Gomez-Uriz, A.M. (Ana María)
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- Abnormal Distribution and Function of Circulating Monocytes and Enhanced Bacterial Translocation in Major Depressive Disorder(Frontiers Media SA, 2019) Gomez-Uriz, A.M. (Ana María); Díaz-Valle, D. (David); Álvarez-Mon, M. (Melchor); Monserrat, J. (Jorge); Lahera, G. (G.); Álvarez-Mon, M.Á. (Miguel Ángel); Aubá-Guedea, E. (Enrique); Sosa, M.D. (Maria Dolores); Orozco, A. (Arancha); Albillos, A. (Agustín)Introduction: Major depressive disorder (MDD) patients experience a systemic inflammatory stage. Monocytes play an important role in innate inflammatory responses and may be modulated by bacterial translocation. Our aim was to investigate the subset distribution and function of circulating monocytes, levels of proinflammatory cytokines, gut barrier damage, and bacterial translocation in MDD patients. Methods: Twenty-two MDD patients without concomitant diseases and 14 sex- and age-matched healthy controls were studied. The levels of circulating CD14++CD16- (classical), CD14++CD16++ (intermediate) and CD14- CD16++ (nonclassical) monocytes and the intracytoplasmic tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 expression in the presence or absence of lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. The serum TNF-α, IL-1β, IL-6, and IL-10 levels were measured by Luminex. LPS-binding protein (LBP), intestinal fatty acidbinding protein (I-FABP), and zonulin were measured by enzyme-linked immunosorbent assay (ELISA). Results: MDD patients had a significant increase in the frequency of intermediate monocytes and a significant decrease in the frequency of classical monocytes compared to those in the healthy controls. MDD patients had a significantly increased percentage of classical monocytes that expressed IL-1β, intermediate monocytes that expressed IL-1β and IL6 and nonclassical monocytes that expressed IL-1β, and decreased levels of nonclassical monocytes that expressed IL6 compared to those in the healthy controls. MDD patients had significantly increased levels of circulating TNF-α, IL-1β, LBP, and I-FABP compared to those in the healthy controls. MDD patients with high LBP levels had a significant reduction in the number of circulating monocytes compared to that in the normal-LBP MDD patients, which can be mainly ascribed to a decrease in the number of intermediate and nonclassical monocytes. Conclusions: We have demonstrated that compared to the healthy controls, MDD patients show a marked alteration in circulating monocytes, with an expansion of the intermediate subset with increased frequency of IL-1β and IL-6 producing cells. These patients also exhibited a systemic proinflammatory state, which was characterized by the enhanced serum TNF-α and IL-1β levels compared to those in the healthy controls. Furthermore, MDD patients showed increased LBP and I-FABP levels compared to those in healthy controls, indicating increased bacterial translocation and gut barrier damage.
- Obesity and ischemic stroke modulate the methylation levels of KCNQ1 in white blood cells(Oxford University Press, 2015) Martinez, J.A. (José Alfredo); Gomez-Uriz, A.M. (Ana María); Blazquez, V. (Vanessa); De-Arce, A. (Ana); Milagro-Yoldi, F.I. (Fermín Ignacio); Goyenechea, E. (Estíbaliz); Cordero, P. (Paul); Mansego-Talavera, M.L. (María Luisa); Martinez-Zabaleta, M. (Maite); Abete, I. (Itziar); Campión-Zabalza, J. (Javier); Lopez-de-Munain, A. (Adolfo)ABSTRACT Obesity and stroke are multifactorial diseases in which genetic, epigenetic and lifestyle factors are involved. The research aims were, first, the description of genes with differential epigenetic regulation obtained by an “omics” approach in patients with ischemic stroke and, second, to determine the importance of some regions of these selected genes in biological processes depending on the BMI. A case-control study using two populations was designed. The first population consisted of 24 volunteers according to stroke/non-stroke and normal weight/obesity conditions. The second population included 60 stroke patients and 55 controls classified by adiposity. DNA from the first population was analyzed with a methylation microarray, showing 80 CpG sites differentially methylated in stroke and 96 CpGs in obesity, whereas 59 CpGs showed interaction. After validating these data by MassArray Epityper, the promoter region of PM20D1 gene was significantly hypermethylated in stroke patients. One CpG site at CALD1 gene showed an interaction between stroke and obesity. Two CpGs located in the genes WT1 and KCNQ1 were significantly hypermethylated in obese patients. In the second population, KCNQ1 was also hypermethylated in the obese subjects. Two CpGs of this gene were subsequently validated by methylation-sensitive high-resolution melting. Moreover, KCNQ1 methylation levels were associated with plasma KCNQ1 protein concentrations. In conclusion, obesity induced changes in the KCNQ1 methylation pattern which were also dependent on stroke. Furthermore, the epigenetic marks differentially methylated in the stroke patients were dependent on the previous obese state. These DNA methylation patterns could be used as future potential stroke biomarkers.
- Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet(Springer, 2013) Martinez, J.A. (José Alfredo); Gomez-Uriz, A.M. (Ana María); Milagro-Yoldi, F.I. (Fermín Ignacio); Cordero, P. (Paul); Campión-Zabalza, J. (Javier)Non-alcoholic fatty liver disease (NAFLD) is one of the first hepatic manifestations of metabolic syndrome, whose progression can lead to cirrhosis and hepatic carcinoma. Interestingly, methyl donor supplementation could improve obesogenic diet-induced hepatic triglyceride accumulation. The aim of this research is to describe methyl donor effects on a high-fat-sucrose (HFS) diet in both sexes and epigenetic changes induced on fatty acid synthase (FASN) promoter methylation pattern as well as gene expression of NAFLD key metabolic genes. Twenty-four male and 28 female Wistar rats were assigned to three dietary groups: control, HFS, and HFS supplemented with methyl donors (choline, betaine, vitamin B12, and folic acid). After 8 weeks of treatment, somatic, biochemical, mRNA, and epigenetic measurements were performed. Rats fed the HFS diet presented an overweight phenotype and alterations in plasma biochemical measurements. Methyl donor supplementation reverted the HFS-diet-induced hepatic triglyceride accumulation. Analysis of FASN promoter cytosine methylation showed changes in both sexes due to the obesogenic diet at -1,096, -780, -778, and -774 CpG sites with respect to the transcriptional start site. Methyl donor supplementation modified DNA methylation at -852, -833, -829, -743, and -733 CpGs depending on the sex. RT-PCR analysis confirmed that FASN expression tended to be altered in males. Our findings reinforce the hypothesis that methyl donor supplementation can prevent hepatic triglyceride accumulation induced by obesogenic diets in both sexes. Changes in liver gene expression profile and epigenetic-mediated mechanisms related to FASN DNA hypermethylation could be involved in methyl donor-induced NAFLD improvement.
- Identificación de modificaciones epigenéticas como posibles biomarcadores de la obesidad y el ictus.(2016-05-31) Gomez-Uriz, A.M. (Ana María); Milagro-Yoldi, F.I. (Fermín Ignacio); Campión-Zabalza, J. (Javier)DNA methylation is an epigenetic mechanism that regulates gene expression. These epigenetic marks are modified by some pathology such as obesity, and it could be change by stroke. The main objective of this work was to determine the influence of ischemic stroke in the epigenetic pattern of genes involved in cerebrovascular disease and obesity, and their interaction with body mass index and the study of the effect of a hypocaloric diet in these epigenetic changes. In order to realize this objective this work was consisted in a case-control design with four populations. In all populations cases were selected from the Neurology Service of Hospital Donostia, with a first episode of ischemic stroke, evaluated in the first 24 hours for a neurologist of the onset of symptoms. The control groups were constituted by non-vascular neurological disorder patients that were matched by sex and age with the cases. Cases and controls were divided in bothgroups using the BMI classification criteria proposed by the WHO. In the first place it was studied the changes in epigenetic profile of human tumor necrosis factor (TNFα) and paraoxonase (PON) promoters and the relationship with the susceptibility to stroke when considering body composition and dietary intake. In the other hand, it was raised to describe candidate genes with differential epigenetic regulation in patients with ischemic stroke and, to determine the importance of some regions of these candidate genes in different biological processes mediated by BMI. Fist an array was realized and the results were validated with this population and the methylation from regions of four genes was measured in other 115 individuals (PM20D1, CALD1, WT1 and KCNQ1). Modifications in KCNQ1 region was observed and translated in changes of the protein levels. Finally 40 obese patients with and without previous ischemic stroke was included in a 20 week nutritional intervention. Methylation levels of WT1 and KCNQ1 regions were measured, at the beginning and at the end of the treatment. It was observed changes in methylation levels and inflammatory response biomarkers produced by the hypocaloric diet. It can be concluded in general that an ischemic stroke modifies the epigenetic pattern of genes involved in cerebrovascular and metabolic diseases. These changes are depended of previous BMI. In particular, KCNQ1, methylation and secretion levels are revealed as a promising biomarker for stroke and obesity.
- A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet-induced weight loss(Federation of American Society of Experimental Biology, 2011) Martinez, J.A. (José Alfredo); Gomez-Uriz, A.M. (Ana María); Zulet, M.A. (María Ángeles); Milagro-Yoldi, F.I. (Fermín Ignacio); Goyenechea, E. (Estíbaliz); Cordero, P. (Paul); Abete, I. (Itziar); Campión-Zabalza, J. (Javier)Epigenetics could help to explain individual differences in weight loss after an energy-restriction intervention. Here, we identify novel potential epigenetic biomarkers of weight loss, comparing DNA methylation patterns of high and low responders to a hypocaloric diet. Twenty-five overweight or obese men participated in an 8-wk caloric restriction intervention. DNA was isolated from peripheral blood mononuclear cells and treated with bisulfite. The basal and endpoint epigenetic differences between high and low responders were analyzed by methylation microarray, which was also useful in comparing epigenetic changes due to the nutrition intervention. Subsequently, MALDI-TOF mass spectrometry was used to validate several relevant CpGs and the surrounding regions. DNA methylation levels in several CpGs located in the ATP10A and CD44 genes showed statistical baseline differences depending on the weight-loss outcome. At the treatment endpoint, DNA methylation levels of several CpGs on the WT1 promoter were statistically more methylated in the high than in the low responders. Finally, different CpG sites from WT1 and ATP10A were significantly modified as a result of the intervention. In summary, hypocaloric-diet-induced weight loss in humans could alter DNA methylation status of specific genes. Moreover, baseline DNA methylation patterns may be used as epigenetic markers that could help to predict weight loss.