67 research outputs found

    Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes

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    AbstractRecombinant human IL-6 (rhIL-6) is a potent inducer of the synthesis of acute phase proteins in adult human hepatocytes. A wide spectrum of acute phase proteins is regulated by this mediator. After labeling of rhIL-6 stimulated human hepatocytes with [35S]methionine acute phase protein synthesis was measured by immunoprecipitation. Serum amyloid A, C-reactive protein, haptoglobin, α1-antichymotrypsin and fibrinogen were strongly induced (26-, 23-, 8.6-, 4.6- and 3.8-fold increases, respectively). Moderate increases were found for α1-antitrypsin (2.7-fold) and α1-acid glycoprotein (2.7-fold). RhIL-6 had no effect on α1-macroglobulin, whereas fibronectin, albumin and transferrin decreased to 64, 56 and 55% of controls. In the cases of serum amyloid A, haptoglobin, α1-antichymotrypsin, α1-antitrypsin and α1-acid glycoprotein, dexamethasone enhanced the action of rhIL-6. We conclude that rhIL-6 controls the acute phase response in human liver cells

    Superbeam studies at CERN

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    A conventional low-energy neutrino beam of great intensity could be produced by the Super Proton Linac at CERN as a first stage of a Neutrino Factory. Water Cherenkov and liquid scintillator detectors are studied as possible candidates for a neutrino oscillation experiment which could improve our current knowledge of the atmospheric parameters Δmatm2, θ23 and measure or severely constrain θ13. It is also shown that a very large water detector could eventually observe leptonic CP violation

    Cocoa and Cocoa Fibre Intake Modulate Reactive Oxygen Species and Immunoglobulin Production in Rats Submitted to Acute Running Exercise

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    Acute high-intensity exercise can impair the immune system, and lead to oxidative stress. Cocoa intake might help in protecting against oxidative damage and impaired immune functioning. The aim of this study was to establish the effect of cocoa and cocoa fibre on the oxidative status and the immunoglobulin (Ig) production of rats following a bout of acute exercise on a treadmill. The production of reactive oxygen species (ROS) by macrophages and the concentration of serum and mucosal Ig was assessed 16 h after the running session. Exercise increased ROS production and decreased the serum IgG concentration and the salivary gland IgM content. A cocoa fibre-enriched diet prevented the increased ROS production and the reduction in salivary IgM induced by exercise, although it decreased the IgA content in serum and the salivary glands. Overall, cocoa, by means of its fibre content, can partially prevent the alterations in ROS and Ig production induced by a single session of intensive running exercise

    New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease

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    Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis. Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods. miRNA biomarkers were also analyzed in the sera of 44 biopsy-proven NAFLD patients and in 10 controls. Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis

    Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes

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    AbstractThe three monokines interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) modulate acute phase plasma protein synthesis in adult human hepatocytes. Only IL-6 stimulates the synthesis of the full spectrum of acute phase proteins as seen in inflammatory states in humans, i.e. synthesis and secretion of C-reactive protein, serum amyloid A, fibrinogen, α1-antitrypsin, α1-antichymotrypsin and haptoglobin are increased while albumin, transferrin and fibronectin are decreased. IL-1β as well as TNFα, although having a moderate effect on the positive acute phase proteins and inhibiting the synthesis of fibrinogen, albumin and transferrin, fail to induce serum amyloid A and C-reactive protein. These data suggest that IL-6 plays the key role in the regulation of acute phase protein synthesis in human hepatocytes

    A simple national intercomparison of radon in water

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    Radon-222, a naturally occurring radioactive gas, responsible together with its progeny of around 50% of the average effective dose received by the population, has not been regulated by law until the recent Directive 2013/51 /Euratom. Its transposition into Spanish legislation was made in the recent RD 314/2016, which sets at limit value of 500 Bq l¯¹ for radon-222 in water for human consumption. Intercomparison exercises, such as those carried out by IPROMA SL and the Laboratory of Environmental Radioactivity of the Cantabria University (LARUC) in November 2015 and December 2016, represent the most useful tool available for detecting problems and taking corrective actions necessary for an efficient measurement by part of the laboratories. The participants in these exercises used three techniques: liquid scintillation counting, gamma spectrometry and desorption followed by ionisation chamber detection

    Desarrollo, análisis y optimización de modelos celulares hepáticos para estudios de fármaco-toxicología y terapia celular

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    Given the importance of the liver in the metabolism and maintenance of the homeostasis of the organism, many studies have been conducted in the area of toxicology and, more recently, in hepatic cellular therapy. However, the main drawback is the limited availability of viable and functional hepatocytes due to the scarcity of liver tissue. The purpose of this work was based on the development and characterization of hepatic cellular models to become an alternative to hepatocytes in toxicology studies and cellular therapy. To this end, three main objectives have been investigated: 1) to adopt a procedure of hepatocyte isolation from discarded organs for transplantation which determines the optimal conditions for the isolation and culture of hepatocytes, 2) to characterize the cells from the hepatoblastome HepG2, and 3) to develop a hepatogenic differentiation protocol to induce the hepatic differentiation in adipose-derived stem cells (ADSC). In particular, the hepatogenic differentiation of stem cells opens a wide range of possibilities to facilitate the establishment of an adult differentiated cellular model useful for pharmaco-toxicological studies and for hepatic cellular therapy. The use of adult stem cells may allow the establishment of an adult cellular model with properties that others cellular models, like HepG2, do not show. However, it is necessary to optimise the isolation and cryopreservation procedures, as well as the differentiation protocols from adult stem cells and try to acquire a wide knowledge of the cellular and molecular mechanisms that control the transdifferentiation to hepatocytes.Key Words: cellular transplant, esteatosis, human hepatocytes, hepatoblastomes, stem cells.El hígado juega un papel fundamental en el metabolismo de medicamentos y en el mantenimiento de la homeostasis del organismo y, por tanto los modelos celulares hepáticos desempeñan un papel clave para estudios fármaco-toxicológicos y más recientemente en el campo de la terapia celular. Sin embargo, la limitada disponibilidad de hepatocitos viables y funcionales debido a la falta de tejido hepático es la principal limitación para utilizar estos recursos celulares. El objetivo del presente trabajo se ha basado en el desarrollo y caracterización de modelos celulares hepáticos que puedan constituir una alternativa a los hepatocitos para este tipo de aplicaciones. Para ello se han abordado tres estrategias diferentes: 1) optimización del proceso de obtención de hepatocitos a partir de hígados enteros descartados para transplante, determinando las condiciones adecuadas para el aislamiento y cultivo de hepatocitos; 2) caracterización funcional de las células del hepatoblastoma HepG2 y 3) desarrollo de un protocolo para inducir la diferenciación hepatogénica de células madre mesenquimales adultas derivadas de tejido adiposo (ADSC). Para conseguir un buen aprovechamiento de hígados descartados para transplante resulta necesario optimizar los protocolos de aislamiento y criopreservación de hepatocitos. El estudio con células madre adultas se presenta como una alternativa muy válida para la obtención de hepatocitos-like viables y funcionalmente activos útiles a corto plazo en estudios de fármaco-toxicología y en un futuro para terapia celular hepática. El uso de células madre abre un gran abanico de posibilidades facilitando el establecimiento de un modelo celular diferenciado adulto con características que otros modelos celulares, como son el hepatoma humano HepG2, no presentan. No obstante, es necesario adquirir un mayor conocimiento de los mecanismos celulares y moleculares que controlan la transdiferenciación a hepatocitos.Palabras clave: trasplante celular, esteatosis, hepatocitos humanos, hepatoblastomas, células madre

    Identification of Myocardial Insulin Resistance by Using Liver Tests: A Simple Approach for Clinical Practice

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    Cardiovascular risk; Myocardial insulin resistance; Non-alcoholic fatty liver diseaseRiesgo cardiovascular; Resistencia a la insulina del miocardio; Enfermedad del higado graso no alcoholicoRisc cardiovascular; Resistència a la insulina del miocardi; Malaltia del fetge gras no alcohòlicBackground: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. Methods: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic–euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. Results: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. Conclusions: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D.This work was supported by the Carlos III Health Institute and the European Regional Development Fund (PI16/02064, PI20/01588) and the Agency for Management of University and Research Grants (AGAUR) of Catalonia (2017SGR1303)

    Energy Dependence of CP-Violation Reach for Monochromatic Neutrino Beam

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    The ultimate goal for future neutrino facilities is the determination of CP violation in neutrino oscillations. Besides U(e3)0| U(e3) | \ne 0, this will require precision experiments with a very intense neutrino source and energy control. With this objective in mind, the creation of monochromatic neutrino beams from the electron capture decay of boosted ions by the SPS of CERN has been proposed. We discuss the capabilities of such a facility as a function of the energy of the boost and the baseline for the detector. We compare the physics potential for two different configurations: I) γ=90\gamma=90 and γ=195\gamma=195 (maximum achievable at present SPS) to Frejus; II) γ=195\gamma=195 and γ=440\gamma=440 (maximum achievable at upgraded SPS) to Canfranc. We conclude that the SPS upgrade to 1000 GeV is important to reach a better sensitivity to CP violation iff it is accompanied by a longer baseline. In both Setups, the gain in the CP violation sensitivity with a previous knowledge of U(e3)| U(e3) | is apparent.Comment: 11 pages, 7 figure
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