Role Of Gastrin Research Articles

118.6: The role of gastrin in human islet and type 1 diabetes animal model

118.6: The role of gastrin in human islet and type 1 diabetes animal model

An Update on the Role of Immunohistochemistry in the Evaluation of Gastrointestinal Tract Disorders.

As in other organ systems, immunohistochemistry (IHC) serves as an ancillary diagnostic tool for a wide variety of neoplastic and non-neoplastic disorders, including infections, work-up of inflammatory conditions, and subtyping neoplasms of the gastrointestinal (GI) tract. In addition, IHC is also used to detect a variety of prognostic and predictive molecular biomarkers for carcinomas of the GI tract. The purpose of this review is to highlight the use of IHC in common diagnostic scenarios throughout the tubular GI tract. The clinical indication and guidelines for performing IHC for detecting Helicobacter pylori is discussed along with role of gastrin and neuroendocrine markers in the diagnosis of autoimmune metaplastic atrophic gastritis. The major portion of this review discusses the use of IHC in the diagnostic workup of malignant neoplasms of the GI tract, such as adenocarcinoma versus squamous cell carcinoma, workup of poorly differentiated malignant neoplasms, and evaluation of uncommon gastric neoplasms (alpha-feto protein-producing carcinomas) and switch/sucrose-nonfermenting complex-deficient carcinomas. Lastly, localization of neuroendocrine tumors of unknown origin to aid clinical management, as well as HPV-driven anal neoplasia and IHC in the workup of basaloid anal neoplasms are also reviewed.

Gastrin promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in gastric cancer

Angiogenesis is recognized as a sign of cancer and facilitates cancer progression and metastasis. Suppression of angiogenesis is a desirable strategy for gastric cancer (GC) management. In this study, we showed a novel role of gastrin in angiogenesis of GC. We observed that treatment with gastrin 17 (G17) increased the proliferation of AGS cells and enhanced tube formation during normoxia and hypoxia. The expression level of VEGF were increased by G17 treatment as well. Experiments on the mechanism showed that G17 promoted HIF-1α expression, which subsequently enhanced β-catenin nuclear localization and activation of TCF3 and LEF1 and finally resulted in angiogenesis by upregulating VEGF. An in vivo experiment confirmed that G17 enhanced GC cell proliferation and angiogenesis in the resultant tumor. In conclusion, our findings indicate that gastrin promotes angiogenesis via activating HIF-1α/β-catenin/VEGF axis in GC.

Gastrin activates autophagy and increases migration and survival of gastric adenocarcinoma cells

BackgroundThe peptide hormone gastrin exerts a growth-promoting effect in both normal and malignant gastrointestinal tissue. Gastrin mediates its effect via the cholecystokinin 2 receptor (CCKBR/CCK2R). Although a substantial part of the gastric adenocarcinomas express gastrin and CCKBR, the role of gastrin in tumor development is not completely understood. Autophagy has been implicated in mechanisms governing cytoprotection, tumor growth, and contributes to chemoresistance. This study explores the role of autophagy in response to gastrin in gastric adenocarcinoma cell lines.MethodsImmunoblotting, survival assays and the xCELLigence system were used to study gastrin induced autophagy. Chemical inhibitors of autophagy were utilized to assess the role of this process in the regulation of cellular responses induced by gastrin. Further, knockdown studies using siRNA and immunoblotting were performed to explore the signaling pathways that activate autophagy in response to gastrin treatment.ResultsWe demonstrate that gastrin increases the expression of the autophagy markers MAP1LC3B-II and SQSTM1 in gastric adenocarcinoma cells. Gastrin induces autophagy via activation of the STK11-PRKAA2-ULK1 and that this signaling pathway is involved in increased migration and cell survival. Furthermore, gastrin mediated increase in survival of cells treated with cisplatin is partially dependent on induced autophagy.ConclusionThis study reveals a novel role of gastrin in the regulation of autophagy. It also opens up new avenues in the treatment of gastric cancer by targeting CCKBR mediated signaling and/or autophagy in combination with conventional cytostatic drugs.

The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies.

The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin - responsive tumors.

Gastric secretion

The review summarizes the past year's literature, basic science and clinical, regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion. Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B(12), and certain medications (e.g. thyroxin). It also kills ingested microorganisms and prevents bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, nefstatin-1, interleukin-11, and calcitonin gene-related peptide. Helicobacter pylori stimulates or inhibits acid secretion depending upon the time course of infection and the area of the stomach predominantly infected. Acute infection activates calcitonin gene-related peptide sensory neurons coupled to inhibition of histamine and acid secretion. Serum chromogranin A, a marker for neuroendocrine tumors, is elevated in patients taking proton pump inhibitors. Progress continues in our understanding of the regulation of gastric acid secretion in health and disease, as well as the function of gastric neuroendocrine cells. The recognition that gastrin is not only a secretagogue but also a trophic hormone has led to new research into the role of gastrin and its receptor (cholecystokinin-2 receptor) in carcinogenesis and the development of cholecystokinin-2 receptor antagonists.

Role of Gastrin and Histamine in the Anti-ulcerogenic Potential of Compounds-gedunine and Photogedunine

Role of Gastrin and Histamine in the Anti-ulcerogenic Potential of Compounds-gedunine and Photogedunine

The Regenerating Gene IαIs Overexpressed in Atrophic Gastritis Rats with Hypergastrinemia

The role of gastrin on the development of atrophic gastritis (AG) and its relationship with the expression of RegIα in vivo remain unclear. We established experimental AG in rats by combination administration with sodium salicylate, alcohol, and deoxycholate sodium. The mean score of inflammation in gastric antrum in AG rats was significantly elevated (P < 0.05), while the number of glands dramatically decreased (P < 0.05). In addition, the cell proliferation in gastric glands was increased in experimental AG rats, as determined by immunohistochemistry staining of PCNA and GS II. The level of serum gastrin in AG rats was significantly elevated relative to that of normal rats (P < 0.01). Moreover, the expression of RegIα protein and its receptor mRNA was increased in gastric tissues in AG rats (P < 0.05). Taken together, we demonstrated that the overexpression of Reglα is related with hypergastrinemia in AG rats.

Involvement of the growth hormone and insulin in gastric secretion regulation in wrestlers during sport and post-sport ontogeny

The roles of gastrin, somatotropic hormone, insulin, and glucose in the formation of long-term and acute adaptation of gastric secretion in wrestlers during sport and post-sport ontogeny are discussed. The basal secretion of hormones and the blood glucose level have been found to change with age in a wavelike manner. Ascents and declines of different waves of their time course correspond to sensitive stages of ontogeny. Changes in hormone secretion and the glucose level under bicycle ergometry are statistically nonsignificant in 90% of cases, but these changes are enough to obtain a final result, namely, an adequate level of protein hydrolysis as a result of physical activity.

Roles of gastrin and somatostatin in ovarian cancer with gastroparesis syndrome

Roles of gastrin and somatostatin in ovarian cancer with gastroparesis syndrome

Role of gastrin peptides in carcinogenesis

Gastrin gene expression is upregulated in a number of pre-malignant conditions and established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical CCK-2R receptor, CCK-2R isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion. Here we review this network of events, highlighting the importance of cellular context for interpreting the role of gastrin peptides and a possible role for gastrin in supporting the early stage of carcinogenesis.

Differentiation of the Gastric Mucosa II. Role of gastrin in gastric epithelial cell proliferation and maturation

Gastrin is the principal hormonal inducer of gastric acid secretion. The cellular targets for gastrin in the stomach are the acid-secreting parietal cell and histamine-producing enterochromaffin-like (ECL) cell. Gastrin is also a growth factor, with hypergastrinemia resulting in increased proliferation of gastric progenitor cells and a thickened mucosa. This review presents insights into gastrin function revealed by genetically engineered mouse models, demonstrating a new role for gastrin in the maturation of parietal and ECL cells. Thus, gastrin regulates many aspects of gastric physiology, with tight regulation of gastrin levels required to maintain balanced growth and function of gastric epithelial cells.

Is Gastrin Partially Responsible for Body Weight Reduction after Gastric Bypass?

Background: The rationale for bariatric surgery is to reduce food intake by gastric restriction and/or malabsorption by intestinal bypass. Unlike ghrelin, gastrin is released in response to food intake. Here we studied the possible role of gastrin in the reduction of body weight after gastric bypass surgery. Methods: Rats were divided into four experimental groups and were subjected to different treatments: sham operation, gastric bypass, sham operation + gastrin infusion, and gastric bypass + gastrin infusion. The gastric bypass was done by anastomosing the esophagus to the duodenal bulb without bypassing the intestine. Gastrin-17 was infused continuously for 2 months via subcutaneously implanted osmotic minipumps. Body weights were recorded; serum gastrin and ghrelin levels were measured, and the stomachs were analyzed morphologically. Results: Gastric bypass resulted in reducing the body weight, stomach weight, thickness of the oxyntic mucosa, serum gastrin concentration, and activity of the ECL cells. Gastrin infusion prevented mucosal atrophy and ECL cell inactivation, and attenuated the body weight reduction that occurred following gastric bypass. Circulating ghrelin and ghrelin-producing A-like cells in stomachs that had undergone gastric bypass were unchanged with or without gastrin infusion and are thus unlikely to be responsible for the reduced body weight. Conclusion:We suggest that hypogastrinemia and impaired ECL cell function in the oxyntic mucosa of the stomach might be partially responsible for the reduction in body weight that occurs after gastric bypass.

Chronic Helicobacter pylori infection results in gastric hypoacidity and hypergastrinemia in wild-type mice but vagally induced hypersecretion in gastrin-deficient mice

Helicobacter pylori infection is a causal factor of gastric cancer (which is associated with low gastric acid secretion) or duodenal ulcer (high acid secretion). Parietal cells and ECL cells in the stomach are controlled by gastrin, which plays a crucial role in the regulation of acid secretion. The present study was undertaken to identify a possible role of gastrin in determining the different responses of the parietal cells and ECL cells to chronic H. pylori infection. Wild-type (C57BL/6J) gastrin +/+ mice and gastrin −/− knockout mice, generated through targeted gene disruption and backcrossed eight times to C57BL/6J, were infected with H. pylori for 9 months. The acid output was measured 4 h after pylorus ligation (known to cause vagal excitation). The gastric mucosa was examined by immunocytochemistry with antisera to α-subunit of H +/K +–ATPase for the parietal cells, and to histamine and vesicle monoamine transporter-2 for the ECL cells, and by quantitative electron microscopy. In infected gastrin +/+ mice, the acid output and the percentage of secreting parietal cells (freely fed state) were 20–30% of the values in uninfected controls, while the density and ultrastructure of parietal cells were normal. The infected mice had hypergastrinemia and displayed hypertrophy and hyperplasia of ECL cells. Although uninfected gastrin −/− mice had lower the acid output than uninfected gastrin +/+ mice, there was a higher acid output (∼3 times) in infected gastrin −/− mice than their uninfected homologues. The numbers of parietal cells and ECL cells remained unchanged in infected gastrin −/− mice. In conclusion, chronic H. pylori infection results to impaired parietal-cell function (acid hyposecretion), hypergastrinemia and hyperplasia of ECL cells in wild-type mice but leads to vagally induced hypersecretion in gastrin-deficient mice.

Role of gastrin in the development of gastric mucosa, ECL cells and A-like cells in newborn and young rats.

Histamine-producing ECL cells and ghrelin-producing A-like cells are endocrine/paracrine cell populations in the acid-producing part of the rat stomach. While the A-like cells operate independently of gastrin, the ECL cells respond to gastrin with mobilization of histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. Gastrin is often assumed to be the driving force behind the postnatal development of the gastric mucosa in general and the ECL cells in particular. We tested this assumption by examining the oxyntic mucosa (with ECL cells and A-like cells) in developing rats under the influence of YF476, a cholecystokinin-2 (CCK(2)) receptor antagonist. The drug was administered by weekly subcutaneous injections starting at birth. The body weight gain was not affected. Weaning occurred at days 15-22 in both YF476-treated and age-matched control rats. Circulating gastrin was low at birth and reached adult levels 2 weeks after birth. During and after weaning (but not before), YF476 greatly raised the serum gastrin concentration (because of abolished acid feedback inhibition of gastrin release). The weight of the stomach was unaffected by YF476 during the first 2-3 weeks after birth. From 4 to 5 weeks of age, the weight and thickness of the gastric mucosa were lower in YF476-treated rats than in controls. Pancreastatin-immunoreactive cells (i.e. all endocrine cells in the stomach) and ghrelin-immunoreactive cells (A-like cells) were few at birth and increased gradually in number until 6-8 weeks of age (control rats). At first, YF476 did not affect the development of the pancreastatin-immunoreactive cells, but a few weeks after weaning, the cells were fewer in the YF476 rats. The ECL-cell parameters (oxyntic mucosal histamine and pancreastatin concentrations, the histidine decarboxylase (HDC) activity, the HDC mRNA levels and serum pancreastatin concentration) increased slowly until weaning in both YF476-treated and control rats. From then on, there was a further increase in the ECL-cell parameters in control rats but not in YF476 rats. The postnatal development of the ghrelin cells (i.e. the A-like cells) and of the A-like cell parameters (the oxyntic mucosal ghrelin concentration and the serum ghrelin concentrations) was not affected by YF476 at any point. We conclude that gastrin affects neither the oxyntic mucosa nor the endocrine cells before weaning. After weaning, CCK(2) receptor blockade is associated with a somewhat impaired development of the oxyntic mucosa and the ECL cells. While gastrin stimulation is of crucial importance for the onset of acid secretion during weaning and for the activation of ECL-cell histamine formation and secretion, the mucosal and ECL-cell growth at this stage is only partly gastrin-dependent. In contrast, the development of the A-like cells is independent of gastrin at all stages.

The role of gastrin in salivary protection in helicobacter pylori negative asymptomatic volunteers: its potential physiological implications

The role of gastrin in salivary protection in helicobacter pylori negative asymptomatic volunteers: its potential physiological implications

Deletion of functional gastrin gene markedly increases colon carcinogenesis in response to azoxymethane in mice

Background & Aims: We recently reported that transgenic mice overexpressing progastrin were at a higher risk for developing colon cancers in response to azoxymethane (AOM), whereas mice overexpressing gastrin-17 were at a reduced risk. To examine further the role of gastrins in colon carcinogenesis, we generated gastrin gene knockout mice (GAS-KO). Methods: The height and proliferative index (PI) of colonic crypts were similar in GAS-KO and wild-type (WT) mice, suggesting that the absence of gastrins in GAS-KO mice did not significantly affect the growth of colonic mucosa. GAS-KO and WT mice were treated with AOM for 3–4 weeks; control mice received saline. Results: Colonic proliferation in response to AOM was significantly increased in GAS-KO vs. WT mice. Aberrant crypt foci (ACFs) were similarly increased significantly by ~2–5-fold in GAS-KO vs. WT mice after 2 weeks of AOM treatment. Female GAS-KO mice developed adenomas (Ads) and adenocarcinomas (AdCAs) at earlier times (~10 months) than the male GAS-KO mice and the male and female WT mice (~12 months). The total numbers of Ads and AdCAs were significantly higher in GAS-KO than in WT mice. Conclusions: These results suggest the novel possibility that loss of gastrin expression (and hence amidated gastrins) significantly increases susceptibility to colon carcinogenesis in response to AOM. Previous studies with FVB/N transgenic mice similarly suggested a protective role of amidated gastrins against colon carcinogenesis, which supports the present findings of an increase in colon carcinogenesis in GAS-KO mice lacking normal physiological levels of amidated gastrins.GASTROENTEROLOGY 2002;123:516-530

Menetrier's disease-like changes in the gastric mucosa of histamine H2 receptor-deficient mice. Role of gastrin

Menetrier's disease-like changes in the gastric mucosa of histamine H2 receptor-deficient mice. Role of gastrin

Acceleration of ulcer healing by N-alpha methythistamine (NαMH) in rats. Role of gastrin, DNA synthesis and CCKB/gastrin receptors

Acceleration of ulcer healing by N-alpha methythistamine (NαMH) in rats. Role of gastrin, DNA synthesis and CCKB/gastrin receptors

Menetrier's disease-like changes in the gastric mucosa of histamine H2 receptor-deficient mice. Role of gastrin

Menetrier's disease-like changes in the gastric mucosa of histamine H2 receptor-deficient mice. Role of gastrin