Browsing by MeSH term "Intestinal Mucosa"
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Publication Bacterial DNA translocation and liver disease severity among HIV-infected patients with chronic hepatitis C(Lippincott Williams & Wilkins (LWW), 2012-12-15) Garcia-Alvarez, Monica; Berenguer, Juan; Guzman-Fulgencio, Maria; Alvarez, Emilio; Cosín, Jaime; Micheloud, Dariela; Jimenez-Sousa, Maria Angeles; Fernandez-Rodriguez, Amanda; Aldámiz-Echevarría, Teresa; Carrero, Ana; Miralles, Pilar; Resino, Salvador; Instituto de Salud Carlos III; Redes Temáticas de Investigación Cooperativa en Salud (RETICS) (España); Fundación para la Investigación y la Prevención del Sida en EspañaWe carried out a cross-sectional study to explore whether bacterial 16S ribosomal DNA (bactDNA) shows association with severity of liver disease among human immunodeficiency virus/hepatitis C virus coinfected patients. Patients with advanced fibrosis (F3/F4), moderate activity grade (A2/A3), and high fibrosis progression rate (FPR > 0.15) had higher values of plasma bactDNA levels than did patients without these markers of liver disease (P < 0.05). The chance of having a fibrosis stage or activity grade increased was 1.20 [95% confidence interval (CI) = 1.0 to 1.44, P = 0.045] and 1.22 (95% CI = 1.1 to 1.45, P = 0.029) times greater for every 100 copies per microliter of plasma bactDNA. Likewise, the odds of having values of FPR > 0.15 was 1.18 (95% CI = 0.98 to 1.42, P = 0.089). In addition, patients with high bactDNA levels (≥175 copies per microliter) had the highest odds of having high values of Metavir score and FPR (P < 0.05). Our data show that bacterial translocation is associated with severe liver disease among human immunodeficiency virus-infected patients with chronic hepatitis C.Publication CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease.(Multidisciplinary Digital Publishing Institute (MDPI), 2023-01-31) Gomez-Bris, Raquel; Saez, Angela; Herrero-Fernandez, Beatriz; Rius, Cristina; Sanchez-Martinez, Hector; Gonzalez-Granado, Jose M; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNIC; Comunidad de Madrid (España)Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn's disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. This review examines the role of the CD4 T-cells most relevant to IBD, highlighting how these cells adapt to the environment and interact with other cell populations to promote or inhibit the development of IBD.Publication Functional characterization of thioredoxin 3 (TRX-3), a Caenorhabditis elegans intestine-specific thioredoxin(Elsevier, 2014-03) Jiménez-Hidalgo, María; Kurz, Cyril Léopold; Pedrajas, José Rafael; Naranjo-Galindo, Francisco José; González-Barrios, María; Cabello, Juan; Saez, Alberto G; Lozano, Encarnacion; Button, Emma L; Veal, Elizabeth A; Fierro-González, Juan Carlos; Swoboda, Peter; Miranda-Vizuete, Antonio; National Institutes of Health (Estados Unidos); Instituto de Salud Carlos III; Regional Government of Andalusia (España); Unión Europea. Fondo Social Europeo (ESF/FSE); Swedish Research Council; Institut National de la Santé et de la Recherche Médicale (Francia); Ministère de la recherche et de l’éducation (Francia); Universidad de Jaén (España); Ministerio de Ciencia e Innovación (España); Rioja Salud Foundation; Ministry of Education, Culture, Sports, Science, and Technology (Japón)Thioredoxins are a class of evolutionarily conserved proteins that have been demonstrated to play a key role in many cellular processes involving redox reactions. We report here the genetic and biochemical characterization of Caenorhabditis elegans TRX-3, the first metazoan thioredoxin with an intestine-specific expression pattern. By using green fluorescent protein reporters we have found that TRX-3 is expressed in both the cytoplasm and the nucleus of intestinal cells, with a prominent localization at the apical membrane. Although intestinal function, reproductive capacity, longevity, and resistance of trx-3 loss-of-function mutants to many stresses are indistinguishable from those of wild-type animals, we have observed a slight reduction in size and a minor reduction in the defecation cycle timing of trx-3 mutants. Interestingly, trx-3 is induced upon infection by Photorhabdus luminescens and Candida albicans, and TRX-3 overexpression provides a modest protection against these pathogens. Together, our data indicate that TRX-3 function in the intestine is dispensable for C. elegans development but may be important to fight specific bacterial and fungal infections.Publication Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations(Nature Publishing Group, 2016) Varela, Elisa; Muñoz-Lorente, Miguel A; Tejera, Agueda; Ortega Jimenez, Sagrario; Blasco , MA; Ministerio de Economía y Competitividad (España); Unión Europea. Comisión Europea. 7 Programa Marco; Unión Europea. Comisión Europea. European Research Council (ERC); Botín Foundation; Fundación AXA; Comunidad de Madrid (España)Although telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with 'hyper-long' telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression.Publication Gut epithelial barrier markers in patients with obstructive sleep apnea(Elsevier, 2016-10) Barceló Bennasar, Antonia; Esquinas, Cristina; Robles, Juan; Pierola Lopetegui, Javier; de la Pena-Bravo, Monica; Aguilar, Irene; Morell Garcia, Danie; Alonso, Alberto; Toledo Pons, Nuria; Sanchez-de la Torre, Manuel; Barbe, FerranBackground: Obstructive sleep apnea (OSA) is now being recognized as an additional contributing factor to the pathogenesis of obesity-related comorbidities. At the same time, there is now increasing evidence to suggest that intestinal wall permeability plays a role in the development of metabolic syndrome. In the present study, circulating zonulin and fatty acid binding protein (I-FABP) were measured in association with metabolic, hepatic, and inflammatory parameters. Results: Compared with controls, plasma I-FABP levels were significantly higher in patients with OSA (571 pg/mL [IQR 290-950] vs 396 pg/mL [IQR 234-559], p = 0.04). Zonulin levels were similar between groups. Significant relationships were observed between zonulin levels and waist circumference (p < 0.05), glucose (p < 0.05), and insulin (p < 0.05). In addition, in the OSA group, zonulin levels correlated negatively with the mean nocturnal oxygenation saturation (p < 0.05) and positively with total cholesterol (p < 0.05), alanine aminotransferase (ALT) (p < 0.005), aminotransferase (AST) (p < 0.01), gamma glutamyltransferase (GGT) (p < 0.005), and high-sensitivity C-reactive protein (hs-CRP) (p < 0.05). Multivariate analysis showed that associations between zonulin and ALT, AST, and hs-CRP were attenuated, but not eliminated, after adjustment for other variables. Conclusions: The results of this study suggest that OSA is a risk factor for intestinal damage, regardless of metabolic profile, and that intestinal permeability might be a possible contributor to nonalcoholic fatty liver disease in patients with OSA.Publication In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias(Elsevier, 2017) Muñoz, Sergio; Búa, Sabela; Rodriguez-Acebes, Sara; Megias Vazquez, Diego; Ortega Jimenez, Sagrario; de Martino, Alba; Mendez, Juan; Ministerio de Ciencia y Competitividad (España)Mammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo. Here, we have generated mice strains that allow the conditional overexpression of both proteins. Adult mice were unharmed by the individual overexpression of either CDC6 or CDT1, but their combined deregulation led to DNA re-replication in progenitor cells and lethal tissue dysplasias. This study offers mechanistic insights into the necessary cooperation between CDC6 and CDT1 for facilitation of origin reactivation and describes the physiological consequences of DNA overreplication.Publication Pathophysiology of Inflammatory Bowel Disease: Innate Immune System.(Multidisciplinary Digital Publishing Institute (MDPI), 2023-01-12) Saez, Angela; Herrero-Fernandez, Beatriz; Gomez-Bris, Raquel; Sánchez-Martinez, Hector; Gonzalez-Granado, Jose M; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNICInflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.Publication Relationships of Gut Microbiota Composition, Short-Chain Fatty Acids and Polyamines with the Pathological Response to Neoadjuvant Radiochemotherapy in Colorectal Cancer Patients.(2021-09-02) Sánchez-Alcoholado, Lidia; Laborda-Illanes, Aurora; Otero, Ana; Ordóñez, Rafael; González-González, Alicia; Plaza-Andrades, Isaac; Ramos-Molina, Bruno; Gómez-Millán, Jaime; Queipo-Ortuño, María IsabelEmerging evidence has suggested that dysbiosis of the gut microbiota may influence the drug efficacy of colorectal cancer (CRC) patients during cancer treatment by modulating drug metabolism and the host immune response. Moreover, gut microbiota can produce metabolites that may influence tumor proliferation and therapy responsiveness. In this study we have investigated the potential contribution of the gut microbiota and microbial-derived metabolites such as short chain fatty acids and polyamines to neoadjuvant radiochemotherapy (RCT) outcome in CRC patients. First, we established a profile for healthy gut microbiota by comparing the microbial diversity and composition between CRC patients and healthy controls. Second, our metagenomic analysis revealed that the gut microbiota composition of CRC patients was relatively stable over treatment time with neoadjuvant RCT. Nevertheless, treated patients who achieved clinical benefits from RTC (responders, R) had significantly higher microbial diversity and richness compared to non-responder patients (NR). Importantly, the fecal microbiota of the R was enriched in butyrate-producing bacteria and had significantly higher levels of acetic, butyric, isobutyric, and hexanoic acids than NR. In addition, NR patients exhibited higher serum levels of spermine and acetyl polyamines (oncometabolites related to CRC) as well as zonulin (gut permeability marker), and their gut microbiota was abundant in pro-inflammatory species. Finally, we identified a baseline consortium of five bacterial species that could potentially predict CRC treatment outcome. Overall, our results suggest that the gut microbiota may have an important role in the response to cancer therapies in CRC patients.Publication Stage-specific differential gene expression in Leishmania infantum: from the foregut of Phlebotomus perniciosus to the human phagocyte(BioMed Central (BMC), 2014-10-03) Alcolea, Pedro J; Alonso, Ana; Gomez, Manuel J; Postigo, Marina; Molina, Ricardo; Jimenez, Maribel; Larraga, Vicente; Ministerio de Ciencia e Innovación (España); Fundación Ramón ArecesBACKGROUND: Leishmania infantum is the etiological agent of zoonotical visceral leishmaniasis in the Mediterranean basin. A recent outbreak in humans has been recently reported in central Spain. Leishmania spp. parasites are transmitted to the mammalian host by the bite of sand flies. The primary vector of L. infantum in Spain is Phlebotomus perniciosus. For decades, research on these parasites has involved the axenic culture model of the promastigote stage including gene expression profiling studies performed in the post-genome era. Unlike the controversial axenic culturing of amastigotes, promastigote cultures are generally accepted and used, although with the precaution of avoiding excessive culture passage.The primary objective of this differentiation study is to compare the gene expression profiles of promastigotes isolated from the foregut of the sand fly and amastigotes. For this purpose, P. perniciosus sand flies were infected with L. infantum and differentiated promastigotes were extracted by dissection of the foreguts. Shotgun DNA microarray hybridization analyses allowed for transcriptome comparison of these promastigotes with amastigotes obtained by infection of the U937 cell line. The results have been compared with those described in published expression analyses using axenic promastigotes. RESULTS: A total of 277 up-regulated genes were found through this hybridization experiment. The comparison of these particular results with published gene expression profile analyses performed using the same experimental procedure to study cultured promastigotes in stationary phase versus amastigotes revealed considerable differences (approximately 95% of the up-regulated genes were different). We found that the up-regulation rate is lower in amastigotes than in sand fly-derived promastigotes, which is in agreement with the over-expression of genes involved in gene expression regulation and signaling in those promastigote populations. CONCLUSIONS: The up-regulation rate is lower in intracellular amastigotes than in promastigotes obtained from the sand fly gut. This was also reported by us using the promastigote culture model and is an evidence for the hypothesis of promastigote preadaptation towards life in the intracellular environment. Regarding transcript abundance, the set of differentially regulated genes is notably different when using promastigotes from the sand fly foregut instead of axenic cultures.Publication Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review(Baishideng Publishing Group Inc, 2017-07-28) Salaritabar, Ali; Darvishi, Behrad; Hadjiakhoondi, Farzaneh; Manayi, Azadeh; Soldevila Verdeguer, Carla; Nabavi, Seyed Fazel; Fitzpatrick, Leo R; Nabavi, Seyed Mohammad; Bishayee, AnupamThe inflammatory process plays a central role in the development and progression of numerous pathological situations, such as inflammatory bowel disease (IBD), autoimmune and neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn's disease (CD) and ulcerative colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants, including vegetables and fruits which are the major dietary sources of these compounds for humans, together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids, evidencing a remarkable free-radical scavenging capacity. However, accumulating evidence suggests that flavonoids have many other biological properties, including anti-inflammatory, antiviral, anticancer, and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.Publication Transit-amplifying cells control R-spondins in the mouse crypt to modulate intestinal stem cell proliferation.(Rockefeller University Press, 2022-11-07) Chaves-Pérez, Almudena; Santos-de-Frutos, Karla; de la Rosa, Sergio; Herranz-Montoya, Irene; Perna, Cristian; Djouder, Nabil; Djouder, Nabil; Ministerio de Ciencia e Innovación (España); European Union (EU)Intestinal epithelium regenerates rapidly through proliferation of intestinal stem cells (ISCs), orchestrated by potent mitogens secreted within the crypt niche. However, mechanisms regulating these mitogenic factors remain largely unknown. Here, we demonstrate that transit-amplifying (TA) cells, marked by unconventional prefoldin RPB5 interactor (URI), control R-spondin production to guide ISC proliferation. Genetic intestinal URI ablation in mice injures TA cells, reducing their survival capacity, leading to an inflamed tissue and subsequently decreasing R-spondin levels, thereby causing ISC quiescence and disruption of intestinal structure. R-spondin supplementation or restoration of R-spondin levels via cell death inhibition by c-MYC elimination or the suppression of inflammation reinstates ISC proliferation in URI-depleted mice. However, selective c-MYC and p53 suppression are required to fully restore TA cell survival and differentiation capacity and preserve complete intestinal architecture. Our data reveal an unexpected role of TA cells, which represent a signaling platform instrumental for controlling inflammatory cues and R-spondin production, essential for maintaining ISC proliferation and tissue regeneration.Publication Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids(Public Library of Science (PLOS), 2012-05-25) Suárez, Juan; Romero-Zerbo, Yanina; Márquez, Lucia; Rivera, Patricia; Iglesias, Mar; Bermúdez-Silva, Francisco J.; Andreu, Montserrat; Rodríguez de Fonseca, Fernando; [Suárez,J; Romero-Zerbo,Y; Rivera,P; Bermúdez-Silva,FJ; Rodríguez de Fonseca,F] Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Mediterranean Institute for the Advance of Biotechnology and Health Research Fundación, Málaga, Spain. [Márquez,L; Andreu,M] Department of Gastroenterology, Parc de Salut Mar, Universidad Autónoma, Barcelona, Spain. [Suárez,J; Bermúdez-Silva,FJ; Rodríguez de Fonseca,F] El Centro de Investigación Biomédica en Red de Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain. [Iglesias,M] Department of Pathology, Parc de Salut Mar, Universidad Autónoma, Barcelona, Spain.Studies in animal models and humans suggest anti-inflammatory roles on the N acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.Publication URI is required to maintain intestinal architecture during ionizing radiation.(American Association for the Advancement of Science (AAAS), 2019-05-31) Chaves-Pérez, Almudena; Yilmaz, Mahmut; Perna, Cristian; de la Rosa, Sergio; Djouder, Nabil; Fundación La Caixa; European Union (EU); Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España)Ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a lethal disorder, by means of unknown mechanisms. We show that high-dose irradiation increases unconventional prefoldin RPB5 interactor (URI) levels in mouse intestinal crypt, but organ regeneration correlates with URI reductions. URI overexpression in intestine protects mice from radiation-induced GIS, whereas halving URI expression sensitizes mice to IR. URI specifically inhibits β-catenin in stem cell-like label-retaining (LR) cells, which are essential for organ regeneration after IR. URI reduction activates β-catenin-induced c-MYC expression, causing proliferation of and DNA damage to LR cells, rendering them radiosensitive. Therefore, URI labels LR cells which promote tissue regeneration in response to high-dose irradiation, and c-MYC inhibitors could be countermeasures for humans at risk of developing GIS.