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)

The reported incidence of "pathogenic" bacteria, as judged by serotype, in the stools of children with acute diarrhoea has varied from 4 to 33% over the last twenty years. Techniques such as tissue culture provide a means for detecting enterotoxin-producing strains of bacteria, strains which often do not possess "pathogenic" serotypes. "Pathogenicity" requires redefinition, and the aetiological importance of bacteria in diarrhoea is probably considerably greater than previous reports have indicated. Colonization of the bowel by a pathogen will result in structural and/or mucosal abnormalities, and will depend on a series of complex interactions between the external environment, the pathogen, and the host and its resident bacterial flora. Enteropathogenic bacteria may be broadly classified as (i) invasive (e.g. Shigella, Salmonella and some Escherichia coli) which predominantly affect the distal bowel, or (ii) non-invasive (e.g. Vibrio cholerae and E. coli) which affect the proximal bowel. V. cholerae and E. coli elaborate heat-labile enterotoxins which activate adenylate cyclase and induce small intestinal secretion; the secretory effects of heat-stable E. coli and heat-labile Shigella dysenteriae enterotoxins are not accompanied by cyclase activation. The two major complications of acute diarrhoea are (i) hypernatraemic dehydration with its attendant neurological, renal and vascular lesions, and (ii) protracted diarrhoea which may lead to severe malnutrition. Deconjugation of bile salts and colonization of the small bowel with toxigenic strains of E. coli may be important in the pathophysiology of the protracted diarrhoea syndrome. The control of bacterial diarrhoea requires a corrdinated political, educational, social, public health and scientific attack. Bacterial diarrhoea is a major health problem throughout the world, and carries an appreciable morbidity and mortality. This is particularly the case during infancy, and in those developing parts of the world where malnutrition is common. This paper is concerned mainly with acute bacterial diarrhoea, and reviews the problem as a whole.
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PMID:The problem of bacterial diarrhoea. 79 97

It is apparent that there are considerable similarities between many of the enterotoxins produced by enteric pathogens. Although the effect of most of these toxins is restricted to the intestine in vivo, many cells are also sensitive to intoxication in vitro. The resultant in-vitro biochemical changes may have no pathological significance but serve to underline the central role of cyclic nucleotides in cellular fluid regulation. The biological activity of these enterotoxins is the result of interaction with membrane-bound adenylate cyclase, leading to persistent elevation of intracellular levels of cAMP. Stimulation of adenylate cyclase occurs consistently after a characteristic lag phase which varies somewhat between toxins. The duration and degree of stimulation of adenylate cyclase by the various toxins may point to possible differences in affinity, dissociation and mechanism of activation of the cyclase molecule. Subtle events at, or within, the cell membrane must occur during intoxication and may include complex associations of toxin with membrane lipid and protein components. The heat-labile toxins of V. cholerae, E. coli, Salmonella spp., A. hydrophila and Y. enterocolitica have much in common in their structures, membrane receptors and biochemical modes of action. Similarly the heat-stable toxins of E. coli and Y. enterocolitica, match each other in their biological activities. Classified along with the enterotoxin of C. perfringens, the enterotoxin produced by Sh. dysenteriae (and possibly some strains of E. coli) appears to differ from the other enterotoxins by acting on protein biosynthesis primarily and not on the nucleotide cyclase activation systems. In another category must be placed the various enterotoxins produced by Staph. aureus until more is known. Surprisingly little research has been directed towards the elucidation of their mode of action, although much is known of their serological and structural differences. Evidence to date suggests that staphylococcal enterotoxins differ from the other diarrhoeagenic agents discussed in this review. The structural and immunological similarities between the various heat-labile enterotoxins suggest a common genetic origin with gene transfer between the different bacterial species being responsible for the spread of enterotoxigenicity. It is possible that many of the "newer" enterotoxins owe their origin to genetic recombination with the "older" enteropathogens like V. cholerae.
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PMID:Comparative study of the nature and biological activities of bacterial enterotoxins. 632 86

In the present study, the effect of prostaglandin E2 (PGE2) on intercellular adhesion molecule-1 (ICAM-1) expression in human gingival fibroblasts (HGF) stimulated with lipopolysaccharides (LPS) was investigated. LPS were isolated from periodontopathic bacteria, Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) and Porphyromonas gingivalis (P. gingivalis), by the phenol-water method and Escherichia coli (E. coli) LPS was used as a control. PGE2 significantly inhibited A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-induced ICAM-1 expression. Next, of four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4), we examined which subtype(s) was involved in inhibition of LPS-elicited ICAM-1 expression by PGE2. Eleven-deoxy-PGE1, a selective EP2/EP4 agonist, and butaprost, a selective EP2 agonist, attenuated A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-elicited ICAM-1 expression, although butaprost was less potent than PGE2 and 11-deoxy-PGE1. Sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, was inert to the LPS-elicited ICAM-1 expression. Furthermore, dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, downregulated A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-elicited ICAM-1 expression in HGF. Our data suggest that PGE2 downregulates A. actinomycetemcomitans- and P. gingivalis-LPS-induced ICAM-1 expression in HGF, via EP2/EP4 receptors by cAMP-dependent signaling pathways. The cAMP-elevating agents such as EP2/EP4 receptor activators may serve to control inflammatory and immune responses in periodontal disease.
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PMID:Downregulation of lipopolysaccharide-induced intercellular adhesion molecule-1 expression via EP2/EP4 receptors by prostaglandin E2 in human fibroblasts. 1132 62

Infections with enteric pathogens like enterotoxigenic Escherichia coli (ETEC) is a major health issue worldwide and while diarrhea is the major problem, prolonged, severe, and dual infections with multiple pathogens may also compromise the nutritional status of the infected individuals. There is almost nothing currently known about the effect of ETEC infection on intestinal absorptions of water-soluble vitamins including thiamin. We examined the effect of ETEC infection on intestinal uptake of the thiamin using as a model the human-derived intestinal epithelial Caco-2 cells. The results showed that infecting confluent Caco-2 monolayers with live ETEC (but not with boiled/killed ETEC or nonpathogenic E. coli) or treatment with bacterial culture supernatant led to a significant inhibition in thiamin uptake. This inhibition appears to be caused by a heat-labile and -secreted ETEC component and is mediated via activation of the epithelial adenylate cyclase system. The inhibition in thiamin uptake by ETEC was associated with a significant reduction in expression of human thiamin transporter-1 and -2 (hTHTR1 and hTHTR2) at the protein and mRNA levels as well as in the activity of the SLC19A2 and SLC19A3 promoters. Dual infection of Caco-2 cells with ETEC and EPEC (enteropathogenic E. coli) led to compounded inhibition in intestinal thiamin uptake. These results show for the first time that infection of human intestinal epithelial cells with ETEC causes a significant inhibition in intestinal thiamin uptake. This inhibition is mediated by a secreted heat-labile toxin and is associated with a decrease in the expression of intestinal thiamin transporters.
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PMID:Enterotoxigenic Escherichia coli infection and intestinal thiamin uptake: studies with intestinal epithelial Caco-2 monolayers. 2413 60