RNA expression changes driven by altered epigenetics status related to NASH etiology

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem due to the increased obesity rates, among other factors. In its more severe stage (NASH), inflammation, hepatocellular ballooning and fibrosis are present in the liver, which can further evolve to total liver dysfunction or even hepatocarcinoma. As a metabolic disease, is associated to environmental factors such as diet and lifestyle conditions, which in turn can influence the epigenetic landscape of the cells, affecting to the gene expression profile and chromatin organization. In this study we performed ATAC-sequencing and RNA-sequencing to interrogate the chromatin status of liver biopsies in subjects with and without NASH and its effects on RNA transcription and NASH etiology. NASH subjects showed transcriptional downregulation for lipid and glucose metabolic pathways (e.g., ABC transporters, AMPK, FoxO or insulin pathways). A total of 229 genes were differentially enriched (ATAC and mRNA) in NASH, which were mainly related to lipid transport activity, nuclear receptor-binding, dicarboxylic acid transporter, and PPARA lipid regulation. Interpolation of ATAC data with known liver enhancer regions showed differential openness at 8 enhancers, some linked to genes involved in lipid metabolism, (i.e., FASN) and glucose homeostasis (i.e., GCGR). In conclusion, the chromatin landscape is altered in NASH patients compared to patients without this liver condition. This alteration might cause mRNA changes explaining, at least partially, the etiology and pathophysiology of the disease.Partial funding for open access charge: Universidad de Málaga / CBU

8-oxoguanine DNA glycosylase 1 upregulation as a risk factor for obesity and colorectal cancer

DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)—a DNA repair enzyme—may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants (p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients (p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients (p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.Partial funding for open access charge: Universidad de Málag

Microbiome alterations and Alzheimer's Disease: modeling strategies with transgenic mice.

In the last decade, the role of the microbiota-gut-brain axis has been gaining momentum in the context of many neurodegenerative and metabolic disorders, including Alzheimer's disease (AD) and diabetes, respectively. Notably, a balanced gut microbiota contributes to the epithelial intestinal barrier maintenance, modulates the host immune system, and releases neurotransmitters and/or neuroprotective short-chain fatty acids. However, dysbiosis may provoke immune dysregulation, impacting neuroinflammation through peripheral-central immune communication. Moreover, lipopolysaccharide or detrimental microbial end-products can cross the blood-brain barrier and induce or at least potentiate the neuropathological progression of AD. Thus, after repeated failure to find a cure for this dementia, a necessary paradigmatic shift towards considering AD as a systemic disorder has occurred. Here, we present an overview of the use of germ-free and/or transgenic animal models as valid tools to unravel the connection between dysbiosis, metabolic diseases, and AD, and to investigate novel therapeutical targets. Given the high impact of dietary habits, not only on the microbiota but also on other well-established AD risk factors such as diabetes or obesity, consistent changes of lifestyle along with microbiome-based therapies should be considered as complementary approaches.Partial funding for open access charge: Universidad de Málaga/CBU

Oligodendrocyte metabolism throughout its differentiation: immunocytochemistry study and its impact in remyelination

Introduction: Oligodendrocytes (OL) role in demyelinating pathologies such as multiple sclerosis and other neurodegenerative diseases is only recently being subject of extensive research. While the genetic and molecular aspects have been thoroughly studied, their metabolism was overshadowed. In order to develop new therapies to promote remyelination of already damaged axons, we need to accurately describe how OL metabolism affects axon myelination and trophic support (1). The objective of this study is to obtain cytological evidence of the extent of both glycolytic metabolism and oxidative phosphorylation by immunocytochemistry throughout the development of OL. Methods: Oligodendroglia cells from post-natal mice cortices were obtained and cultured. A wide assortment of differentiation-stage-specific cell surface antigens, a glycolytic and an oxidative phosphorylation marker were combined in several immunofluorescences to study both metabolic pathways in each step of differentiation. Results: After analysing them under confocal microscopy and imaging software, we observed a constant upregulation of glycolytic metabolism throughout differentiation, while oxidative phosphorylation seemed to increase with differentiation to then decrease when oligodendrocytes achieved their final maturation stage. Conclusions: Therefore, oxidative phosphorylation may be crucial in the differentiation of precursors and glycolysis would thus be the preferred metabolic pathway for fully matured OL. [1] Rosko L. et al. Neuroscientist. 2019;25(4):334–43.Supported by UMA and IBIMA and funding from two ongoing projects: - ‘Modulation of oligodendrocyte metabolism via blood vessel remodelling as target to promote remyelination’ (funding by NEURATRIS). - ‘Blood vessel remodelling modulates remyelination by oligodendrocyte metabolic reprogramming’ (funding by Arsep Foundation). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Gastrointestinal Stromal Tumor (GIST) and its relationship with germline mutations

We present the case of a 38-year-old man with a history of abdominal paraganglioma 10 years ago, who consulted for hematemesis and asthenia of 5 days' evolution. An upper gastrointestinal endoscopy was performed where a raised submucosal lesion, about 2 cm, with ulceration on its surface, was observed at the corporal-antral junction. The CT scan revealed nodular thickening of the gastric wall at the level of the lesser curvature. After the resolution of his hematemesis, it was decided to intervene on the patient, performing a partial gastrectomyUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Non‑alcoholic fatty liver disease in patients with morbid obesity: the gut microbiota axis as a potential pathophysiology mechanism

Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy.Funding for open Access charge: Universidad de Málaga / CBUA. This work was supported in part by a grant from the Ministry of Health and Families of Junta de Andalucía (PI-0108-2022). (“A way to make Europe”). This study was co-funded by FEDER funds. I.C.-P. was the recipient of a postdoctoral grant (Río Hortega CM 17/00169), and is now the recipient of a post-doctoral grant (Juan Rodes JR 19/00054) from the Instituto de Salud Carlos III and co-funded by Fondo Europeo de Desarrollo Regional-FEDER. L.G.-S. is supported by the Nicolas Monardes program from Consejería de Salud de Andalucía (Spain) (C-0028-2018). C.G.-R. was supported by the Miguel Servet program from the Instituto de Salud Carlos III (CP20/00066)

Gastrointestinal cancer: Relationship between histology and microbiota

Este trabajo fue presentado como comunicación tipo póster en el citado congreso.Objectives: Review of the published literature concerning the relationship between microbiome and gastrointestinal cancer. Methods: Present work is focused on systematic research in the most prominent biomedical databases finds relevant works in Pubmed and the library’s catalog of the University of Málaga (Jábega) of published journals in the last 5 years. Results: In this work, the mechanisms used by the microbiome to damage gastrointestinal epithelial cells and cause cancer are explained. Some of them are the dysbiosis, destruction of the mucosal barrier, chronic inflammation, damage caused by metabolites produced in the digestion and the direct attack of certain toxins to the cell’s DNA. These mechanisms adjust the immune response, by activation or inhibition using different cytokines. There is also a deeper look into several microorganisms and how they cause gastrointestinal cancer using toxins or virulence factors to activate them. Conclusions: The evidence found so far about the microbiota and gastrointestinal cancer is enough to assume the relationship between them, although there is much left to research. With these findings, it can be expected that in a near future certain microorganisms could be used for screening purposes, due to their increase in early stages of the tumor genesis and also, in a preventive way to try to eradicate them, even avoid cancer. Studies on the microbiota are hardly beginning, and results appear to be promising.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Gazpacho consumption is associated with lower blood pressure and reduced hypertension in a high cardiovascular risk cohort. Cross-sectional study of the PREDIMED trial

Hypertension is a major public health problem and a leading cause of death and disability in both developed and developing countries, affecting onequarter of the world"s adult population. Our aim was to evaluate whether the consumption of gazpacho, a Mediterranean vegetable-based cold soup rich in phytochemicals, is associated with lower blood pressure (BP) and/or reduced prevalence of hypertension in individuals at high cardiovascular risk. Methods and results: We selected 3995 individuals (58% women, mean age 67 y) at high cardiovascular risk (81% hypertensive) recruited into the PREDIMED study. BP, weight, and dietary and physical activity data were collected. In multivariate linear regression analyses, after adjustment, moderate and high gazpacho consumption categories were associated with reduced mean systolic BP of 1.9 mm Hg [95% confidence interval (CI): 3.4; 0.6] and 2.6 mm Hg (CI: 4.2; 1.0), respectively, and reduced diastolic BP of 1.5 mm Hg (CI: 2.3; 0.6) and 1.9 mm Hg (CI: 2.8; 1.1). By multiple-adjusted logistic regression analysis, gazpacho consumption was associated with a lower prevalence of hypertension, with OR Z 0.85 (CI: 0.73; 0.99) for each 250 g/week increase and OR Z 0.73 (CI: 0.55; 0.98) for high gazpacho consumption groups compared to the no-consumption group. Conclusions: Gazpacho consumption was inversely associated with systolic and diastolic BP and prevalence of hypertension in a cross-sectional Mediterranean population at high cardiovascular risk. The association between gazpacho intake and reduction of BP is probably due to synergy among several bioactive compounds present in the vegetable ingredients used to make the recipe

Evaluación del perfil competencial del estudiantado UCM por nivel de iniciativa emprendedora y género. Validación del Modelo Entrecomp de competencias emprendedoras

Examinar la relación entre las competencias emprendedoras propuestas por el Marco Europeo de Competencias Emprendedoras (Entrecomp) y el nivel de intención emprendedora. Se consideran las siguientes variables: sexo, estudios que realiza, si compagina trabajo y estudio, y Universidad en la que estudia

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics