UNIPROT:P61278 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The growth of pancreatic cancers may be influenced by certain gut peptides. However, the alteration of gut peptide receptors in the progress of pancreatic carcinogenesis is largely unknown. With storage phosphor autoradiography, this study visualized and characterized receptors for cholecystokinin (CCK), somatostatin (SST), bombesin (BBS), secretin and vasoactive intestinal peptide (VIP) in pancreata of control hamsters (n = 7) and pancreatic preneoplastic lesions (n = 10) or adenocarcinomas (n = 10) of N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. The specific CCK-A and secretin receptors expressed in normal pancreata were markedly reduced in pancreatic preneoplastic lesions and absent in adenocarcinomas. In the development of pancreatic tumours, the subgroup of SST receptors did not change, but both the affinity and binding capacity declined. In comparison with the binding of VIP to normal pancreata, specific VIP binding was significantly lower in preneoplastic lesions and almost absent in pancreatic adenocarcinomas. No specific binding for BBS was detected in normal pancreas or (pre)neoplastic lesions of hamster pancreas. The reduction or absence of receptors for CCK, secretin, SST and VIP in hamster pancreas with the progress of carcinogenesis suggests that in BOP-treated hamsters, pancreatic adenocarcinomas have, to a large extent, lost the hormone-dependent characteristics of the original tissue.
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PMID:Expression of receptors for gut peptides in pancreata of BOP-treated and control hamsters. 889 85

Intraduodenal fat inhibits gastric acid secretion via the release of one or more hormonal enterogastrones thought to arise from ileocolonic mucosa. This study determined whether glucagon-like peptide-1 (GLP-1)-(7-36) amide and peptide YY (PYY), colocalized in L cells found in the ileum, mediate intraduodenal fat-induced inhibition of stimulated gastric acid, and evaluated the influence of cholecystokinin-A (CCK-A) receptor activation. Gastric acid secretion in response to duodenal perfusions of 8% peptone was measured in conscious dogs with gastric and duodenal cannulas. Intraduodenal administration of a 10% fat emulsion suppressed gastric acid secretion by 72 +/- 4% (P < 0.001) and increased plasma levels of GLP-1 and PYY by 44 +/- 5 and 46 +/- 4 fmol/ml, respectively (both P < 0.01). Pretreatment with the CCK-A receptor antagonist MK-329 completely reversed the inhibition of gastric acid by fat, suppressed rises of plasma GLP-1 (maximum change, 23 +/- 4 fmol/ml), and reduced plasma PYY responses to baseline. Intravenous infusions of 50 pmol/kg x h GLP-1 or PYY, which reproduced plasma elevations after intraduodenal fat, inhibited gastric acid secretion by 66 +/- 5% and 51 +/- 6%, respectively (both P < 0.01); coinfusions of GLP-1 and PYY abolished gastric acid secretion (P < 0.001) without influencing plasma gastrin or somatostatin. Pretreatment with 1500 pmol/kg x h of the GLP-1 antagonist exendin-(9-39) amide did not alter the magnitude of inhibition of gastric acid caused by exogenous GLP-1. These results indicate that GLP-1 and PYY released by intraduodenal fat, in part through CCK-dependent pathways, are major enterogastrones in dogs. This inhibitory action occurs independent of circulating concentrations of somatostatin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects.
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PMID:Glucagon-like peptide-1-(7-36) amide and peptide YY mediate intraduodenal fat-induced inhibition of acid secretion in dogs. 942 14

1. Cholecystokinin (CCK) and gastrin both stimulate gastric somatostatin (SOM) secretion in vitro and thus have the potential to modulate their direct effects on the parietal cell. However, the relative potencies and the mechanisms of action of CCK and gastrin on SOM secretion in vivo have not been determined. 2. The objectives of the present study were to compare the in vivo potencies of the sulphated(s) and non-sulphated (ns) forms of gastrin heptadecapeptide (G-17) and CCK octapeptide (CCK-8) on SOM secretion, and to determine the nature of the receptors involved by repeating the studies in the presence of the CCK-A and CCK-B/gastrin receptor antagonists L-364,718 and L-365,260, respectively. All experiments were performed in the chronically cannulated sheep. 3. Dose-response experiments revealed the following potencies for SOM secretion: G-17s = CCK-8s > G-17 ns >> CCK-8ns. However, based on the plasma levels achieved and a higher metabolic clearance rate (MCR) for CCK, CCK-8s was the most potent. 4. Both the CCK-A and CCK-B/gastrin receptor antagonists suppressed CCK-8s-stimulated SOM output. In contrast, G-17s-stimulated SOM output was inhibited by only the CCK-B/gastrin receptor antagonist. 5. Both receptor antagonists increased basal plasma gastrin and CCK levels. 6. The predominant circulating SOM molecular form after both gastrin and CCK stimulation was SOM-14. 7. In conclusion, the sulphated forms of CCK and gastrin are more potent than the non-sulphated forms. Despite sharing a common biologically active carboxy terminus, CCK stimulates SOM secretion by both the CCK-A and CCK-B/gastrin receptors, while gastrin acts via the CCK-B/gastrin receptor alone. These findings explain in part why CCK is a net inhibitor of gastric acid secretion in vivo.
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PMID:Cholecystokinin (CCK) regulates somatostatin secretion through both the CCK-A and CCK-B/gastrin receptors in sheep. 945 54

We examined the cholecystokinin (CCK)-B/gastrin receptor, H+/K+-ATPase and somatostatin gene expression, the histology and immunohistochemistry of gastrin and somatostatin of the stomach, plasma gastrin levels, and gastric acid secretion in naturally occurring CCK-A receptor gene knockout (Otsuka Long-Evans Tokushima fatty, OLETF) rats. The CCK-B/ gastrin receptor, H+/K+-ATPase and somatostatin mRNAs were determined by Northern transfer analysis. The gastric acid secretion and the plasma gastrin level were measured in vivo. The levels of CCK-B/gastrin receptor mRNA in the forestomach and the glandular stomach in OLETF rats were 2-fold higher than those of control rats, although those of H+/ K+-ATPase and somatostatin mRNAs were not different. Histological examination revealed thickening of the fundic mucosa, and hyperplasia and hypertrophy of parietal cells, although immunohistochemistry of gastrin and somatostatin revealed no significant difference from the control rats. Gastric acid secretion stimulated by gastrin or histamine was enhanced, whereas the fasting plasma gastrin level was not significantly different from that in control rats. The overexpression of CCK-B/gastrin receptor mRNA and the hyperfunction of parietal cells were observed in rats without CCK-A receptor gene expression.
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PMID:Overexpression of cholecystokinin-B/gastrin receptor gene in the stomach of naturally occurring cholecystokinin-A receptor gene knockout rats. 946 95

Receptors for regulatory peptides such as somatostatin or vasoactive intestinal polypeptide are expressed by a number of human neoplasms and can be visualized in vivo with peptide receptor scintigraphy. Recently, the CCK-B receptor, which binds both gastrin and cholecystokinin with high affinity, was shown using in vitro methods to be overexpressed in a number of human tumor tissues, including medullary thyroid carcinomas, small cell lung cancers, astrocytomas, gastrointestinal tumors, and stromal ovarian cancers. In the present study, we have designed novel, unsulfated CCK octapeptide analogs linked to the metal chelating DTPA and DOTA, and have tested them for their binding affinity to CCK-B receptor-positive tissue from human tumors: The most potent compounds assayed were DTPA-[Nle28, 31]-CCK(26-33) (MP2286) and DTPA-[d-Asp26,Nle28,31]-CCK(26-33) (MP2288) with an IC50 of 1.5 nM. For comparison, analogs with C-terminal DTPA, such as [Nle28,31,Aphe33(p-NH-DTPA)]-CCK(26-33) and CCK-(26-33)-NH(CH2)2 NH-DTPA, had an IC50 of >100 nM. DOTA-[D-Asp26, Nle28,31]-CCK(26-33) had an IC50 of 3.9 nM. The compounds were selective for CCK-B receptors as they did not bind with high affinity to CCK-A receptors expressed in human tumors (meningiomas or gastroenteropancreatic tumors). In vivo rat biodistribution studies with indium-111 labeled MP2286 and MP2288 showed that the primary mode of clearance was renal, and the primary sites of uptake (% ID/g 24 h p.i.) were kidneys (0.270 and 0.262, respectively) and the gastrointestinal tract. The CCK-B receptor-expressing gastric mucosa showed specific in vivo accumulation of 111In-labeled MP2288 which could be blocked in the presence of excess unlabeled MP2288. 111In-labeled MP2286 and MP2288 were also found to be stable in human plasma whereas both compounds were degraded in urine (>40% after 3 h at 37 degrees C). The affinity, specificity, biodistribution, and stability of these two DTPA-CCK analogs indicate that these compounds have substantial promise for use in the in vivo visualization of CCK-B receptor-expressing tumors.
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PMID:Unsulfated DTPA- and DOTA-CCK analogs as specific high-affinity ligands for CCK-B receptor-expressing human and rat tissues in vitro and in vivo. 957 43

CCK and gastrin stimulate somatostatin (SOM) secretion and thus modulate their direct effects on the parietal cell. Although SOM is stored in D cells of the fundus and antrum, the nature of the cell type differs, and it is not known whether both regions respond to the stimulatory effects of CCK and gastrin. The objectives of the present study were to determine the separate effects of CCK and gastrin on fundic and antral SOM secretion and to assess the type of receptor involved, using CCK-A (L-364,718) and CCK-B/gastrin (L-365,260) receptor antagonists. Changes in SOM were measured in plasma collected from cannulas draining blood from the fundus (gastric vein) and antrum (gastroepiploic vein) in anesthetized sheep. Both CCK and gastrin significantly stimulated SOM from the fundus and antrum. Sulfated CCK-8 (CCK-8S) increased SOM secretion from the fundus and antrum through interaction with both type A and B receptors. In contrast to CCK-8S, sulfated gastrin-17 (G-17S) stimulated SOM from the fundus via the type B receptor alone, whereas in the antrum G-17S stimulated SOM secretion independent of the A and B receptors. Histamine mediated, at least in part, the SOM-stimulatory effects; an H2-receptor antagonist blocked CCK-stimulated SOM secretion in both the fundus and antrum and reduced gastrin-stimulated SOM secretion in the fundus. The present study demonstrates regionally distinct regulatory mechanisms for gastric SOM secretion by CCK and gastrin.
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PMID:Regulation of fundic and antral somatostatin secretion by CCK and gastrin. 957 57

Duodenal fat such as oleate is known to influence gut functions by release of cholecystokinin (CCK), but the contribution of CCK endogenously released by duodenal fat or by diversion of pancreatic juice from the duodenum in the mechanism of mucosal integrity and gastroprotection has been little studied. This study was designed to compare the effect of CCK-8 and intraduodenal (i.d.) instillation of sodium oleate, or diversion of the pancreatic biliary secretions that are known to release CCK, on the gastric mucosal lesions induced by topical application of 100% ethanol or acidified aspirin (ASA) in rats with or without the pretreatment with a CCK-A receptor antagonist, loxiglumide, or with L-365,260 to block CCK-B receptors. In addition, the effect of suppression of prostaglandin (PG) biosynthesis by indomethacin (5 mg/kg i.p.), inhibition of nitric oxide (NO)-synthase by L-NAME (5 mg/kg i.v.), or blockade of sensory nerves by capsaicin (125 mg/kg s.c.) on the protective activity of sodium oleate was determined. Sodium oleate (50-200 mM i.d.), or diversion of pancreatic juice from the duodenum for 3 h that produced significant rise in plasma CCK levels, significantly reduced gastric lesions induced by 100% ethanol to an extent similar to that induced by exogenous CCK-8 (5 nmol/kg s.c.). The protective effect of oleate or diversion of pancreatic juice was accompanied by an increase in gastric blood flow (GBF). Both protection and accompanying hyperemia were completely abolished by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an antagonist of CCK-B receptors, had no effect. Oleate given i.d. significantly attenuated acidified ASA-induced gastric lesions and gastric secretion while increasing the luminal concentration of somatostatin. These effects were significantly reduced by loxiglumide but not by L-365,260. In contrast, CCK-8, which stimulated gastric acid secretion, failed to affect the lesions induced by acidified ASA and the decrease in the GBF produced by this ulcerogen. Indomethacin, which suppressed PG generation by approximately 90%, failed to influence the protective activity of oleate or CCK-8 against ethanol-induced lesions, whereas L-NAME, vagotomy, or sensory denervation significantly attenuated this protection and accompanying hyperemia. Addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK-8 and duodenal oleate against gastric lesions induced by ethanol or acidified ASA. We conclude that endogenous CCK released by oleate or diversion of pancreatic secretion exerts a potent gastroprotective action on the stomach involving predominantly CCK-A receptors and depending on vagal activity, and hyperemia mediated by NO and sensory nerves but unrelated to acid secretory effects and endogenous PG.
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PMID:Involvement of endogenous cholecystokinin and somatostatin in gastroprotection induced by intraduodenal fat. 987 9

Receptors for cholecystokinin (CCK), gastrin, neurotensin, somatostatin and vasoactive intestinal peptide (VIP) are over-expressed in several human tumors, where they have diagnostic and therapeutic implications. Since reports on the expression of these peptide receptors in primary gastric and colonic adenocarcinomas are either non-existent or conflicting, a detailed evaluation with particular emphasis on the tissue localization was undertaken. CCK-A, CCK-B, neurotensin, somatostatin and VIP receptors were localized by in vitro receptor autoradiography with iodinated radioligands on histological sections of surgical samples of 27 gastric and 25 colonic adenocarcinomas. CCK-A, CCK-B and neurotensin-1 receptors were found in a minority of both tumor types. Somatostatin receptors were found in 18/27 gastric and 2/25 colonic cancers. VIP receptors were found in 14/26 gastric and 23/25 colonic cancers; subtype characterization suggests VIP1 receptors. In addition, resected tumor samples contained non-malignant tissues (mucosa, smooth muscle, nerves or vessels) with high amounts of the various peptide receptors. Therefore, regulatory peptide receptors are expressed differentially in gastric and colonic cancers but also very frequently in "contaminating" non-malignant tissues. Since results using morphological techniques are superior to those using homogenates, we recommend that localization of these receptors to the tissues should always be attempted, to minimize receptor over-estimation in tumors and to prevent spurious results.
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PMID:Receptor autoradiographic evaluation of cholecystokinin, neurotensin, somatostatin and vasoactive intestinal peptide receptors in gastro-intestinal adenocarcinoma samples: where are they really located? 1020 52

CCK exhibits a potent cytoprotective activity against acute gastric lesions, but its role in ulcer healing has been little examined. In this study we determined whether exogenous CCK or endogenously released CCK by camostate, an inhibitor of luminal proteases, or by the diversion of pancreatico-biliary secretion from the duodenum, could affect ulcer healing. In addition, the effects of antagonism of CCK-A receptors (by loxiglumide, LOX) or CCK-B receptors (by L-365,260), an inhibition of NO-synthase by N(G)-nitro-L-arginine (L-NNA), or sensory denervation by large neurotoxic dose of capsaicin on CCK-induced ulcer healing were examined. Gastric ulcers were produced by serosal application of acetic acid and animals were sacrificed 9 days after ulcer induction. The area of ulcers and blood flow at the ulcer area were determined. Plasma levels of gastrin and CCK and luminal somatostatin were measured by RIA and mucosal biopsy samples were taken for histological evaluation and measurement of DNA synthesis. CCK given s.c. reduced dose dependently the ulcer area; the threshold dose of CCK being 1 nmol/kg and the dose inhibiting this area by 50% being 5 nmol/kg. This healing effect of CCK was accompanied by a significant increase in the GBF at ulcer margin and the rise in luminal NO production, plasma gastrin level and DNA synthesis. Concurrent treatment with LOX, completely abolished the CCK-8-induced acceleration of the ulcer healing and the rise in the GBF at the ulcer margin, whereas L-365,260 remained without any influence. Treatment with camostate or diversion of pancreatic juice that raised plasma CCK level to that observed with administration of CCK-8, also accelerated ulcer healing and this effect was also attenuated by LOX but not by L-365,260. Inhibition of NO-synthase by L-NNA significantly delayed ulcer healing and reversed the CCK-8 induced acceleration of ulcer healing, hyperemia at the ulcer margin and luminal NO release, and these effects were restored by the addition to L-NNA of L-arginine but not D-arginine. Capsaicin denervation attenuated CCK-induced ulcer healing, and the accompanying rise in the GBF at the ulcer margin and decreased plasma gastrin and luminal release of somatostatin when compared to those in rats with intact sensory nerves. Detectable signals for CCK-A and B receptor mRNAs as well as for cNOS mRNA expression were recorded by RT-PCR in the vehicle control gastric mucosa. The expression of CCK-A receptor mRNA and cNOS mRNA was significantly increased in rats treated with CCK-8 and camostate, whereas CCK-B receptor mRNA remained unaffected. We conclude that CCK accelerates ulcer healing by the mechanism involving upregulation of specific CCK-A receptors, enhancement of somatostatin release, stimulation of sensory nerves and hyperemia in the ulcer area, possibly mediated by NO.
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PMID:Acceleration of ulcer healing by cholecystokinin (CCK): role of CCK-A receptors, somatostatin, nitric oxide and sensory nerves. 1045 43

Numerous studies have reported diverse effects of gut-derived regulatory peptides on growth of the normal pancreas, pancreatic neoplasms induced experimentally in animals, and pancreatic cancer cell lines, but the results of these investigations are rather controversial. The stimulatory effect of epidermal growth factor (EGF) on cell proliferation of pancreatic cell lines is well established. Whether this action can be modulated by somatostatin is not clear. Furthermore, it is not certain whether another regulatory peptide, cholecystokinin (CCK), affects the proliferation of these cells. In the present study we investigated the presence of CCK-A and CCK-B, as well as somatostatin-2 (SSTR2) receptors by RT-PCR, and studied the actions of EGF, CCK and octreotide on DNA synthesis in the human pancreatic adenocarcinoma cell line Capan-2. Octreotide, a long-acting somatostatin analogue was used as somatostatin agonist. Cells were cultured in RPMI-1640 medium. They were incubated in serum free medium containing 0.2% BSA in the absence (control) or the presence of the peptides. [3H]-thymidine incorporation into DNA was measured after 48 h of incubation. By means of RT-PCR analysis we were able to demonstrate SSTR2 expression, but not CCK-A or CCK-B receptor mRNA in Capan-2 cells. DNA synthesis evaluated by [3H]-thymidine incorporation was found to be increased by 45.2 +/- 5.6% in response to EGF (10(-8) M) and decreased by 11.7 +/- 2.6% to octreotide (10(-8) M) compared to controls (P < 0.01). The increase in [3H]-thymidine incorporation was significantly lower when EGF treatment was combined with octreotide administration (10.1 +/- 2.5% over control). In the concentration range of 10(-11)-10(-8) M, CCK did not alter significantly the incorporation of [3H]-thymidine into DNA in Capan-2 cells. In conclusion, these data support a role for EGF as a growth factor for the human pancreatic cancer cell Capan-2. Somatostatin may play an important role in regulating cell proliferation in Capan-2 cells both under basal, and growth factor-stimulated conditions. Our results suggest, however, that CCK receptors are not expressed, and CCK does not affect cell proliferation in this transformed pancreatic cell line.
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PMID:Inhibitory effect of a long-acting somatostatin analogue on EGF-stimulated cell proliferation in Capan-2 cells. 1076 90

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