Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The in vitro pharmacological characterization of the sodium salt of 2-naphthalenesulphonyl 1-aspartyl-(2-phenethyl)amide [2-NAP], a hydrophilic compound derived from the C-terminal aspartate-phenylalanine dipeptide of cholecystokinin (CCK), is described. 2. 2-NAP behaved as a competitive antagonist of sulphated cholecystokinin octapeptide (CCK-8) at CCKA-receptors in both intact tissue bioassays (guinea-pig gall bladder, pancreas and ileum, human and rabbit gall bladder) and a radioligand displacement assay (guinea-pig pancreatic cells). The mean pKB, over assays, was 6.5. 3. Compared to the other assays, the rabbit gall bladder assay gave a significantly higher pKB estimate [7.0] for 2-NAP and a significantly lower estimate [8.9] for devazepide (formerly L-364,718 and MK-329), a well-characterized CCKA-receptor antagonist; these anomalous results suggest that a different class of CCKA-receptors may be involved. 4. 2-NAP, was found to be highly selective, having at least 300 fold greater affinity for CCKA-receptors than for 50 other pharmacological loci, including gastrin/CCKB, as estimated by bioassay or radioligand displacement.
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PMID:2-Naphthalenesulphonyl L-aspartyl-(2-phenethyl)amide (2-NAP)--a selective cholecystokinin CCKA-receptor antagonist. 768 35

RP 73870, the racemic potassium salt of (([N-(methoxy-3-phenyl)-N-(N-methyl-N-phenyl-carbamoylmethyl)- carbamoylmethyl]-3-ureido)-3-phenyl)-2-ethylsulfonate-(RS) is a potent, reversible antagonist of both gastrin and cholecystokinin-B receptors in guinea pig and rat tissues. This compound is a potent inhibitor of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach. RP 73870 also inhibits basal gastric acid secretion in the rat, although at doses higher than that required for inhibition of pentagastrin-stimulated gastric acid secretion. RP 73870 is a potent inhibitor of aspirin-induced gastric damage in the rat. In the prevention of aspirin-induced gastric damage, RP 73870, given p.o., was 10-fold less potent than when given i.v. RP 73870 was as potent as a H2 receptor antagonist or proton pump inhibitor in the prevention of cysteamine-induced duodenal ulcers in the rat. Relative to other gastrin/cholecystokinin-B antagonists, RP 73870 demonstrates greater affinity to gastrin binding sites, and possesses a unique spectrum of in vivo biological activities appropriate for an anti-ulcer indication.
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PMID:RP 73870, a gastrin/cholecystokinin-B receptor antagonist with potent anti-ulcer activity in the rat. 779 Oct 71

Transactivation of human immunodeficiency virus (HIV) gene expression depends upon the interaction of the viral regulatory protein Tat with the transactivation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-end of all mRNAs. We have used a site-directed RNA-cleaving strategy to determine the neighborhood of the core domain of a Tat fragment in the Tat-TAR complex. We synthesized a 35-amino acid fragment containing arginine-rich RNA-binding domain of Tat(38-72) and attached an EDTA analog to its amino terminus. A derivative of (p-aminobenzyl)-EDTA tetra-tert-butyl ester was synthesized and attached to the amino terminus of the Tat peptide by standard peptide coupling methods. Cleavage from the resin and deprotection of the peptide were carried out in trifluoroacetic acid which also generated unprotected metal binding EDTA moieties. We used this EDTA-Tat conjugate to form a specific complex with TAR RNA. This sequence-specific RNA-binding peptide was converted into a sequence-specific RNA-cleaving peptide by the addition of Fe(II) salt, ascorbate, and H2O2. Hydroxyl radicals generated from the tethered Fe(II) cleaved the TAR RNA backbone in two localized regions. Site-specific cleavage of TAR RNA was observed at the bulge residues (U23, C24, and U25), in the loop region (G34 and A35), and at the strand opposite the bulge (U40 and C41). These results demonstrate that, in the three-dimensional structure of the Tat-TAR complex, the Phe38 of Tat(38-72) is located in the proximity of the bulge region and two nucleotides from the loop sequence.
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PMID:Probing the proximity of the core domain of an HIV-1 Tat fragment in a Tat-TAR complex by affinity cleaving. 937 65

Helicobacter pylori infection increases gastric acid secretion in patients with duodenal ulcers but diminishes acid output in patients with gastric cancer and their relatives. Investigation of the basic mechanisms may show how H. pylori causes different diseases in different persons. Infection of the gastric antrum increases gastrin release. Certain cytokines released in H. pylori gastritis, such as tumor necrosis factor alpha and specific products of H. pylori, such as ammonia, release gastrin from G cells and might be responsible. The infection also diminishes mucosal expression of somatostatin. Exposure of canine D cells to tumor necrosis factor alpha in vitro reproduces this effect. These changes in gastrin and somatostatin increase acid secretion and lead to duodenal ulceration. But the acid response depends on the state of the gastric corpus mucosa. The net effect of corpus gastritis is to decrease acid secretion. Specific products of H. pylori inhibit parietal cells. Also, interleukin 1 beta, which is overexpressed in H. pylori gastritis, inhibits both parietal cells and histamine release from enterochromaffin-like cells. H. pylori also promotes gastric atrophy, leading to loss of parietal cells. Factors such as a high-salt diet and a lack of dietary antioxidants, which also increase corpus gastritis and atrophy, may protect against duodenal ulcers by decreasing acid output. However, the resulting increase of intragastric pH may predispose to gastric cancer by allowing other bacteria to persist and produce carcinogens in the stomach.
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PMID:How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. 939 59

It is unclear why Helicobacter pylori produces different diseases in different persons. High and low acid secretion rates probably contribute to duodenal ulceration and gastric carcinogenesis, respectively. Both of these changes seem to be corrected by eradicating Helicobacter pylori. We are therefore exploring the basic mechanisms and asking why patients react differently? Helicobacter pylori products and certain cytokines released in Helicobacter pylori gastritis release gastrin from G-cells but inhibit parietal cells. Also tumour necrosis factor alpha inhibits somatostatin-cells and interleukin 1 beta inhibits enterochromaffin-like cells. The net result is that antral gastritis tends to increase, whilst corpus gastritis tends to decrease acid secretion. Corpus atrophy further lowers acid through loss of parietal cells. Factors postulated to increase corpus gastritis include host genetics, early acquisition of Helicobacter pylori, more aggressive strains, poor general health and diets high in salt or lacking in antioxidant vitamins. Further research should address the interaction of bacterium, host and environment with a view to preventing the serious clinical outcomes.
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PMID:Host mechanisms: are they the key to the various clinical outcomes of Helicobacter pylori infection? 947 95

Tham et al. show that Helicobacter pylori infection lowers the density of immunoreactive somatostatin cells (D-cells) in the antral mucosa and elevates plasma gastrin concentrations. According to current hypothesis, the lack of inhibition by somatostatin allows excessive release of gastrin, which stimulates acid secretion and thus causes duodenal ulcers. The cytokine tumour necrosis factor-alpha which is released in H. pylori gastritis inhibits D-cells in culture and may be responsible. Why do not all infected persons get duodenal ulcers? Recent work shows that more aggressive strains of H. pylori have greater effects on somatostatin/gastrin physiology. Another variable is whether the infection causes corpusitis or not. Inflammation of the gastric corpus diminishes acid secretion, which greatly decreases the likelihood of duodenal ulcers but increases the risk of gastric cancer. Factors which promote corpusitis include diets with high salt content or lacking in antioxidant vitamins. Work in this area is elucidating how H. pylori causes different diseases. Hopefully this will allow us to predict and prevent its serious sequelae.
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PMID:Helicobacter pylori and somatostatin cells. 985 43

Helicobacter pylori plays major causative roles in peptic ulcer disease and gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs) contributes to duodenal injury, and diminished acid secretion in patients with gastric cancer allows carcinogen-producing bacteria to colonize the stomach. Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU patients and hypo-secreting relatives of gastric cancer patients. Therefore, we and others have asked how H. pylori causes these disparate changes in acid secretion. H. pylori gastritis more or less restricted to the gastric antrum in DU patients is associated with increased acid secretion. This is probably because gastritis increases release of the antral acid-stimulating hormone gastrin and diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines including TNFalpha may cause these changes in endocrine function. Gastritis involving the gastric corpus tends to diminish acid secretion, probably because bacterial products and cytokines including IL-1 inhibit parietal cells. Pharmacological inhibition of acid secretion increases corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric hypo-secretion of any cause might become self-perpetuating. H. pylori-associated mucosal atrophy will also contribute to acid hypo-secretion and is more likely in when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric acid secretion in patients with esophagitis are limited but suggest that acid secretion is normal or slightly diminished. Nevertheless, H. pylori infection may be relevant to the management of esophagitis because: (i) H. pylori infection increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump inhibitors may increase the tendency of H. pylori to cause atrophic gastritis; and (iii) successful eradication of H. pylori is reported to increase the likelihood of esophagitis developing in patients who had DU disease. Points (ii) and (iii) remain controversial and more work is clearly required to elucidate the relationship between H. pylori, acid secretion, gastric mucosa atrophy and esophagitis.
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PMID:Helicobacter pylori modulation of gastric acid. 1078 May 81

Absorption of the 4, 10 and 34 amino acid forms of gastrin from the small intestine has been investigated in anaesthetized rats. The method of assessment of successful absorption of the hormone into the systemic circulation was when the amount of acid secreted by the stomach over consecutive 15-min periods was increased. When the natural hormones were infused into the ileum in a relatively high dose, there was no increase in gastric acid secretion, indicating that they had not been absorbed. Each of the forms of gastrin was conjugated at the free amino terminus to the carboxyl group of cholic acid. Subsequent infusion of the conjugated form of gastrin into the ileum, this time in relatively low doses, resulted in substantial and prolonged increases in gastric acid secretion, indicating that these hormones had been successfully absorbed. In addition, conjugation of the 10 and 34 amino acid forms of gastrin with cholic acid was shown to increase markedly the potency in evoking an increase in gastric acid secretion in response to intravenous injection of the hormone. Absorption of the gastrin conjugates was specific to the ileum thus indicating that they had been absorbed through the bile salt transporters.
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PMID:Absorption of biologically active peptide hormones from the small intestine of rat. 1239

Previous studies from our group have shown that hypergastrinemia in mice can synergize with Helicobacter felis infection to induce gastric carcinoma. In addition, epidemiological evidence and a recent study with C57BL/6 mice have strongly suggested a link between a high-salt diet during Helicobacter pylori infection and the development of hypergastrinemia and preneoplastic gastric lesions. To address the possible relationship between the two cofactors (gastrin and salt) and whether H. pylori can also lead to gastric cancer in this model, we undertook a longitudinal study involving 86 INS-GAS mice. The mice were fed either a high-salt (7.5%) or basal (0.25%) diet, and half were infected with H. pylori. Necropsies at 5 and 7 months postinfection included histopathological examination, quantitative culturing for bacterial colonization levels, and serology to estimate the magnitude of the Th1 and Th2 systemic inflammatory responses. Lesions consistent with in situ and intramucosal carcinoma were seen in H. pylori-infected male mice only. There was a highly significant main effect for Helicobacter infection status for all fundic and antral lesion parameters (P < 0.0001), as well as significant interactions of infection status with diet for all of the fundic parameters (all P < 0.03), except intestinal metaplasia. In subsequent ANOVAs in which the data were limited to that from infected animals, there was a highly significant main effect for time, diet, and gender (all P < 0.02) on all of the corpus lesion parameters scored (inflammation, atrophy, hyperplasia, metaplasia, and dysplasia/neoplasia). In addition, gender interacted significantly with time (all P < 0.03), and. H. pylori colonization increased quantitatively over the course of the experiment but were independent of either diet or gender. The Th1-associated serum IgG2a responses to H. pylori increased from the time of experimental infection to necropsy at 5 or 7 months and were similar among all experimentally infected mice with no influence of gender (P > 0.10) or dietary salt (P > 0.27). In contrast, the Th2-associated serum IgG1 response to H. pylori was significantly increased in infected male INS-GAS mice on the high-salt diet at 7 months postinfection (P < 0.012). These results show that H. pylori can also accelerate the development of gastric cancer in the INS-GAS mouse model, and the results suggest that salt has less of a procarcinogenic effect in the setting of endogenous hypergastrinemia. The increased Th2-associated humoral response of the infected male mice on the high-salt diet correlated with less severe gastric lesions. In the INS-GAS mouse model, male gastric tissue responded more rapidly and aggressively to H. pylori infection, high-salt diet, and the combination when compared with females; a finding that appears consistent with the greater incidence of gastric carcinoma in men. This study highlights the importance of using both genders to investigate the pathogenesis of H. pylori.
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PMID:Helicobacter pylori-associated gastric cancer in INS-GAS mice is gender specific. 1261 7

Gastric cancer is the second most common cause of cancer-related mortality world-wide. In most cases, it develops via the pre-malignant stages of atrophic gastritis, intestinal metaplasia and dysplasia, following Helicobacter pylori infection of susceptible individuals. A number of rodent models have recently provided valuable insights into the host, bacterial and environmental factors involved in gastric carcinogenesis. Wild-type rodents do not develop gastric adenocarcinoma, but early studies showed that the disease could be induced in several rodent species by chemical carcinogens. More recently, it has been demonstrated that gastric adenocarcinoma can be induced in Mongolian gerbils by H. pylori infection and in C57BL/6 mice by long-term H. felis infection. These models have allowed the importance of Helicobacter virulence genes, host factors, such as gender, strain and immune response, and environmental factors, such as dietary salt, to be explored. A number of transgenic mice with alterations in various pathways, including the immune response, gastrin biosynthesis, parietal cell development, growth factors and tumour suppressors, have also provided models of various stages of gastric carcinogenesis. One model that has proved to be particularly valuable is the hypergastrinaemic INS-GAS mouse, in which gastric carcinoma develops spontaneously in old animals, but the process is greatly accelerated by Helicobacter infection.
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PMID:Review article: How useful are the rodent animal models of gastric adenocarcinoma? 1508 Aug 46


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