HDL molecular patholgy

Aunque existe una considerable evidencia epidemiológica sobre el carácter ateroprotector de las HDL, se conocen muy pocas alteraciones genéticas que expliquen los bajos niveles plasmáticos de las HDL que suponen riesgo aterosclerótico. Se sabe, no obstante, que algunas de estas alteraciones afectan a la estructura de las HDL: deficiencia de apoA-I, producción de apoA-I anormales y deficiencia de apoA-II. Otras alteraciones genéticas afectan al metabolismo de las HDL. Las deficiencias de la lipasa hepática o de la CETP originan aumentos de las HDL mientras que las deficiencias de la lipoproteín lipasa o la LCAT se traducen en un descenso. También disminuyen los niveles de HDL en la enfermedad de Tangier ya que estas lipoproteínas se captan y se degradan de forma excesiva por los macrófagos.Although there is considerable epidemiological evidence on the atheroprotective function of HDL, relatively little is known about the genetic disorders causing low HDL plasmatic levels linked with atherosclerotic risk. Nevertheless, it seems clear that some of these disorders affect HDL structure: apoA-I deficiency, apoA-I structural anomalies and apoAII deficiency. Other genetic disorders affect HDL metabolism. Hepatic lipase and CETP deficiencies produce HDL increase whereas lipoprotein lipase and LCAT deficiencies cause HDL reductions. Tangier disease is also characterized by a severe lowering of HDL due to their excesive uptake and degradation by macrophages

Impact of alternative splicing on mechanisms of resistance to anticancer drugs

This study was funded by the CIBERehd (EHD15PI05/2016) and "Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III", Spain (PI16/00598 and PI19/00819, co-funded by European Regional Development Fund/European Social Fund, "Investing in your future"); Spanish Ministry of Economy, Industry and Competitiveness (SAF201675197-R, SAF2017-88457-R, AGL2017-85270-R); "Junta de Castilla y Leon" (SA063P17); "Junta de Andalucia (CTS235, CTS164); AECC Scientific Foundation (2017/2020), Spain; "Proyectos de Investigacion. Modalidad C2", University of Salamanca (18.K137/463AC01 and 18. K140/463AC01); "Centro Internacional sobre el Envejecimiento" (OLDHEPAMARKER, 0348_CIE_6_E), Spain and Fundacion University of Salamanca, Spain (PC-TCUE18-20_051); Fundacio Marato TV3 (Ref. 201916-31). M.R. was supported by a predoctoral scholarships (FPU) funded by the Ministry of Science, Innovation and Universities, Spain.A shared characteristic of many tumors is the lack of response to anticancer drugs. Multiple mechanisms of pharmacoresistance (MPRs) are involved in permitting cancer cells to overcome the effect of these agents. Pharmacoresistance can be primary (intrinsic) or secondary (acquired), i.e., triggered or enhanced in response to the treatment. Moreover, MPRs usually result in the lack of sensitivity to several agents, which accounts for diverse multidrug-resistant (MDR) phenotypes. MPRs are based on the dynamic expression of more than one hundred genes, constituting the so-called resistome. Alternative splicing (AS) during pre-mRNA maturation results in changes affecting proteins involved in the resistome. The resulting splicing variants (SVs) reduce the efficacy of anticancer drugs by lowering the intracellular levels of active agents, altering molecular targets, enhancing both DNA repair ability and defensive mechanism of tumors, inducing changes in the balance between pro-survival and pro-apoptosis signals, modifying interactions with the tumor microenvironment, and favoring malignant phenotypic transitions. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the impact of AS on MPR in cancer cells.CIBERehd EHD15PI05/2016Instituto de Salud Carlos III PI16/00598 PI19/00819European Regional Development Fund/European Social Fund, "Investing in your future"Spanish Ministry of Economy, Industry and Competitiveness SAF201675197-R SAF2017-88457-R AGL2017-85270-RJunta de Castilla y Leon SA063P17Junta de Andalucia CTS235 CTS164AECC Scientific Foundation, SpainUniversity of Salamanca 18.K137/463AC01 18. K140/463AC01"Centro Internacional sobre el Envejecimiento" (OLDHEPAMARKER), Spain 0348_CIE_6_EFundacion University of Salamanca, Spain PC-TCUE18-20_051Fundacio Marato TV3 201916-31Ministry of Science, Innovation and Universities, Spai

Determinación de ácido quinolínico en corteza renal de rata

Se describe una modificación al método descrito por McDaniel y col. (8) para la determinación de ácido quinolínico en diferentes tejidos animales. El método consiste en la extracción con ácido perclórico, adsorción selectiva sobre carbón activado y descarboxilación hasta ácido nicotínico, que se mide colorimétricamente. Con este método se han medido las concentraciones de ácido qUinolínico en corteza renal tras la administración de triptófano a las ratas, encontrándose que ninguno de los valores es suficiente para producir una inhibición de la fosfoenolpiruvato carboxicinasa y por tanto de la capacidad gluconeogénica renal.We have described a method based on McDaniel's (8) for the determination of quinolinic acid in several animal tissues. The method consist in the extraction of quinolinic acid, selective adsortion on activated charco al and decarboxylation to nicotinic acid which have been measured by colorimetric reaction. With this method we have measured the concentrations of quinolinic acid in rat renal cortex after the tryptophan injection to rato We have found that anyone of values is enough to make an inhibition of phosphoenol pyruvate carboxykinase activity and t he renal gluconeogenic capacity

Immunomodulatory properties of the protein fraction from Phorphyra columbina

The phycobiliproteins from Rhodophyta, R-phycoerythrin (R-PE) and C-phycocyanin (C-PC), have been shown to exert immunomodulatory effects. This study evaluated the effects of a Phorphyra columbina protein fraction (PF) and R-PE and C-PC on rat primary splenocytes, macrophages, and T-lymphocytes in vitro. PF featured various protein species, including R-PE and C-PC. PF showed mitogenic effects on rat splenocytes and was nontoxic to cells except at 1 g L-1 protein. IL-10 secretion was enhanced by PF in rat splenocytes, macrophages, and especially T-lymphocytes, whereas it was markedly diminished by R-PE and C-PC. The production of pro-inflammatory cytokines by macrophages was inhibited. The effect of PF on IL-10 was evoked by JNK/p38 MAPK and NF-κB-dependent pathways in macrophages and T-lymphocytes. It was concluded that PF has immunomodulatory effects on macrophages and lymphocytes that appear to be predominantly anti-inflammatory via up-regulated IL-10 production and cannot be accounted for by R-PE and C-PC.Fil: Cian, Raúl Esteban. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Agroindustria. Instituto de Tecnología de Alimentos; Argentina. Universidad Nacional del Litoral. Facultad de Ingeniería Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López Posadas, Rocío. Universidad de Granada; EspañaFil: Drago, Silvina Rosa. Universidad Nacional del Litoral. Facultad de Ingeniería Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sánchez De Medina, Fermín. Universidad de Granada; EspañaFil: Martínez Augustin, Olga. Universidad de Granada; Españ

Influencia de la dieta sobre los niveles sanguíneos y hepáticos de diferentes metabolitos en la trucha

Se han determinado los niveles sanguíneos de glucosa, lactato, colesterol, ácidos grasos libres y cuerpos cetónicos así como los de glucógeno hepático en truchas a intervalos de dos horas durante un ciclo de 24 y tras suministrarles una dieta comercial de piscifactoría. Ninguno de los parámetros estudiados ha mostrado una respuesta clara a la comida, en contraste con lo que ocurre para alguno de ellos en mamíferos, lo cual pone de manifiesto una vez más las peculiaridades digestivas y metabólicas de la trucha.The evolution of the blood levels of glucose, lacta te, cholesterol, free fatty acids, ketonic bodies and liver glycogen content were determined in rainbow trout (Salmo gairdneri) at fixed intervals (2 hrs.) during a 24 hrs. period after a meal consisting in a commercial dieto None of the parameters studied show a definite response to food in contrast to that observed for sorne of these parameters in mammals. This fact provides a further evidence about the metabolic and digestive peculiarities of the trout

Evolución de la actividad de la fosfoenolpiruvato carvoxicinasa en hígado y riñón de rata a lo largo del día

The activities of hepatic and renal phosphoenolpyruvate carboxykinase, liver glycogen content, renal gluconeogenic capacity and blood glu­cose and lactate concentrations were determined at several times of the day in rats with free access to food and in rats deprived of food during the experience. The evolution of these biochemical parameters was similar in both groups of animals and generally agreed with the data obtained by other investigators in similar conditions but at different times of the day.Se han determinado las actividades de la fosfoenolpiruvato, carboxicinasa hepática y renal, el contenido en glucógeno hepático, la capacidad gluconeogénica renal y las concentraciones de glucosa y lactato en sangre a lo largo del dia en ratas con acceso a la comida y en animales a los que se privó de alimento al comenzar la experiencia. La evolución de estos parámetros bioquímicos fue muy semejante en ambos grupos y concordó en general con los datos obtenidos en condiciones semejantes, aunque a distintos tiempos, por otros investigadores

Mice carrying an epithelial deletion of the glucocorticoid receptor NR3C1 develop a higher tumor load in experimental colitis associated cancer

The glucocorticoid receptor NR3C1 is expressed in multiple cell types in the gut and elsewhere. Intestinal epithelial cells both produce and respond to glucocorticoids in different physiological and pathological contexts. In experimental colitis glucocorticoids have been shown to exert a dual role, dampening inflammation while producing a deterioration in animal status, including death. Mice with tamoxifen inducible, intestinal epithelial specific deletion of NR3C1 (NR3C1IEC mice) are protected against experimental colitis, suggesting glucocorticoid epithelial actions are deleterious. Since glucocorticoids modulate epithelial proliferation it follows that they may affect the development of colon cancer. In this study we set out to test this hypothesis using the dextran sulfate sodium - azoxymethane model of colitis-associated cancer. KO mice were found to exhibit a 2-fold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend to the submucosal layer (36% vs. 0%) in NR3C1IEC mice, and overexpressed Lgr5, Egfr and Myc, consistent with increased proliferation and neoplastic transformation. Snai1 and Snai2 were upregulated specifically in tumors of NR3C1ΔIEC mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial GC receptor. We conclude that endogenous GC epithelial signaling is involved in colitis associated cancer.This work was supported by funds from the Ministry of Economy and Competitivity, partly with Fondo Europeo de Desarrollo Regional (FEDER) funds [SAF2017-88457-R, AGL2017-85270-R, BFU2014-57736-P, AGL2014-58883-R] and by Junta de Andalucía [CTS235, CTS164]. MA and CJA were supported by the University of Granada (Contrato Puente Program - Plan Propio) and the Ministry of Education [Spain], respectively. CIBERehd is funded by Instituto de Salud Carlos III

Modulation of intestinal barrier function by glucocorticoids: Lessons from preclinical models

This work was supported by the "Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd)", belonging to Instituto de Salud Carlos III, Spain, and grants from: Ministry of Economy and Competitivity, partly with Fondo Europeo de Desarrollo Regional FEDER funds [SAF2017-88457-R, AGL2017-85270-R]; "Junta de Andalucia", Spain [CTS235, CTS164]; "Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III", Spain (PI19/00819), co-funded by European Regional Development Fund/European Social Fund, "Investing in your future"; "Junta de Castilla y Leon" (SA074P20),Spain; "Fundacio Marato TV3'' (201916-31), Spain; AECC Scientific Foundation (2017/2020), Spain; and "Centro Internacional sobre el Envejecimiento" (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. MAA and MTG were supported by fellowships from the Ministry of Education. MA was supported by a postdoctoral contract with the CIBERehd. Funding for open access charge: Universidad de Granada/CBUA.Glucocorticoids (GCs) are widely used drugs for their anti-inflammatory and immunosuppressant effects, but they are associated with multiple adverse effects. Despite their frequent oral administration, relatively little attention has been paid to the effects of GCs on intestinal barrier function. In this review, we present a summary of the published studies on this matter carried out in animal models and cultured cells. In cultured intestinal epithelial cells, GCs have variable effects in basal conditions and generally enhance barrier function in the presence of inflammatory cytokines such as tumor necrosis factor (TNF). In turn, in rodents and other animals, GCs have been shown to weaken barrier function, with increased permeability and lower production of IgA, which may account for some features observed in stress models. When given to animals with experimental colitis, barrier function may be debilitated or strengthened, despite a positive anti-inflammatory activity. In sepsis models, GCs have a barrier-enhancing effect. These effects are probably related to the inhibition of epithelial cell proliferation and wound healing, modulation of the microbiota and mucus production, and interference with the mucosal immune system. The available information on underlying mechanisms is described and discussed."Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, SpainMinistry of Economy and CompetitivityEuropean Commission SAF2017-88457-R AGL2017-85270-RJunta de Andalucia European Commission CTS235 CTS164Instituto de Salud Carlos III PI19/00819European Regional Development Fund/European Social Fund, "Investing in your future"Junta de Castilla y Leon SA074P20Fundacio Marato TV3, Spain 201916-31AECC Scientific Foundation, Spain"Centro Internacional sobre el Envejecimiento" (OLD-HEPAMARKER), Spain 0348_CIE_6_EMinistry of EducationCIBERehdUniversidad de Granada/CBU

Disturbances in metabolic, transport and structural genes in experimental colonic inflammation in the rat: a longitudinal genomic analysis

Background: Trinitrobenzenesulphonic acid (TNBS) induced rat colitis is one of the most widely used models of inflammatory bowel disease (IBD), a condition whose aetiology and pathophysiology are incompletely understood. We have characterized this model at the genomic level using a longitudinal approach. Six control rats were compared with colitic animals at 2, 5, 7 and 14 days after TNBS administration (n = 3). The Affymetrix Rat Expression Array 230 2.0 system was used. Results: TNBS-induced colitis had a profound impact on the gene expression profile, which was maximal 5 and 7 days post-induction. Most genes were affected at more than one time point. They were related to a number of biological functions, not only inflammation/immunity but also transport, metabolism, signal transduction, tissue remodeling and angiogenesis. Gene changes generally correlated with the severity of colitis. The results were successfully validated in a subset of genes by real-time PCR. Conclusion: The TNBS model of rat colitis has been described in detail at the transcriptome level. The changes observed correlate with pathophysiological disturbances such as tissue remodelling and alterations in ion transport, which are characteristic of both this model and IBD.This study was supported by the Instituto de Investigación Carlos III (PI051651, PI051625), the Spanish Junta de Andalucía (ARM/LD 43035), the Ministry of Industry, and Fundación Genoma España