval, 1.15-3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratioIVvsI quartile, 2.13; 95% confidence interval, 1.10-4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratioIVvsI quartile, 1.12; 95% confidence interval, 0.49-2.55; fully adjusted model)., Conclusions: Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes., (© 2015 American Heart Association, Inc.)

Published
2015
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49. Both red and blond orange juice intake decreases the procoagulant activity of whole blood in healthy volunteers.

Author

Napoleone E, Cutrone A, Zurlo F, Di Castelnuovo A, D'Imperio M, Giordano L, De Curtis A, Iacoviello L, Rotilio D, Cerletti C, de Gaetano G, Donati MB, and Lorenzet R

Subjects
Adult, Blood Coagulation physiology, Cross-Over Studies, Healthy Volunteers, Humans, Male, Risk Factors, Thromboplastin metabolism, Beverages, Blood Coagulation drug effects, Citrus sinensis, Fruit
Abstract

Aim: Numerous epidemiological studies suggest that exposure to flavonoid-rich fruits has beneficial influence on risk factors for cardiovascular disease. We investigated whether intake of orange juice (OJ) could affect whole blood (WB) procoagulant activity., Methods: 17 healthy subjects (aged 31 ± 1.5 SEM 10 males) were randomized to receive, according to a cross-over design, either red or blond OJ, enriched or free of anthocyanins, respectively. After one week run-in period on a controlled diet, the subjects were randomly allocated to receive either type of OJ for 4 weeks, with a 4-week wash-out period. Venous blood was collected on citrate before and at the end of each treatment period. WB was incubated with or without an inflammatory stimulus (tumor necrosis factor-α or bacterial endotoxin LPS). Procoagulant activity was evaluated by a one-stage clotting assay. Tissue factor (TF) and TF pathway inhibitor (TFPI) were measured in plasma by ELISA., Results: Intake of either type of OJ caused a prolongation of unstimulated and stimulated WB clotting times, without any difference between the two treatments. Intake of OJ did not modify TF levels. On the contrary, an increase in circulating TFPI antigen was detected following either treatment., Conclusions: Orange juice intake by healthy volunteers decreases procoagulant activity, possibly through mechanisms independent of its anthocyanin content., (© 2013.)

Published
2013
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50. Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells.

Author

Napoleone E, Cutrone A, Cugino D, Amore C, Di Santo A, Iacoviello L, de Gaetano G, Donati MB, and Lorenzet R

Subjects
Adenocarcinoma blood supply, Adenocarcinoma metabolism, Adenocarcinoma pathology, Breast Neoplasms blood supply, Breast Neoplasms metabolism, Breast Neoplasms pathology, Captopril pharmacology, Cell Line, Tumor, Down-Regulation, Enalapril pharmacology, Female, Humans, MCF-7 Cells, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Renin-Angiotensin System genetics, Thromboplastin genetics, Thromboplastin metabolism, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Adenocarcinoma drug therapy, Angiotensin-Converting Enzyme Inhibitors pharmacology, Breast Neoplasms drug therapy, Renin-Angiotensin System drug effects, Thromboplastin biosynthesis, Vascular Endothelial Growth Factor A biosynthesis
Abstract

Introduction: The renin-angiotensin system (RAS) promotes angiogenesis and growth of neoplastic cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer. Tissue factor (TF), for its involvement in tumor growth, angiogenesis, and metastasis is considered a hallmark of cancer progression. In this study we evaluated whether RAS blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB-231 cell line., Materials and Methods: Cell TF activity was assessed by one stage clotting time, TF and VEGF antigens and mRNA levels by ELISA and RT-PCR, respectively. AT(1) was detected by flow-cytometry and angiotensin-II levels by EIA., Results: Captopril reduced in a concentration-dependent way both the strong constitutive TF activity (983.2±55.2 vs. 686.7±135.1U/5×10(5) cells with 10μg/ml captopril) and antigen (32.3±5.9 vs. 13.2±6.6ng/ml) in MDA-MB-231. Similar results were observed with enalapril. AT1 was present on cell membrane and losartan, a competitive inhibitor of AT1, reduced TF expression to a degree similar as that exerted by ACE inhibitors. Moreover, captopril and losartan downregulated the constitutive mRNA TF expression by ~35%. Similar results were observed with anti-AT1 and angiotensin II antibodies. In addition, the constitutive VEGF antigen and mRNA levels were reduced in the presence of captopril or losartan, and an anti-VEGF antibody downregulated cell TF activity by ~40%., Conclusions: These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2012
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