Disease relevance of Gast

• RESULTS: Gastrin -/- mice exhibit fasting hypoglycemia and significantly reduced glycemic excursion following glucose challenge [1].
• The present studies were directed to determine whether changes in PPARgamma expression might mediate the effects of gastrin on the proliferation of colorectal cancer (CRC) [2].
• The growth factor, gastrin, has previously been shown to be a downstream target of the Wnt pathway and a promoter of gastrointestinal cancer [3].
• CONCLUSION: Persistent activation of innate immunity in the stomach induced gastric mucosal hyperplasia through upregulation of gastrin synthesis in Aalpha0/0 mice, suggesting a pathophysiology similar to the gastric changes in patients with AIDS [4].
• Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma [5].

Psychiatry related information on Gast

• Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet precursors in fetal pancreatic ducts [6].
• The influence of the CCK-A antagonist devazepide and the CCK-B/gastrin antagonist L-365,260 on the locomotor activity of mice was studied [7].

High impact information on Gast

• Excitation of the non-cholinergic nerves stimulates amylase secretion by a different intracellular coupling mechanism from that activated by cholinergic nerves or by peptides belonging to the cholecystokinin, gastrin or bombesin families [8].
• In addition, there was a twofold increase in activated parietal cells resulting in a twofold increase in basal and stimulated gastric acid output and an undetectable serum gastrin level [9].
• Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors [10].
• APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number [10].
• Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression [10].

Chemical compound and disease context of Gast

• Moreover, the glucagon response but not the epinephrine response to hypoglycemia was significantly attenuated in gastrin -/- compared with gastrin +/+ mice (P < 0.05) [1].
• When omeprazole-treated mice were treated with antibiotics alone, elevated plasma gastrin levels returned to baseline and D cell numbers returned to resting levels despite persistent hypochlorhydria [11].
• Helicobacter pylori can induce heparin-binding epidermal growth factor expression via gastrin and its receptor [12].
• Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively) [13].
• Effects of gastrin, proglumide, and somatostatin on growth of human colon cancer [14].

Biological context of Gast

• Both parietal cell number and level of H(+)/K(+)-ATPase messenger RNA (mRNA) were reduced in the mutant strains, but gastrin-CCK double-KO mice displayed more active parietal cells and larger acid output than the gastrin KO mice [15].
• CONCLUSIONS: These findings show an essential physiologic role for gastrin in glucose homeostasis; however, the gastrin gene is not essential for murine islet development or the adaptive islet proliferative response to beta-cell injury [1].
• Peroxisome proliferators-activated receptor gamma (PPARgamma) has been shown to suppress cell proliferation and tumorigenesis, whereas the gastrointestinal regulatory peptide gastrin stimulates the growth of neoplastic cells [2].
• The results of these studies demonstrate that the trophic properties of gastrin in CRC may be mediated in part by transactivation of the EGFR and phosphorylation of ERK1/2, leading to degradation of PPARgamma protein and a decrease in PPARgamma activation [2].
• Gross morphology and histology of 12-month-old wild-type (WT), gastrin-deficient (G-/-) and somatostatin-deficient (SOM-/-) mice were examined [5].

Anatomical context of Gast

• Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice [15].
• Oxyntic D-cell density was the same in both mutant strains, but the D cells were more active in the gastrin KO than in the double-KO mice [15].
• METHODS: Acid was measured after pylorus ligation, and biopsies from gastrin knockout (KO), gastrin-CCK double-KO, and wild-type (WT) mice were collected for biochemical, immunocytochemical, and electron-microscopic examination [15].
• Initially, using growth assays, we determined that the human CRC cell line DLD-1 expressed both functional PPARgamma and gastrin receptors [2].
• To clarify the roles of hypergastrinaemia in the gastric mucosa, a gastrin receptor antagonist (AG041R) was administered [4].

Associations of Gast with chemical compounds

• The acid response to histamine in double-KO mice was unchanged whereas that to gastrin was diminished, but it could be restored by infusion of gastrin [15].
• Furthermore, mutation of PPARgamma at serine 84 reduced the effects of G-17, as evident by inability of G-17 to attenuate PPARgamma promoter activity, degrade PPARgamma, or inhibit the growth suppressing effects of PPARgamma [2].
• Gastrin 17 and pentagastrin did not affect glucose- or carbachol-induced insulin release, whereas they inhibited L-IPNA-induced insulin secretion [16].
• However, co-stimulation with EGF and gastrin synergistically induced COX-2 protein and mRNA expression and PGE2 secretion [17].
• Inhibition of de novo protein synthesis by cycloheximide did not block COX-2 mRNA induction by gastrin [17].

Physical interactions of Gast

• Gastrin stabilises beta-catenin protein in mouse colorectal cancer cells [18].
• No saturable gastrin binding to normal nontransgenic mouse pancreas was found [19].
• Unique roles of G protein-coupled histamine H2 and gastrin receptors in growth and differentiation of gastric mucosa [20].

Regulatory relationships of Gast

• Gastrin dose dependently induced COX-2 protein levels in a time dependent manner [17].
• Gastrin-specific MAb inhibited gastrin-17- but not pentagastrin-stimulated gastric acid secretion and had no effect on cholecystokinin (CCK)-stimulated pancreatic secretion [21].
• Gastrin dose dependently induced CCKB-R expression in GSM06 cells and stimulated their growth [22].
• Gastric mucosal hyperplasia via upregulation of gastrin induced by persistent activation of gastric innate immunity in major histocompatibility complex class II deficient mice [4].
• Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells [6].

Other interactions of Gast

• In the gastrin-CCK double-KO mice, acid secretion is only controlled by cholinergic vagal stimulation, which normalizes the acid output [15].
• The results suggest that VIP, secretin and gastrin display their effects on insulin secretion through different mechanisms [16].
• Recent studies suggest that COX-2 expression levels could mediate the growth effects of gastrin [17].
• Effect of carboxypeptidase E deficiency on progastrin processing and gastrin messenger ribonucleic acid expression in mice with the fat mutation [23].
• In wild-type mice, somatostatin-14, SMS 201-995, and the SSTR2-preferential agonist, DC 32-87, inhibited gastrin-stimulated acid secretion with an order of potency SMS 201-995>DC 32-87>somatostatin-14 [24].

Analytical, diagnostic and therapeutic context of Gast

• D cells were quantified by morphometry and flow cytometry in 16-wk-old wild-type (G+/+) and gastrin-deficient (G-/-) mice [11].
• Immunocytochemistry showed that PT contained gastrin [25].
• Immunohistochemistry, radioimmunoassay and quantitative real-time polymerase chain reaction techniques were employed to examine the expression of genes belonging to the G-cell secretory pathway in gastrin and gastrin-CCK knockout mice [26].
• Serum gastrin was measured by means of radioimmunoassay in specimens of mouse blood taken before and 5 minutes after intraperitoneal injection of secretin (100 micrograms/kg) [25].
• Insulin was localized specifically to antral G cells of G-InsKi mice by double immunofluorescence staining using antibodies against insulin and gastrin [27].

References