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World Journal of Clinical Cases Oct 2021Neuroendocrine tumors (NETs) are a rare and heterogeneous disease group and constitute 0.5% of all malignancies. The annual incidence of NETs is increasing worldwide.... (Review)
Review
Neuroendocrine tumors (NETs) are a rare and heterogeneous disease group and constitute 0.5% of all malignancies. The annual incidence of NETs is increasing worldwide. The reason for the increase in the incidence of NETs is the detection of benign lesions, incidental detection due to the highest use of endoscopic and imaging procedures, and higher recognition rates of pathologists. There have been exciting developments regarding NET biology in recent years. Among these, first of all, somatostatin receptors and downstream pathways in neuroendocrine cells have been found to be important regulatory mechanisms for protein synthesis, hormone secretion, and proliferation. Subsequently, activation of the mammalian target of rapamycin pathway was found to be an important mechanism in angiogenesis and tumor survival and cell metabolism. Finally, the importance of proangiogenic factors (platelet-derived growth factor, vascular endothelial growth factor, fibroblastic growth factor, angiopoietin, and semaphorins) in the progression of NET has been determined. Using the combination of biomarkers and imaging methods allows early evaluation of the appropriateness of treatment and response to treatment.
PubMed: 34734042
DOI: 10.12998/wjcc.v9.i29.8627 -
Gastroenterology Jun 2021Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine [5-HT]), which is primarily produced by enterochromaffin (EC) cells in the GI tract....
BACKGROUND & AIMS
Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine [5-HT]), which is primarily produced by enterochromaffin (EC) cells in the GI tract. However, the precise roles of EC cell-derived 5-HT in regulating gastric motility remain a major point of conjecture. Using a novel transgenic mouse line, we investigated the distribution of EC cells and the pathophysiologic roles of 5-HT deficiency in gastric motility in mice and humans.
METHODS
We developed an inducible, EC cell-specific Tph1 mouse, which was used to generate a reporter mouse line, Tph1-tdTom, and an EC cell-depleted line, Tph1-DTA. We examined EC cell distribution, morphology, and subpopulations in reporter mice. GI motility was measured in vivo and ex vivo in EC cell-depleted mice. Additionally, we evaluated 5-HT content in biopsy and plasma specimens from patients with idiopathic gastroparesis (IG).
RESULTS
Tph1-tdTom mice showed EC cells that were heterogeneously distributed throughout the GI tract with the greatest abundance in the antrum and proximal colon. Two subpopulations of EC cells were identified in the gut: self-renewal cells located at the base of the crypt and mature cells observed in the villi. Tph1-DTA mice displayed delayed gastric emptying, total GI transit, and colonic transit. These gut motility alterations were reversed by exogenous provision of 5-HT. Patients with IG had a significant reduction of antral EC cell numbers and 5-HT content, which negatively correlated with gastric emptying rate.
CONCLUSIONS
The Tph1 mouse provides a powerful tool to study the functional roles of EC cells in the GI tract. Our findings suggest a new pathophysiologic mechanism of 5-HT deficiency in IG.
Topics: Animals; Cell Line; Enterochromaffin Cells; Gastric Emptying; Gastrointestinal Transit; Humans; Mice; Mice, Transgenic; Serotonin; Tryptophan Hydroxylase
PubMed: 33662386
DOI: 10.1053/j.gastro.2021.02.060 -
Acta Gastro-enterologica Belgica Mar 2016Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder, characterized by abdominal pain and altered intestinal motility. Visceral... (Review)
Review
Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder, characterized by abdominal pain and altered intestinal motility. Visceral hypersensitivity is an important hallmark feature of IBS and is believed to underlie abdominal pain in patients with IBS. The two main risk factors associated with the development of IBS are gastrointestinal inflammation and psychological distress. On a peripheral level, visceral sensitivity seems to be modulated by several mechanisms. Immune cells in the mucosal wall, such as mast cells, and enterochromaffin cells may sensitize afferent nerves by release of their mediators. Furthermore, increased mucosal permeability, altered intestinal microflora and dietary habits may contribute to this feature. On a central level, an increased prevalence of psychiatric comorbidities is demonstrated in IBS patients, alongside alterations in the hormonal brain-gut axis, increased vigilance towards intestinal stimuli and functional and structural changes in the brain. The pathogenesis of IBS is complicated and multifactorial and the treatment remains clinically challenging. Dietary measures and symptomatic control are the cornerstones for IBS treatment and may be sufficient for patients experiencing mild symptoms, alongside education, reassurance and an effective therapeutic physician-patient relationship. New pharmacological therapies are aimed at interfering with mediator release and/or blockade of the relevant receptors within the gut wall, while modulation of the intestinal flora and diet may also be of therapeutic benefit. Tricyclic anti-depressants and serotonin reuptake inhibitors act both on a central and peripheral level by modulating pain signalling pathways.
Topics: Abdominal Pain; Brain; Humans; Hyperalgesia; Hyperesthesia; Intestines; Irritable Bowel Syndrome; Stress, Psychological
PubMed: 26852761
DOI: No ID Found -
Immunological Investigations Nov 2023Autoimmune gastritis (AIG) is an autoimmune disease of the stomach characterized by the destruction of the oxyntic mucosa, which stops producing acid and becomes both...
BACKGROUND
Autoimmune gastritis (AIG) is an autoimmune disease of the stomach characterized by the destruction of the oxyntic mucosa, which stops producing acid and becomes both functionally and morphologically atrophic. The pathogenic mechanisms behind the disease are still poorly understood. There is no early diagnosis and specific AIG therapy. To elucidate the pathogenesis of AIG, to search for early diagnostic markers, as well as to test new therapeutic approaches, an adequate and easily reproducible experimental model for autoimmune gastritis (EAG) is needed. Existing EAG models have some limitations, including slow development of signs, absence of advanced gastritis, irrational use of animals to obtain antigen. The aim was to find out whether it is possible to cause autoimmune gastritis similar to human disease in Wistar rats through immunization with a homologous gastric mucosa extract.
METHODS
Wistar rats were immunized with gastric mucosa extract. Histology studies and evaluation of serological parameters were performed 56 and 91 days later.
RESULTS
Destruction of oxyntic glands by infiltrating T lymphocytes were detected in rats on 56 and 91 days after initial immunization with gastric mucosa extract. Hyperplasia of enterochromaffin-like (ECL) cells was detected on the 91st day. Antral mucosa remained unchanged.
CONCLUSION
Wistar rats, immunized with gastric mucosa extract, developed EAG similar to human AIG. The advantages of received EAG model are the ease of obtaining, the rapid development of oxyntic mucosa damage, which may progress to ECL cell hyperplasia.
Topics: Humans; Rats; Animals; Hyperplasia; Rats, Wistar; Gastritis; Gastric Mucosa; Autoimmune Diseases
PubMed: 37962068
DOI: 10.1080/08820139.2023.2283103 -
Scientific Reports Nov 2021Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically...
Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase in the enterochromaffin cells of the small intestine, we found high and differential expression of EZH2 in primary SI-NETs and corresponding metastases. Silencing EZH2 in the SI-NET cell line CNDT2.5 reduced cell proliferation and induced apoptosis. Furthermore, EZH2 knockout inhibited tumor progression in a CNDT2.5 SI-NET xenograft mouse model, and treatment of SI-NET cell lines CNDT2.5 and GOT1 with the EZH2-specific inhibitor CPI-1205 decreased cell viability and promoted apoptosis. Moreover, CPI-1205 treatment reduced migration capacity of CNDT2.5 cells. The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Recently, metformin has received wide attention as a therapeutic option in diverse cancers. In CNDT2.5 and GOT1 cells, metformin suppressed EZH2 expression, and inhibited cell proliferation. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs.
Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Drug Therapy, Combination; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoglycemic Agents; Indoles; Intestinal Neoplasms; Intestine, Small; Metformin; Mice; Mice, Nude; Neuroendocrine Tumors; Piperidines; Prognosis; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 34815475
DOI: 10.1038/s41598-021-02181-7 -
Current Opinion in Gastroenterology Nov 2015This review summarizes the past year's literature regarding the neuroendocrine and intracellular regulation of gastric acid secretion, discussing both basic and clinical... (Review)
Review
PURPOSE OF REVIEW
This review summarizes the past year's literature regarding the neuroendocrine and intracellular regulation of gastric acid secretion, discussing both basic and clinical aspects.
RECENT FINDINGS
Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High acidity kills ingested microorganisms and limits bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. The main stimulants of acid secretion are gastrin, released from antral gastrin cells; histamine, released from oxyntic enterochromaffin-like cells; and acetylcholine, released from antral and oxyntic intramural neurons. Ghrelin and coffee also stimulate acid secretion whereas somatostatin, cholecystokinin, glucagon-like peptide-1, and atrial natriuretic peptide inhibit acid secretion. Although 95% of parietal cells are contained within the oxyntic mucosa (fundus and body), 50% of human antral glands contain parietal cells. Proton pump inhibitors are considered well tolerated drugs, but concerns have been raised regarding dysbiosis, atrophic gastritis, hypergastrinemia, hypomagnesemia, and enteritis/colitis.
SUMMARY
Our understanding of the functional anatomy and physiology of gastric secretion continues to advance. Such knowledge is crucial for improved management of acid-peptic disorders, prevention and management of neoplasia, and the development of novel medications.
Topics: Gastric Acid; Gastrins; H(+)-K(+)-Exchanging ATPase; Histamine; Humans; Neurosecretory Systems; Proton Pump Inhibitors; Signal Transduction
PubMed: 26376477
DOI: 10.1097/MOG.0000000000000213 -
Journal of Pediatric Gastroenterology... Feb 2020To bring heightened awareness to a condition, autoimmune gastritis (AIG), which is a well-established entity in adults; however, rarely described in pediatrics.... (Review)
Review
OBJECTIVES
To bring heightened awareness to a condition, autoimmune gastritis (AIG), which is a well-established entity in adults; however, rarely described in pediatrics. Currently, the literature describes AIG in pediatric patients who also suffer from other autoimmune disorders, which precedes the diagnosis of AIG, and often presents with unexplained anemia. Additionally, there have been case reports describing patients with immunodeficiencies and AIG, which progress to gastric adenocarcinoma. AIG is a histopathologic diagnosis, demonstrating chronic inflammatory process with loss of parietal cells with or without intestinal metaplasia and enterochromaffin-like cell hyperplasia. Management of these patients includes nutritional replacement as well as routine surveillance endoscopy with biopsy in search of metaplastic and dysplastic changes.
METHODS
We queried the pathology database at Children's Hospital Los Angeles (CHLA) for cases with a final diagnosis of AIG and for those with a differential diagnosis that includes AIG in the diagnostic comment. All cases that were identified were selected as long as they did not only meet the histopathologic criteria, but also the biochemical criteria for this condition.
RESULTS
Of the 3 patients, 2 were referred to gastroenterology for the evaluation of iron-deficiency anemia in the context of diabetes mellitus and Addison's disease; and diabetes mellitus and Hashimoto's thyroiditis. AIG was confirmed on the biopsies, which showed a reduction in parietal cell mass, pseudopyloric metaplasia and enterochromafin-like cell hyperplasia. Both patients were treated with iron replacement therapy. The third patient presented with symptomatic anemia and diagnosed with pernicious anemia without other autoimmune disorders. She was successfully treated with oral vitamin supplementation. In this case, serial gastric biopsies demonstrated stable intestinal metaplasia without evidence of dysplasia.
CONCLUSION
Although AIG is rare in children, pediatric gastroenterologists and pathologists should have a heightened suspicion for this entity in those patients with a history of autoimmune disorders and/or pernicious anemia.
Topics: Adult; Autoimmune Diseases; Child; Female; Gastritis; Humans; Metaplasia; Parietal Cells, Gastric; Pediatrics
PubMed: 31978028
DOI: 10.1097/MPG.0000000000002547 -
Trends in Pharmacological Sciences Jun 2018The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct... (Review)
Review
The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds.
Topics: Animals; Disease Models, Animal; Drug Design; Enterochromaffin Cells; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Serotonin; Tryptophan Hydroxylase
PubMed: 29628275
DOI: 10.1016/j.tips.2018.03.004 -
Cell Proliferation Oct 2020Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor...
OBJECTIVES
Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor (GDNF)-rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF-RET in the pathophysiology of diarrhoea-predominant irritable bowel syndrome (IBS-D).
MATERIALS AND METHODS
GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS-D patients and healthy controls. Stress was induced by using a wrap-restraint stress (WRS) procedure to serve as an acute stress-induced IBS model. The function of GDNF-RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro.
RESULTS
GDNF-RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS-D patients. WRS mice showed increased GDNF-RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF-RET. Furthermore, GDNF-treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose-dependent manner.
CONCLUSIONS
We identified GDNF-RET was presented in colonic epithelium of patients with IBS-D. GDNF-RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS-D.
Topics: Adult; Animals; Enterochromaffin Cells; Female; Glial Cell Line-Derived Neurotrophic Factor; Homeostasis; Humans; Intestinal Mucosa; Intestines; Irritable Bowel Syndrome; Male; Mice, Inbred C57BL; Middle Aged; Proto-Oncogene Proteins c-ret; Stress, Physiological
PubMed: 32808420
DOI: 10.1111/cpr.12889 -
Comprehensive Physiology Apr 2021The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that... (Review)
Review
The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that communicate the metabolic state to specific nuclei in the hindbrain and the hypothalamus. The present overview gives emphasis on seven peptides that are produced by and secreted from specialized enteroendocrine cells along the gastrointestinal tract in relation with the nutritional status. These established modulators of feeding are ghrelin and nesfatin-1 secreted from gastric X/A-like cells, cholecystokinin (CCK) secreted from duodenal I-cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY) secreted from intestinal L-cells and uroguanylin (UGN) released from enterochromaffin (EC) cells. © 2021 American Physiological Society. Compr Physiol 11:1679-1730, 2021.
Topics: Cholecystokinin; Eating; Glucagon-Like Peptide 1; Oxyntomodulin; Peptide YY
PubMed: 33792904
DOI: 10.1002/cphy.c200007