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Frontiers in Cellular Neuroscience 2022Most peripheral serotonin (5-HT) is synthesized in enterochromaffin cells, and most circulating 5-HT is stored in platelets. As a monoamine, 5-HT has several functions... (Review)
Review
Most peripheral serotonin (5-HT) is synthesized in enterochromaffin cells, and most circulating 5-HT is stored in platelets. As a monoamine, 5-HT has several functions in various non-neuronal and neuronal systems. In the central nervous system, it functions as a neurotransmitter to modulate feeding behavior and mood. Numerous clinical trials have focused on increasing 5-HT activation in the central nervous system, including those involving anti-obesity drugs currently in the market, although severe side effects on peripheral system can lead to the withdrawal of certain drugs. Recent studies have revealed that both the peripheral and central serotonergic systems play a vital role in diabetes and its complications. This review summarizes the roles of the serotonergic system in blood glucose regulation, diabetic macroangiopathy, diabetic peripheral neuropathy, and diabetic encephalopathy, indicating its potential clinical significance as a therapeutic target for the treatment of diabetes and its complications.
PubMed: 35910256
DOI: 10.3389/fncel.2022.899069 -
Histochemistry and Cell Biology Dec 2018Recent advances in neurogastroenterology have extended and refined our knowledge on the roles monoamines play in physiology and pathophysiology of the gastrointestinal... (Review)
Review
Recent advances in neurogastroenterology have extended and refined our knowledge on the roles monoamines play in physiology and pathophysiology of the gastrointestinal tract. The catecholamine noradrenaline, as the primary transmitter of postganglionic sympathetic neurons, orchestrates motility and secretory reflexes and controls arterial perfusion as well as immune functions. The catecholamine dopamine is produced by a subpopulation of enteric neurons which possibly use it as transmitter. Serotonin, largely produced by enterochromaffin cells and to a small extent by enteric neurons profoundly affects gut motility, enteric neuron development and is also involved in immunomodulation. However, its mode of action and the relative contribution of non-neuronal versus neuronal serotonin was recently subject to debate again. Histamine, although entirely of non-neuronal origin, is pivotal for gastrointestinal neuroimmunomodulation besides its paracrine effect in gastric HCl production.
Topics: Amines; Catecholamines; Enteric Nervous System; Humans; Serotonin
PubMed: 30250972
DOI: 10.1007/s00418-018-1723-4 -
Brain Research Aug 2018The gastrointestinal (GI) tract's normal function depends on its ability to propel, mix, and store contents in a highly coordinated fashion. An ability to sense... (Review)
Review
The gastrointestinal (GI) tract's normal function depends on its ability to propel, mix, and store contents in a highly coordinated fashion. An ability to sense mechanical forces is therefore fundamental to normal GI tract operation. There are several mechanosensory circuits distributed throughout the GI tract. These circuits rely on a range of proposed specialized and non-specialized mechanosensory cells that include epithelial enterochromaffin (EC) cells, both intrinsic and extrinsic sensory neurons, glia, interstitial cells of Cajal (ICC), and smooth muscle cells. While the anatomy of these circuits is established, the molecular mechanisms and functions are still poorly understood. In this review, we focus on the neuro-epithelial mechanosensory circuit in the gut, composed of epithelial EC cells and sensory neurons, both intrinsic and extrinsic. Intriguingly, this circuit closely resembles the light touch circuit in the skin that is composed of an epithelial Merkel cell and an afferent sensory neuron, suggesting that the basic building blocks may be retained in diverse mechanosensory systems. We compare the gross and molecular anatomy and physiology of these circuits and dissect the roles of GI neuro-epithelial mechanosensory, or "GI touch", circuitry in GI health and disease.
Topics: Animals; Gastrointestinal Tract; Humans; Mechanotransduction, Cellular; Skin; Touch
PubMed: 29903622
DOI: 10.1016/j.brainres.2018.02.039 -
Cellular and Molecular Gastroenterology... Jul 2017Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain.... (Review)
Review
Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin's actions are mediated through the G-protein-coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor-induced hypergastrinemia and infection with increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune-based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer.
PubMed: 28560291
DOI: 10.1016/j.jcmgh.2017.03.004 -
Neurogastroenterology and Motility Jul 2015The role of serotonin (5-hydroxytryptamine [5-HT]) in gastrointestinal motility has been studied for over 50 years. Most of the 5-HT in the body resides in the gut wall,... (Review)
Review
The role of serotonin (5-hydroxytryptamine [5-HT]) in gastrointestinal motility has been studied for over 50 years. Most of the 5-HT in the body resides in the gut wall, where it is located in subsets of mucosal cells (enterochromaffin cells) and neurons (descending interneurons). Many studies suggest that 5-HT is important to normal and dysfunctional gut motility and drugs affecting 5-HT receptors, especially 5-HT3 and 5-HT4 receptors, have been used clinically to treat motility disorders; however, cardiovascular side effects have limited the use of these drugs. Recently studies have questioned the importance and necessity of 5-HT in general and mucosal 5-HT in particular for colonic motility. Recent evidence suggests the importance of 5-HT3 and 5-HT4 receptors for initiation and generation of one of the key colonic motility patterns, the colonic migrating motor complex (CMMC), in rat. The findings suggest that 5-HT3 and 5-HT4 receptors are differentially involved in two different types of rat CMMCs: the long distance contraction (LDC) and the rhythmic propulsive motor complex (RPMC). The understanding of the role of serotonin in colonic motility has been influenced by the specific motility pattern(s) studied, the stimulus used to initiate the motility (spontaneous vs induced), and the route of administration of drugs. All of these considerations contribute to the understanding and the controversy that continues to surround the role of serotonin in the gut.
Topics: Animals; Colon; Gastrointestinal Motility; Intestinal Mucosa; Rats; Serotonin
PubMed: 26095115
DOI: 10.1111/nmo.12617 -
Pharmacological Reviews Dec 2023Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord.... (Review)
Review
Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.
Topics: Humans; Chronic Pain; Parkinson Disease; Dysbiosis; Pain Perception; Gastrointestinal Microbiome; Dopaminergic Neurons
PubMed: 37863655
DOI: 10.1124/pharmrev.122.000674 -
Internal and Emergency Medicine Sep 2023The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally... (Review)
Review
The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally by a mucus layer, consisting mainly of mucins, antimicrobial peptides, and secretory immunoglobulin A (sIgA), which serves as the first interaction with the intestinal microbiota. Below is placed the epithelial monolayer, comprising enterocytes and specialized cells, such as goblet cells, Paneth cells, enterochromaffin cells, and others, each with a specific protective, endocrine, or immune function. This layer interacts with both the luminal environment and the underlying lamina propria, where mucosal immunity processes primarily take place. Specifically, the interaction between the microbiota and an intact mucosal barrier results in the activation of tolerogenic processes, mainly mediated by FOXP3 regulatory T cells, underlying intestinal homeostasis. Conversely, the impairment of the mucosal barrier function, the alteration of the normal luminal microbiota composition (dysbiosis), or the imbalance between pro- and anti-inflammatory mucosal factors may result in inflammation and disease. Another crucial component of the intestinal barrier is the gut-vascular barrier, formed by endothelial cells, pericytes, and glial cells, which regulates the passage of molecules into the bloodstream. The aim of this review is to examine the various components of the intestinal barrier, assessing their interaction with the mucosal immune system, and focus on the immunological processes underlying homeostasis or inflammation.
Topics: Humans; Immunity, Mucosal; Endothelial Cells; Intestinal Mucosa; Inflammation; Homeostasis
PubMed: 37402104
DOI: 10.1007/s11739-023-03329-1 -
Life Sciences Dec 2019Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key... (Review)
Review
Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.
Topics: Animals; Colon; Enterochromaffin Cells; Humans; Hyperplasia; Infections; Inflammation; Intestines; Irritable Bowel Syndrome; Serotonin; Stress, Physiological
PubMed: 31678286
DOI: 10.1016/j.lfs.2019.116886 -
International Journal of Molecular... Dec 2022Normal gastrointestinal function relies on sensing and transducing mechanical signals into changes in intracellular signaling pathways. Both specialized mechanosensing... (Review)
Review
Normal gastrointestinal function relies on sensing and transducing mechanical signals into changes in intracellular signaling pathways. Both specialized mechanosensing cells, such as certain enterochromaffin cells and enteric neurons, and non-specialized cells, such as smooth muscle cells, interstitial cells of Cajal, and resident macrophages, participate in physiological and pathological responses to mechanical signals in the gastrointestinal tract. We review the role of mechanosensors in the different cell types of the gastrointestinal tract. Then, we provide several examples of the role of mechanotransduction in normal physiology. These examples highlight the fact that, although these responses to mechanical signals have been known for decades, the mechanosensors involved in these responses to mechanical signals are largely unknown. Finally, we discuss several diseases involving the overstimulation or dysregulation of mechanotransductive pathways. Understanding these pathways and identifying the mechanosensors involved in these diseases may facilitate the identification of new drug targets to effectively treat these diseases.
Topics: Mechanotransduction, Cellular; Gastrointestinal Tract; Signal Transduction; Intestine, Small; Interstitial Cells of Cajal
PubMed: 36613619
DOI: 10.3390/ijms24010177 -
World Journal of Gastrointestinal... Aug 2020Gastric neuroendocrine tumors are gastric neoplasms originating from enterochromaffin type cells and are inserted in a larger group, named gastroenteropancreatic... (Review)
Review
Gastric neuroendocrine tumors are gastric neoplasms originating from enterochromaffin type cells and are inserted in a larger group, named gastroenteropancreatic neuroendocrine tumors. They are considered rare and variable in terms of their clinical, morphological and functional characteristics and may be indolent or aggressive. They are classified into types I, II and III, according to their pathophysiology, behavior and treatment. Their diagnosis occurs, in most cases, incidentally during upper digestive endoscopies, presenting as simple gastric polyps. Most cases (type I and type II) are related to hypergastrinemia, can be multiple and are treated by endoscopic resection, whenever possible. The use of somatostatin analogs for tumor control may be one of the options for therapy, in addition to total or subtotal gastrectomy for selected cases. Adjuvant chemotherapy is only reserved for poorly differentiated neuroendocrine carcinomas. Although rare, gastric neuroendocrine tumors have an increasing incidence over the years, therefore deserving more comprehensive studies on its adequate treatment. The present study reviews and updates management recommendations for gastric neuroendocrine tumors.
PubMed: 32879663
DOI: 10.4251/wjgo.v12.i8.850