Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute bacterial diarrheal disease is a worldwide problem of enormous magnitude. In recent years a number of bacteria have been added to the list of recognized etiologic agents causing acute diarrheal disease. This was made possible by our increased understanding of the mechanisms by which such bacteria cause diarrhea and by the development of methods to detect these bacterial enteropathogens. We are now able to define an etiologic agent in 50-80% of cases of acute diarrhea, depending on the particular population. The bacterial agents recently incriminated as important causes of diarrhea include E coli Y. enterocolitica, B. cereus, C. fetus, V. parahemolyticus, and many other coliform organisms. Establishment of an enteric infection depends upon a complex interplay between host defense mechanisms and bacterial virulence factors adapted to overcome these defenses. Bacterial enteropathogens cause diarrhea primarily by elaborating enterotoxins (which also requires the organisms to adhere to the surface of the intestinal cell) and by invading the intestinal mucosa. The number of known bacterial enterotoxins has rapidly increased. Enterotoxins cause intestinal secretion and diarrhea by stimulating the adenyl cyclase system or the guanyl cyclase system and by other mechanisms yet to be defined. The ability of enterotoxigenic bacteria to adhere to the intestine involves a specific binding interaction between bacterial structures called pili or fimbriae and specific receptors on the surface of intestinal cells. Both bacterial pili and the intestinal receptors are under genetic control. A variety of other bacteria, Salmonellae, Shigellae, Y. enterocolitica etc, must invade the mucosa to cause diarrheal disease. The ability to invade is essential to the pathogenesis of disease and requires particular surface characteristics of the bacterium as well as the active participation of both the bacterium and the host cell. The bacteria probably elaborate substances that signal the host cell to initiate the invasive process, i.e. endocytosis. The mechanism by which invasive bacteria evoke intestinal secretion is uncertain but is probably a multifactorial process involving products elaborated by the mucosal acute inflammatory reaction and enterotoxins elaborated by the bacteria.
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PMID:Pathogenesis of acute bacterial diarrheal disorders. 701 73

In detail, exoproducts of Aeromonas hydrophila and Plesiomonas shigelloides were studied on the pathogenesis of diarrhoea. Enterotoxin, hemolysin and a cytotoxic factor were found in a fraction of culture filtrates of Aeromonas hydrophila with a molecular weight of approximatley 60,000. Apart there from a cytotoxic factor was also found in a fraction with molecular weight above 100,000. This fraction contained also endotoxin which was hemolytic, too. Enterotoxic activity was expressed by an accumulation of fluid in the ligated ileal loop and by increased vascular permeability in the skin of rabbit. Activation of adenylate cyclase was not found. Cytotoxic activity was represented by hemorrhagic reaction in the skin of rabbit, in some cases by sanguinous and mucous fluid in the ligated ileal loop and by significant morphological alterations on Vero cells leading to the death of cells. Culture filtrates of Plesiomonas shigelloides show only very low activity in biological experiments. Separation and purification steps led to a more concentrated and active material.
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PMID:Toxic factors of Aeromonas hydrophila and Plesiomonas shigelloides. 718 Feb 35

Unabsorbed dietary unsaturated fatty acids may cause diarrhea in patients with steatorrhea, but their ability to cause colonic fluid secretion is not known. The present study investigated the effect of several dietary long-chain unsaturated fatty acids on colonic absorption and morphology in the rat colon in vivo. The fatty acids tested induced concentration-dependent net water secretion. The ability of these fatty acids to induce net water secretion varied as follows: linolenic acid (18:3) > linoleic acid (18:2), ricinoleic acid (18:1 OH) > oleic acid (18:1), palmitoleic acid (16:1). Net absorption of sodium and chloride were decreased in fatty acid perfusions. Mucosal activity of sodium potassium adenosine triphosphate and adenyl cyclase were not significantly altered by fatty acids. Epithelial cell damage was noted and correlated with the ability of the fatty acid to induce fluid secretion. Unsaturated fatty acids induce epithelial cell damage and fluid secretion in the colon, their effect being related to the degree of unsaturation.
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PMID:Alteration of colonic absorption by long-chain unsaturated fatty acids. Influence of hydroxylation and degree of unsaturation. 790 28

Prostaglandins of the E series (PGE) are known to stimulate intestinal water and electrolyte secretions via the activation of the enterocyte adenylate cyclase. Their methylated synthetic analogs misoprostol and enprostil induced diarrhea in 5-13% of the patients in most clinical studies. In order to elucidate the role of PGE-adenylate cyclase interaction in these phenomena, we studied the stimulation of adenylate cyclase by native prostaglandin E2 (PGE2) and synthetic PGE analogs on isolated guinea pig intestinal epithelial cells. PGE2 stimulation of adenylate cyclase was dose-dependent, reaching a maximum for 3 x 10(-4) M, with an EC50 of 3.7 x 10(-6) M. The Hill analysis of the concentration-response curve gave a straight line, with a slope close to 1. The effect of PGE2 was strictly additive to that of 10(-5) M forskolin, whereas it was decreased in terms of potency by 10(-9) M cholera toxin. Somatostatin-14 markedly inhibited PGE2 stimulation by 37% and 45% with 10(-9) M and 10(-6) M, respectively. The two PGE methylated analogs misoprostol and enprostil were less potent than PGE2 in stimulating adenylate cyclase in our model.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of PGE2, misoprostol, and enprostil on guinea pig enterocyte adenylate cyclase. Clinical implications. 842 43

Vibrio cholerae produce a variety of extracellular products that have deleterious effects on eukaryotic cells. The massive diarrhoea produced by V. cholerae is caused by cholera toxin (CT). CT is composed of 1A and 5B units. CT causes a significant amount of fluid secretion and haemorrhage in the ligated rabbit ileal loops. Its action involves the role of various biochemical pathways. CT acts by activation of adenylate cyclase-cAMP system located at the basolateral membrane of intestinal epithelial cells. The increase in cyclic AMP levels is mainly responsible for the altered transport of Na+ and Cl-. Besides activating cAMP, CT is also known to act through release of prostaglandins and involvement of intramural nerves. Besides CT, other bacterial toxins like Escherichia coli LT, Salmonella toxin, Shigella toxin and Campylobacter toxin also possess A-B structure. The structure and function of E. coli LT resembles closely that of CT. Most of the bacterial toxins exert their effect through involvement of ADP-ribosylating proteins whereas other toxins involve guanylate cyclase system, calcium and protein kinases for their ultimate action.
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PMID:Mechanism of action of cholera toxin & other toxins. 878 5

Current advances in the study of gut mucosal immunology and molecular biology have enhanced our ability to understand the pathogenesis of enteric bacterial infections as well as the role of the immune system in mediating both tissue injury and protection. In this article, we review the immunopathogenesis and the protective immune response to three enteric pathogens, Vibrio cholerae, Shigella, and Salmonella. Each of these pathogens has a distinctive mechanism by which it causes disease, ie, epithelial attachment, epithelial invasion, and epithelial invasion with systemic dissemination. Pathogenicity and immune response can be conceptualized in terms of the interaction of these enteric pathogens with the gut epithelial compartment, immune inductive sites (Peyer's patch of the small intestine and lymphoid follicles of the colon), and a common immune effector compartment in the laimina propria where protective antibody is secreted. V cholerae, the representative noninvasive pathogen, has fimbrial adhesins that mediate attachment and colonization of the luminal surface of epithelial cells where organisms secrete cholera toxin (CT), a potent enterotoxin that induces a voluminous diarrhea via adenylate cyclase-dependent chloride secretion. Protective immunity is based on secretory (s) immunoglobulin A directed against whole-cell components that prevent attachment to gut epithelial cells and is enhanced by CT, an immunogen with potent adjuvant activity. Shigella, an enteric pathogen that locally invades gut epithelium, subverts the usual mechanism of immune sampling by initially invading via M cells overlying inductive sites. Subsequent macrophage invasion induces apoptosis and the release of interleukin-1, a proinflammatory cytokine. This seems to be a critical initiating event in immune-mediated tissue injury. Protective immunity is serotype specific. Infection caused by Salmonella is characterized by mucosal invasion and systemic spread mediated by the organisms ability to survive within macrophages. Both antibody and cell-mediated immunity are important for protection against Salmonella.
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PMID:Mucosal immune responses to intestinal bacterial pathogens. 881 67

Infant rabbits (10-12-day old) were infected with El Tor 5879 culture via stomach. During the period of cholera vibrio adhesion (within 4 hr) and twice on the following day the animals were injected intraperitoneally with alpha- and beta-adrenoblockers pyrroxan and obsidan. It was established that mono- or combined therapy with adrenergic blocking agents prevents the vibrio adhesion, cholera vibrios were detected mainly in the small intestine lumen. In addition, adrenoblockers arrest adenylate cyclase activation realized through cAMP formation and subsequent diarrhea development.
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PMID:[The effect of adrenoblockers on the ultrastructural changes in the epithelium and neural elements of the small intestine of suckling rabbits with experimental cholera]. 913 94

In the rapidly increasing elderly population, diarrhoea as a result of drug therapy is an important consideration. The elderly consume a disproportionately large number of drugs for multiple acute and chronic diseases. Drugs can compromise both immune and nonimmune responses. Aging decreases the quality and proportion of T cells which in turn reduces the production of secretory IgA, the primary immune response of the gut. Acid production in the stomach decreases with increasing age and this compromise its vital 'self-sterilising' function, thus increasing the risk of diarrhoea due to viral, bacterial and protozoal pathogens. Other nonimmune defence mechanisms include the motility of the small intestine and the host-protective commensal bacteria of the colon. Drug induced hypomotility may result in bacterial overgrowth, deconjugation of bile salts and diarrhoea. Less commonly, diarrhoea may occur due to hypermotility because of a cholinergic-like syndrome. In the colon the host-protective commensal bacteria provide a powerful defence against pathogens. Disruption of this commensal population by antibiotic therapy may result in Clostridium difficile supra-infection which causes diarrhoea through toxin production. This is especially important in the elderly patient on chemotherapy for malignancy and those with multiple diseases. The organism responds to vancomycin, metronidazole and bacitracin. Metronidazole is the suggested drug of choice, with vancomycin reserved for relapses. Drugs also cause diarrhoea by interfering with normal physiological processes. Drugs impair fluid absorption by activating adenylate cyclase within the small intestinal enterocyte which increases the level of cyclic AMP. This causes active secretion of Cl- and HCO3-, passive efflux of Na+, K+ and water and inhibition of Na+ and Cl- into the enterocyte. Examples of these drugs (secretagogues) are bisacodyl, misoprostol and chenodeoxycholic acid (used to dissolve cholesterol gallstones). Drugs may also affect a second mechanism that regulates water and electrolyte transport, the Na+, K+ exchange pump. The energy for this pump is provided by the ATPase mediated breakdown of ATP. ATPase may be inhibited by digoxin, auranofin, colchicine and olsalazine. A number of drugs cause osmotic diarrhoea including antacids containing magnesium trisilicate or hydroxide. Lactulose is being used increasingly in compensated liver disease to increase protein tolerance and prevent hepatic encephalopathy. Sorbitol, an osmotic laxative agent also used in some liquid pharmaceutical preparations, induces diarrhoea by virtue of its osmotic potential. Another mechanism by which drugs cause diarrhoea is by mucosal damage of the small and large bowel. In the small intestine mucosal damage causes diarrhoea and fat malabsorption, as may occur with neomycin and colchicine. In the colon, for example, gold salts and penicillamine cause colitis of varying severity. Though the causes of diarrhoea are diverse, a drug-associated aetiology should always be considered and actively sought and addressed to prevent the complications of dehydration, electrolyte imbalance and undernutrition.
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PMID:Mechanisms of drug-induced diarrhoea in the elderly. 978 28

Genus Vibrio includes some pathogenic species which are classified into two groups: a gastrointestinal infection group and an extraintestinal infection group. The vibrios produce various toxic proteins. Cholera toxin (CT) produced by V. cholerae O1 and O139 is a factor causing diarrhea with severe dehydration by ADP-ribosylation of the alpha subunit of the GTP-binding protein which stimulates adenylate cyclase activity. CT-like toxins are found in some strains of V. cholerae non-O1 or V. mimicus, but not in V. parahaemolyticus, another major diarrheagenic vibrio species. A thermostable direct hemolysin (TDH) is thought to be the pathogenic factor causing diarrhea in the vibrio. Hemolysin is the most widely distributed toxin in the pathogenic vibrios and plays various roles in the infection process. Protease activity is also common in the vibrios. Many of the proteases produced by the vibrios are a metalloprotease having a zinc atom immunologically cross reactive to each other. The proteases act not only for processing and activation of protein toxins but also direct toxic factors causing edematous or hemorrhagic skin lesions or disturbance of host defense system.
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PMID:Protein toxins produced by pathogenic vibrios. 1041 Mar 36

The mechanisms by which enteropathogenic Escherichia coli (EPEC), an important cause of diarrhea among infants in developing countries, induce symptoms are not defined. EPEC have a type III secretion system required for characteristic attaching and effacing changes that modify the cytoskeleton and apical surface of host cells. Infection of polarized intestinal epithelial cell monolayers by EPEC leads to a loss of transepithelial electrical resistance, which also requires the type III secretion system. We demonstrate here that EspF, a protein that is secreted by EPEC via the type III secretion system, is not required for quantitatively and qualitatively typical attaching and effacing lesion formation in intestinal epithelial cells. However, EspF is required in a dose-dependent fashion for the loss of transepithelial electrical resistance, for increased monolayer permeability, and for redistribution of the tight junction-associated protein occludin. Furthermore, the analysis of EPEC strains expressing EspF-adenylate cyclase fusion proteins indicates that EspF is translocated via the type III secretion system to the cytoplasm of host cells, a result confirmed by immunofluorescence microscopy. These studies suggest a novel role for EspF as an effector protein that disrupts intestinal barrier function without involvement in attaching and effacing lesion formation.
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PMID:Translocated EspF protein from enteropathogenic Escherichia coli disrupts host intestinal barrier function. 1123 63


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