cyclic-gmp and Inflammatory-Bowel-Diseases

Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C is also causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. These advances have been fueled in part by identifying mutations or changes in gene expression in GC-C or its ligands, that disrupt the delicate balance of intracellular cGMP levels and are associated with a wide range of clinical phenotypes. In this review, we highlight aspects of the current knowledge of the GC-C signaling pathway in homeostasis and disease, emphasizing recent advances in the field. The review summarizes extra gastrointestinal functions for GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has expanded the homeostatic role of GC-C and implicated it in regulating the ion-microbiome-immune axis, which acts as a mechanistic driver in inflammatory bowel disease. The development of transgenic and knockout mouse models allowed for in-depth studies of GC-C and its relationship to whole-animal physiology. A deeper understanding of the various aspects of GC-C biology and their relationships with pathologies such as inflammatory bowel disease, colorectal cancer, and obesity can be leveraged to devise novel therapeutics.

Topics: Animals; Cyclic GMP; Inflammatory Bowel Diseases; Mice; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Signal Transduction

Guanylate cyclase C (GC-C) receptor is a transmembrane receptor, predominantly expressed in intestinal epithelial cells, which is considered to play a main role in homeostasis and function of the digestive tract. The endogenous ligands for this receptor are the paracrine hormones uroguanylin and guanylin. Upon ligand binding, GC-C receptors increase cyclic guanosine monophosphate (cGMP) levels, regulating a variety of key cell-type specific processes such as chloride and bicarbonate secretion, epithelial cell growth, regulation of intestinal barrier integrity and visceral sensitivity. It has been suggested that GC-C acts as an intestinal tumor suppressor with the potential to prevent the initiation and progression of colorectal cancer. In fact, loss of ligand expression is a universal step in sporadic colorectal carcinogenesis. Interestingly, the role of GC-C is not limited to the digestive tract but it has been extended to several other systems such as the cardiovascular system, kidney, and the central nervous system, where it has been involved in a gut-hypothalamus endocrine axis regulating appetite. Objetive: In this review we summarize the physiology of the GC-C receptor and its ligands, focusing on newly developed drugs like linaclotide, and their suggested role to reverse/prevent the diseases in which the receptor is involved.. Available data points toward a relationship between uroguanylin and guanylin and their receptor and pathological processes like gastrointestinal and renal disorders, colorectal cancer, obesity, metabolic syndrome and mental disorders among others. Recent pharmacological developments in the regulation of GC-receptor may involve further improvements in the treatment of relevant diseases.

Topics: Animals; Colorectal Neoplasms; Cyclic GMP; Gastrointestinal Hormones; Guanylate Cyclase; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Kidney Diseases; Natriuretic Peptides; Obesity; Protein Binding; Protein Transport; Receptors, Peptide; Signal Transduction

Inflammatory bowel disease (IBD) symbolizes a group of intestinal disorders in which prolonged inflammation occur in the digestive tract (esophagus, large intestine, small intestine mouth, stomach). Both genetic and environmental factors (infections, stress, diet) are involved in the development of IBD. As we know that bacteria are found in the intestinal mucosa of human and clinical observations revealed bacterial biofilms associated with patients of IBD. Various factors and microbes are found to play an essential role in biofilm formation and mucosal colonization during IBD. Biofilm formation in the digestive tract is dependent on an extracellular matrix synthesized by the bacteria and it has an adverse effect on the immune response of the host. There is no satisfactory and safe treatment option for IBD. Therefore, the current research aims to disrupt biofilm in IBD and concentrates predominantly on improving the drug. Here, we review the literature on bacterial biofilm and IBD to gather new knowledge on the current understanding of biofilm formation in IBD, host immune deregulation and dysbiosis in IBD, molecular mechanism, bacteria involved in biofilm formation, current and future regimen. It is urgently required to plan new ways to control and eradicate bacteria in biofilms that will open up novel diagnostic and therapeutic avenues for IBD. This article includes the mechanism of signaling molecules with respect to the biofilm-related genes as well as the diagnostic methods and new technologies involved in the treatment of IBD.

Topics: Anti-Inflammatory Agents; Bacteria; Biofilms; Cyclic GMP; Dysbiosis; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Immunosuppressive Agents; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Quorum Sensing; Stomach

Topics: Animals; Chloramines; Colitis; Cyclic GMP; Diarrhea; Disease Models, Animal; Free Radicals; Humans; Hydrogen Peroxide; Inflammatory Bowel Diseases; Ion Transport; Nitric Oxide; Nitrogen; Rats; Reactive Oxygen Species

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1

Topics: Animals; Cyclic AMP; Cyclic GMP; Inflammatory Bowel Diseases; Mice; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases

Activating mutations in receptor guanylyl cyclase C (GC-C), the target of gastrointestinal peptide hormones guanylin and uroguanylin, and bacterial heat-stable enterotoxins cause early-onset diarrhea and chronic inflammatory bowel disease (IBD). GC-C regulates ion and fluid secretion in the gut via cGMP production and activation of cGMP-dependent protein kinase II. We characterize a novel mouse model harboring an activating mutation in Gucy2c equivalent to that seen in an affected Norwegian family. Mutant mice demonstrated elevated intestinal cGMP levels and enhanced fecal water and sodium content. Basal and linaclotide-mediated small intestinal transit was higher in mutant mice, and they were more susceptible to DSS-induced colitis. Fecal microbiome and gene expression analyses of colonic tissue revealed dysbiosis, up-regulation of IFN-stimulated genes, and misregulation of genes associated with human IBD and animal models of colitis. This novel mouse model thus provides molecular insights into the multiple roles of intestinal epithelial cell cGMP, which culminate in dysbiosis and the induction of inflammation in the gut.

Topics: Animals; Colitis; Colon; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type II; Disease Models, Animal; Dysbiosis; Gene Expression; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Mice; Mutation; Receptors, Enterotoxin; Signal Transduction

Matrix metalloproteinase-9 is upregulated in inflammatory bowel disease. Barbiturate nitrate hybrid compounds have been designed to inhibit MMP secretion and enzyme activity. In this study, we investigated the mechanism of action of barbiturate-nitrate hybrid compounds and their component parts using models of intestinal inflammation in vitro. Cytokine-stimulated Caco-2 cells were used in all in vitro experiments. The NO donors SNAP and DETA-NONOate were used to study the effect of NO on MMP-9 mRNA. Mechanistic elucidation was carried out using the soluble guanylate cyclase (sGC) inhibitor, ODQ, and the cGMP analogue, 8-Bromo-cGMP. Further experiments were carried out to elucidate the role of NF-κB. NO donors exerted an inhibitory effect on MMP-9 mRNA in cytokine-stimulated cells. While the non-nitrate barbiturates had a limited effect on MMP-9 expression, the hybrid compounds inhibited MMP-9 expression through its NO-mimetic properties. No effect could be observed on mRNA for MMP-1 or MMP-2. The sGC inhibitior, ODQ, abolished the nitrate-barbiturate inhibition of MMP-9 gene expression, an effect which was reversed by 8-Br-cGMP. This study shows that the barbiturate scaffold is suitable for hybrid design as an MMP-9 inhibitor in cytokine-stimulated Caco-2 cells. The inhibition of MMP-9 levels was largely mediated through a reduction in its mRNA by a sGC/cGMP pathway mediated mechanism.

Topics: Anti-Inflammatory Agents; Barbiturates; Caco-2 Cells; Cyclic GMP; Humans; Inflammatory Bowel Diseases; Matrix Metalloproteinase 9; Nitrates; Nitric Oxide; Signal Transduction; Up-Regulation

Nitric oxide stimulates intestinal ion transport via the activation of enteric nerves, but it is not known whether it regulates intestinal transport function by acting on the epithelium directly. The aim of this study was to determine the influence of nitric oxide on epithelial electrogenic ion secretion, measured as the short-circuit current (Isc), using the human colonic carcinoma cell line Caco-2. The cellular mechanisms were examined by measuring epithelial cGMP production, and nitrite release was monitored as an index of nitric oxide synthesized. The nitric oxide substrate L-arginine methyl ester increased nitrite release, electrogenic secretion and cell cGMP production. Pretreatment with L-NAME (Nomega-nitro-L-arginine methyl ester, 1 mM), but not the D-isomer, significantly reduced the electrogenic secretion and cGMP production evoked by L-arginine methyl ester, implicating nitric oxide synthase involvement. Pretreatment with cystamine, but not Methylene Blue, significantly reduced the maximum Isc and the cGMP release induced by L-arginine methyl ester and the nitric oxide donor sodium nitroprusside, implicating the involvement of particulate guanylate cyclase. In conclusion, nitric oxide stimulates electrogenic ion secretion and cGMP production in intestinal epithelial cells by activating particulate guanylate cyclase. The direct action of nitric oxide on the intestinal epithelium may be important in the regulation of intestinal transport function in health and in inflammatory bowel disease.

Topics: Arginine; Caco-2 Cells; Cyclic GMP; Cystamine; Enzyme Inhibitors; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Ion Transport; Isomerism; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Nitroprusside