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

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

Immunoregulatory Effects of Porcine Plasma Protein Concentrates on Rat Intestinal Epithelial Cells and Splenocytes

This study was funded by APC Europe and 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]. CHC, CJA and BO 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.Blood contains proteins which have interest as products that may regulate immune function. For this reason some protein-based products are currently used as nutritional supplements for animals, for instance two porcine concentrates, spray dried serum (SDS), and an immunoglobulin concentrate (IC). These products have shown to protect against colonic inflammation in rodents. In the present study we characterize the ability of these products to modulate immune function in isolated cells, namely intestinal epithelial cells (IEC18 cells) and rat spleen cells. Our data indicate that both porcine protein concentrates indeed alter immune cell function, based on the secretion of the modulators known as cytokines. In intestinal epithelial IEC18 cells they promoted the secretion of GRO alpha and MCP-1 cytokines. In spleen cells they mainly inhibited the production of TNF, a key proinflammatory cytokine. In addition, the IC product augmented the release of IL-10, an anti-inflammatory cytokine. Taken together, our data indicate that the immunomodulatory effects observed in vivo are consistent with the direct actions of the protein concentrates on epithelial cells, T lymphocytes, and monocytes. Serum protein concentrates have been shown to exert in vivo anti-inflammatory effects. Specific effects on different cell types and their mechanism of action remain unraveled. We aimed to characterize the immunomodulatory effect of two porcine plasma protein concentrates, spray dried serum (SDS) and an immunoglobulin concentrate (IC), currently used as animal nutritional supplements with established in vivo immunomodulatory properties. Cytokine production by the intestinal epithelial cell line IEC18 and by primary cultures of rat splenocytes was studied. The molecular pathways involved were explored with specific inhibitors and gene knockdown. Our results indicate that both products induced GRO alpha and MCP-1 production in IEC18 cells by a MyD88/NF-kappa B-dependent mechanism. Inhibition of TNF production was observed in rat primary splenocyte cultures. The immunoglobulin concentrate induced IL-10 expression in primary splenocytes and lymphocytes. The effect on TNF was independent of IL-10 production or the stimulation of NF-kB, MAPKs, AKT, or RAGE. In conclusion, SDS and IC directly regulate intestinal and systemic immune response in murine intestinal epithelial cells and in T lymphocytes and monocytes.APC EuropeMinistry of Economy and CompetitivityEuropean Commission SAF2017-88457-R AGL2017-85270R BFU2014-57736-P AGL2014-58883-RJunta de Andalucia CTS235 CTS164University of Granada (Contrato Puente Program-Plan Propio)Ministry of Education [Spain]Instituto de Salud Carlos IIIEuropean Commissio

Food Derived Bioactive Peptides and Intestinal Barrier Function

A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action

Leptin-resistant Zucker rats with trinitrobenzene sulfonic acid colitis present a reduced inflammatory response but enhanced epithelial damage

The study was funded the following grants of the Ministerio de Economía y Competitividad and the Fondo Europeo de Desarrollo Regional FEDER (SAF2011-22922, SAF2011-22812, BFU2014- 57736-P, and AGL2014-58883-R) and Junta de Andalucía (CTS164, CTS235, and CTS6736). B. Rivero-Guti errez, R. Gámez-Belmonte, and M. Arredondo-Amador were supported by fellowships from the Ministerio de Educación.The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.Ministerio de Economía y Competitividad and the Fondo Europeo de Desarrollo Regional FEDER (SAF2011-22922, SAF2011-22812, BFU2014- 57736-P, and AGL2014-58883-R)Junta de Andalucía (CTS164, CTS235, and CTS6736)Ministerio de Educació

Proteins and Carbohydrates from Red Seaweeds: Evidence for Beneficial Effects on Gut Function and Microbiota

Based on their composition, marine algae, and namely red seaweeds, are good potential functional foods. Intestinal mucosal barrier function refers to the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules. Here, we will first outline the component of seaweeds and will summarize the effects of these on the regulation of mucosal barrier function. Special attention will be paid to unique components of red seaweeds: proteins and derived peptides (e.g., phycobiliproteins, glycoproteins that contain “cellulose binding domains”, phycolectins and the related mycosporine-like amino acids) together with polysaccharides (e.g., floridean starch and sulfated galactans, such as carrageenans, agarans and “dl-hybrid”) and minerals. These compounds have been shown to exert prebiotic effects, to regulate intestinal epithelial cell, macrophage and lymphocyte proliferation and differentiation and to modulate the immune response. Molecular mechanisms of action of peptides and polysaccharides are starting to be elucidated, and evidence indicating the involvement of epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), Toll-like receptors (TLR) and signal transduction pathways mediated by protein kinase B (PKB or AKT), nuclear factor-κB (NF-κB) and mitogen activated protein kinases (MAPK) will also be summarized. The need for further research is clear, but in vivo experiments point to an overall antiinflammatory effect of these algae, indicating that they can reinforce membrane barrier function