CHD4 ensures stem cell lineage fidelity during skeletal muscle regeneration.

Regeneration of skeletal muscle requires resident stem cells called satellite cells. Here, we report that the chromatin remodeler CHD4, a member of the nucleosome remodeling and deacetylase (NuRD) repressive complex, is essential for the expansion and regenerative functions of satellite cells. We show that conditional deletion of the Chd4 gene in satellite cells results in failure to regenerate muscle after injury. This defect is principally associated with increased stem cell plasticity and lineage infidelity during the expansion of satellite cells, caused by de-repression of non-muscle-cell lineage genes in the absence of Chd4. Thus, CHD4 ensures that a transcriptional program that safeguards satellite cell identity during muscle regeneration is maintained. Given the therapeutic potential of muscle stem cells in diverse neuromuscular pathologies, CHD4 constitutes an attractive target for satellite cell-based therapies.

Well-Being and the Lifestyle Habits of the Spanish Population: The Association between Subjective Well-Being and Eating Habits.

The so-called Mediterranean diet is not simply a collection of foodstuffs but an expression of the culture of the countries of the south of Europe, declared Intangible Cultural Heritage by UNESCO. Despite the link between food and culture, little has been studied about how diet contributes to the well-being of the population. This article aims to analyze the association between subjective well-being and the eating habits of the Spanish population in order to gain a better understanding of the subjective well-being that food culture produces. For this study, we used a representative sample of the Spanish adult population from a survey by the Sociological Research Center (CIS 2017). Three indicators of subjective well-being were used: perceived health, life satisfaction, and feeling of happiness. The independent variables relating to eating habits considered in the analysis were, among others, how often meat, fish, vegetables, fruit, and sweets were consumed; how the food was prepared; how often meals were eaten out at restaurants or cafés and how often they were eaten with family or friends. Other independent variables related to lifestyle habits were also included in the analysis, in particular, physical exercise and body mass index. We used ordinal logistic regressions and multiple linear regression models. Our findings coincide in large measure with those obtained in earlier studies where perceived health and income play a key role in evaluating subjective well-being. In turn, several variables related to lifestyle habits, such as consuming sweets and fruits, social interaction around meals, exercising, and body mass index, were also associated with subjective well-being.

The changing chromatome as a driver of disease: A panoramic view from different methodologies.

Chromatin-bound proteins underlie several fundamental cellular functions, such as control of gene expression and the faithful transmission of genetic and epigenetic information. Components of the chromatin proteome (the "chromatome") are essential in human life, and mutations in chromatin-bound proteins are frequently drivers of human diseases, such as cancer. Proteomic characterization of chromatin and de novo identification of chromatin interactors could, thus, reveal important and perhaps unexpected players implicated in human physiology and disease. Recently, intensive research efforts have focused on developing strategies to characterize the chromatome composition. In this review, we provide an overview of the dynamic composition of the chromatome, highlight the importance of its alterations as a driving force in human disease (and particularly in cancer), and discuss the different approaches to systematically characterize the chromatin-bound proteome in a global manner.

The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation.

Adult hematopoietic stem cells (HSCs) are rare multipotent cells in bone marrow that are responsible for generating all blood cell types. HSCs are a heterogeneous group of cells with high plasticity, in part, conferred by epigenetic mechanisms. PHF19, a subunit of the Polycomb repressive complex 2 (PRC2), is preferentially expressed in mouse hematopoietic precursors. Here, we now show that, in stark contrast to results published for other PRC2 subunits, genetic depletion of Phf19 increases HSC identity and quiescence. While proliferation of HSCs is normally triggered by forced mobilization, defects in differentiation impede long-term correct blood production, eventually leading to aberrant hematopoiesis. At molecular level, PHF19 deletion triggers a redistribution of the histone repressive mark H3K27me3, which notably accumulates at blood lineage-specific genes. Our results provide novel insights into how epigenetic mechanisms determine HSC identity, control differentiation, and are key for proper hematopoiesis.

Social Inequalities in Following Official Guidelines on Healthy Diet During the Period of Economic Crisis in Spain.

In Spanish society, social inequalities continue in connection with diet; however, no data examines whether these inequalities altered during the period of economic crisis. This article aims to analyze trends in inequalities related to adherence to government guidelines concerning healthy diet during the period of economic crisis based on the data obtained from the National Health Surveys conducted by the National Statistics Institute. The approach involves studying first the data from the 2006 survey, shortly before the crisis, and then comparing these with the data from the 2011-2012 survey. Applying models of logistic regression shows that certain social inequalities were accentuated by the crisis. However, the general and widespread pattern of eating habits does not disappear in times of crisis. Inequalities are more commonly seen when socioeconomic factors affect foods that the guidelines indicate should be eaten daily. However, with respect to more expensive products, socioeconomic factors did not have so much negative effect on how far a healthy diet was followed because it is recommended that consumption of these foods should be limited. The results suggest that food policy should have specific focuses during times of economic recession.

Eating out in Spain: Motivations, sociability and consumer contexts.

Eating out is a consumer practice which is difficult to define. The study of this practice has traditionally been based on the work/leisure dichotomy. However, in Spain this is not so clear. If we analyse profiles, motivations, places and relationships, we discover an eating-out food model which is specific to Spain and in which food is not limited by this dual link with work and leisure. Eating linked to work does not respond only to instrumental needs. Leisure eating is not always a choice based on preference. Both contain a strong element of sociability which acts as a motivator and are linked to the familisme of Spanish society, whilst at the same time de-routinizing daily life, both at home and at work. This study is based on a national survey carried out in 2014 and helps to understand this consumer practice and those elements which are specific to Spain.

Human mesenchymal stromal cell lysates as a novel strategy to recover liver function.

AIM: It is unknown if the beneficial effects of mesenchymal stromal cells (MSC) transplantation into the liver are dependent on their anchorage and differentiation into hepatocytes or rather the result of the release of stem cell intracellular content with hepatoprotector properties. MATERIALS & METHODS: The effects of intact MSC transplantation were compared with the infusion of MSC lysates in an experimental rat model of acute liver failure. RESULTS: A more powerful hepatoprotective and antiapoptotic effect was obtained after infusion of MSC lysates than intact MSC. Changes in IL-6 levels and miRNAs might explain the beneficial effects of MSC lysates. CONCLUSION: Infusion of MSC lysates show a better hepatoprotective effect than the transplantation of intact MSC.

Nuclear translocation of ß-catenin during mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.

Wnt/ß-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/ß-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, ß-catenin nuclear translocation, up-regulation of genes related to the Wnt/ß-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/ß-catenin inactivation. Hepatocytes with nuclear translocation of ß-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase ß-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin ß-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/ß-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis.

Cholestatic liver injury following extra- or intrahepatic bile duct obstruction causes nonparenchymal cell proliferation and matrix deposition leading to end-stage liver disease and cirrhosis. In cholestatic conditions, nitric oxide (NO) is mainly produced by a hepatocyte-inducible NO synthase (iNOS) as a result of enhanced inflow of endotoxins to the liver and also by accumulation of bile salts in hepatocytes and subsequent hepatocellular injury. This study was aimed to investigate the role of NO and S-nitrosothiol (SNO) homeostasis in the development of hepatocellular injury during cholestasis induced by bile duct ligation (BDL) in rats. Male Wistar rats (200-250 g) were divided into four groups (n=10 each), including sham-operated (SO), bile duct-ligated (BDL), tauroursodeoxycholic acid (TUDCA, 50 mg/kg) and S-methylisothiourea (SMT, 25 mg/kg) treated. After 7 days, BDL rats showed elevated serum levels of gamma-glutamiltranspeptidase, aspartate aminotransferase, alanine aminotransferase, LDH, and bilirubin, bile duct proliferation and fibrosis, compared with the SO group. TUDCA treatment did not significantly alter these parameters, but the iNOS inhibitor SMT ameliorated hepatocellular injury, as shown by lower levels of circulating hepatic enzymes and bilirubin, and a decreased grade of bile duct proliferation and fibrosis. Both TUDCA and SMT treatments reversed Mrp2 canalicular pump expression to control levels. However, only SMT treatment significantly lowered the increased levels of plasma NO and S-nitrosation (S-nitrosylation) of liver proteins in BDL rats. Moreover, BDL resulted in a reduction of the S-nitrosoglutathione reductase (GSNOR/Adh5) enzymatic activity and a downregulation of the GSNOR/Adh5 mRNA expression that was reverted by SMT, but not TUDCA, treatment. A total of 25 liver proteins, including S-adenosyl methionine synthetase, betaine-homocysteine S-methyltransferase, Hsp90 and protein disulfide isomerase, were found to be S-nitrosated in BDL rats. In conclusion, the inhibition of NO production during induced cholestasis ameliorates hepatocellular injury. This effect is in part mediated by the improvement of cell proficiency in maintaining SNO homeostasis.

Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats.

Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.

IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients.

BACKGROUND: Lipid accumulation and other histological liver markers characterize patients with non-alcoholic steatohepatitis (NASH). The identification of non-invasive prognostic factors of liver steatosis and NASH are relevant for the unravelling of the mechanisms of this disease, as well as for the clinical diagnoses of these patients. METHODS: 36 patients with morbid obesity and 12 healthy subjects were consecutively enrolled in this cross-sectional study to determine the serological parameters associated with the degree of hepatic steatosis and NASH. Clinical, biochemical and histologic variables were examined in blood and liver biopsies by descriptive, univariate and multivariate regression analysis. RESULTS: The patients were distributed as non-NASH (14), probably-NASH (13) and NASH (9), according to the Non-alcoholic fatty liver disease Activity Score (NAS). The study identified remarkable differences in liver steatosis, and glucose, insulin, IL-6 and IGF-1 concentrations in blood among patients with morbid obesity. IL-6 was correlated with the degree of liver steatosis until the morbidly obese patients fulfil the criteria of NASH. The patients with NASH reduced IL-6 concentration in blood. IGF-1 decreased throughout the progression of NASH. TNF-alpha concentration was not related to liver steatosis or NASH in morbidly obese patients. The multivariate regression analysis identified glucose >110 mg/dL, IL-6 >4.81 pg/mL and IGF-1 <130 ng/mL, and homeostasis model assessment (HOMA) >4.5 and IGF-1 <110 ng/mL as independent predictors of hepatic steatosis and NASH, respectively. CONCLUSIONS: The concentration of glucose, insulin, IL-6 and IGF-1 in blood are useful markers for the selection of patients with liver steatosis or NASH.

Protective effect of red wine on oxidative stress and antioxidant enzyme activities in the brain and kidney induced by feeding high cholesterol in rats.

The effect of red wine (400 ml/70 kg) on brain and kidney oxidative stress and antioxidative enzymes activities induced by cholesterol-enriched diet (supplemented with 1.65% of cholesterol (w/w) for 4 weeks) was studied in rats. When red wine (Montilla-Moriles, Cordoba, Spain) was simultaneously supplemented to high-cholesterol diet for 4 weeks, total cholesterol and lipid peroxidation products in the brain, kidney and erythrocytes significantly decreased compared with the high-cholesterol, while GSH content and antioxidative enzymes activities enhanced. On the other hand, the urinary excretion of urea, creatinine and albumin decreased significantly. These results suggest that red wine may have a neuro-nephroprotective effect against oxidative stress and hypercholesterolemia.

Hepato- and neurotoxicity induced by thioacetamide: protective effects of melatonin and dimethylsulfoxide.

The effects of melatonin and dimethylsulfoxide (DMSO) on liver and brain oxidative stress, hepatic failure and blood urea nitrogen (BUN) level changes produced by a single dose of thioacetamide (TAA) in Wistar rats were studies. A dose of either melatonin (3 mg kg(-1)day(-1)) or DMSO (2 g kg(-1)day(-1)) was injected for 3 days before and for 2 days after the administration of TAA (150 mg kg(-1) i.p.). Blood samples were taken from the neck vascular in order to determine ammonium, BUN and liver enzymes. We estimated lipid peroxidation products, reduced glutathione (GSH) content and catalase activity in liver and brain homogenates. TAA caused significant increases in ammonium and in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) enzymes, while it decreased BUN values. TAA also increased lipid peroxidation product levels, but reduced GSH content and catalase activity in the liver and brain. Both melatonin and DMSO, although melatonin more significantly, decreased the intensity of the changes produced by the administration of TAA alone. Furthermore, melatonin alone or combined with TAA increased the BUN levels and decreased the ammonia values compared with control animals. These results support the antioxidative and neuro-/hepato-protective action of melatonin and a lesser action of DMSO. Likewise, these data seem to support the hypothesis of an effect of melatonin on urea synthesis.

[Clinical significance of increased serum ferritin levels]. / Significado clínico de los valores elevados de ferritina sérica.

BACKGROUND AND OBJECTIVE: We aimed to determine the diagnostic alternatives indicated by serum ferritin levels (2000 ng/ml, and to establish the clinical processes associated with very high levels (5000-10 000 ng/ml). PATIENTS AND METHOD: We retrospectively analyzed cases with serum levels of ferritin serum equal to or greater than 2000 ng/ml between March 2000 and November 2001. Data were obtained from the laboratory's computerized database. Patients' medical records were reviewed by means of a protocol which established the clinical conditions associated with these serum ferritin values. RESULTS: The study involved 135 patients with ferritin levels equal to or greater than 2000 ng/ml. Clinical syndromes included hematological diseases (45.9%), liver diseases (23%), chronic renal failure (17.78%), neoplastic diseases (10.4%), systemic inflammatory diseases (7.4%), chronic transfusions (7.4%), and non-HIV systemic infections (5.9%). Syndromes which are not usually associated with extreme serum ferritin levels were identified in 3.7% of the patients. The highest concentrations were seen in the systemic inflammatory disease group: 5856 (2492) ng/ml. Within this group, four patients with adult onset Still's disease (AOSD) displayed the highest mean ferritin levels: 11 322 (5474) ng/ml. CONCLUSIONS: Elevated serum ferritin levels act as a non-specific marker for a large number of disorders. In certain inflammatory diseases such as adult onset Still's disease (AOSD), this finding may be an important tool.