Jesús Cosín-Roger

Jesús Cosín-Roger
Hospital Universitario Doctor Peset · Unidad Mixta Farmacología Hospital Dr Peset-Universidad de Valencia

BSc, MSc, PhD Biomedicine and Pharmacology

About

81
Publications
5,701
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933
Citations
Additional affiliations
January 2021 - present
Hospital Universitario Doctor Peset
Position
  • Investigador Miguel Servet
June 2017 - December 2020
Hospital Universitario Doctor Peset
Position
  • PostDoc Position
February 2016 - May 2017
University Hospital of Zurich
Position
  • PostDoc Position

Publications

Publications (81)
Article
Full-text available
Background: Fibrosis is a common complication of Crohn's disease (CD) in which macrophages play a central role. Epithelial-mesenchymal transition (EMT) and the WNT pathway have been associated with fibrosis. We aim to analyse the relevance of the tissue microenvironment in macrophage phenotype and the EMT process. Methods: Intestinal surgical re...
Article
Full-text available
Intestinal epithelial cells (IECs) constitute a defensive physical barrier in mucosal tissues and their disruption is involved in the etiopathogenesis of several inflammatory pathologies, such as Ulcerative Colitis (UC). Recently, the succinate receptor SUCNR1 was associated with the activation of inflammatory pathways in several cell types, but li...
Article
Full-text available
Local extracellular acidification occurs at sites of inflammation. Proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) responds to decreases in extracellular pH. Our previous studies show a role for OGR1 in the pathogenesis of mucosal inflammation, suggesting a link between tissue pH and immune responses. Addition...
Article
Background Macrophages contribute to fibrosis by releasing different mediators and the pattern of secretion may vary depending on the surrounding environment. We previously described that the mRNA expression of IFNγ was significantly higher in intestinal samples from CD patients. Methods The aim of the present study is to analyze the role of IFNγ-...
Article
Background Ulcerative colitis (UC) is characterized by a diffuse, continuous, and chronic inflammation of mucosa and submucosa layers in the colon whose etiology is still unknown. Intestinal microbiota dysbiosis and alterations in the metabolomic profile have been reported in mucosal biopsies from Inflammatory Bowel Disease (IBD) patients. We aim t...
Article
Background Crohn′s disease (CD) is often complicated by the appearance of intestinal stenosis (B2 behaviour) or fistulas (B3 behaviour), and the factors determining the pattern of disease and the etiology of these lesions, both associated with fibrosis and requiring surgery, are poorly defined. Our aim has been to detect transcriptomic alterations...
Article
Background Metabolomics is a recent technique that has bounced into Inflammatory Bowel Diseases (IBD) due to its capacity to elucidate specific metabolites involved in the pathology and changes in the metabolomic profile have been detected in urine, blood or feces from UC patients. G-protein coupled receptors (GPCRs) have been recently identified a...
Chapter
Autoimmune and inflammatory-mediated disorders, such as rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), and Sjögren syndrome (SS), among others, are multifactorial complex diseases characterized by chronic inflammation and autoimmunity, which produce damage of target organ systems and as a consequence high rates of disability and como...
Article
Full-text available
Fibrosis is a pathophysiological process of wound repair that leads to the deposit of connective tissue in the extracellular matrix. This complication is mainly associated with different pathologies affecting several organs such as lung, liver, heart, kidney, and intestine. In this fibrotic process, macrophages play an important role since they can...
Article
Full-text available
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-...
Article
Background Fibrosis is a complication commonly present in Crohn’s disease (CD) patients with a structuring (B2) or penetrating (B3) phenotype, with no effective treatment. This process is characterized by a disequilibrium between the production and degradation of the extracellular matrix (ECM), mainly regulated by myofibroblasts. We aim to analyse...
Article
Background Fibrosis constitute the main complications associated to Crohn’s disease (CD). Notch signalling has been implicated in lung, kidney, liver and cardiac fibrosis. Macrophages contribute to fibrosis through the release of different mediators and the pattern of secretion may vary according to their microenvironment. The aim of the present st...
Article
Background Ulcerative colitis (UC) is characterized by a diffuse, continuous, and chronic inflammation of mucosa and submucosa layers in the colon1. Inflammasome complex is involved in the intestinal homeostasis regulation, but its role in UC has not been established yet. We have recently reported that SUCNR1 mediates intestinal inflammation and fi...
Article
Background Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract whose etiology is unknown. CD is associated with complications such as fibrosis or fistula, which cannot be pharmacologically reversed, requiring repeated surgery. Although a profibrotic effect of the P2X7 receptor has been described in some scenarios s...
Article
Background The Krebs cycle metabolite succinate contributes to inflammatory conditions like arthritis and colitis by activating its receptor SUCNR1. We aimed to analyze whether the succinate-SUCNR1 pathway contributes to the leukocyte-endothelial cell interactions that initiate the inflammatory response. Methods We evaluated leukocyte rolling and...
Article
Background Macrophages contribute to fibrosis by releasing different mediators and the pattern of secretion may vary depending on the surrounding environment. We previously described that the mRNA expression of IFNγ was significantly higher in intestinal samples from CD patients. The aim of the present study is to analyze the role of IFNγ-treated m...
Article
Background Crohn’s Disease (CD) patients often develop stenotic complications as immunomodulatory treatments do not prevent the fibrogenic response in the affected tissues, where a dysregulated activation of stromal cells provokes an excessive deposition of extracellular matrix (ECM). Recent evidences support the notion that local cells can sense t...
Article
Background Vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors that plays an immunomodulatory role in the gastrointestinal tract through binding Vitamin D. Single-nucleotide polymorphisms (SNPs) in the VDR gene have been related to inflammatory bowel disease. Indeed, Crohn′s disease (CD) patients carrying th...
Article
Full-text available
Introduction: Intestinal fibrosis, characterized by excessive deposition of extracellular matrix proteins, is a common and severe clinical complication of inflammatory bowel disease (IBD). However, the mechanisms underlying fibrosis remain elusive, and currently, there are limited effective pharmacologic treatments that target the development of f...
Article
Full-text available
Inflammatory bowel disease (IBD) is a relapsing chronic disorder of the gastrointestinal tract characterized by disruption of epithelial barrier function and excessive immune response to gut microbiota. The lack of biomarkers providing early diagnosis or defining the status of the pathology difficulties an accurate assessment of the disease. Given...
Article
Full-text available
G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. T...
Article
The synonymous single nucleotide polymorphism (SNP) rs731236, located in the vitamin D receptor (VDR) gene (Taq I) has been associated with both decreased levels of the protein in peripheral blood mononuclear cells and a fibrosis-related complication in Crohn´s disease (CD). Interactions between VDR and a protein-disulfide isomerase-associated 3 (P...
Article
Full-text available
The pathogenesis of Crohn’s disease-associated fibrostenosis and fistulas imply the epithelial-to-mesenchymal transition (EMT) process. As succinate and its receptor (SUCNR1) are involved in intestinal inflammation and fibrosis, we investigated their relevance in EMT and Crohn’s disease (CD) fistulas. Succinate levels and SUCNR1-expression were ana...
Article
Full-text available
Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression...
Article
Full-text available
Proton-sensing ovarian cancer G-protein coupled receptor (OGR1) plays an important role in pH homeostasis. Acidosis occurs at sites of intestinal inflammation and can induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), an evolutionary mechanism that enables cells to cope with stressful conditions. ER stress activates a...
Article
Background Intestinal fistula is a common complication in CD patients whose aetiology is still not well-characterised. It is associated with an exacerbated inflammation and epithelial-to-mesenchymal transition (EMT), a process which allows a switch from epithelial towards a fibrotic behaviour. We have recently reported that SUCNR1 mediates intestin...
Article
Background Macrophages contribute to fibrosis through the release of different mediators and the pattern of secretion may vary according to their phenotype. Methods The aim of the present study is to analyse the pattern of expression of macrophages, of EMT-related genes and cytokines in surgical resections from Crohn’s disease (CD, n = 43) patient...
Article
Background Fibrosis is a common complication in Crohn’s disease (CD) patients and fibroblasts play an important role in the fibrogenic process. Low vitamin D (VD) levels and a defective VD-signalling pathway have been reported in CD. VD signals through both vitamin D receptor (VDR) and protein disulfide-isomerase A3 (PDIA3) and we have previously d...
Article
Full-text available
The Wnt signaling pathway is a conserved pathway involved in important cellular processes such as the control of embryonic development, cellular polarity, cellular migration, and cell proliferation. In addition to playing a central role during embryogenesis, this pathway is also an essential part of adult homeostasis. Indeed, it controls the prolif...
Article
Full-text available
We recently observed reduced autophagy in Crohn’s disease patients and an anti-inflammatory effect of autophagy stimulation in murine colitis, but both anti- and pro-fibrotic effects are associated with autophagy stimulation in different tissues, and fibrosis is a frequent complication of Crohn’s disease. Thus, we analyzed the effects of pharmacolo...
Article
Full-text available
Background and Aims Epithelial-mesenchymal transition (EMT) has been related to fibrosis and fistula formation, common complications associated to Crohn´s disease (CD). The WNT signaling pathway mediates EMT and specific WNT/FZD interactions have been related with the activation of this process in several diseases. We aim to analyze the relevance o...
Article
Background Environmental hypoxia influences the development of inflammatory bowel diseases. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are tightly regulated by oxygen- and iron-dependent hydroxylases. Regulation of uptake, storage and export of iron is mediated by signals reflecting oxygen and intracellular...
Article
Background Intestinal fibrosis is a common complication of Crohn’s disease (CD) patients and it requires surgery. GWAS studies have identified several polymorphisms in genes involved in autophagy, which predispose to CD. It has been reported that this process is impaired in IBD patients, but the relevance of autophagy in intestinal fibrosis remains...
Article
Background Macrophages contribute to fibrosis through the release of different mediators and the pattern of secretion may vary according to their phenotype. The expression of WNT ligands has been related with the macrophage phenotype and strong evidence identifies the WNT signalling pathway as an emerging modulator of fibrosis. Methods The aim of...
Article
Background Vitamin D deficiency and a defective signalling has been reported in Crohn’s disease (CD) patients. Vitamin D signals through the vitamin D receptor (VDR) which is a member of the nuclear receptor family of transcription factors that play an immunoregulatory role in the gut. We have previously demonstrated that a single-nucleotide polymo...
Article
Background Fibrosis and fistula development constitute the main complications associated to Crohn’s disease. Notch signalling has been implicated in lung, kidney, liver, and cardiac fibrosis and in various disease conditions such as scleroderma. We aim to analyse here the pattern of NOTCH ligands, receptors, and effectors expression in surgical res...
Article
Background Intestinal fistula is a common complication in CD patients whose aetiology is unknown. It is associated with an exacerbated inflammation and epithelial-to-mesenquimal transition (EMT), a process which allows a switch from epithelial towards a fibrotic phenotype. Under inflammatory conditions, succinate is accumulated and activates its re...
Article
Full-text available
Background Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We...
Article
Background: Tissue inflammation in inflammatory bowel diseases [IBD] is associated with local acidification. Genetic variants in the pH-sensing G protein-coupled receptor 65, also known as T cell death-associated gene 8 [TDAG8], have been implicated in IBD and other autoimmune diseases. Since the role of TDAG8 in intestinal inflammation remains un...
Article
Full-text available
Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal su...
Article
Full-text available
Background & Aims Hypoxia-associated pathways influence the development of inflammatory bowel disease. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are regulated by iron-dependent hydroxylases. Signals reflecting oxygen tension and iron levels in enterocytes regulate iron metabolism. Conversely, iron availabil...
Article
Full-text available
Gp96 is an endoplasmic reticulum chaperone for multiple protein substrates. Its lack in intestinal macrophages of Crohn’s disease (CD) patients is correlated with loss of tolerance against the host gut flora. Gp96 has been stablished to be an essential chaperone for Toll-like receptors (TLRs). We studied the impact of gp96-knockdown on TLR-function...
Data
Purity of peritoneal macrophages before FACS analysis. Peritoneal macrophages from both WT and conditional gp96-KO mice were obtained and, purity of macrophages was analysed by flow cytometry for the expression of the macrophage markers CD64 and F4/80. The dot plots are representative for one out of three independent experiments. (TIF)
Article
Full-text available
Background Intestinal fibrosis is a common complication associated with Crohn’s Disease (CD) which cannot be reverted with any drug and forces repeated surgery. It has been reported that succinate, a metabolite accumulated in inflammatory pathologies, plays an important role in the activation of synovial fibroblasts and hepatic stellate cells throu...
Article
Full-text available
Background Fibrosis and fistula development constitute the main complications associated to Crohn′s disease. The Wnt signalling pathway induces fibroblast activation and EMT which are involved in these complications. We aim to analyse here the pattern of Wnt ligands expression in surgical resections from stenotic and fistulising CD patients and to...
Article
Full-text available
Background Vitamin D signals through the vitamin D receptor (VDR) which is a member of the nuclear receptor family of transcription factors that play an immunoregulatory role in the gut. Defective signalling due to vitamin D deficiency or decreased mucosal VDR levels has been related to Crohn’s disease (CD). We aim to analyse the acute effects of V...
Article
Full-text available
Hypoxia regulates autophagy and nucleotide-binding oligomerization domain receptor, pyrin domain containing (NLRP)3, two innate immune mechanisms linked by mutual regulation and associated to IBD. Here we show that hypoxia ameliorates inflammation during the development of colitis by modulating autophagy and mammalian target of rapamycin (mTOR)/NLR...
Article
Full-text available
Background and pourpose: A defective autophagy is involved in the pathogenesis of inflammatory disorders such as IBD. Cross talk interactions between autophagy and inflammation have been reported and we analyse the effects of autophagy stimulators on murine colitis. Experimental approach: Mice were treated with intrarectal administration of TNBS...
Article
Heat shock proteins (HSPs) play an important role in innate immune function of the intestinal mucosa and in the barrier function of intestinal epithelial cells. Among the HSPs expressed in epithelial cells, as well as cells of the innate immune system is Grp94/Gp96. Differences in protein expression of Gp96 have been observed in patients with infla...
Article
Background An imbalance between cellular antioxidant defense system(s) and reactive oxygen species (ROS)-driven oxidative stress has been implicated in the pathogenesis of inflammatory bowel disease. Peroxiredoxin (PRDX) 6, contributes to an appropriate redox balance by clearing ROS and reducing peroxidized membrane phospholipids. Aims We here stu...
Article
Background: The impact of hypoxia on inflammatory bowel disease (IBD) is controversial with studies showing detrimental and protective effects. Hypoxia regulates autophagy and nucleotide-binding oligomerization domain receptor, pyrin domain containing (NLRP)3, two innate immune mechanisms linked by mutual regulation that have been associated to the...
Poster
Background: A family of pH-sensing G-protein coupled receptors (GPCRs), including ovarian cancer G-protein coupled receptor 1 (OGR1), T-cell death-associated gene 8 (TDAG8 or GPR65) and G-protein coupled receptor 4 (GPR4) play an important role in physiological pH homeostasis. Gut-wall inflammation in both forms of inflammatory bowel disease (IBD),...
Article
Full-text available
Background: A defective autophagy is involved in the pathogenesis of inflammatory disorders such as IBD. Cross talk interactions between autophagy and inflammation have been reported and we analyse the effects of autophagy stimulators on murine colitis. Methods: Mice were treated with intrarectal administration of TNBS (3.5 mg/20 mg mice) and body...
Article
Background: Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are typically associated with a decrease in local pH. Genome-wide association studies (GWAS) identified over 200 non-overlapping single-nucleotide polymorphism (SNP) genetic risk loci for IBD. The proton-sensing G-protein-coupled receptor T-cell death a...
Article
Background: Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are typically associated with a decrease in local pH. Genome-wide association studies (GWAS) revealed a strong genetic impact on IBD, identifying over 200 non-overlapping single-nucleotide polymorphism (SNP) genetic risk loci for IBD. G-protein-coupled...
Article
Full-text available
Background & Aims A novel family of proton-sensing G-protein–coupled receptors, including ovarian cancer G-protein–coupled receptor 1 (OGR1) (GPR68) has been identified to play a role in pH homeostasis. Hypoxia is known to change tissue pH as a result of anaerobic glucose metabolism through the stabilization of hypoxia-inducible factor-1α. We inves...
Poster
Intestinal fibrosis, which is caused by excessive extracellular matrix deposition, is a common complication of inflammatory bowel disease. Macrophages assume a wide spectrum of different functional phenotypes (M1, M2a, M2b, and M2c) that differ in the expression of surface proteins, transcription factors, and cytokine production. It is believed tha...
Article
Background: Fibrosis as a common problem in patients with Crohn's disease is a result of an imbalance toward excessive tissue repair. At present, there is no specific treatment option. Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis with both antifibrotic and anti-inflammatory effects. We subsequently investigated the im...
Article
Full-text available
Background & aims: IBD is a chronic disorder of the gastrointestinal tract characterized by mucosal inflammation and epithelial damage. Biologic therapy has significantly improved the course of the disease but there are still a high percentage of patients that do not respond to current therapies. We aim to determine the effects of the flesh ethano...
Article
Full-text available
Background: The Notch signaling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and HIF. We aim to analyze the role of HIF in the expression...