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Qin LL, Yu M, Yang P, Zou ZM. The rhizomes of Atractylodes macrocephala relieve loperamide-induced constipation in rats by regulation of tryptophan metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2024; 322:117637. [PMID: 38135226 DOI: 10.1016/j.jep.2023.117637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/17/2023] [Accepted: 12/19/2023] [Indexed: 12/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Constipation is one of the most prevalent gastrointestinal tract diseases that seriously affects health-related quality of human life and requires effective treatments without side effect. The rhizome of Atractylodes macrocephala Koidz. (Compositae), called Atractylodes Macrocephala Rhizome (AMR), a commonly used traditional Chinese medicine, has been used to relieve the clinical symptoms of patients with constipation. AIM OF THE STUDY To reveal the dose-dependent laxative effect and potential mechanism of AMR on loperamide-induced slow transit constipation (STC) rats. MATERIALS AND METHODS Loperamide-induced constipation rat model was established and the dose-dependent laxative effect of AMR was investigated. Untargeted metabolomics based on an UPLC-Q/TOF-MS technique combined with western blot analysis was used to explain the potential mechanism of AMR relieve loperamide-induced constipation in rats. RESULTS The results showed that medium dose of AMR (AMR-M, 4.32 g raw herb/kg) and high dose of AMR (AMR-H, 8.64 g raw herb/kg) treatments significantly increased the fecal water content, Bristol score, gastrointestinal transit rate, and recovered the damaged colon tissues of constipated rats, but low dose of AMR (AMR-L, 2.16 g raw herb/kg) did not show laxative effect. Both AMR-M and AMR-H treatments also remarkably reduced the serum levels of vasoactive intestinal peptide (VIP), somatostatin (SS) and dopamine (DA), and increased the levels of motilin (MTL), gastrin (GAS) and 5-hydroxytryptamine (5-HT). Urine metabolomics revealed that constipation development was mainly ascribed to the perturbed tryptophan metabolism, and AMR-M and AMR-H markedly corrected the abnormal levels of five urine tryptophan metabolites, namely 4,6-dihydroxyquinoline, indole, 4,8-dihydroxyquinoline, 5-hydroxytryptamine, and kynurenic acid. Additionally, western blot analysis confirmed that the abnormal expression of rate-limiting enzyme involving in tryptophan metabolism, including tryptophan hydroxylase (TPH), monoamine oxidase (MAO) and indoleamine-2,3-dioxygenase (IDO) in the colon of constipated rats, were mediated by AMR-M and AMR-H. CONCLUSIONS The findings provide insight into the mechanisms of STC and AMR could be developed as new therapeutic agent for prevention or healing of constipation.
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Affiliation(s)
- Ling-Ling Qin
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China.
| | - Meng Yu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China.
| | - Peng Yang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China.
| | - Zhong-Mei Zou
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China.
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Grondin JA, Khan WI. Emerging Roles of Gut Serotonin in Regulation of Immune Response, Microbiota Composition and Intestinal Inflammation. J Can Assoc Gastroenterol 2024; 7:88-96. [PMID: 38314177 PMCID: PMC10836984 DOI: 10.1093/jcag/gwad020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2024] Open
Abstract
Although the exact etiology of inflammatory bowel diseases (IBD) is unknown, studies have shown that dysregulated immune responses, genetic factors, gut microbiota, and environmental factors contribute to their pathogenesis. Intriguingly, serotonin (5-hydroxytryptamine or 5-HT) seems to be a molecule with increasingly strong implications in the pathogenesis of intestinal inflammation, affecting host physiology, including autophagy and immune responses, as well as microbial composition and function. 5-HT may also play a role in mediating how environmental effects impact outcomes in IBD. In this review, we aim to explore the production and important functions of 5-HT, including its impact on the gut. In addition, we highlight the bidirectional impacts of 5-HT on the immune system, the gut microbiota, and the process of autophagy and how these effects contribute to the manifestation of intestinal inflammation. We also explore recent findings connecting 5-HT signalling and the influence of environmental factors, particularly diet, in the pathogenesis of IBD. Ultimately, we explore the pleiotropic effects of this ancient molecule on biology and health in the context of intestinal inflammation.
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Affiliation(s)
- Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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Tang LQ, Fraebel J, Jin S, Winesett SP, Harrell J, Chang WH, Cheng SX. Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice. World J Gastroenterol 2024; 30:268-279. [PMID: 38314127 PMCID: PMC10835527 DOI: 10.3748/wjg.v30.i3.268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/01/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system. Calcium-sensing receptor (CaSR) inhibits both actions. The latter has been well documented in vitro but not in vivo. The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo. AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin (CTX) in mice. METHODS CTX was given orally to C57BL/6 mice to induce diarrhea. Calcium and calcimimetic R568 were used to activate CaSR. To maximize their local intestinal actions, calcium was administered luminally via oral rehydration solution (ORS), whereas R568 was applied serosally using an intraperitoneal route. To verify that their actions resulted from the intestine, effects were also examined on Cre-lox intestine-specific CaSR knockouts. Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl- or clinically by assessing stool consistency and weight loss. RESULTS CTX induced secretory diarrhea, as evidenced by increases in fecal Cl-, stool consistency, and weight loss following CTX exposure, but did not alter CaSR, neither in content nor in function. Accordingly, calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines. Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts (villinCre/Casrflox/flox) and neuronal CaSR knockouts (nestinCre/Casrflox/flox). CONCLUSION Treatment of acute secretory diarrheas remains a global challenge. Despite advances in diarrhea research, few have been made in the realm of diarrhea therapeutics. ORS therapy has remained the standard of care, although it does not halt the losses of intestinal fluid and ions caused by pathogens. There is no cost-effective therapeutic for diarrhea. This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.
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Affiliation(s)
- Lie-Qi Tang
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
| | - Johnathan Fraebel
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
- College of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Shi Jin
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
| | - Steven P Winesett
- Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32610, United States
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, Gainesville, FL 32610, United States
| | - Jane Harrell
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
| | - Wen-Han Chang
- Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94121, United States
| | - Sam Xianjun Cheng
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Florida Shands Children’s Hospital, Gainesville, FL 32608, United States
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Punukollu RS, Chadalawada AK, Siddabattuni K, Gogineni NT. A blend of Withania somnifera (L.) Dunal root and Abelmoschus esculentus (L.) Moench fruit extracts relieves constipation and improves bowel function: A proof-of-concept clinical investigation. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116997. [PMID: 37543151 DOI: 10.1016/j.jep.2023.116997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Withania somnifera (L.) Dunal (WS) and Abelmoschus esculentus (L.) Moench (AE) are known as Ashwagandha and Okra, respectively, important herbs in traditional medicine for their diverse therapeutic values. WS root is an adaptogen that relieves stress and anxiety and promotes sleep. AE fruit or Okra is widely consumed as a vegetable and is traditionally used to treat diabetes, gastric irritations, ulcers, and obesity. AIM OF THE STUDY The present randomized, double-blind, placebo-controlled study aimed to establish a proof-of-concept evaluating the efficacy and tolerability of a proprietary blend of standardized extracts of WS root and AE fruit, CL18100F4 in relieving constipation and improving quality of life in adults. MATERIALS AND METHODS Forty-eight male and female participants (age: 25-60 years) with functional constipation (following Rome-III criteria) were randomized into placebo, 300 or 500 mg of CL18100F4 groups, and supplemented for fourteen consecutive days. RESULTS CL18100F4 supplementation significantly (p < 0.0001) reduced the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), and Gastrointestinal Symptom Rating Scale (GSRS) scores. CL18100F4 supplementation improved sleep quality and reduced stress (p < 0.0001). At the end of the study, CL18100F4-500 subjects showed significant increases in serum serotonin, gastrin, and interleukin-10 and decrease in interleukin-6 and cortisol levels. Participants' hematology, total blood chemistry, vital signs, and urinalysis parameters were within the normal ranges. No adverse events were reported. CONCLUSIONS This short-duration, single-site clinical investigation demonstrates that CL18100F4 supplementation is tolerable, helps relieve constipation, reduces stress, and improves gastrointestinal function, sleep quality, and general wellness in adults. TRIAL REGISTRATION Clinical Trials Registry- India (CTRI/2020/11/029320); Registered on 24/11/2020. Available at: http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=49391&EncHid=&userName=CL18100F4.
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Affiliation(s)
- Raghu Sarath Punukollu
- Department of Urology, Aditya Multi Speciality Hospital, Guntur 522001, Andhra Pradesh, India.
| | - Arun Kumar Chadalawada
- Department of Clinical Research, Aditya Multi Speciality Hospital, Guntur 522001, Andhra Pradesh, India.
| | - Kalyani Siddabattuni
- Department of Clinical Research, Aditya Multi Speciality Hospital, Guntur 522001, Andhra Pradesh, India.
| | - Naga Tejaswi Gogineni
- Department of General Medicine, Aditya Multi Speciality Hospital, Guntur 522001, Andhra Pradesh, India.
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Elfers K, Schäuffele S, Hoppe S, Michel K, Zeller F, Demir IE, Schemann M, Mazzuoli-Weber G. Distension evoked mucosal secretion in human and porcine colon in vitro. PLoS One 2023; 18:e0282732. [PMID: 37053302 PMCID: PMC10101454 DOI: 10.1371/journal.pone.0282732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 02/20/2023] [Indexed: 04/15/2023] Open
Abstract
It was suggested that intestinal mucosal secretion is enhanced during muscle relaxation and contraction. Mechanisms of mechanically induced secretion have been studied in rodent species. We used voltage clamp Ussing technique to investigate, in human and porcine colonic tissue, secretion evoked by serosal (Pser) or mucosal (Pmuc) pressure application (2-60 mmHg) to induce distension into the mucosal or serosal compartment, respectively. In both species, Pser or Pmuc caused secretion due to Cl- and, in human colon, also HCO3- fluxes. In the human colon, responses were larger in proximal than distal regions. In porcine colon, Pmuc evoked larger responses than Pser whereas the opposite was the case in human colon. In both species, piroxicam revealed a strong prostaglandin (PG) dependent component. Pser and Pmuc induced secretion was tetrodotoxin (TTX) sensitive in porcine colon. In human colon, a TTX sensitive component was only revealed after piroxicam. However, synaptic blockade by ω-conotoxin GVIA reduced the response to mechanical stimuli. Secretion was induced by tensile rather than compressive forces as preventing distension by a filter inhibited the secretion. In conclusion, in both species, distension induced secretion was predominantly mediated by PGs and a rather small nerve dependent response involving mechanosensitive somata and synapses.
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Affiliation(s)
- Kristin Elfers
- Institute for Physiology and Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany
| | | | - Susanne Hoppe
- Institute for Physiology and Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Klaus Michel
- Chair of Human Biology, Technical University of Munich, Freising, Germany
| | | | - Ihsan Ekin Demir
- University Hospital Rechts der Isar, Technical University of Munich, München, Germany
| | - Michael Schemann
- Chair of Human Biology, Technical University of Munich, Freising, Germany
| | - Gemma Mazzuoli-Weber
- Institute for Physiology and Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany
- Center for Systems Neuroscience (ZSN), Hannover, Germany
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Baidoo N, Crawley E, Knowles CH, Sanger GJ, Belai A. Total collagen content and distribution is increased in human colon during advancing age. PLoS One 2022; 17:e0269689. [PMID: 35714071 PMCID: PMC9205511 DOI: 10.1371/journal.pone.0269689] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 05/25/2022] [Indexed: 12/26/2022] Open
Abstract
Background The effect of ageing on total collagen content of human colon has been poorly investigated. The aim of this study was to determine if ageing altered total collagen content and distribution in the human colon. Methods Macroscopically normal ascending colon was obtained at surgery from cancer patients (n = 31) without diagnosis of diverticular disease or inflammatory bowel disease. Masson’s trichrome and Picrosirius red stains were employed to identify the total collagen content and distribution within the sublayers of the colonic wall for adult (22–60 years; 6 males, 6 females) and elderly (70 – 91years; 6 males, 4 female) patients. A hydroxyproline assay evaluated the total collagen concentration for adult (30–64 years; 9 male, 6 female) and elderly (66–91 years; 8 male, 8 female) patients. Key results Histological studies showed that the percentage mean intensity of total collagen staining in the mucosa, submucosa and muscularis externa was, respectively, 14(1.9) %, 74(3.2) % and 12(1.5) % in the adult ascending colon. Compared with the adults, the total collagen fibres content was increased in the submucosa (mean intensity; 163.1 ± 11.1 vs. 124.5 ± 7.8; P < 0.05) and muscularis externa (42.5 ± 8.0 vs. 20.6 ± 2.8; P < 0.01) of the elderly patients. There was no change in collagen content of the mucosa. The total collagen concentration was increased in the elderly by 16%. Sex-related differences were not found, and data were combined for analysis. Conclusions Greater total collagen content was found in the submucosa and muscularis externa of the elderly human male and female colon. These changes may contribute to a possible loss of function with ageing.
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Affiliation(s)
- Nicholas Baidoo
- University of Roehampton, School of Life Sciences, London, United Kingdom
| | - Ellie Crawley
- Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Charles H. Knowles
- Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Gareth J. Sanger
- Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Abi Belai
- University of Roehampton, School of Life Sciences, London, United Kingdom
- * E-mail:
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Simpson S, Mclellan R, Wellmeyer E, Matalon F, George O. Drugs and Bugs: The Gut-Brain Axis and Substance Use Disorders. J Neuroimmune Pharmacol 2022; 17:33-61. [PMID: 34694571 PMCID: PMC9074906 DOI: 10.1007/s11481-021-10022-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/06/2021] [Indexed: 02/07/2023]
Abstract
Substance use disorders (SUDs) represent a significant public health crisis. Worldwide, 5.4% of the global disease burden is attributed to SUDs and alcohol use, and many more use psychoactive substances recreationally. Often associated with comorbidities, SUDs result in changes to both brain function and physiological responses. Mounting evidence calls for a precision approach for the treatment and diagnosis of SUDs, and the gut microbiome is emerging as a contributor to such disorders. Over the last few centuries, modern lifestyles, diets, and medical care have altered the health of the microbes that live in and on our bodies; as we develop, our diets and lifestyle dictate which microbes flourish and which microbes vanish. An increase in antibiotic treatments, with many antibiotic interventions occurring early in life during the microbiome's normal development, transforms developing microbial communities. Links have been made between the microbiome and SUDs, and the microbiome and conditions that are often comorbid with SUDs such as anxiety, depression, pain, and stress. A better understanding of the mechanisms influencing behavioral changes and drug use is critical in developing novel treatments for SUDSs. Targeting the microbiome as a therapeutic and diagnostic tool is a promising avenue of exploration. This review will provide an overview of the role of the gut-brain axis in a wide range of SUDs, discuss host and microbe pathways that mediate changes in the brain's response to drugs, and the microbes and related metabolites that impact behavior and health within the gut-brain axis.
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Affiliation(s)
- Sierra Simpson
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US.
| | - Rio Mclellan
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Emma Wellmeyer
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Frederic Matalon
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Olivier George
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
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Keely SJ, Barrett KE. Intestinal secretory mechanisms and diarrhea. Am J Physiol Gastrointest Liver Physiol 2022; 322:G405-G420. [PMID: 35170355 PMCID: PMC8917926 DOI: 10.1152/ajpgi.00316.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/31/2023]
Abstract
One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. Secretory diarrheas are common and include those induced by pathogenic bacteria and viruses, allergens, and disruptions to bile acid homeostasis, or as a side effect of many drugs. Here, we review the cellular and molecular mechanisms by which Cl- and fluid secretion in the intestine are regulated, how these mechanisms become dysregulated in conditions of secretory diarrhea, currently available and emerging therapeutic approaches, and how new strategies to exploit intestinal secretory mechanisms are successfully being used in the treatment of constipation.
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Affiliation(s)
- Stephen J Keely
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Kim E Barrett
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California
- Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, California
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Xu G, Lei H, Zhou Y, Huang L, Tian H, Zhou Z, Zhao L, Liang F. Acupuncture for Quality of Life of Patients with Defecation Dysfunction after Sphincter Preserving Surgery for Rectal Cancer: A Systematic Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:7858252. [PMID: 34956383 PMCID: PMC8694980 DOI: 10.1155/2021/7858252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/09/2021] [Accepted: 11/23/2021] [Indexed: 12/04/2022]
Abstract
PURPOSE To evaluate the effectiveness and safety of acupuncture for quality of life of patients with defecation dysfunction (DD) after sphincter preserving surgery for rectal cancer. METHODS We searched nine online databases from inception to July 1, 2021, and did not restrict the type of language. Then, studies were independently selected by two research team members with screening criteria and risk bias assessment, and the data were extracted. The primary outcome was Quality of Life Questionnaire-Core 29 (QLQ-CR29). The data were then synthesized using the RevMan V.5.2 by random-effects model. Also, we used the standardized mean differences with 95% credible interval (CI) to describe the outcome of the analysis. RESULTS A total of 6 randomized controlled trials (RCTs) (with 439 patients) were included in the systematic review, and data from 2 RCTs (with 200 patients) were used in the meta-analysis. Five studies (83%) were judged to have a medium risk of bias, and one was at high risk of bias. For synthesis, data from two medium-risk studies found that acupuncture or electropuncture may improve the QLQ-CR29 with urination (mean difference, -0.39 points; 95%CI, -0.46 to -0.32; I 2 = 34%), abdominal pain (mean difference, -0.71 points; 95%CI, -0.89 to -0.54; I 2 = 9%), stool (mean difference, -0.49 points; 95%CI, -0.77 to -0.20; I 2 = 57%), defecation (mean difference, -0.59 points; 95% CI, -0.85 to -0.33; I 2 = 51%), sexual function (mean difference, 0.93 points; 95% CI, 0.48 to 1.38; I 2 = 90%), and self-feelings (mean difference, 1.04 points; 95% CI, 0.36 to 1.73; I 2 = 94%). CONCLUSION Findings in this study indicate that acupuncture or electropuncture may be effective and safe for DD, but the quality of included studies was very low. So, more large-scale, multicenter, long-term, and high-quality original research is still expected in the future.
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Affiliation(s)
- Guixing Xu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hanzhou Lei
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanfang Zhou
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liuyang Huang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hao Tian
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhuo Zhou
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ling Zhao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fanrong Liang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Zhang Z, Yang S, Lin X, Huang Y, Wei X, Zhou J, Li R, Deng B, Fu C. Metabolomics of Spleen-Yang deficiency syndrome and the therapeutic effect of Fuzi Lizhong pill on regulating endogenous metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114281. [PMID: 34087403 DOI: 10.1016/j.jep.2021.114281] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/25/2021] [Accepted: 05/30/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spleen-Yang deficiency (SYD) is one of the primary causes of many digestive diseases, such as ulcerative colitis (UC), and irritable bowel syndrome (IBS), but its endogenous metabolic characteristics are still unclear. Fuzi Lizhong pill (FLZP) is well-known for its powerful capacity for treating SYD; however, its mechanisms require further study. AIM OF THE STUDY Herein, our present study aimed to investigate the essence of SYD from the perspective of metabolomics, and tried to reveal the anti-SYD action mechanisms of FLZP. MATERIALS AND METHODS Firstly, the compound factor modeling method with the principle of "indiscipline in diet + excessive fatigue + intragastric administration of Senna water extracts" was used to establish Sprague Dawley (SD) rats as SYD model. Then, the visceral index, motilin (MTL), malonaldehyde (MDA), Interleukin 1 alpha (IL-1α), and Interleukin 6 (IL-6) levels were used to verify the anti-SYD effect of FLZP. In addition, serum samples were analyzed by UPLC-QE/MS metabolomics technique. Finally, the metabolic pathways associated with specific biomarkers were analyzed to research the possible mechanism underlying the action of FLZP. RESULTS The expression of MTL, MDA, IL-1α, and IL-6 were regulated by FLZP, which suggested that it has relieved diarrhea and gastrointestinal motility disorder caused by SYD and had an anti-peroxidation, anti-inflammatory, and immune regulation effect. A total of 75 metabolites were found to be the potential biomarkers of SYD. Moreover, FLZP regulates 21 metabolites and 10 vital pathways including the tricarboxylic acid (TCA) cycle, sphingolipid metabolism, and histidine metabolism. CONCLUSION SYD primarily causes disorders of amino acid metabolism, lipid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, nucleotide metabolism, and translation. In addition, FLZP regulated carbohydrate, lipid, and amino acid metabolisms, gastrointestinal motility, digestive juice secretion, immune regulation, as well as antioxidant effects. Hence, FLZP had a good therapeutic effect on treatment of SYD. It might be a promising therapeutic agent for the treatment of SYD-related diseases.
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Affiliation(s)
- Zhen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Quality Control and Efficacy Evaluation of Traditional Chinese Medicine Formula Granules, Sichuan New Green Medicine Science and Technology Development Co., Ltd., Pengzhou, 610031, China.
| | - Shasha Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xia Lin
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - You Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xinyi Wei
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jinwei Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Rui Li
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Bin Deng
- Chengdu Di'ao Pharmaceutical Group Co. Ltd, Chengdu, 611137, China
| | - Chaomei Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
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11
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Abstract
Rotavirus infection is highly prevalent in children, and the most severe effects are diarrhea and vomiting. It is well accepted that the enteric nervous system (ENS) is activated and plays an important role, but knowledge of how rotavirus activates nerves within ENS and to the vomiting center is lacking. Serotonin is released during rotavirus infection, and antagonists to the serotonin receptor subtype 3 (5-HT3 receptor) can attenuate rotavirus-induced diarrhea. In this study, we used a 5-HT3 receptor knockout (KO) mouse model to investigate the role of this receptor in rotavirus-induced diarrhea, motility, electrolyte secretion, inflammatory response, and vomiting reflex. The number of diarrhea days (P = 0.03) and the number of mice with diarrhea were lower in infected 5-HT3 receptor KO than wild-type pups. In vivo investigation of fluorescein isothiocyanate (FITC)-dextran transit time showed that intestinal motility was lower in the infected 5-HT3 receptor KO compared to wild-type mice (P = 0.0023). Ex vivo Ussing chamber measurements of potential difference across the intestinal epithelia showed no significant difference in electrolyte secretion between the two groups. Immediate early gene cFos expression level showed no difference in activation of the vomiting center in the brain. Cytokine analysis of the intestine indicated a low effect of inflammatory response in rotavirus-infected mice lacking the 5-HT3 receptor. Our findings indicate that the 5-HT3 receptor is involved in rotavirus-induced diarrhea via its effect on intestinal motility and that the vagus nerve signaling to the vomiting center occurs also in the absence of the 5-HT3 receptor. IMPORTANCE The mechanisms underlying rotavirus-induced diarrhea and vomiting are not yet fully understood. To better understand rotavirus pathophysiology, characterization of nerve signaling within the ENS and through vagal efferent nerves to the brain, which have been shown to be of great importance to the disease, is necessary. Serotonin (5-HT), a mediator of both diarrhea and vomiting, has been shown to be released from enterochromaffin cells in response to rotavirus infection and the rotavirus enterotoxin NSP4. Here, we investigated the role of the serotonin receptor 5-HT3, which is known to be involved in the nerve signals that regulate gut motility, intestinal secretion, and signal transduction through the vagus nerve to the brain. We show that the 5-HT3 receptor is involved in rotavirus-induced diarrhea by promoting intestinal motility. The findings shed light on new treatment possibilities for rotavirus diarrhea.
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12
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Wongdee K, Chanpaisaeng K, Teerapornpuntakit J, Charoenphandhu N. Intestinal Calcium Absorption. Compr Physiol 2021; 11:2047-2073. [PMID: 34058017 DOI: 10.1002/cphy.c200014] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In this article, we focus on mammalian calcium absorption across the intestinal epithelium in normal physiology. Intestinal calcium transport is essential for supplying calcium for metabolism and bone mineralization. Dietary calcium is transported across the mucosal epithelia via saturable transcellular and nonsaturable paracellular pathways, both of which are under the regulation of 1,25-dihydroxyvitamin D3 and several other endocrine and paracrine factors, such as parathyroid hormone, prolactin, 17β-estradiol, calcitonin, and fibroblast growth factor-23. Calcium absorption occurs in several segments of the small and large intestine with varying rates and capacities. Segmental heterogeneity also includes differential expression of calcium transporters/carriers (e.g., transient receptor potential cation channel and calbindin-D9k ) and the presence of favorable factors (e.g., pH, luminal contents, and gut motility). Other proteins and transporters (e.g., plasma membrane vitamin D receptor and voltage-dependent calcium channels), as well as vesicular calcium transport that probably contributes to intestinal calcium absorption, are also discussed. © 2021 American Physiological Society. Compr Physiol 11:1-27, 2021.
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Affiliation(s)
- Kannikar Wongdee
- Faculty of Allied Health Sciences, Burapha University, Chonburi, Thailand.,Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Krittikan Chanpaisaeng
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.,Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand
| | - Jarinthorn Teerapornpuntakit
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.,Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Narattaphol Charoenphandhu
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.,Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.,Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.,The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
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13
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Koo A, Fothergill LJ, Kuramoto H, Furness JB. 5-HT containing enteroendocrine cells characterised by morphologies, patterns of hormone co-expression, and relationships with nerve fibres in the mouse gastrointestinal tract. Histochem Cell Biol 2021; 155:623-636. [PMID: 33608804 DOI: 10.1007/s00418-021-01972-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 12/19/2022]
Abstract
5-HT containing enteroendocrine cells (EEC), the most abundant type of EEC in the gut, regulate many functions including motility, secretion and inflammatory responses. We examined the morphologies of 5-HT cells from stomach to rectum, patterns of hormone co-expression in the stomach and colon, and the relationship of 5-HT cells with nerve fibres. We also reviewed some of the relevant literature. The morphologies of 5-HT cells were distinct, depending on their location in the gut. A noticeable feature of some 5-HT cells in the antrum and colon was their long basal processes, which resembled processes of neurons, whereas 5-HT cells in the small intestinal mucosa lacked basal processes. In the stomach, numerous 5-HT cells, including cells with basal processes, were identified as enterochromaffin-like cells by their expression of histidine decarboxylase. In the colon, we observed a small number of 5-HT cells that were in close contact with, but distinct from, oxyntomodulin (OXM) and PYY immunoreactive EEC. We did not find specific relationships between nerve fibres and the processes of colonic 5-HT cells. We conclude that five major features, i.e., gut region, morphology, hormone content, receptor repertoire and cell lineage, can be used to define 5-HT cells.
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Affiliation(s)
- Ada Koo
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Linda J Fothergill
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia
| | - Hirofumi Kuramoto
- Department of Applied Biology, Kyoto Institute of Technology, Kyoto, 606-8585, Japan
| | - John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia. .,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia.
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14
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Chandramowlishwaran P, Vijay A, Abraham D, Li G, Mwangi SM, Srinivasan S. Role of Sirtuins in Modulating Neurodegeneration of the Enteric Nervous System and Central Nervous System. Front Neurosci 2020; 14:614331. [PMID: 33414704 PMCID: PMC7783311 DOI: 10.3389/fnins.2020.614331] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022] Open
Abstract
Neurodegeneration of the central and enteric nervous systems is a common feature of aging and aging-related diseases, and is accelerated in individuals with metabolic dysfunction including obesity and diabetes. The molecular mechanisms of neurodegeneration in both the CNS and ENS are overlapping. Sirtuins are an important family of histone deacetylases that are important for genome stability, cellular response to stress, and nutrient and hormone sensing. They are activated by calorie restriction (CR) and by the coenzyme, nicotinamide adenine dinucleotide (NAD+). Sirtuins, specifically the nuclear SIRT1 and mitochondrial SIRT3, have been shown to have predominantly neuroprotective roles in the CNS while the cytoplasmic sirtuin, SIRT2 is largely associated with neurodegeneration. A systematic study of sirtuins in the ENS and their effect on enteric neuronal growth and survival has not been conducted. Recent studies, however, also link sirtuins with important hormones such as leptin, ghrelin, melatonin, and serotonin which influence many important processes including satiety, mood, circadian rhythm, and gut homeostasis. In this review, we address emerging roles of sirtuins in modulating the metabolic challenges from aging, obesity, and diabetes that lead to neurodegeneration in the ENS and CNS. We also highlight a novel role for sirtuins along the microbiota-gut-brain axis in modulating neurodegeneration.
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Affiliation(s)
- Pavithra Chandramowlishwaran
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Anitha Vijay
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States
| | - Daniel Abraham
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
| | - Ge Li
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Simon Musyoka Mwangi
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
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15
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Greig CJ, Armenia SJ, Cowles RA. The M1 muscarinic acetylcholine receptor in the crypt stem cell compartment mediates intestinal mucosal growth. Exp Biol Med (Maywood) 2020; 245:1194-1199. [PMID: 32611198 DOI: 10.1177/1535370220938375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
IMPACT STATEMENT Localization of a specific subtype of the muscarinic acetylcholine receptor in the crypt stem cell compartment suggests a critical role in intestinal mucosal homeostasis. Here we demonstrate the localization of the M1 muscarinic acetylcholine receptor to the stem cell compartment and demonstrate increase morphometric and proliferative parameters when this is stimulated in vivo. These data provide novel information about this complex signaling microenvironment and offer potential future therapeutic targets for future study.
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Affiliation(s)
- Chasen J Greig
- Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Sarah J Armenia
- Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Robert A Cowles
- Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
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16
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Xu G, Xiao Q, Lei H, Fu Y, Kong J, Zheng Q, Zhao L, Liang F. Effectiveness and safety of acupuncture and moxibustion for defecation dysfunction after sphincter-preserving surgery for rectal cancer: protocol for systematic review and meta-analysis. BMJ Open 2020; 10:e034152. [PMID: 32381535 PMCID: PMC7223156 DOI: 10.1136/bmjopen-2019-034152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Defecation dysfunction (DD) is one of the most common complications following sphincter-preserving surgery for rectal cancer. And there is no effective treatment of DD after sphincter-preserving surgery for rectal cancer. Although some studies suggested that acupuncture and moxibustion (AM) is effective and safe for DD after sphincter-preserving surgery for rectal cancer, lacking strong evidence, for instance, the relevant systematic review, meta-analysis and randomised controlled trial (RCT) of a large, multicentre sample, makes the effects and safety remain uncertain. The present protocol is described for a systematic review and meta-analysis to investigate the effectiveness and safety of AM for DD after sphincter-preserving surgery for rectal cancer. METHODS AND ANALYSIS We will search nine online databases from inception to 1 October 2019; the language of included trials will not be restricted. This study will include RCTs that performed AM as the main method of the experimental group for patients with DD after sphincter-preserving surgery for rectal cancer. Two of the researchers will independently select the studies, conduct risk of bias assessment and extract the data. We will use the fixed-effects model or random-effects model of RevMan V.5.2 software to analyse data synthesis. The risk ratios with 95% CIs and weighted mean differences or standardised mean differences with 95% CIs will be used to present the data synthesis outcome of dichotomous data respectively and the continuous data. Evidence quality of outcome will be assessed by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. ETHICS AND DISSEMINATION Ethical approval is not required in this secondary research evidence, and we will publish the results of this study in a journal or concerned conferences. TRIAL REGISTRATION NUMBER CRD42019140097.
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Affiliation(s)
- Guixing Xu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiwei Xiao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hanzhou Lei
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanan Fu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Kong
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qianhua Zheng
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ling Zhao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fanrong Liang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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17
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Liao S, Gan L, Lv L, Mei Z. The regulatory roles of aquaporins in the digestive system. Genes Dis 2020; 8:250-258. [PMID: 33997172 PMCID: PMC8093583 DOI: 10.1016/j.gendis.2019.12.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/15/2019] [Accepted: 12/31/2019] [Indexed: 12/22/2022] Open
Abstract
Aquaporins (AQPs) are highly conserved small transmembrane proteins, which are responsible for the water transport across the cell membrane. AQPs are abundantly expressed in numerous types of cells such as epithelial and endothelial cells. The expression of AQP-1, -3, -4, -5, -8 and -9 were found in the digestive system, where these six AQP isoforms serve essential roles including mediating the transmembrane water transport and regulating the secretion of gastrointestinal (GI) fluids, consequently facilitating the digestion and absorption of GI contents. In addition, the expression levels of AQPs are controlled by various factors, and AQPs can stimulate numerous signaling pathways; however, aberrant expression of AQPs in the GI tracts are associated with the initiation and development of numerous diseases. Thus, this review provides an overview of the expression and functions of AQPs in the digestive system.
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Affiliation(s)
- Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Li Gan
- Teaching and Research Section of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, PR China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
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18
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Karaki SI. Effects of an Enteral Formula Containing Fermented Dairy Products on Epithelial Ion Transport in Rat Intestines. J Nutr Sci Vitaminol (Tokyo) 2020; 65:498-506. [PMID: 31902863 DOI: 10.3177/jnsv.65.498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Diarrhea is the most common complication of enteral nutrition (EN). Pro/prebiotics are typically used to prevent diarrhea during EN. This study aimed to demonstrate the effects of enteral formula containing fermented dairy products (FDPs) and galacto-oligosaccharides on intestinal mucosal functions in rats. After feeding rats with regular rodent chow (RRC), standard formula (STD-F), and FDP-containing formula (FDP-F) for 2 wk, the rats were sacrificed with their intestines removed. Then, the electrophysiological properties of intestinal epithelia were measured using the Ussing chamber. In addition, organic acids and microbiota in the cecal contents were analyzed. In FDP-F-fed rats, electrical nerve activation-evoked increase in short-circuit current (Isc) in the cecum and middle colon was reduced compared with STD-F-fed rats. Mucosal propionate-evoked changes in Isc in FDP-F-fed rats were also reduced in the terminal ileum. The total cecal organic acid concentration in STD-F-fed rats decreased compared with RRC-fed rats, and approximately half was recovered in FDP-F-fed rats, which contributed to the recovery of acetate and butyrate concentrations. In microbiota analysis, the density of total bacteria, particularly Bifidobacterium, in cecal contents increased in FDP-F-fed rats. In conclusion, the consumption of FDP-F changed the total amounts and components of gut microbiota and organic acids, and resulted in inhibitory changes in mucosal luminal stimulant- and nervous system-mediated fluid secretory function. These findings suggest that FDP-F might prevent the incidence of diarrhea during EN.
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Affiliation(s)
- Shin-Ichiro Karaki
- Laboratory of Physiology, Department of Environmental and Life Sciences, School of Food and Nutritional Sciences, University of Shizuoka
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19
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SUGAWARA T, SAWADA D, KAJI I, KARAKI SI, KUWAHARA A. The effects of viable and non-viable Lactobacillus gasseri CP2305 cells on colonic ion transport and corticotropin releasing factor-induced diarrhea. Biomed Res 2019; 40:225-233. [DOI: 10.2220/biomedres.40.225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Tomonori SUGAWARA
- Research Unit for Epithelial Physiology, Research Organization of Science and Technology, Ritsumeikan University
| | - Daisuke SAWADA
- Research Unit for Epithelial Physiology, Research Organization of Science and Technology, Ritsumeikan University
| | - Izumi KAJI
- Section of Surgical Sciences, School of Medicine, Vanderbilt University
| | | | - Atsukazu KUWAHARA
- Research Unit for Epithelial Physiology, Research Organization of Science and Technology, Ritsumeikan University
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20
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Lee B, Hong GS, Lee SH, Kim H, Kim A, Hwang EM, Kim J, Lee MG, Yang JY, Kweon MN, Tse CM, Mark D, Oh U. Anoctamin 1/TMEM16A controls intestinal Cl - secretion induced by carbachol and cholera toxin. Exp Mol Med 2019; 51:1-14. [PMID: 31383845 PMCID: PMC6802608 DOI: 10.1038/s12276-019-0287-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/07/2019] [Accepted: 03/11/2019] [Indexed: 12/17/2022] Open
Abstract
Calcium-activated chloride channels (CaCCs) mediate numerous physiological functions and are best known for the transport of electrolytes and water in epithelia. In the intestine, CaCC currents are considered necessary for the secretion of fluid to protect the intestinal epithelium. Although genetic ablation of ANO1/TMEM16A, a gene encoding a CaCC, reduces the carbachol-induced secretion of intestinal fluid, its mechanism of action is still unknown. Here, we confirm that ANO1 is essential for the secretion of intestinal fluid. Carbachol-induced transepithelial currents were reduced in the proximal colon of Ano1-deficient mice. Surprisingly, cholera toxin-induced and cAMP-induced fluid secretion, believed to be mediated by CFTR, were also significantly reduced in the intestine of Ano1-deficient mice. ANO1 is largely expressed in the apical membranes of intestines, as predicted for CaCCs. The Ano1-deficient colons became edematous under basal conditions and had a greater susceptibility to dextran sodium sulfate-induced colitis. However, Ano1 depletion failed to affect tumor development in a model of colorectal cancer. We thus conclude that ANO1 is necessary for cAMP- and carbachol-induced Cl− secretion in the intestine, which is essential for the protection of the intestinal epithelium from colitis. An ion channel, a membrane protein allowing ion transport, that controls the flow of chloride is needed for proper secretion of protective fluids in the intestine. Uhtaek Oh from the Korea Institute of Science & Technology in Seoul, South Korea, and colleagues showed that cells lining the intestinal surface express a calcium-activated chloride channel called anoctamin-1 (ANO1) that regulates fluid secretion in the gut. Compared to control animals, ANO1-deficient mice released less fluid into their intestines following exposure to a diarrhea-inducing toxin or to a chloride transport–stimulating signaling molecule. This fluid secretion was previously thought to be mediated via a different ion channel. The ANO1-deficient mice accumulated fluid within colonic tissues, which increased their susceptibility to colitis. The findings point to ANO1 activation as a potential therapeutic strategy for treating colitis.
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Affiliation(s)
- Byeongjun Lee
- College of Pharmacy, Seoul National University, Seoul, 08826, Korea
| | - Gyu-Sang Hong
- Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul, 02792, Korea
| | - Sung Hoon Lee
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Korea
| | - Hyungsup Kim
- Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul, 02792, Korea
| | - Ajung Kim
- Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul, 02792, Korea
| | - Eun Mi Hwang
- Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul, 02792, Korea
| | - Jiyoon Kim
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Min Goo Lee
- Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Jin-Young Yang
- Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, 05505, Korea
| | - Mi-Na Kweon
- Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, 05505, Korea
| | - Chung-Ming Tse
- Departments of Physiology and Medicine, Division of Gastroenterois maintained by the opening of plasmalogy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Donowitz Mark
- Departments of Physiology and Medicine, Division of Gastroenterois maintained by the opening of plasmalogy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Uhtaek Oh
- College of Pharmacy, Seoul National University, Seoul, 08826, Korea. .,Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul, 02792, Korea.
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21
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Delvalle NM, Fried DE, Rivera-Lopez G, Gaudette L, Gulbransen BD. Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol 2018; 315:G473-G483. [PMID: 29927320 PMCID: PMC6230698 DOI: 10.1152/ajpgi.00155.2018] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The reflexive activities of the gastrointestinal tract are regulated, in part, by precise interactions between neurons and glia in the enteric nervous system (ENS). Intraganglionic enteric glia are a unique type of peripheral glia that surround enteric neurons and regulate neuronal function, activity, and survival. Enteric glia express numerous neurotransmitter receptors that allow them to sense neuronal activity, but it is not clear if enteric glia monitor acetylcholine (ACh), the primary excitatory neurotransmitter in the ENS. Here, we tested the hypothesis that enteric glia detect ACh and that glial activation by ACh contributes to the physiological regulation of gut functions. Our results show that myenteric enteric glia express both the M3 and M5 subtypes of muscarinic receptors (MRs) and that muscarine drives intracellular calcium (Ca2+) signaling predominantly through M3R activation. To elucidate the functional effects of activation of glial M3Rs, we used GFAP::hM3Dq mice that express a modified human M3R (hM3Dq) exclusively on glial fibrillary acidic protein (GFAP) positive glia to directly activate glial hM3Dqs using clozapine- N-oxide. Using spatiotemporal mapping analysis, we found that the activation of glial hM3Dq receptors enhances motility reflexes ex vivo. Continuous stimulation of hM3Dq receptors in vivo, drove changes in gastrointestinal motility without affecting neuronal survival in the ENS and glial muscarinic receptor activation did not alter neuron survival in vitro. Our results provide the first evidence that GFAP intraganglionic enteric glia express functional muscarinic receptors and suggest that the activation of glial muscarinic receptors contributes to the physiological regulation of functions. NEW & NOTEWORTHY Enteric glia are emerging as novel regulators of enteric reflex circuits, but little is still known regarding the effects of specific transmitter pathways on glia and the resulting consequences on enteric reflexes. Here, we provide the first evidence that enteric glia monitor acetylcholine in the enteric nervous system and that glial activation by acetylcholine is a physiological mechanism that contributes to the functional regulation of intestinal reflexes.
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Affiliation(s)
| | - David E. Fried
- 2Department of Physiology, Michigan State University, East Lansing, Michigan
| | | | - Luke Gaudette
- 1Neuroscience Program, Michigan State University, East Lansing, Michigan
| | - Brian D. Gulbransen
- 1Neuroscience Program, Michigan State University, East Lansing, Michigan,2Department of Physiology, Michigan State University, East Lansing, Michigan
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22
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Tang L, Jiang L, McIntyre ME, Petrova E, Cheng SX. Calcimimetic acts on enteric neuronal CaSR to reverse cholera toxin-induced intestinal electrolyte secretion. Sci Rep 2018; 8:7851. [PMID: 29777154 PMCID: PMC5959902 DOI: 10.1038/s41598-018-26171-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 05/08/2018] [Indexed: 01/19/2023] Open
Abstract
Treatment of acute secretory diarrheal illnesses remains a global challenge. Enterotoxins produce secretion through direct epithelial action and indirectly by activating enteric nervous system (ENS). Using a microperfused colonic crypt technique, we have previously shown that R568, a calcimimetic that activates the calcium-sensing receptor (CaSR), can act on intestinal epithelium and reverse cholera toxin-induced fluid secretion. In the present study, using the Ussing chamber technique in conjunction with a tissue-specific knockout approach, we show that the effects of cholera toxin and CaSR agonists on electrolyte secretion by the intestine can also be attributed to opposing actions of the toxin and CaSR on the activity of the ENS. Our results suggest that targeting intestinal CaSR might represent a previously undescribed new approach for treating secretory diarrheal diseases and other conditions with ENS over-activation.
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Affiliation(s)
- Lieqi Tang
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Lingli Jiang
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Megan E McIntyre
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Ekaterina Petrova
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Sam X Cheng
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA. .,Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL, 32610, USA.
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Yakabi S, Wang L, Karasawa H, Yuan PQ, Koike K, Yakabi K, Taché Y. VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats. Am J Physiol Gastrointest Liver Physiol 2018; 314:G610-G622. [PMID: 29420068 PMCID: PMC6008061 DOI: 10.1152/ajpgi.00308.2017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 01/31/2018] [Accepted: 02/06/2018] [Indexed: 01/31/2023]
Abstract
We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF1 receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe6, Leu17]VIP injected intraperitoneally completely prevented CRF (10 µg/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP-positive neurons and 31.1% of non-VIP-labeled neurons. CRF1 receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 ± 2.4 vs. 0.4 ± 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 ± 0.3 vs. 2.5 ± 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF1 receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF.
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Affiliation(s)
- Seiichi Yakabi
- CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan
| | - Lixin Wang
- CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Hiroshi Karasawa
- CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Pu-Qing Yuan
- CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan
| | - Koji Yakabi
- Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University , Saitama , Japan
| | - Yvette Taché
- CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, University of California, Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
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24
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Struller F, Weinreich FJ, Horvath P, Kokkalis MK, Beckert S, Königsrainer A, Reymond MA. Peritoneal innervation: embryology and functional anatomy. Pleura Peritoneum 2017; 2:153-161. [PMID: 30911646 DOI: 10.1515/pp-2017-0024] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 11/03/2017] [Indexed: 12/14/2022] Open
Abstract
The parietal peritoneum (PP) is innervated by somatic and visceral afferent nerves. PP receives sensitive branches from the lower intercostal nerves and from the upper lumbar nerves. Microscopically, a dense network of unmyelinated and myelinated nerve fibers can be found all over the PP. The unmyelinated fibers are thin and are ending just underneath the PP. The myelinated fibers can penetrate the PP to reach the peritoneal cavity, where they lose their myelin sheath and are exposed to somatic and nociceptive stimuli. PP is sensitive to pain, pressure, touch, friction, cutting and temperature. Noxious stimuli are perceived as a localized, sharp pain. The visceral peritoneum (VP) itself is not innervated, but the sub-mesothelial tissue is innervated by the autonomous nerve system. In contrast to the PP, the visceral submesothelium also receives fibers from the vagal nerve, in addition to the spinal nerves. VP responds primarily to traction and pressure; not to cutting, burning or electrostimulation. Painful stimuli of the VP are poorly localized and dull. Pain in a foregut structure (stomach, duodenum or biliary tract) is referred to the epigastric region, pain in a midgut structure (appendix, jejunum, or ileum) to the periumbilical area and pain from a hindgut source (distal colon or rectum) is referred to the lower abdomen or suprapubic region. Peritoneal adhesions can contain nerve endings. Neurotransmitters are acetylcholine, VIP, serotonin, NO, encephalins, CGRP and substance P. Chronic peritoneal pain can be exacerbated by neurogenic inflammation, e.g. by endometriosis.
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Affiliation(s)
- Florian Struller
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
| | - Frank-Jürgen Weinreich
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
| | - Philipp Horvath
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
| | - Marios-Konstantinos Kokkalis
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
| | - Stefan Beckert
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
| | - Alfred Königsrainer
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
| | - Marc A Reymond
- Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.,National Centre for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany
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25
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McQuade RM, Stojanovska V, Donald EL, Rahman AA, Campelj DG, Abalo R, Rybalka E, Bornstein JC, Nurgali K. Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons. Front Physiol 2017. [PMID: 28642718 PMCID: PMC5462962 DOI: 10.3389/fphys.2017.00391] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal dysfunction is a common side-effect of chemotherapy leading to dose reductions and treatment delays. These side-effects may persist up to 10 years post-treatment. A topoisomerase I inhibitor, irinotecan (IRI), commonly used for the treatment of colorectal cancer, is associated with severe acute and delayed-onset diarrhea. The long-term effects of IRI may be due to damage to enteric neurons innervating the gastrointestinal tract and controlling its functions. Balb/c mice received intraperitoneal injections of IRI (30 mg/kg−1) 3 times a week for 14 days, sham-treated mice received sterile water (vehicle) injections. In vivo analysis of gastrointestinal transit via serial x-ray imaging, facal water content, assessment of gross morphological damage and immunohistochemical analysis of myenteric neurons were performed at 3, 7 and 14 days following the first injection and at 7 days post-treatment. Ex vivo colonic motility was analyzed at 14 days following the first injection and 7 days post-treatment. Mucosal damage and inflammation were found following both short and long-term treatment with IRI. IRI-induced neuronal loss and increases in the number and proportion of ChAT-IR neurons and the density of VAChT-IR fibers were associated with changes in colonic motility, gastrointestinal transit and fecal water content. These changes persisted in post-treatment mice. Taken together this work has demonstrated for the first time that IRI-induced inflammation, neuronal loss and altered cholinergic expression is associated with the development of IRI-induced long-term gastrointestinal dysfunction and diarrhea.
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Affiliation(s)
- Rachel M McQuade
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia
| | - Vanesa Stojanovska
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia
| | - Elizabeth L Donald
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia
| | - Ahmed A Rahman
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia
| | - Dean G Campelj
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia.,Institute of Sport, Exercise and Active Living, Victoria UniversityMelbourne, VIC, Australia.,Australian Institute of Musculoskeletal Science, Western HealthMelbourne, VIC, Australia
| | - Raquel Abalo
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica y al Instituto de Investigación en Ciencias de la Alimentación del Consejo Superior de Investigaciones Científicas, Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor, Universidad Rey Juan CarlosAlcorcón, Spain
| | - Emma Rybalka
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia.,Institute of Sport, Exercise and Active Living, Victoria UniversityMelbourne, VIC, Australia.,Australian Institute of Musculoskeletal Science, Western HealthMelbourne, VIC, Australia
| | - Joel C Bornstein
- Department of Physiology, Melbourne UniversityMelbourne, VIC, Australia
| | - Kulmira Nurgali
- College of Health and Biomedicine, Victoria UniversityMelbourne, VIC, Australia
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26
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Liu GX, Gan HT. Effect of enteric nervous system on intestinal epithelial barrier in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2017; 25:107-113. [DOI: 10.11569/wcjd.v25.i2.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Both enteric nervous system and intestinal epithelial barrier are vital components to ensure gut homeostasis. Recent studies have shown the implications of their close relationship for gut health and disease. By secreting neurotransmitters, the enteric nervous system plays an important role in regulating the epithelial barrier function. Meanwhile, communicating largely through the vagal nerve, the central nervous system could also interact with the intestinal epithelium through the enteric nervous system. Although the etiology and pathogenesis of inflammatory bowel disease remain elusive, increasing evidence has shown that the dysregulation of enteric nervous system affects both epithelial integrity and barrier function, which contributes to the occurrence and development of inflammatory bowel disease. This review will summarize the current knowledge regarding the effect of enteric nervous system on intestinal epithelial barrier and its implication in the development of inflammatory bowel disease.
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27
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Zhu X, Liu Z, Niu W, Wang Y, Zhang A, Qu H, Zhou J, Bai L, Yang Y, Li J. Effects of electroacupuncture at ST25 and BL25 in a Sennae-induced rat model of diarrhoea-predominant irritable bowel syndrome. Acupunct Med 2016; 35:216-223. [PMID: 27852563 DOI: 10.1136/acupmed-2016-011180] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2016] [Indexed: 11/03/2022]
Abstract
BACKGROUND Electroacupuncture (EA) may have a role in the treatment of diarrhoea symptoms. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal (GI) tract, which initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. In addition, according to the results of our previous report, EA stimulation mediates GI peristalsis by increasing expression of 5-HT and tryptophan hydroxylase (TPH). AIM To investigate the effect of EA at acupuncture points ST25 and BL25 in a rat model of diarrhoea. METHODS A diarrhoea-predominant irritable bowel syndrome (IBS-D) model was induced by Folium Sennae in 24 rats, which remained untreated (n=6) or received EA at ST25 (n=6), BL25 (n=6) or the combination of ST25 and BL25 (n=6). A control group of healthy rats was also included (n=6). After treatment, changes in loose stool and small intestine transit rates, enterochromaffin (EC) cell number, expression of TPH, and faecal/colonic 5-HT contents were measured. RESULTS Loose stool and small intestine transit rates, EC cell numbers, colonic TPH expression and faecal/colonic 5-HT content of IBS-D rats were significantly increased relative to controls (p<0.05) and all these parameters were improved by EA at ST25, BL25, or ST25 and BL25 in combination (all p<0.05 vs untreated IBS-D rats). CONCLUSIONS EA at ST25 and/or BL25 had a positive effect on objective markers of diarrhoea in a IBS-D rat model and induced changes in EC cell number, colonic TPH and 5-HT contents. The effects of EA stimulation at ST25/BL25 on IBS-D rats may be mediated by excitation of sympathetic nerves.
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Affiliation(s)
- Xianwei Zhu
- Innovation Research Centre of Acupuncture Combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xi'an City, Shaanxi Province, China
| | - Zhibin Liu
- Innovation Research Centre of Acupuncture Combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xi'an City, Shaanxi Province, China.,Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xianyang City, Shaanxi Province, China
| | - Wenmin Niu
- Innovation Research Centre of Acupuncture Combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xi'an City, Shaanxi Province, China.,Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xianyang City, Shaanxi Province, China
| | - Yuan Wang
- Innovation Research Centre of Acupuncture Combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xi'an City, Shaanxi Province, China
| | - Aimin Zhang
- Department of Urologic Surgery, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xi'an City, Shaanxi Province, China
| | - Hongyan Qu
- Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xianyang City, Shaanxi Province, China
| | - Jing Zhou
- College of Public Hygiene, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xianyang, Shaanxi Province, China
| | - Lu Bai
- Department of English, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xi'an, Shaanxi Province, China
| | - Yong Yang
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xianyang, Shaanxi Province, China
| | - Jie Li
- Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Ecomic Zone, Xianyang City, Shaanxi Province, China
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28
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Lehmann A, Hornby PJ. Intestinal SGLT1 in metabolic health and disease. Am J Physiol Gastrointest Liver Physiol 2016; 310:G887-98. [PMID: 27012770 DOI: 10.1152/ajpgi.00068.2016] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 03/21/2016] [Indexed: 01/31/2023]
Abstract
The Na(+)-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na(+) gradient created by Na(+)-K(+)-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na(+) homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.
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Affiliation(s)
- Anders Lehmann
- Division of Endocrinology, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; and
| | - Pamela J Hornby
- Cardiovascular and Metabolic Disease, Janssen Research and Development, LLC, Spring House, Pennsylvania
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Qu MH, Ji WS, Zhao TK, Fang CY, Mao SM, Gao ZQ. Neurophysiological mechanisms of bradykinin-evoked mucosal chloride secretion in guinea pig small intestine. World J Gastrointest Pathophysiol 2016; 7:150-159. [PMID: 26909238 PMCID: PMC4753181 DOI: 10.4291/wjgp.v7.i1.150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Revised: 04/29/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism for bradykinin (BK) to stimulate intestinal secretomotor neurons and intestinal chloride secretion.
METHODS: Muscle-stripped guinea pig ileal preparations were mounted in Ussing flux chambers for the recording of short-circuit current (Isc). Basal Isc and Isc stimulated by BK when preincubated with the BK receptors antagonist and other chemicals were recorded using the Ussing chamber system. Prostaglandin E2 (PGE2) production in the intestine was determined by enzyme immunologic assay (EIA).
RESULTS: Application of BK or B2 receptor (B2R) agonist significantly increased the baseline Isc compared to the control. B2R antagonist, tetrodotoxin and scopolamine (blockade of muscarinic receptors) significantly suppressed the increase in Isc evoked by BK. The BK-evoked Isc was suppressed by cyclooxygenase (COX)-1 or COX-2 specific inhibitor as well as nonselective COX inhibitors. Preincubation of submucosa/mucosa preparations with BK for 10 min significantly increased PGE2 production and this was abolished by the COX-1 and COX-2 inhibitors. The BK-evoked Isc was suppressed by nonselective EP receptors and EP4 receptor antagonists, but selective EP1 receptor antagonist did not have a significant effect on the BK-evoked Isc. Inhibitors of PLC, PKC, calmodulin or CaMKII failed to suppress BK-induced PGE2 production.
CONCLUSION: The results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2R, through COX increasing PGE2 production. The post-receptor transduction cascade includes activation of PLC, PKC, CaMK, IP3 and MAPK.
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30
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Zhu T, Qiu J, Wan J, Wang F, Tang X, Guo H. Expression of serotonin receptors in the colonic tissue of chronic diarrhea rats. Saudi J Gastroenterol 2016; 22:234-9. [PMID: 27184643 PMCID: PMC4898094 DOI: 10.4103/1319-3767.182460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND/AIMS This study aimed to investigate the difference among the expression of serotonin receptors (5-HT3, 5-HT4, and 5-HT7receptors) in colonic tissue of chronic diarrhea rats. MATERIALS AND METHODS A rat model of chronic diarrhea was established by lactose diet. The expression of 5-HT3, 5-HT4, and 5-HT7receptors in the colonic tissue was detected using immunohistochemistry, real-time PCR and Western blotting techniques. RESULTS There is no significant difference on the protein expression of 5-HT3receptor between the normal group and the chronic diarrhea model group. The mRNA expression of 5-HT3receptor in the chronic diarrhea model group was significantly lower than that in the normal group (n = 10; P< 0.01). The protein and mRNA expression of 5-HT4receptor in the chronic diarrhea model group were significantly higher than those in the normal group (n = 10; P< 0.05, P< 0.01). On the contrary, the protein and mRNA expressions of 5-HT7receptor in the chronic diarrhea model group were significantly decreased compared with the normal group (n = 10; P< 0.01, P< 0.01). CONCLUSIONS The results suggested the receptors of 5-HT4and 5-HT7may be involved in inducing diarrhea by lactose diet.
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Affiliation(s)
- Tong Zhu
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Juanjuan Qiu
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Jiajia Wan
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Fengyun Wang
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Xudong Tang
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China,Address for correspondence: Prof. Huishu Guo, Central Laboratory, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, Liaoning 116011, P.R. China. E-mail: Prof. Xudong Tang, Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China. E-mail:
| | - Huishu Guo
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China,Address for correspondence: Prof. Huishu Guo, Central Laboratory, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, Liaoning 116011, P.R. China. E-mail: Prof. Xudong Tang, Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China. E-mail:
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Min YW, Rhee PL. The clinical potential of ramosetron in the treatment of irritable bowel syndrome with diarrhea (IBS-D). Therap Adv Gastroenterol 2015; 8:136-42. [PMID: 25949526 PMCID: PMC4416292 DOI: 10.1177/1756283x15572580] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder. Serotonin (5-HT) is known to play a physiological and pathophysiological role in the regulation of gastrointestinal function. In experimental studies, 5-HT3 receptor antagonists have been reported to slow colon transit, to blunt gastrocolonic reflex, and to reduce rectal sensitivity. Alosetron and cilansetron, potent and selective 5-HT3 receptor antagonists, have proven efficacy in the treatment of IBS with diarrhea (IBS-D). However, alosetron was voluntarily withdrawn due to postmarketing reports of ischemic colitis and complications of constipation, and cilansetron was never marketed. Currently alosetron is available under a risk management program for women with severe IBS-D. Ramosetron is another potent and selective 5-HT3 receptor antagonist, which has been marketed in Japan, South Korea, and Taiwan. In animal studies, ramosetron reduced defecation induced by corticotrophin-releasing hormone and had inhibitory effects on colonic nociception. In two randomized controlled studies including 957 patients with IBS-D, ramosetron increased monthly responder rates of patient-reported global assessment of IBS symptom relief compared with placebo. Ramosetron was also as effective as mebeverine in male patients with IBS-D. In a recent randomized controlled trial with 343 male patients with IBS-D, ramosetron has proved effective in improving stool consistency, relieving abdominal pain/discomfort, and improving health-related quality of life. Regarding safety, ramosetron is associated with a lower incidence of constipation compared with other 5-HT3 receptor antagonists and has not been associated with ischemic colitis. Although further large prospective studies are needed to assess whether ramosetron is effective for female patients with IBS-D and to evaluate its long-term safety, ramosetron appears to be one of the most promising agents for patients with IBS-D.
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Affiliation(s)
- Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea
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Abstract
Bone metabolism is regulated by the action of two skeletal cells: osteoblasts and osteoclasts. This process is controlled by many genetic, hormonal and lifestyle factors, but today more and more studies have allowed us to identify a neuronal regulation system termed 'bone-brain crosstalk', which highlights a direct relationship between bone tissue and the nervous system. The first documentation of an anatomic relationship between nerves and bone was made via a wood cut by Charles Estienne in Paris in 1545. His diagram demonstrated nerves entering and leaving the bones of a skeleton. Later, several studies were conducted on bone innervation and, as of today, many observations on the regulation of bone remodeling by neurons and neuropeptides that reside in the CNS have created a new research field, that is, neuroskeletal research.
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Affiliation(s)
- Alessia Metozzi
- a 1 Department of Surgery and Translational Medicine, Metabolic Bone Diseases Unit, University of Florence, Largo Palagi 1, 50138 Florence, Italy
| | - Lorenzo Bonamassa
- a 1 Department of Surgery and Translational Medicine, Metabolic Bone Diseases Unit, University of Florence, Largo Palagi 1, 50138 Florence, Italy
| | - Gemma Brandi
- b 2 Public Mental Health system 1-4 of Florence, Florence, Italy
| | - Maria Luisa Brandi
- c 3 Department of Surgery and Translational Medicine, Metabolic Bone Diseases Unit, AOUC Careggi, University of Florence, Largo Palagi 1, 50138 Florence, Italy
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33
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Jury NJ, McCormick BA, Horseman ND, Benoit SC, Gregerson KA. Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation. PLoS One 2015; 10:e0117339. [PMID: 25689282 PMCID: PMC4331562 DOI: 10.1371/journal.pone.0117339] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Accepted: 12/23/2014] [Indexed: 11/22/2022] Open
Abstract
The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD.
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Affiliation(s)
- Nicholas J. Jury
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
- * E-mail:
| | - Betsy A. McCormick
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
| | - Nelson D. Horseman
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
| | - Stephen C. Benoit
- Department of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Karen A. Gregerson
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, 45267, United States of America
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Guo H, Zhang J, Gao W, Qu Z, Liu C. Gastrointestinal effect of methanol extract of Radix Aucklandiae and selected active substances on the transit activity of rat isolated intestinal strips. PHARMACEUTICAL BIOLOGY 2014; 52:1141-9. [PMID: 24649908 DOI: 10.3109/13880209.2013.879601] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
CONTEXT Radix Aucklandiae, the dry rhizome of Aucklandia lappa Decne (Asteraceae), enjoyed traditional popularity for its antidiarrheal effects. Although there are many investigations on its chemical constituents and pharmacologic actions, few studies explaining its activity and mechanism in gastrointestinal disorders are available. OBJECTIVE In this paper, we focused on the effects of the methanol extract of R. Aucklandiae (RA ext) on gastrointestinal tract, so as to assess some of the possible mechanisms involved in the clinical treatment. MATERIALS AND METHODS In vivo, in neostigmine-induced mice and normal mice, after intragastric administration, RA ext (100, 200, 300, and 400 mg/kg) was studied on gastrointestinal transit including gastric emptying and small intestinal motility. Meanwhile, in vitro, the effect of it (0.1, 0.2, 0.3, and 0.4 mg/mL) on the isolated tissue preparations of rat jejunum was also investigated, as well as costunolide and dehydrocostuslactone which were the main constituents. RESULTS In vivo, the gastric emptying increased and intestinal transit decreased after the administration of RA ext in normal mice. However, RA ext inhibited the gastric emptying and the intestinal transit throughout the concentrations in neostigmine-induced mice. In vitro, RA ext caused inhibitory effect on the spontaneous contraction of rat-isolated jejunum in a dose-dependent manner ranging from 0.1 to 0.4 mg/mL, and it also relaxed the acetylcholine chloride (Ach, 10(-5) M), 5-hydroxytryptamine (5-HT, 200 μM)-induced, and K(+) (60 mM)-induced contractions. RA ext shifted the Ca(2+) concentration-response curves to right, similar to that caused by verapamil (0.025 mM). The Ca(2+) concentration-response curves were shifted by costunolide (CO) (5.4, 8.1, and 10.8 μg/mL), dehydrocostuslactone (DE) (4.6, 6.9, and 9.2 μg/mL), costunolide-dehydrocostuslactone (CO-DE) (5.4-4.6, 8.1-6.9, and 10.8-9.2 μg/mL) to the right, similar to that caused by verapamil (0.01 mM). DISCUSSION AND CONCLUSION These results indicate that RA ext played a spasmolytic role in gastrointestinal motility, which is probably mediated through the inhibition of muscarinic receptors, 5-HT receptors, and calcium influx. The presence of cholinergic and calcium antagonist constituents may be the compatibility of CO and DE. All these results provide a pharmacological basis for its clinical use in the gastrointestinal tract.
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Affiliation(s)
- Huimin Guo
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , Tianjin , China
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Joscelyn J, Kasper LH. Digesting the emerging role for the gut microbiome in central nervous system demyelination. Mult Scler 2014; 20:1553-9. [PMID: 25070675 DOI: 10.1177/1352458514541579] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The fields of microbiology, immunology, neurology and nutrition are rapidly converging, as advanced sequencing and genomics-based methodologies have enabled the mapping out of the microbial diversity of humans for the first time. Bugs, guts, brains and behavior were once believed to be separate domains of clinical practice and research; however, recent observations in our understanding of the microbiome indicate that the boundaries between domains are becoming permeable. This permeability is multidirectional: Biological systems are operating simultaneously in a vastly complex and interconnected web. Understanding the microbiome-gut-brain axis will entail fleshing out the mechanisms by which transduction across each domain occurs, allowing us ultimately to appreciate the role of commensal organisms in shaping and modulating host immunity. This article will highlight animal and human research to date, as well as highlight directions for future research. We speculate that the gut microbiome is potentially the premier environmental risk factor mediating inflammatory central nervous system demyelination, in particular multiple sclerosis.
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Affiliation(s)
| | - Lloyd H Kasper
- Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
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Filippova LV, Bystrova EY, Malyshev FS, Shpanskaya AA, Nozdrachev AD. Location of pattern-recognizing and vanilloid receptors in the nerve plexuses of the rat intestine. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2013; 452:269-72. [PMID: 24150644 DOI: 10.1134/s0012496613050074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Indexed: 11/23/2022]
Affiliation(s)
- L V Filippova
- Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia
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Hübsch M, Neuhuber WL, Raab M. Muscarinic acetylcholine receptors in the mouse esophagus: focus on intraganglionic laminar endings (IGLEs). Neurogastroenterol Motil 2013; 25:e560-73. [PMID: 23742744 DOI: 10.1111/nmo.12161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 05/04/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND IGLEs represent the only low-threshold vagal mechanosensory terminals in the tunica muscularis of the esophagus. Previously, close relationships of vesicular glutamate transporter 2 (VGLUT2) immunopositive IGLEs and cholinergic varicosities suggestive for direct contacts were described in almost all mouse esophageal myenteric ganglia. Possible cholinergic influence on IGLEs requires specific acetylcholine receptors. In particular, the occurrence and location of neuronal muscarinic acetylcholine receptors (mAChR) in the esophagus were not yet characterized. METHODS This study aimed at specifying relationships of VGLUT2 immunopositive IGLEs and vesicular acetylcholine transporter (VAChT)-immunopositive varicosities using pre-embedding electron microscopy and the location of mAChR1-3 (M1-3) within esophagus and nodose ganglia using multilabel immunofluorescence and retrograde tracing. KEY RESULTS Electron microscopy confirmed synaptic contacts between cholinergic varicosities and IGLEs. M1- and M2-immunoreactivities (-iry; -iries) were colocalized with VGLUT2-iry in subpopulations of IGLEs. Retrograde Fast Blue tracing from the esophagus showed nodose ganglion neurons colocalizing tracer and M2-iry. M1-3-iries were detected in about 80% of myenteric ganglia and in about 67% of myenteric neurons. M1- and M2-iry were present in many fibers and varicosities within myenteric ganglia. Presynaptic M2-iry was detected in all, presynaptic M3-iry in one-fifth of motor endplates of striated esophageal muscles. M1-iry could not be detected in motor endplates of the esophagus, but in sternomastoid muscle. CONCLUSIONS & INFERENCES Acetylcholine probably released from varicosities of both extrinsic and intrinsic origin may influence a subpopulation of esophageal IGLEs via M2 and M1-receptors.
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Affiliation(s)
- M Hübsch
- Institute of Anatomy I, University of Erlangen-Nuremberg, Erlangen, Germany
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Abstract
Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Novel gastrointestinal functions of 5-HT continue to be discovered, as well as distant actions of gut-derived 5-HT, and we are learning how 5-HT signalling is altered in gastrointestinal disorders. Conventional functions of 5-HT involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion and vasodilation. Activation of extrinsic vagal and spinal afferent fibres results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts nonconventional actions such as promoting inflammation and serving as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, originating in the gut, promotes haemostasis, influences bone development and serves many other functions. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhoea or constipation, respectively, and the synthetic enzyme tryptophan hydroxylase has also been targeted. Emerging evidence suggests that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies. We provide an overview of these serotonergic actions and treatment strategies.
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Yang N, Garcia MAS, Quinton PM. Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis. J Physiol 2013; 591:4581-93. [PMID: 23818690 DOI: 10.1113/jphysiol.2013.257436] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3- is required for gel-forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen. Exactly where HCO3- becomes crucial in these processes is unknown, but we observed that in the presence of HCO3-, stimulating dissected segments of native mouse intestine with 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild-type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)-dependent HCO3- secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3-, when WT intestines were stimulated only with a Ca2+-mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+-mediated agonist was combined with a cAMP-mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3- both normal exocytosis and normal discharge was observed. These results indicate that normal mucus formation requires concurrent activation of a Ca2+-mediated exocytosis of mucin granules and an independent cAMP-mediated, CFTR-dependent, HCO3- secretion that appears to mainly enhance the extracellular phases of mucus excretion.
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Affiliation(s)
- Ning Yang
- N. Yang: Division of Respiratory Medicine, Department of Pediatrics, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0830, USA.
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Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol 2013; 304:G949-57. [PMID: 23538492 PMCID: PMC3680683 DOI: 10.1152/ajpgi.00493.2012] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The enteric nervous system (ENS), referred to as the "second brain," comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.
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Affiliation(s)
- Bindu Chandrasekharan
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
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Mahavadi S, Bhattacharya S, Kim J, Fayed S, Al-Shboul O, Grider JR, Murthy KS. Caveolae-dependent internalization and homologous desensitization of VIP/PACAP receptor, VPAC₂, in gastrointestinal smooth muscle. Peptides 2013; 43:137-45. [PMID: 23499767 PMCID: PMC4026926 DOI: 10.1016/j.peptides.2013.03.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 03/06/2013] [Accepted: 03/07/2013] [Indexed: 12/18/2022]
Abstract
The main membrane proteins of caveolae (caveolin-1, -2 and -3) oligomerize within lipid rich domains to form regular invaginations of smooth muscle plasma membrane and participate in receptor internalization and desensitization independent of clathrin-coated vesicle endocytosis. We have previously shown that Gs-coupled VIP/PACAP receptors, VPAC2, predominantly expressed in smooth muscle cells of the gut, are exclusively phosphorylated by GRK2 leading to receptor internalization and desensitization. Herein, we characterized the role of caveolin-1 in VPAC2 receptor internalization and desensitization in gastric smooth muscle using three approaches: (i) methyl β-cyclodextrin (MβCD) to deplete cholesterol and disrupt caveolae in dispersed muscle cells, (ii) caveolin-1 siRNA to suppress caveolin-1 expression in cultured muscle cells, and (iii) caveolin-1 knockout mice (caveolin-1(-/-)). Pretreatment of gastric muscle cells with VIP stimulated tyrosine phosphorylation of caveolin-1, and induced VPAC2 receptor internalization (measured as decrease in (125)I-VIP binding after pretreatment) and desensitization (measured as decrease in VIP-induced cAMP formation after pretreatment). Caveolin-1 phosphorylation, and VPAC2 receptor internalization and desensitization were blocked by disruption of caveolae with MβCD, suppression of caveolin-1 with caveolin-1 siRNA or inhibition of Src kinase activity by PP2. Pretreatment with VIP significantly inhibited adenylyl cyclase activity and muscle relaxation in response to subsequent addition of VIP in freshly dispersed muscle cells and in muscle strips isolated from wild type and caveolin-1(-/-) mice; however, the inhibition was significantly attenuated in caveolin-1(-/-) mice. These results suggest that caveolin-1 plays an important role in VPAC2 receptor internalization and desensitization.
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Affiliation(s)
| | | | | | | | | | | | - Karnam S. Murthy
- Corresponding author at: Department of Physiology, Virginia Commonwealth University, Richmond, VA 23298-0551, United States. Tel.: +1 804 828 0029; fax: +1 804 827 0947. (K.S. Murthy)
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Damen R, Haugen M, Svejda B, Alaimo D, Brenna O, Pfragner R, Gustafsson BI, Kidd M. The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease. PLoS One 2013; 8:e62607. [PMID: 23638125 PMCID: PMC3637445 DOI: 10.1371/journal.pone.0062607] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 03/27/2013] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE We recently demonstrated that hypoxia, a key feature of IBD, increases enterochromaffin (EC) cell 5-HT secretion, which is also physiologically regulated by the ADORA2B mechanoreceptor. Since hypoxia is associated with increased extracellular adenosine, we wanted to examine whether this nucleotide amplifies HIF-1α-mediated 5-HT secretion. DESIGN The effects of hypoxia were studied on IBD mucosa, isolated IBD-EC cells, isolated normal EC cells and the EC cell tumor derived cell line KRJ-1. Hypoxia (0.5% O2) was compared to NECA (adenosine agonist), MRS1754 (ADORA2B receptor antagonist) and SCH442146 (ADORA2A antagonist) on HIF signaling and 5-HT secretion. Antisense approaches were used to mechanistically evaluate EC cells in vitro. PCR and western blot were used to analyze transcript and protein levels of HIF-1α signaling and neuroendocrine cell function. An animal model of colitis was evaluated to confirm hypoxia:adenosine signaling in vivo. RESULTS HIF-1α is upregulated in IBD mucosa and IBD-EC cells, the majority (~90%) of which express an activated phenotype in situ. Hypoxia stimulated 5-HT release maximally at 30 mins, an effect amplified by NECA and selectively inhibited by MRS1754, through phosphorylation of TPH-1 and activation of VMAT-1. Transient transfection with Renilla luciferase under hypoxia transcriptional response element (HRE) control identified that ADORA2B activated HIF-1α signaling under hypoxic conditions. Additional signaling pathways associated with hypoxia:adenosine included MAP kinase and CREB. Antisense approaches mechanistically confirmed that ADORA2B signaling was linked to these pathways and 5-HT release under hypoxic conditions. Hypoxia:adenosine activation which could be reversed by 5'-ASA treatment was confirmed in a TNBS-model. CONCLUSION Hypoxia induced 5-HT synthesis and secretion is amplified by ADORA2B signaling via MAPK/CREB and TPH-1 activation. Targeting ADORA2s may decrease EC cell 5-HT production and secretion in IBD.
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Affiliation(s)
- Rikard Damen
- Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Martin Haugen
- Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Bernhard Svejda
- Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Daniele Alaimo
- Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Oystein Brenna
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Roswitha Pfragner
- Institute of Pathophysiology and Immunology, Centre for Molecular Medicine, Graz, Austria
| | - Bjorn I. Gustafsson
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Mark Kidd
- Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
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Filippova LV, Malyshev FS, Bykova AA, Nozdrachev AD. Expression of toll-like receptors 4 in nerve plexuses of the rat duodenum, jejunum, and colon. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2012; 445:215-7. [PMID: 22945519 DOI: 10.1134/s0012496612040114] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Indexed: 11/23/2022]
Affiliation(s)
- L V Filippova
- Pavlov Institute of Physiology of the Russian Academy of Sciences, St. Petersburg, Russia
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Wojtkiewicz J, Równiak M, Crayton R, Majewski M, Gonkowski S. Chemical coding of zinc-enriched neurons in the intramural ganglia of the porcine jejunum. Cell Tissue Res 2012; 350:215-23. [PMID: 22918698 PMCID: PMC3480586 DOI: 10.1007/s00441-012-1486-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 08/02/2012] [Indexed: 11/30/2022]
Abstract
Zinc ions in the synaptic vesicles of zinc-enriched neurons (ZEN) seem to have an important role in normal physiological and pathophysiological processes in target organ innervation. The factor directly responsible for the transport of zinc ions into synaptic vesicles is zinc transporter 3 (ZnT3), a member of the divalent cation zinc transporters and an excellent marker of ZEN neurons. As data concerning the existence of ZEN neurons in the small intestine is lacking, this study was designed to disclose the presence and neurochemical coding of such neurons in the porcine jejunum. Cryostat sections (10 mμ thick) of porcine jejunum were processed for routine double- and triple-immunofluorescence labeling for ZnT3 in various combinations with immunolabeling for other neurochemicals including pan-neuronal marker (PGP9.5), substance P (SP), somatostatin (SOM), vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS), leu-enkephalin (LENK), vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), galanin (GAL), and calcitonin-gene related peptide (CGRP). Immunohistochemistry revealed that approximately 39%, 49%, and 45% of all PGP9.5- positive neurons in the jejunal myenteric (MP), outer submucous (OSP), and inner submucous (ISP) plexuses, respectively, were simultaneously ZnT3+. The majority of ZnT3+ neurons in all plexuses were also VAChT-positive. Both VAChT-positive and VAChT-negative ZnT3+ neurons co-expressed a variety of active substances with diverse patterns of co-localization depending on the plexus studied. In the MP, the largest populations among both VAChT-positive and VAChT-negative ZnT3+ neurons were NOS-positive cells. In the OSP and ISP, substantial subpopulations of ZnT3+ neurons were VAChT-positive cells co-expressing SOM and GAL, respectively. The broad-spectrum of active substances that co-localize with the ZnT3+ neurons in the porcine jejunum suggests that ZnT3 takes part in the regulation of various processes in the gut, both in normal physiological and during pathophysiological processes.
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Affiliation(s)
- Joanna Wojtkiewicz
- Faculty Medical Sciences, Department of Neurology and Neurosurgery, Stem Cell Research Laboratory, University of Warmia and Mazury, ul. Warszawska 30, 10-082, Olsztyn, Poland.
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Gross ER, Gershon MD, Margolis KG, Gertsberg ZV, Cowles RA, Cowles RA. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 2012; 143:408-17.e2. [PMID: 22609381 PMCID: PMC3687781 DOI: 10.1053/j.gastro.2012.05.007] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2011] [Revised: 04/13/2012] [Accepted: 05/01/2012] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS The enteric abundance of serotonin (5-HT), its ability to promote proliferation of neural precursors, and reports that 5-HT antagonists affect crypt epithelial proliferation led us to investigate whether 5-HT affects growth and maintenance of the intestinal mucosa in mice. METHODS cMice that lack the serotonin re-uptake transporter (SERTKO mice) and wild-type mice were given injections of selective serotonin re-uptake inhibitors (gain-of-function models). We also analyzed mice that lack tryptophan hydroxylase-1 (TPH1KO mice, which lack mucosal but not neuronal 5-HT) and mice deficient in tryptophan hydroxylase-2 (TPH2KO mice, which lack neuronal but not mucosal 5-HT) (loss-of-function models). Wild-type and SERTKO mice were given ketanserin (an antagonist of the 5-HT receptor, 5-HT(2A)) or scopolamine (an antagonist of the muscarinic receptor). 5-HT(2A) receptors and choline acetyltransferase were localized by immunocytochemical analysis. RESULTS Growth of the mucosa and proliferation of mucosal cells were significantly greater in SERTKO mice and in mice given selective serotonin re-uptake inhibitors than in wild-type mice, but were diminished in TPH2KO (but not in TPH1KO) mice. Ketanserin and scopolamine each prevented the ability of SERT knockout or inhibition to increase mucosal growth and proliferation. Cholinergic submucosal neurons reacted with antibodies against 5-HT(2A). CONCLUSIONS 5-HT promotes growth and turnover of the intestinal mucosal epithelium. Surprisingly, these processes appear to be mediated by neuronal, rather than mucosal, 5-HT. The 5-HT(2A) receptor activates cholinergic neurons, which provide a muscarinic innervation to epithelial effectors.
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Affiliation(s)
- Erica R. Gross
- Division of Pediatric Surgery, College of Physicians and Surgeons,
Columbia University and New York-Presbyterian Hospital, New York, New York
| | - Michael D. Gershon
- Department of Pathology and Cell Biology, Columbia University,
New York, New York
| | - Kara G. Margolis
- Department of Pediatric Gastroenterology, College of Physicians
and Surgeons, Columbia University and New York-Presbyterian Hospital, New York, New York
| | - Zoya V. Gertsberg
- Division of Pediatric Surgery, College of Physicians and Surgeons,
Columbia University and New York-Presbyterian Hospital, New York, New York
| | - Robert A. Cowles
- Division of Pediatric Surgery, College of Physicians and Surgeons,
Columbia University and New York-Presbyterian Hospital, New York, New York
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Neurochemical characterization of zinc transporter 3-like immunoreactive (ZnT3(+)) neurons in the intramural ganglia of the porcine duodenum. J Mol Neurosci 2012; 48:766-76. [PMID: 22791190 PMCID: PMC3447136 DOI: 10.1007/s12031-012-9855-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 07/01/2012] [Indexed: 12/24/2022]
Abstract
The SLC30 family of divalent cation transporters is thought to be involved in the transport of zinc in a variety of cellular pathways. Zinc transporter 3 (ZnT3) is involved in the transport of zinc into synaptic vesicles or intracellular organelles. As the presence of ZnT3 immunoreactive neurons has recently been reported in both the central and peripheral nervous systems of the rat, the present study was aimed at disclosing the presence of a zinc-enriched neuron enteric population in the porcine duodenum to establish a preliminary insight into their neurochemical coding. Double- and triple-immunofluorescence labeling of the porcine duodenum for ZnT3 with the pan-neuronal marker (PGP 9.5), substance P, somatostatin, vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS), leu-enkephalin, vesicular acetylcholine transporter (VAChT), neuropeptide Y, galanin (GAL), and calcitonin gene-related peptide were performed. Immunohistochemistry revealed that approximately 35, 43, and 48 % of all PGP9.5-postive neurons in the myenteric (MP), outer submucous (OSP), and inner submucous (ISP) plexuses, respectively, of the porcine duodenum were simultaneously ZnT3+. In the present study, ZnT3+ neurons coexpressed a broad spectrum of active substances, but co-localization patterns unique to the plexus were studied. In the ISP, all ZnT3+ neurons were VAChT positive, and the largest populations among these cells formed ZnT3+/VAChT+/GAL+ and ZnT3+/VAChT+/VIP+ cells. In the OSP and MP, the numbers of ZnT3+/VAChT+ neurons were two times smaller, and substantial subpopulations of ZnT3+ neurons in both these plexuses formed ZnT3+/NOS+ cells. The large population of ZnT3+ neurons in the porcine duodenum and a broad spectrum of active substances which co-localize with this peptide suggest that ZnT3 takes part in the regulation of various processes in the gut both in normal physiology and during pathological processes.
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Cheng SX. Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 2012; 303:G60-70. [PMID: 22517767 PMCID: PMC3404579 DOI: 10.1152/ajpgi.00425.2011] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Bacterial toxins such as cholera toxin induce diarrhea by both direct epithelial cell generation of cyclic nucleotides as well as stimulation of the enteric nervous system (ENS). Agonists of the extracellular calcium-sensing receptor (CaSR) can reduce toxin-stimulated fluid secretion in ENS-absent colonic epithelial crypts by increasing phosphodiesterase-dependent cyclic-nucleotide degradation. Here we show that the CaSR is also highly expressed in tetrodotoxin (TTX)-sensitive neurons comprising the ENS, suggesting that CaSR agonists might also function through neuronal pathways. To test this hypothesis, rat colon segments containing intact ENS were isolated and mounted on Ussing chambers. Basal and cyclic nucleotide-stimulated electrolyte secretions were monitored by measuring changes in short-circuit current (I(sc)). CaSR was activated by R-568 and its effects were compared in the presence and absence of TTX. Consistent with active regulation of anion secretion by the ENS, a significant proportion of I(sc) in the proximal and distal colon was inhibited by serosal TTX, both at basal and under cyclic AMP-stimulated conditions. In the absence of TTX, activation of CaSR with R-568 significantly reduced basal I(sc) and cyclic AMP-stimulated I(sc); it also completely reversed the cAMP-stimulated secretory responses if the drug was applied after the forskolin stimulation. Such inhibitory effects of R-568 were either absent or significantly reduced when serosal TTX was present, suggesting that this agonist exerts its antisecretory effect on the intestine by inhibiting ENS. The present results suggest a new model for regulating intestinal fluid transport in which neuronal and nonneuronal secretagogue actions are modulated by the inhibitory effects of CaSR on the ENS. The ability of a CaSR agonist to reduce secretagogue-stimulated Cl(-) secretion might provide a new therapeutic approach for secretory and other ENS-mediated diarrheal conditions.
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Affiliation(s)
- Sam X. Cheng
- 1Department of Pediatrics, School of Medicine, Yale University, New Haven, Connecticut; and ,2Department of Pediatrics, School of Medicine, University of Florida, Gainesville, Florida
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48
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Laforenza U. Water channel proteins in the gastrointestinal tract. Mol Aspects Med 2012; 33:642-50. [PMID: 22465691 DOI: 10.1016/j.mam.2012.03.001] [Citation(s) in RCA: 132] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 03/09/2012] [Accepted: 03/11/2012] [Indexed: 12/24/2022]
Abstract
Water transport through the human digestive system is physiologically crucial for maintaining body water homeostasis and ensure digestive and absorptive functions. Within the gastrointestinal tract, water recirculates, being secreted with the digestive juices and then almost entirely absorbed by the small and large intestine. The importance of aquaporins (AQPs), transmembrane water channel proteins, in the rapid passage of water across plasma membranes in the gastrointestinal tract appears immediately evident. Several AQP isoforms are found in gastrointestinal epithelia, with AQP1, 3, 7, 10 and 11 being the most abundantly expressed in the whole gut. On the other hand, AQP4 and 8 are located selectively in the stomach and colon, respectively. Here we review AQP expression and localization at the tissue, cellular and subcellular level in gastrointestinal epithelia, and their modification in various gut diseases.
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Affiliation(s)
- Umberto Laforenza
- Department of Molecular Medicine, Section of Human Physiology, University of Pavia, Via Forlanini 6, I-27100 Pavia, Italy.
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Chin A, Svejda B, Gustafsson BI, Granlund AB, Sandvik AK, Timberlake A, Sumpio B, Pfragner R, Modlin IM, Kidd M. The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion. Am J Physiol Gastrointest Liver Physiol 2012; 302:G397-405. [PMID: 22038827 PMCID: PMC3287403 DOI: 10.1152/ajpgi.00087.2011] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98-99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 × 10-6 M; IC50 = 3.7 × 10-8 M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT₁ (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT₁ transcription was regulated by PKA/MAPK and PI₃K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.
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Affiliation(s)
- A. Chin
- 1Gastrointestinal Surgery, and
| | | | - B. I. Gustafsson
- 3Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim; ,4Department of Gastroenterology, St. Olav's University Hospital, Trondheim, Norway; and
| | - A. B. Granlund
- 3Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim;
| | - A. K. Sandvik
- 3Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim; ,4Department of Gastroenterology, St. Olav's University Hospital, Trondheim, Norway; and
| | | | - B. Sumpio
- 2Vascular Surgery, Yale University School of Medicine, New Haven, Connecticut;
| | - R. Pfragner
- 5Institute of Pathophysiology and Immunology, Center for Molecular Medicine, Medical University of Graz, Graz, Austria
| | | | - M. Kidd
- 1Gastrointestinal Surgery, and
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Abstract
Na(+) and Cl(-) movement across the intestinal epithelium occurs by several interconnected mechanisms: (a) nutrient-coupled Na(+) absorption, (b) electroneutral NaCl absorption, (c) electrogenic Cl(-) secretion by CFTR, and (d) electrogenic Na(+) absorption by ENaC. All these transport modes require a favorable electrochemical gradient maintained by the basolateral Na(+)/K(+)-ATPase, a Cl(-) channel, and K(+) channels. Electroneutral NaCl absorption is observed from the small intestine to the distal colon. This transport is mediated by apical Na(+)/H(+) (NHE2/3) and Cl(-)/HCO(3)(-) (Slc26a3/a6 and others) exchangers that provide the major route of NaCl absorption. Electroneutral NaCl absorption and Cl(-) secretion by CFTR are oppositely regulated by the autonomic nerve system, the immune system, and the endocrine system via PKAα, PKCα, cGKII, and/or SGK1. This integrated regulation requires the formation of macromolecular complexes, which are mediated by the NHERF family of scaffold proteins and involve internalization of NHE3. Through use of knockout mice and human mutations, a more detailed understanding of the integrated as well as subtle regulation of electroneutral NaCl absorption by the mammalian intestine has emerged.
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Affiliation(s)
- Akira Kato
- Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
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