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Virchows Archiv : An International... Jun 2024Mixed adenoma-neuroendocrine tumor (MANET) comprises adenoma and well-differentiated neuroendocrine tumor (NET) components. Given the limited information on this due to...
Mixed adenoma-neuroendocrine tumor (MANET) comprises adenoma and well-differentiated neuroendocrine tumor (NET) components. Given the limited information on this due to its rarity, we aimed to clarify the clinicopathologic features and optimal management of gastric MANETs in a case series and literature review. Nine patients with gastric MANETs, including eight male and one female patient (mean age, 72 years), were identified from the institutional pathology archive. Endoscopically, the tumors appeared as flat elevated lesions with sizes ranging from 0.8 to 4.4 cm. One patient had familial adenomatous polyposis, and no patient had autoimmune gastritis. All MANETs developed in the gastric body mucosa exhibiting chronic metaplastic atrophic gastritis. The glandular components were intestinal-type low-grade adenoma, and focal high-grade dysplasia was also recognized in three cases. The NET component was in middle/deep lamina propria in six cases and confined to deep lamina propria in the remaining three cases. Minimal cytologic atypia was found in the NET component, with no recognizable mitosis and a Ki-67 labeling index of < 2%. The NET component mostly showed diffuse positivity for serotonin and CDX2, suggesting that it consists of enterochromaffin cells. Diffuse p53 immunostaining was observed only in the high-grade adenomatous component of one case. No recurrence was observed during the follow-up period of 2-94 months. Correct distinction between the NET and poorly differentiated carcinoma components is crucial to prevent overtreatment of gastric MANETs. Considering its indolent nature, endoscopic resection is the primary recommendation for gastric MANETs as well as for pure adenomas.
PubMed: 38922356
DOI: 10.1007/s00428-024-03851-3 -
Food & Function Jun 2024AR495 is a widely used probiotic for the treatment of various digestive diseases, including irritable bowel syndrome (IBS). However, the specific mechanisms of AR495...
AR495 is a widely used probiotic for the treatment of various digestive diseases, including irritable bowel syndrome (IBS). However, the specific mechanisms of AR495 in alleviating IBS remain unclear. Abnormal intestinal tryptophan metabolism can cause disordered immune responses, gastrointestinal peristalsis, digestion and sensation, which is closely related to IBS pathogenesis. The aim of this study is to explore the effects and mechanisms of AR495 in regulating tryptophan metabolism. Primarily, tryptophan and its related metabolites in patients with IBS and healthy people were analyzed, and an IBS rat model of acetic acid enema plus restraint stress was established to explore the alleviation pathway of AR495 in tryptophan metabolism. It was found that the 5-HT pathway was significantly changed, and the 5-HTP and 5-HT metabolites were significantly increased in the feces of patients with IBS, which were consistent with the results obtained for the IBS rat model. Maladjusted 5-HT could increase intestinal peristalsis and lead to an increase in the fecal water content and shapeless stool in rats. On the contrary, these two metabolites could be restored to normal levels intragastric administration of AR495. Further study of the metabolic pathway showed that AR495 could effectively reduce the abundance of 5-HT by inhibiting the expression of enterochromaffin cells rather than promoting its decomposition. In addition, the results showed that AR495 did not affect the expression of SERT. To sum up, AR495 could restore the normal levels of 5-HT by inhibiting the abnormal proliferation of enterochromaffin cells and the excessive activation of TPH1 to inhibit the intestinal peristalsis in IBS. These findings provide insights for the use of probiotics in the treatment of IBS and other diarrheal diseases.
PubMed: 38899520
DOI: 10.1039/d4fo01087f -
Chinese Medicine Jun 2024Shaoyao Decoction (SYD) is a widely recognized herbal formula utilized in traditional Chinese medicine for the treatment of diarrhea. Although it has demonstrated...
BACKGROUND
Shaoyao Decoction (SYD) is a widely recognized herbal formula utilized in traditional Chinese medicine for the treatment of diarrhea. Although it has demonstrated significant effectiveness in clinical practice for treating ulcerative colitis, the precise mechanisms by which it operates remain largely elusive.
METHODS
The active ingredients of SYD were obtained by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), which were used to explore the potential pharmacological mechanism based on TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and PANTHER (Protein Analysis Through Evolutionary Relationships) classification system. In a mouse model of dextran sulfate sodium (DSS)-induced colitis, mRNA sequencing, 16S rDNA sequencing and targeted metabolomics techniques were used to elucidate the mechanisms of SYD, and immunohistochemistry, immunofluorescence, enzyme linked immunosorbent assay, real time quantitative polymerase chain reaction and western blot were used to test the key targets. In addition, QGP-1 and H9 cells were performed to validate the discoveries from the animal experiments.
RESULTS
In the mouse model of DSS-induced colitis, SYD effectively alleviated symptoms such as bloody stool, tissue damage, inflammation, intestinal flora dysbiosis and abnormal gene expression. Analyses of both differential expressed genes in colonic tissue and predicted 16S rDNA genes, as well as the analyses of targeted genes from TCMSP based on the active ingredients in UPLC-MS/MS of SYD, uncovered the enrichment of pathways involved in the biosynthesis and degredation of 5-hydroxytryptamine (5-HT). Interestingly, SYD suppressed the relative abundance of key genes in 5-HT synthesis, Tph1(Tryptophan hydroxylase 1) and Ddc (Dopa decarboxylase), in faeces from DSS-induced mice, leading to a reduction in the concentration of fecal 5-HT. Moreover, SYD augmented the production of butyric acid. Subsequently, increasing butyric acid influenced the metabolism of 5-HT in the organism through G protein-coupled receptor 43 by impeding its synthesis, facilitating its transport and degredation. These findings were additionally corroborated in a model utilizing enterochromaffin cell (QGP-1 cells). Furthermore, reduced levels of 5-HT hindered the activation of T lymphocytes (H9 cells) via the PKC (Protein kinase C) and NF-κB (Nuclear factor kappa-B) signaling pathways, by means of HTR1A (5-HT receptor 1A) and HTR3 (5-HT receptor 3). Additionally, diminished secretion of 5-HT resulted in reduced secretion of associated cytokines, thereby alleviating inflammation in the colon.
CONCLUSION
Through modulation of T lymphocyte activation mediated by 5-HT metabolism in the local colon via the intestinal flora and its metabolite, SYD effectively mitigated colonic inflammation in DSS-induced mice.
PubMed: 38879471
DOI: 10.1186/s13020-024-00958-2 -
Diseases (Basel, Switzerland) May 2024Appendiceal neuroendocrine tumors (NETs) rank as the third most frequent neoplasm affecting the appendix, originating from enterochromaffin cells. This study aims to...
BACKGROUND
Appendiceal neuroendocrine tumors (NETs) rank as the third most frequent neoplasm affecting the appendix, originating from enterochromaffin cells. This study aims to evaluate the influence of various prognostic factors on the mortality rates of patients diagnosed with NETs of the appendix.
METHODS
Conducted retrospectively, the study involved 3346 patients, utilizing data sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis centered on investigating demographic characteristics, clinical features, overall mortality (OM), and cancer-specific mortality (CSM) among the cohort. Variables showing a -value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox regression analysis. A Hazard Ratio (HR) > 1 indicated an unfavorable prognosis.
RESULTS
In the multivariate analysis, higher OM and CSM were observed in males, older age groups, tumors with distant metastasis, poorly differentiated tumors, and those who underwent chemotherapy. Non-Hispanic Black individuals showed elevated mortality rates.
CONCLUSION
Delayed diagnosis may contribute to the increased mortality in this community. Improved access to healthcare and treatment is crucial for addressing these disparities. Larger prospective studies are needed to pinpoint the underlying causes of elevated mortality in non-Hispanic Black populations, and randomized controlled trials (RCTs) are warranted to evaluate therapies for advanced-stage appendix NETs.
PubMed: 38785751
DOI: 10.3390/diseases12050096 -
Cell Stem Cell May 2024Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis...
Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and cis-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct ASCL1 and HES6 cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind cis-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.
PubMed: 38733993
DOI: 10.1016/j.stem.2024.04.015 -
Scientific Reports May 2024Enterochromaffin (EC) cells located within the intestinal mucosal epithelium release serotonin (5-HT) to regulate motility tones, barrier function and the immune system....
Enterochromaffin (EC) cells located within the intestinal mucosal epithelium release serotonin (5-HT) to regulate motility tones, barrier function and the immune system. Electroanalytical methodologies have been able to monitor steady state basal extracellular 5-HT levels but are unable to provide insight into how these levels are influenced by key regulatory processes such as release and uptake. We established a new measurement approach, amperometry approach curve profiling, which monitors the extracellular 5-HT level at different electrode-tissue (E-T) distances. Analysis of the current profile can provide information on contributions of regulatory components on the observed extracellular 5-HT level. Measurements were conducted from ex vivo murine ileum and colon using a boron-doped diamond (BDD) microelectrode. Amperometry approach curve profiling coupled with classical pharmacology demonstrated that extracellular 5-HT levels were significantly lower in the colon when compared to the ileum. This difference was due to a greater degree of activity of the 5-HT transporter (SERT) and a reduced amount of 5-HT released from colonic EC cells. The presence of an inhibitory 5-HT autoreceptor was observed in the colon, where a 40% increase in extracellular 5-HT was the half maximal inhibitory concentration for activation of the autoreceptor. This novel electroanalytical approach allows estimates of release and re-uptake and their contribution to 5-HT extracellular concentration from intestinal tissue be obtained from a single series of measurements.
Topics: Serotonin; Animals; Mice; Ileum; Intestinal Mucosa; Colon; Enterochromaffin Cells; Microelectrodes; Serotonin Plasma Membrane Transport Proteins; Male; Electrochemical Techniques; Mice, Inbred C57BL
PubMed: 38714793
DOI: 10.1038/s41598-024-61296-9 -
Microorganisms Apr 2024Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate...
Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type () or tryptophanase-encoding tnaA knockout mutant indole-non-producing . Indole mutant mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed-frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline.
PubMed: 38674663
DOI: 10.3390/microorganisms12040719 -
Clinical Journal of Gastroenterology Apr 2024A 47-year-old woman presented with multiple gastric tumors, each up to 10 mm in diameter, in the gastric body and fundus without mucosal atrophy. White spots and...
A 47-year-old woman presented with multiple gastric tumors, each up to 10 mm in diameter, in the gastric body and fundus without mucosal atrophy. White spots and numerous transparent, light-brownish, small, and rounded spots were observed in the background gastric mucosa. Biopsy specimens obtained from the tumors revealed gastric neuroendocrine tumors. The patient exhibited hypergastrinemia and achlorhydria and tested negative for serum parietal cell antibody, intrinsic factor antibody, and Helicobacter pylori infection. Moreover, no additional lesions were detected on imaging. These findings were inconsistent with Rindi's classification. The tumor was resected via endoscopic submucosal resection. Histopathological examination revealed gastric neuroendocrine tumors G2 infiltrating the submucosa with no atrophy of the gastric mucosa, dilated fundic glands, parietal cell protrusions, and hyperplasia of enterochromaffin-like cells. Immunohistochemically, the parietal cells were negative for both α- and β-subunits of H/K ATPase, suggesting parietal cell dysfunction. A genomic variant was identified in adenosine triphosphatase H/K transporting subunit alpha. After 7 years of treatment, there was no evidence of residual or metastatic lesions. Modification of adenosine triphosphatase H/K transporting subunit alpha may be a significant factor in the pathogenesis of multiple gastric neuroendocrine tumors in the context of gastric parietal cell dysfunction.
PubMed: 38635098
DOI: 10.1007/s12328-024-01969-0 -
The Journal of Comparative Neurology Apr 2024How the gastrointestinal tract communicates with the brain, via sensory nerves, is of significant interest for our understanding of human health and disease....
How the gastrointestinal tract communicates with the brain, via sensory nerves, is of significant interest for our understanding of human health and disease. Enterochromaffin (EC) cells in the gut mucosa release a variety of neurochemicals, including the largest quantity of 5-hydroxytryptamine (5-HT) in the body. How 5-HT and other substances released from EC cells activate sensory nerve endings in the gut wall remains a major unresolved mystery. We used in vivo anterograde tracing from nodose ganglia to determine the spatial relationship between 5-HT synthesizing and peptide-YY (PYY)-synthesizing EC cells and their proximity to vagal afferent nerve endings that project to the mucosa of mouse small intestine. The shortest mean distances between single 5-HT- and PYY-synthesizing EC cells and the nearest vagal afferent nerve endings in the mucosa were 33.1 ± 14.4 µm (n = 56; N = 6) and 70.3 ± 32.3 µm (n = 16; N = 6). No morphological evidence was found to suggest that 5-HT- or PYY-containing EC cells form close morphological associations with vagal afferents endings, or varicose axons of passage. The large distances between EC cells and vagal afferent endings are many hundreds of times greater than those known to underlie synaptic transmission in the nervous system (typically 10-15 nm). Taken together, the findings lead to the inescapable conclusion that communication between 5-HT-containing EC cells and vagal afferent nerve endings in the mucosa of the mouse small intestinal occurs in a paracrine fashion, via diffusion. New and Noteworthy None of the findings here are consistent with a view that close physical contacts occur between 5-HT-containing EC cells and vagal afferent nerve endings in mouse small intestine. Rather, the findings suggest that gut-brain communication between EC cells and vagal afferent endings occurs via passive diffusion. The morphological data presented do not support the view that EC cells are physically close enough to vagal afferent endings to communicate via fast synaptic transmission.
Topics: Mice; Humans; Animals; Serotonin; Vagus Nerve; Sensory Receptor Cells; Brain; Intestine, Small; Nerve Endings; Neurons, Afferent
PubMed: 38625817
DOI: 10.1002/cne.25613 -
Journal of Clinical Medicine Mar 2024Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently,... (Review)
Review
Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.
PubMed: 38610738
DOI: 10.3390/jcm13071970