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Damasceno N.R.T.,University of Sao Paulo | Sala-Vila A.,CIBER ISCIII | Cofan M.,CIBER ISCIII | Perez-Heras A.M.,CIBER ISCIII | And 12 more authors.
Atherosclerosis | Year: 2013

Objective: The PREDIMED trial showed that Mediterranean diets supplemented with either extra-virgin olive oil or nuts reduced incident cardiovascular events compared to a control diet. Consumption of both supplemental foods has been associated with reduced LDL-cholesterol, but it is unknown whether they can shift lipoprotein subfractions to a less atherogenic pattern. We investigated changes in adiposity and lipoprotein subfractions after consumption of the PREDIMED diets. Methods: In a PREDIMED sub-cohort (n=169), lipoprotein subclasses (particle concentrations and size) were determined by nuclear magnetic resonance spectroscopy at baseline and after intervention for 1 year. Results: Participants allocated to the Mediterranean diet supplemented with nuts showed significant reductions from baseline of waist circumference (mean [95% CI];-5cm [-7;-3]) and concentrations of medium-small (-27nmol/l [-46;-8]) and very small LDL (-111nmol/l [-180;-42]); decreased LDL particle number (a nuclear magnetic resonance-specific measurement) (-98nmol/l [-184;-11]); and an increase of large LDL concentrations (54nmol/l [18; 90]), with a net increase (0.2nmol/l [0.1; 0.4]) of LDL size. The Mediterranean diets with olive oil and nuts increased large HDL concentrations (0.6μM [0.0; 1.1] and 1.0μM [0.4; 1.5], respectively). Compared to the other two intervention groups, participants in the nut-enriched diet showed significantly reduced waist circumference (p≤0.006, both) and increased LDL size (p<0.05, both). Conclusion: Lipoprotein subfractions are shifted to a less atherogenic pattern by consumption of Mediterranean diets enriched with nuts. The results contribute mechanistic evidence for the reduction of cardiovascular events observed in the PREDIMED trial. © 2013 Elsevier Ireland Ltd.

Forn M.,Institute of Predictive and Personalized Medicine of Cancer IMPPC | Diez-Villanueva A.,Institute of Predictive and Personalized Medicine of Cancer IMPPC | Merlos-Suarez A.,Barcelona Institute for Research in Biomedicine | Munoz M.,Institute of Predictive and Personalized Medicine of Cancer IMPPC | And 7 more authors.
PLoS ONE | Year: 2015

Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of tumorigenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2high), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of tumorigenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes associated with the intestinal stem cell signature and the PRC2 complex. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+ mice, but at lower levels than advanced cancers. This study provides a reference framework to decipher the mechanisms driving mouse intestinal tumorigenesis and also the human counterpart. © 2015 Forn et al.

Forn M.,Institute of Predictive and Personalized Medicine of Cancer IMPPC | Munoz M.,Institute of Predictive and Personalized Medicine of Cancer IMPPC | Tauriello D.V.F.,Barcelona Institute for Research in Biomedicine | Merlos-Suarez A.,Barcelona Institute for Research in Biomedicine | And 6 more authors.
Molecular Oncology | Year: 2013

DNA methylation and chromatin remodeling are frequently implicated in the silencing of genes involved in carcinogenesis. Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types. However, it is unknown whether there is a coordinated regulation of the genes embedded in these regions in normal cells and in early stages of tumor progression. To better characterize the molecular events associated with the regulation and remodeling of these regions we analyzed two regions undergoing LRES in human colon cancer in the mouse model. We demonstrate that LRES also occurs in murine cancer invivo and mimics the molecular features of the human phenomenon, namely, downregulation of gene expression, acquisition of inactive histone marks, and DNA hypermethylation of specific CpG islands. The genes embedded in these regions showed a dynamic and autonomous regulation during mouse intestinal cell differentiation, indicating that, in the framework considered here, the coordinated regulation in LRES is restricted to cancer. Unexpectedly, benign adenomas in ApcMin/+ mice showed overexpression of most of the genes affected by LRES in cancer, which suggests that the repressive remodeling of the region is a late event. Chromatin immunoprecipitation analysis of the transcriptional insulator CTCF in mouse colon cancer cells revealed disrupted chromatin domain boundaries as compared with normal cells. Malignant regression of cancer cells by invitro differentiation resulted in partial reversion of LRES and gain of CTCF binding. We conclude that genes in LRES regions are plastically regulated in cell differentiation and hyperproliferation, but are constrained to a coordinated repression by abolishing boundaries and the autonomous regulation of chromatin domains in cancer cells. © 2013 Federation of European Biochemical Societies.

Loading Institute Hospital del Mar dInvestigacio Medica IMIM collaborators
Loading Institute Hospital del Mar dInvestigacio Medica IMIM collaborators