Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the interactions of 5-aminosalicylic acid with nitric oxide (NO). Phenylephrine-precontracted rat aortic strips with intact endothelium were further contracted by 5-aminosalicylic acid (50-200 microM) in a concentration-dependent manner. Removal of endothelium, inhibition of guanylate cyclase by methylene blue, inhibition of NO biosynthesis by NG-nitro-L-arginine as well as in inactivation of NO by oxyhemoglobin abolished the effect of 5-aminosalicylic acid. The antiaggregatory effects of 3-morpholinosydnonimine and rat peritoneal neutrophils, which are due to release of NO, were diminished in a concentration-dependent manner by 5-aminosalicylic acid (50-250 microM). In both experimental models the effects of 5-aminosalicylic acid were significantly reduced by superoxide dismutase in a concentration which alone exhibited no effect. Since NO might act as a cytotoxic and vasodilating mediator, our results suggest that inactivation of NO by 5-aminosalicylic acid could contribute to the therapeutic activity of the drug in inflammatory bowel disease.
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PMID:Interaction of 5-aminosalicylic acid with nitric oxide on rat aortic strips and human platelets. 749 69

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.
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PMID:Nitric oxide stimulates cyclic guanosine monophosphate production and electrogenic secretion in Caco-2 colonocytes. 991 96

Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the conversion of cyclooxygenase-derived prostaglandin (PG) H(2) to PGE(2). Increased amounts of mPGES-1 were detected in inflamed intestinal mucosa from patients with inflammatory bowel disease (IBD). Treatment with tumor necrosis factor (TNF)-alpha stimulated mPGES-1 transcription in human colonocytes, resulting in increased amounts of mPGES-1 mRNA and protein. The inductive effect of TNF-alpha localized to the GC box region of the mPGES-1 promoter. Binding of Egr-1 to the GC box region of the mPGES-1 promoter was enhanced by treatment with TNF-alpha. Notably, increased Egr-1 expression and binding activity were also detected in inflamed mucosa from IBD patients. Treatment with TNF-alpha induced the activities of phosphatidylcholine-phospholipase C (PC-PLC) and protein kinase (PK) C and enhanced NO production. A pharmacological approach was used to implicate PC-PLC --> PKC --> NO signaling as being important for the induction of mPGES-1 by TNF-alpha. TNF-alpha also enhanced guanylate cyclase activity and inhibitors of guanylate cyclase activity blocked the induction of mPGES-1 by TNF-alpha. YC-1, an activator of guanylate cyclase, induced mPGES-1. Overexpressing a dominant negative form of PKG blocked TNF-alpha-mediated stimulation of the mPGES-1 promoter. Taken together, these results suggest that overexpression of mPGES-1 in IBD is the result of Egr-1-mediated activation of transcription. Moreover, TNF-alpha induced mPGES-1 by stimulating PC-PLC --> PKC --> NO --> cGMP --> PKG signal transduction pathway.
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PMID:Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1. 3190 Mar 75

Nitric oxide (NO) has been associated with a spectrum of harmful to protective roles in inflammatory bowel disease. The involvement of soluble guanylate cyclase (sGC)--the downstream effector of NO--in the negative effect of NO in inflammatory models has been proposed but this has not been evaluated in inflammatory bowel diseases. The present study investigates therefore the influence of colonic inflammation on sGC activity, as well as the effect of in vivo sGC inhibition on colonic inflammation and on in vitro changes in colonic motility in the dextran sulfate sodium (DSS)-model of colitis in rat. Administration of 7% DSS in the drinking water for 6 days resulted in colonic inflammation as judged from histology and myeloperoxidase activity, accompanied by weight loss and bloody stools. Plasma and colonic tissue cyclic guanosine 3',5'-monophosphate (cGMP) levels were decreased in DSS-treated rats. Colonic levels of neuronal NO synthase (nNOS) mRNA and immunoreactivity were not influenced, while those of inducible NO synthase (iNOS) and colonic nitrite/nitrate levels were increased by DSS exposure. Circular muscle strips from inflamed distal colon showed decreased inhibitory responses towards electrical field stimulation and exogenous NO, while methacholine-induced phasic activity was suppressed. Inhibition of sGC by in vivo treatment with ODQ further reduced cGMP levels but did not prevent the inflammation and motility alterations. These results suggest that DSS-induced colitis in rats is accompanied by a reduced sensitivity of sGC, leading to reduced basal cGMP levels and decreased colonic responsiveness towards nitrergic stimuli, but pharmacological reduction of cGMP generation does not prevent the development of DSS-induced colitis.
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PMID:Influence of soluble guanylate cyclase inhibition on inflammation and motility disturbances in DSS-induced colitis. 1802 54

The scientific community has witnessed an exponential growth curve in the number of nitric oxide (NO) related publications over the last ten years. This diatomic radical is remarkably entangled (directly and indirectly) in a multitude of physiological and pathophysiological processes, including blood pressure regulation, inflammation, apoptosis, platelet adhesion, neurotransmission and host-defense mechanisms. Of the three known isozymes responsible for catalyzing the production of NO from L-arginine (L-Arg), it is the inducible form of nitric oxide synthase (iNOS) that we wish to examine here due to its involvement in a collection of diseases, including septic- and cytokine-induced shock, immune-type diabetes, rheumatoid arthritis, tissue damage, inflammation, and inflammatory bowel disease. Controlling the unregulated overproduction of NO from iNOS has been a formidable task; therapeutic intervention strategies range from preventing iNOS mRNA expression (anticytokine antibodies/receptor antagonists) to impeding NO action (NO scavengers, guanylyl cyclase inhibitors). Within these extremes lies the most conventional tactic, prohibiting NO production from iNOS with L-arginine competitive antagonists or irreversible enzyme inhibitors. This review will cover the more recent accounts gauged toward the identification and development of novel inhibitors of iNOS.
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PMID:Inhibition on inducible nitric oxide synthase. 1964 18

Mesenteric lymphatic vessels actively transport lymph, immune cells, fat, and other macromolecules from the intestine via a rhythmical contraction-relaxation process called lymphatic pumping. We have previously demonstrated that mesenteric lymphatic pumping was compromised in the guinea pig model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis, corroborating clinical and experimental observations of a dilated and/or obstructed phenotype of these vessels in inflammatory bowel disease. Many mediators released during the inflammatory process have been shown to alter lymphatic contractile activity. Among them, nitric oxide (NO), an inflammatory mediator abundantly released during intestinal inflammation, decreases the frequency of lymphatic contractions through activation of ATP-sensitive potassium (K(ATP)) channels. The objective of this study was to investigate the role of NO and K(ATP) channels in the lymphatic dysfunction observed in the guinea pig model of TNBS-induced ileitis. Using quantitative real-time PCR, we demonstrated that expression of Kir6.1, SUR2B, and inducible NO synthase (iNOS) mRNAs was significantly upregulated in TNBS-treated animals. Pharmacological studies performed on isolated, luminally perfused mesenteric lymphatic vessels showed that the K(ATP) channels blocker glibenclamide, the selective iNOS inhibitor 1400W, and the guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly improved lymphatic pumping in quiescent lymphatic vessels from TNBS-treated animals. Membrane potential measurement with intracellular microelectrodes revealed that vessels from TNBS-treated animals were hyperpolarized compared with their sham counterpart and that the hyperpolarization was significantly attenuated in the presence of glibenclamide and ODQ. Our findings suggest that NO and K(ATP) play a major role in the lymphatic contractile dysfunction that occurred as a consequence of the intestinal inflammation caused by TNBS.
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PMID:Involvement of the NO-cGMP-K(ATP) channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis. 2327 12

Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.
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PMID:Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. 2635 73

Congenital diarrheal disorders (CDDs) represent a group of challenging clinical conditions for pediatricians because of the severity of the presentation and the broad range of possible differential diagnoses. CDDs arise from alterations in the transport of nutrients and electrolytes across the intestinal mucosa, from enterocyte and enteroendocrine cell differentiation and/or polarization defects, and from the modulation of the intestinal immune response. Advances were made recently in deciphering the etiology and pathophysiology of one of these disorders, congenital sodium diarrhea (CSD). CSD refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. A syndromic form of CSD features choanal and intestinal atresias as well as recurrent corneal erosions. Small bowel histology frequently detects an epithelial "tufting" dysplasia. It is autosomal recessively inherited, and caused by SPINT2 mutations. The nonsyndromic form of CSD can be caused by dominant activating mutations in GUCY2C, encoding intestinal receptor guanylate cyclase C (GC-C), and by autosomal recessive SLC9A3 loss-of-function mutations. SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease. Both the number of recognized CDD forms as well as the number of underlying disease genes are gradually increasing. Knowledge of these CDD genes enables noninvasive, next-generation gene panel-based testing to facilitate an early diagnosis in CDD. Primary Na/H antiporter 3 and GC-C malfunction is implicated as a predisposition for inflammatory bowel disease in subset of patients.
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PMID:Congenital Sodium Diarrhea: A Form of Intractable Diarrhea, With a Link to Inflammatory Bowel Disease. 2683 7

The transmembrane receptor guanylate cyclase-C (GC-C) signaling pathway has been implicated in several gastrointestinal disorders. Activation of GC-C via guanylin (Gn) and uroguanylin (Ugn) regulates intestinal fluid and electrolyte homeostasis. However, how it regulates the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we investigated the activation of GC-C signaling in ulcerative colitis (UC) of different clinical severities. A total of 60 UC patients and 20 normal controls were recruited. Evaluation of the UC disease activity index (DAI) was performed using a modified Mayo scoring system. The expression of GC-C, Gn and Ugn in the colonic mucosa was measured by quantitative real-time PCR and Western blot. We found that the UC patients had significantly lower expression of GC-C, Gn and Ugn than the controls. Furthermore, there were significant differences for GC-C, Gn and Ugn expression for the UC groups of Grade 1, 2 and 3, and their expression levels were reduced with increases in their DAI. Taken together, our results demonstrate that GC-C, Gn and Ugn are downregulated in UC, and this downregulation is more significant with aggravation of the clinical condition. Therefore, the GC-C signaling pathway may be implicated in the progression of UC.
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PMID:Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index. 2712 48

Inflammatory bowel diseases are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Peptides as small as three amino acids have been shown to have anti-inflammatory activity in mouse models of colitis, but they are likely to be unstable, limiting their development as drug leads. Here, we have grafted a tripeptide from the annexin A1 protein into linaclotide, a 14-amino-acid peptide with three disulfide bonds, which is currently in clinical use for patients with chronic constipation or irritable bowel syndrome. This engineered disulfide-rich peptide maintained the overall fold of the original synthetic guanylate cyclase C agonist peptide, and reduced inflammation in a mouse model of acute colitis. This is the first study to show that this disulfide-rich peptide can be used as a scaffold to confer a new bioactivity.
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PMID:Engineering of an Anti-Inflammatory Peptide Based on the Disulfide-Rich Linaclotide Scaffold. 3030 Dec


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