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1
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Bubeck M, Becker C, Patankar JV. Guardians of the gut: influence of the enteric nervous system on the intestinal epithelial barrier. Front Med (Lausanne) 2023; 10:1228938. [PMID: 37692784 PMCID: PMC10485265 DOI: 10.3389/fmed.2023.1228938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/24/2023] [Indexed: 09/12/2023] Open
Abstract
The intestinal mucosal surface forms one of the largest areas of the body, which is in direct contact with the environment. Co-ordinated sensory functions of immune, epithelial, and neuronal cells ensure the timely detection of noxious queues and potential pathogens and elicit proportional responses to mitigate the threats and maintain homeostasis. Such tuning and maintenance of the epithelial barrier is constantly ongoing during homeostasis and its derangement can become a gateway for systemic consequences. Although efforts in understanding the gatekeeping functions of immune cells have led the way, increasing number of studies point to a crucial role of the enteric nervous system in fine-tuning and maintaining this delicate homeostasis. The identification of immune regulatory functions of enteric neuropeptides and glial-derived factors is still in its infancy, but has already yielded several intriguing insights into their important contribution to the tight control of the mucosal barrier. In this review, we will first introduce the reader to the current understanding of the architecture of the enteric nervous system and the epithelial barrier. Next, we discuss the key discoveries and cellular pathways and mediators that have emerged as links between the enteric nervous, immune, and epithelial systems and how their coordinated actions defend against intestinal infectious and inflammatory diseases. Through this review, the readers will gain a sound understanding of the current neuro-immune-epithelial mechanisms ensuring intestinal barrier integrity and maintenance of intestinal homeostasis.
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Affiliation(s)
- Marvin Bubeck
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Jay V. Patankar
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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2
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González-Vergara A, Benavides B, Julio-Pieper M. Mapping and quantifying neuropeptides in the enteric nervous system. J Neurosci Methods 2023; 393:109882. [PMID: 37172914 DOI: 10.1016/j.jneumeth.2023.109882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/09/2023] [Indexed: 05/15/2023]
Abstract
Neuropeptides are a highly diverse group of signaling molecules found in the central nervous system (CNS) and peripheral organs, including the enteric nervous system (ENS). Increasing efforts have been focused on dissecting the role of neuropeptides in both neural- and non-neural-related diseases, as well as their potential therapeutic value. In parallel, accurate knowledge on their source of production and pleiotropic functions is still needed to fully understand their implications in biological processes. This review will focus on the analytical challenges involved in studying neuropeptides, particularly in the ENS, a tissue where their abundance is low, together with opportunities for further technical development.
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Affiliation(s)
- Alex González-Vergara
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Benjamín Benavides
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Marcela Julio-Pieper
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
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3
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Yin Z, Zhou Y, Turnquist HR, Liu Q. Neuro-epithelial-ILC2 crosstalk in barrier tissues. Trends Immunol 2022; 43:901-916. [PMID: 36253275 DOI: 10.1016/j.it.2022.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 01/12/2023]
Abstract
Group 2 innate lymphoid cells (ILC2s) contribute to the maintenance of mammalian barrier tissue homeostasis. We review how ILC2s integrate epithelial signals and neurogenic components to preserve the tissue microenvironment and modulate inflammation. The epithelium that overlies barrier tissues, including the skin, lungs, and gut, generates epithelial cytokines that elicit ILC2 activation. Sympathetic, parasympathetic, sensory, and enteric fibers release neural signals to modulate ILC2 functions. We also highlight recent findings suggesting neuro-epithelial-ILC2 crosstalk and its implications in immunity, inflammation and resolution, tissue repair, and restoring homeostasis. We further discuss the pathogenic effects of disturbed ILC2-centered neuro-epithelial-immune cell interactions and putative areas for therapeutic targeting.
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Affiliation(s)
- Ziyi Yin
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen Key Laboratory of Cardiovascular Health and Precision Medicine, Shenzhen, Guangdong Province 518055, China
| | - Yawen Zhou
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen Key Laboratory of Cardiovascular Health and Precision Medicine, Shenzhen, Guangdong Province 518055, China
| | - Hēth R Turnquist
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Quan Liu
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen Key Laboratory of Cardiovascular Health and Precision Medicine, Shenzhen, Guangdong Province 518055, China.
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4
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Xu J, Wang L, Chen X, Le W. New Understanding on the Pathophysiology and Treatment of Constipation in Parkinson’s Disease. Front Aging Neurosci 2022; 14:917499. [PMID: 35813960 PMCID: PMC9257174 DOI: 10.3389/fnagi.2022.917499] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/27/2022] [Indexed: 11/13/2022] Open
Abstract
Constipation, one of the most common prodromal non-motor symptoms of Parkinson’s disease (PD), usually occurs several years earlier than the onset of motor symptoms. Previous studies have shown that constipation occurrence increases as the disease progresses. However, the mechanism underlying this pathologic disorder is not clear yet. Moreover, chronic constipation causes slowness in gastric emptying and, therefore, may lead to a delay in the absorption of medications for PD, including levodopa and dopamine agonists. Accordingly, it is necessary to understand how the pathophysiological factors contribute to constipation during PD as well as pursue precise and effective treatment strategies. In this review, we encapsulate the molecular mechanism of constipation underlying PD and update the progress in the treatments of PD-associated constipation.
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Affiliation(s)
- Jianli Xu
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lei Wang
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Xi Chen
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Xi Chen Weidong Le
| | - Weidong Le
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Xi Chen Weidong Le
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5
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Characterization of Neurochemical Signature Alterations in the Enteric Nervous System in Autoimmune Encephalomyelitis. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12125974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
To date, it has remained unclear whether gastrointestinal symptoms, which are frequently observed in patients with multiple sclerosis (MS), are accompanied by pathology of the enteric nervous system (ENS). Here, the neurotransmitter signature of ENS neurons and morphological alterations of interstitial cells of Cajal (ICCs) were studied in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE), which is an animal model of MS. Immunohistochemical analysis was performed on colonic whole mounts from mice with EAE and on paraffin-embedded sections of intestinal tissue from patients with MS. Antibodies against neurotransmitters or their enzymes (including vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and choline acetyltransferase (ChAT)) were used in conjunction with pan-neuronal markers. In addition, the presence of anoctamin 1 (ANO1)-expressing ICCs was studied. ENS changes were observed in the myenteric plexus, but they were absent in the submucosal plexus of both EAE mice and patients with MS. There was a significant decrease in the percentage of ChAT-positive neurons in EAE mice as opposed to a trend toward an increase in patients with MS. Moreover, while ANO1 expression was decreased in EAE mice, patients with MS displayed a significant increase. Although additional studies are necessary to accomplish an in-depth characterization of ENS alterations in MS, our results imply that such alterations exist and may reveal novel insights into the pathophysiology of MS.
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Pascal M, Kazakov A, Chevalier G, Dubrule L, Deyrat J, Dupin A, Saha S, Jagot F, Sailor K, Dulauroy S, Moigneu C, Belkaid Y, Lepousez G, Lledo PM, Wilhelm C, Eberl G. The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding. Mucosal Immunol 2022; 15:629-641. [PMID: 35501356 DOI: 10.1038/s41385-022-00516-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 04/08/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023]
Abstract
The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake.
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Affiliation(s)
- Maud Pascal
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France. .,Institut Pasteur, Université Paris Cité, INSERM U1224, Microenvironment and Immunity Unit, F-75015, Paris, France. .,PhD program 'Cerveau, Cognition, Comportement' (ED3C), Université Paris Sciences & Lettres, Paris, France.
| | - Alexander Kazakov
- Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, 53127, Bonn, Germany
| | - Grégoire Chevalier
- Institut Pasteur, Université Paris Cité, INSERM U1224, Microenvironment and Immunity Unit, F-75015, Paris, France
| | - Lola Dubrule
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Julie Deyrat
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Alice Dupin
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Soham Saha
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Ferdinand Jagot
- Institut Pasteur, Université Paris Cité, INSERM U1224, Microenvironment and Immunity Unit, F-75015, Paris, France
| | - Kurt Sailor
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Sophie Dulauroy
- Institut Pasteur, Université Paris Cité, INSERM U1224, Microenvironment and Immunity Unit, F-75015, Paris, France
| | - Carine Moigneu
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Immune System Biology, and NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Gabriel Lepousez
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France
| | - Pierre-Marie Lledo
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Memory Unit, F-75015, Paris, France.
| | - Christoph Wilhelm
- Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, 53127, Bonn, Germany
| | - Gérard Eberl
- Institut Pasteur, Université Paris Cité, INSERM U1224, Microenvironment and Immunity Unit, F-75015, Paris, France.
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7
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Abdulnour-Nakhoul SM, Nakhoul NL. Ussing Chamber Methods to Study the Esophageal Epithelial Barrier. Methods Mol Biol 2021; 2367:215-233. [PMID: 32946026 DOI: 10.1007/7651_2020_324] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The Ussing chamber was developed in 1949 by Hans Ussing and quickly became a powerful tool to study ion and solute transport in epithelia. The chamber has two compartments strictly separating the apical and basolateral sides of the tissue under study. The two sides of the tissue are connected via electrodes to a modified electrometer/pulse generator that allows measurement of electrical parameters, namely, transepithelial voltage, current, and resistance. Simultaneously, permeability of the tissue to specific solutes or markers can be monitored by using tracers or isotopes to measure transport from one side of the tissue to the other. In this chapter, we will describe the use of the Ussing chamber to study the barrier properties of the mouse esophageal epithelium. We will also briefly describe the use of the modified Ussing chamber to simultaneously study transepithelial and cellular electrophysiology in the rabbit esophageal epithelium. Lastly, we will cover the use of the Ussing chamber to study bicarbonate secretion in the pig esophagus. These examples highlight the versatility of the Ussing chamber technique in investigating the physiology and pathophysiology of epithelia including human biopsies.
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Affiliation(s)
| | - Nazih L Nakhoul
- Departments of Medicine and Physiology, Tulane University School of Medicine, New Orleans, LA, USA
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8
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Afroze F, Bloom S, Bech P, Ahmed T, Sarker SA, Clemens JD, Islam F, Nalin D. Cholera and Pancreatic Cholera: Is VIP the Common Pathophysiologic Factor? Trop Med Infect Dis 2020; 5:tropicalmed5030111. [PMID: 32630790 PMCID: PMC7559706 DOI: 10.3390/tropicalmed5030111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/20/2020] [Accepted: 06/30/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Cholera remains a major global health problem, causing high output diarrhea leading to severe dehydration and shock in developing countries. We aimed to determine whether vasoactive intestinal polypeptide (VIP), the mediator of pancreatic cholera syndrome, has a role in the pathophysiology of human cholera. Methods: We conducted a prospective observational study of cholera cases hospitalized with severe dehydration. Plasma and stool water levels of VIP were measured just after admission, after complete rehydration (3–4 h), at 24 h post-rehydration and at discharge after diarrhea ceased. Results: In total, 23 cholera patients were examined between January and August 2018. The geometric mean of stool VIP (sVIP) and plasma VIP (pVIP) on admission were 207.67 and 8.34 pmol/L, respectively. pVIP values were all within the normal range (</= 30 pcmol/L); however, sVIP levels were very high at all timepoints, though less so just after rehydration. In multivariable GEE models, after adjustment for covariates, sVIP levels were significantly associated with duration of hospitalization (p = 0.026), total stool volume (p = 0.023) as well as stool output in the first 24 h (p = 0.013). Conclusions: The data suggest that VIP, which is released by intestinal nerves, may play an important role in human choleragenesis, and inhibitors of intestinal VIP merit testing for potential therapeutic benefits.
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Affiliation(s)
- Farzana Afroze
- International Centre for Diarrheal Disease Research (icddr,b), Dhaka 1212, Bangladesh; (F.A.); (T.A.); (S.A.S.); (J.D.C.); (F.I.)
| | - Steven Bloom
- North West London Pathology Consortium, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, UK; (S.B.); (P.B.)
| | - Paul Bech
- North West London Pathology Consortium, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, UK; (S.B.); (P.B.)
| | - Tahmeed Ahmed
- International Centre for Diarrheal Disease Research (icddr,b), Dhaka 1212, Bangladesh; (F.A.); (T.A.); (S.A.S.); (J.D.C.); (F.I.)
| | - Shafiqul Alam Sarker
- International Centre for Diarrheal Disease Research (icddr,b), Dhaka 1212, Bangladesh; (F.A.); (T.A.); (S.A.S.); (J.D.C.); (F.I.)
| | - John D. Clemens
- International Centre for Diarrheal Disease Research (icddr,b), Dhaka 1212, Bangladesh; (F.A.); (T.A.); (S.A.S.); (J.D.C.); (F.I.)
| | - Farhana Islam
- International Centre for Diarrheal Disease Research (icddr,b), Dhaka 1212, Bangladesh; (F.A.); (T.A.); (S.A.S.); (J.D.C.); (F.I.)
| | - David Nalin
- Department of Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208, USA
- Correspondence: ; Tel.: +1-484-653-9945; Fax: +1-610-4301-6004
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9
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Das S, Gordián-Vélez WJ, Ledebur HC, Mourkioti F, Rompolas P, Chen HI, Serruya MD, Cullen DK. Innervation: the missing link for biofabricated tissues and organs. NPJ Regen Med 2020; 5:11. [PMID: 32550009 PMCID: PMC7275031 DOI: 10.1038/s41536-020-0096-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/29/2020] [Indexed: 12/15/2022] Open
Abstract
Innervation plays a pivotal role as a driver of tissue and organ development as well as a means for their functional control and modulation. Therefore, innervation should be carefully considered throughout the process of biofabrication of engineered tissues and organs. Unfortunately, innervation has generally been overlooked in most non-neural tissue engineering applications, in part due to the intrinsic complexity of building organs containing heterogeneous native cell types and structures. To achieve proper innervation of engineered tissues and organs, specific host axon populations typically need to be precisely driven to appropriate location(s) within the construct, often over long distances. As such, neural tissue engineering and/or axon guidance strategies should be a necessary adjunct to most organogenesis endeavors across multiple tissue and organ systems. To address this challenge, our team is actively building axon-based "living scaffolds" that may physically wire in during organ development in bioreactors and/or serve as a substrate to effectively drive targeted long-distance growth and integration of host axons after implantation. This article reviews the neuroanatomy and the role of innervation in the functional regulation of cardiac, skeletal, and smooth muscle tissue and highlights potential strategies to promote innervation of biofabricated engineered muscles, as well as the use of "living scaffolds" in this endeavor for both in vitro and in vivo applications. We assert that innervation should be included as a necessary component for tissue and organ biofabrication, and that strategies to orchestrate host axonal integration are advantageous to ensure proper function, tolerance, assimilation, and bio-regulation with the recipient post-implant.
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Affiliation(s)
- Suradip Das
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
| | - Wisberty J. Gordián-Vélez
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA USA
| | | | - Foteini Mourkioti
- Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Panteleimon Rompolas
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - H. Isaac Chen
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
| | - Mijail D. Serruya
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA USA
| | - D. Kacy Cullen
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA USA
- Axonova Medical, LLC., Philadelphia, PA USA
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10
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Iwasaki M, Akiba Y, Kaunitz JD. Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Res 2019; 8. [PMID: 31559013 PMCID: PMC6743256 DOI: 10.12688/f1000research.18039.1] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2019] [Indexed: 12/11/2022] Open
Abstract
Vasoactive intestinal peptide (VIP), a gut peptide hormone originally reported as a vasodilator in 1970, has multiple physiological and pathological effects on development, growth, and the control of neuronal, epithelial, and endocrine cell functions that in turn regulate ion secretion, nutrient absorption, gut motility, glycemic control, carcinogenesis, immune responses, and circadian rhythms. Genetic ablation of this peptide and its receptors in mice also provides new insights into the contribution of VIP towards physiological signaling and the pathogenesis of related diseases. Here, we discuss the impact of VIP on gastrointestinal function and diseases based on recent findings, also providing insight into its possible therapeutic application to diabetes, autoimmune diseases and cancer.
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Affiliation(s)
- Mari Iwasaki
- Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA
| | - Yasutada Akiba
- Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jonathan D Kaunitz
- Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.,Departments of Medicine and Surgery, UCLA School of Medicine, Los Angeles, CA, USA
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11
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Wang Y, Kim R, Sims CE, Allbritton NL. Building a Thick Mucus Hydrogel Layer to Improve the Physiological Relevance of In Vitro Primary Colonic Epithelial Models. Cell Mol Gastroenterol Hepatol 2019; 8:653-655.e5. [PMID: 31356887 PMCID: PMC6889783 DOI: 10.1016/j.jcmgh.2019.07.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 07/18/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
Affiliation(s)
- Y Wang
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - R Kim
- UNC/NC State Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, and North Carolina State University, Raleigh, North Carolina
| | - C E Sims
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - N L Allbritton
- UNC/NC State Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, and North Carolina State University, Raleigh, North Carolina.
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12
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Webb DL. Tests of intestinal mucosal hyperpermeability: Many diseases, many biomarkers and a bright future. Best Pract Res Clin Gastroenterol 2019; 40-41:101636. [PMID: 31594645 DOI: 10.1016/j.bpg.2019.101636] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/18/2019] [Indexed: 01/31/2023]
Abstract
The number of disorders now linked to increased intestinal mucosal permeability implies that a substantial percent of the population is affected. Drug interventions targeting reduced tight junctional permeability are being pursued. Although hyper-permeability in itself is not a clinically recognized disease entity, its relationship to disease processes has driven interest in measuring, and even monitoring mucosal permeability in vivo. Along with improved knowledge of gut barrier physiology, advances have been made in tests and biomarkers of barrier function. Drawing from our experiences in the past decade, considerations and challenges faced in assessing in vivo intestinal permeability are discussed herein, along with indications of what the future might hold.
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Affiliation(s)
- Dominic-Luc Webb
- Gastroenterology and Hepatology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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13
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Abu-Arish A, Pandžić E, Kim D, Tseng HW, Wiseman PW, Hanrahan JW. Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains. J Gen Physiol 2019; 151:834-849. [PMID: 31048413 PMCID: PMC6572005 DOI: 10.1085/jgp.201812143] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 04/05/2019] [Indexed: 01/20/2023] Open
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a tightly regulated anion channel that mediates secretion by epithelia and is mutated in the disease cystic fibrosis. CFTR forms macromolecular complexes with many proteins; however, little is known regarding its associations with membrane lipids or the regulation of its distribution and mobility at the cell surface. We report here that secretagogues (agonists that stimulate secretion) such as the peptide hormone vasoactive intestinal peptide (VIP) and muscarinic agonist carbachol increase CFTR aggregation into cholesterol-dependent clusters, reduce CFTR lateral mobility within and between membrane microdomains, and trigger the fusion of clusters into large (3.0 µm2) ceramide-rich platforms. CFTR clusters are closely associated with motile cilia and with the enzyme acid sphingomyelinase (ASMase) that is constitutively bound on the cell surface. Platform induction is prevented by pretreating cells with cholesterol oxidase to disrupt lipid rafts or by exposure to the ASMase functional inhibitor amitriptyline or the membrane-impermeant reducing agent 2-mercaptoethanesulfonate. Platforms are reversible, and their induction does not lead to an increase in apoptosis; however, blocking platform formation does prevent the increase in CFTR surface expression that normally occurs during VIP stimulation. These results demonstrate that CFTR is colocalized with motile cilia and reveal surprisingly robust regulation of CFTR distribution and lateral mobility, most likely through autocrine redox activation of extracellular ASMase. Formation of ceramide-rich platforms containing CFTR enhances transepithelial secretion and likely has other functions related to inflammation and mucosal immunity.
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Affiliation(s)
- Asmahan Abu-Arish
- Department of Physiology, McGill University, Montréal, Canada
- Department of Physics, McGill University, Montréal, Canada
- Cystic Fibrosis Translational Research Centre, McGill University, Montréal, Canada
| | - Elvis Pandžić
- Department of Physics, McGill University, Montréal, Canada
| | - Dusik Kim
- Department of Physiology, McGill University, Montréal, Canada
- Cystic Fibrosis Translational Research Centre, McGill University, Montréal, Canada
| | - Hsin Wei Tseng
- Department of Physiology, McGill University, Montréal, Canada
| | - Paul W Wiseman
- Department of Physics, McGill University, Montréal, Canada
- Department of Chemistry, McGill University, Montréal, Canada
- Cystic Fibrosis Translational Research Centre, McGill University, Montréal, Canada
| | - John W Hanrahan
- Department of Physiology, McGill University, Montréal, Canada
- Cystic Fibrosis Translational Research Centre, McGill University, Montréal, Canada
- McGill University Health Centre Research Institute, Montréal, Canada
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14
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Hu X, Cao W, Zhao M. Octreotide reverses shock due to vasoactive intestinal peptide-secreting adrenal pheochromocytoma: A case report and review of literature. World J Clin Cases 2018; 6:862-868. [PMID: 30510956 PMCID: PMC6264997 DOI: 10.12998/wjcc.v6.i14.862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 02/05/2023] Open
Abstract
Vasoactive intestinal peptide-producing tumors (VIPoma) usually originate in the pancreas and are characterized by diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). In adults, nonpancreatic VIPoma is very rare. Herein, we report an unusual case of VIP-producing pheochromocytoma marked by persistent shock, flushing, and watery diarrhea and high sensitivity to octreotide. A 53-year-old woman was hospitalized for sudden-onset hypertension with convulsions, which then rapidly evolved to persistent shock, flushing, and watery diarrhea. Abdominal computed tomography indicated a left adrenal mass, accompanied by bleeding; and marked elevations of both plasma catecholamine and VIP concentrations were documented via laboratory testing. Surprisingly, all clinical symptoms responded swiftly to octreotide treatment. Once surgically treated, hormonal levels normalized in this patient, and the clinical symptoms dissipated. Postoperative pathological and immunohistopathological studies confirmed a VIP-secreting pheochromocytoma with strong, diffuse positivity for somatostatin receptor type 2. During a 6-mo follow-up period, she seemed in good health and was symptom-free.
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Affiliation(s)
- Xiao Hu
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Wei Cao
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Min Zhao
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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15
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Mazziotti G, Mosca A, Frara S, Vitale G, Giustina A. Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects. Expert Opin Pharmacother 2017; 18:1679-1689. [PMID: 29067877 DOI: 10.1080/14656566.2017.1391217] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs. Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs. Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.
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Affiliation(s)
| | - Alessandra Mosca
- b Medical Oncology , 'Maggiore della Carità' University Hospital , Novara , Italy
| | - Stefano Frara
- c Chair of Endocrinology , San Raffaele Vita-Salute University , Milan , Italy
| | - Giovanni Vitale
- d Department of Clinical Sciences and Community Health (DISCCO) , University of Milan , Milan , Italy.,e Laboratory of Geriatric and Oncologic Neuroendocrinology Research , Istituto Auxologico Italiano IRCCS , Milan , Italy
| | - Andrea Giustina
- c Chair of Endocrinology , San Raffaele Vita-Salute University , Milan , Italy
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16
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Tornesello AL, Buonaguro L, Tornesello ML, Buonaguro FM. New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology. Molecules 2017; 22:1282. [PMID: 28767081 PMCID: PMC6152110 DOI: 10.3390/molecules22081282] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 07/25/2017] [Indexed: 11/16/2022] Open
Abstract
Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity, the stability and efficacy of peptide analogues currently employed as anticancer drugs or as molecular imaging tracers. The stability of somatostatin, integrins and bombesin analogues in the human body have been significantly increased by cyclization and/or insertion of non-natural amino acids in the peptide sequences. Moreover, the overall pharmacokinetic properties of such analogues and others (including cholecystokinin, vasoactive intestinal peptide and neurotensin analogues) have been improved by PEGylation and glycosylation. Furthermore, conjugation of those peptide analogues to new linkers and bifunctional chelators (such as AAZTA, TETA, TRAP, NOPO etc.), produced radiolabeled moieties with increased half life and higher binding affinity to the cognate receptors. This review describes the most important and recent chemical modifications introduced in the amino acid sequences as well as linkers and new bifunctional chelators which have significantly improved the specificity and sensitivity of peptides used in oncologic diagnosis and therapy.
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Affiliation(s)
- Anna Lucia Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, 80131 Napoli, Italy.
| | - Luigi Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, 80131 Napoli, Italy.
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, 80131 Napoli, Italy.
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, 80131 Napoli, Italy.
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17
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Fujii S, Suzuki K, Kawamoto A, Ishibashi F, Nakata T, Murano T, Ito G, Shimizu H, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Araki A, Ohtsuka K, Okamoto R, Watanabe M. PGE 2 is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells. Sci Rep 2016; 6:36795. [PMID: 27827428 PMCID: PMC5101536 DOI: 10.1038/srep36795] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 10/21/2016] [Indexed: 12/13/2022] Open
Abstract
Intestinal epithelial cells (IECs) play an indispensable role in maintaining body fluid balance partly through their ability to regulate anion/fluid secretion. Yet in various inflammatory gastrointestinal diseases, over-secretion of anions results in symptoms such as severe diarrhoea. Endogenous mediators, such as vasoactive intestinal peptide or prostaglandin E2 (PGE2), regulate intestinal anion/fluid secretion, but their direct effect on purified human IECs has never been described in detail. Based on a previously described intestinal organoid swelling model, we established a 3D-scanner-assisted quantification method to evaluate the anion/fluid secretory response of cultured human IECs. Among various endogenous secretagogues, we found that PGE2 had the lowest EC50 value with regard to the induction of swelling of the jejunal and colonic organoids. This PGE2-mediated swelling response was dependent on environmental Cl- concentrations as well as on several channels and transporters as shown by a series of chemical inhibitor studies. The concomitant presence of various inflammatory cytokines with PGE2 failed to modulate the PGE2-mediated organoid swelling response. Therefore, the present study features PGE2 as a direct and robust mediator of anion/fluid secretion by IECs in the human intestine.
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Affiliation(s)
- Satoru Fujii
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kohei Suzuki
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ami Kawamoto
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fumiaki Ishibashi
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toru Nakata
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuro Murano
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Go Ito
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Tomohiro Mizutani
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigeru Oshima
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuya Nakamura
- Department of Advanced Therapeutics in GI Diseases, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akihiro Araki
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuo Ohtsuka
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Center for Stem Cell and Regenerative Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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18
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Yang J, Yang L, Wang Y, Zhai S, Wang S, Yang Z, Wang W. Effects of dietary protein and energy levels on digestive enzyme activities and electrolyte composition in the small intestinal fluid of geese. Anim Sci J 2016; 88:294-299. [PMID: 27192559 DOI: 10.1111/asj.12557] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 08/19/2015] [Indexed: 11/28/2022]
Abstract
The present study was conducted to evaluate the effects of dietary protein and energy levels on digestive enzymes and electrolyte composition in jejunum of geese. A 3×3 factorial and completely randomized design was adopted with three protein levels and three energy levels. The experiment included four replicates for each treatment, and three geese for each replicate. Isovolumetric supernate from centrifugal jejuna fluid were mixed in each replicate. Activities of digestive enzymes and ions were analyzed. The results showed trypsin and chymotrypsin activities were significantly increased with increasing of dietary protein and energy levels (P<0.05). The concentrations of Ca2+ and pH value were significantly decreased by increased dietary protein and energy levels. However, no significant differences were found for the activities of amylase and cellulase, as well as the concentration of Na+ among groups with different protein and energy levels. In conclusion, digesta enzymes and electrolytes in the small intestine adapted to the protein and energy levels. The activities of protease, rather than amylase and cellulase were induced with increasing of protein and energy levels. The imbalance of positive and negative ions was possibly adjusted by the fluctuant concentrations of K+ , Cl- and Ca2+ for maintaining normal physiological function.
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Affiliation(s)
- Jing Yang
- College of Animal Science, South China Agriculture University, Guangzhou, China.,Guangdong GuangKen Animal Husbandry Co. Ltd., Guangzhou, China
| | - Lin Yang
- College of Animal Science, South China Agriculture University, Guangzhou, China
| | - Yongchang Wang
- College of Animal Science, South China Agriculture University, Guangzhou, China
| | - Shuangshuang Zhai
- College of Animal Science, South China Agriculture University, Guangzhou, China
| | - Shenshen Wang
- College of Animal Science, South China Agriculture University, Guangzhou, China
| | - Zhipeng Yang
- College of Animal Science, South China Agriculture University, Guangzhou, China
| | - Wence Wang
- College of Animal Science, South China Agriculture University, Guangzhou, China
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19
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Doty KA, Wilburn DB, Bowen KE, Feldhoff PW, Feldhoff RC. Co-option and evolution of non-olfactory proteinaceous pheromones in a terrestrial lungless salamander. J Proteomics 2015; 135:101-111. [PMID: 26385001 DOI: 10.1016/j.jprot.2015.09.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 09/07/2015] [Accepted: 09/10/2015] [Indexed: 11/17/2022]
Abstract
Gene co-option is a major force in the evolution of novel biological functions. In plethodontid salamanders, males deliver proteinaceous courtship pheromones to the female olfactory system or transdermally to the bloodstream. Molecular studies identified three families of highly duplicated, rapidly evolving pheromones (PRF, PMF, and SPF). Analyses for Plethodon salamanders revealed pheromone mixtures of primarily PRF and PMF. The current study demonstrates that in Desmognathus ocoee--a plesiomorphic species with transdermal delivery--SPF is the major pheromone component representing >30% of total protein. Chromatographic profiles of D. ocoee pheromones were consistent from May through October. LC/MS-MS analysis suggested uniform SPF isoform expression between individual male D. ocoee. A gene ancestry for SPF with the Three-Finger Protein superfamily was supported by intron-exon boundaries, but not by the disulfide bonding pattern. Further analysis of the pheromone mixture revealed paralogs to peptide hormones that contained mutations in receptor binding regions, such that these novel molecules may alter female physiology by acting as hormone agonists/antagonists. Cumulatively, gene co-option, duplication, and neofunctionalization have permitted recruitment of additional gene families for pheromone activity. Such independent co-option events may be playing a key role in salamander speciation by altering male traits that influence reproductive success.
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Affiliation(s)
- Kari A Doty
- Department of Biochemistry and Molecular Biology,University of Louisville, Louisville, KY
| | - Damien B Wilburn
- Department of Biochemistry and Molecular Biology,University of Louisville, Louisville, KY; Department of Genome Sciences,University of Washington, Seattle, WA.
| | - Kathleen E Bowen
- Department of Biochemistry and Molecular Biology,University of Louisville, Louisville, KY
| | - Pamela W Feldhoff
- Department of Biochemistry and Molecular Biology,University of Louisville, Louisville, KY
| | - Richard C Feldhoff
- Department of Biochemistry and Molecular Biology,University of Louisville, Louisville, KY
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20
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MacEachern SJ, Patel BA, Keenan CM, Dicay M, Chapman K, McCafferty DM, Savidge TC, Beck PL, MacNaughton WK, Sharkey KA. Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis. Gastroenterology 2015; 149:445-55.e3. [PMID: 25865048 PMCID: PMC4516675 DOI: 10.1053/j.gastro.2015.04.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 03/06/2015] [Accepted: 04/06/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in epithelial hyporesponsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulfonic acid- or dextran sodium sulfate-induced colitis and in Il10(-/-) mice. METHODS Electrically evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10(-/-) mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen, and blood of mice. RESULTS Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared with mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulfonic acid-induced colitis and associated bacterial translocation. CONCLUSIONS Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these mice restores epithelial barrier function and reduces bacterial translocation.
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Affiliation(s)
- Sarah J. MacEachern
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Bhavik A. Patel
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Brighton, UK
| | - Catherine M. Keenan
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Michael Dicay
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Kevin Chapman
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Donna-Marie McCafferty
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Tor C. Savidge
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Paul L. Beck
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Wallace K. MacNaughton
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A. Sharkey
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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21
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The enteric nervous system and gastrointestinal innervation: integrated local and central control. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 817:39-71. [PMID: 24997029 DOI: 10.1007/978-1-4939-0897-4_3] [Citation(s) in RCA: 526] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The digestive system is innervated through its connections with the central nervous system (CNS) and by the enteric nervous system (ENS) within the wall of the gastrointestinal tract. The ENS works in concert with CNS reflex and command centers and with neural pathways that pass through sympathetic ganglia to control digestive function. There is bidirectional information flow between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia.The ENS in human contains 200-600 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways. Neurons also project from the ENS to prevertebral ganglia, the gallbladder, pancreas and trachea.The relative roles of the ENS and CNS differ considerably along the digestive tract. Movements of the striated muscle esophagus are determined by neural pattern generators in the CNS. Likewise the CNS has a major role in monitoring the state of the stomach and, in turn, controlling its contractile activity and acid secretion, through vago-vagal reflexes. In contrast, the ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled. The CNS has control of defecation, via the defecation centers in the lumbosacral spinal cord. The importance of the ENS is emphasized by the life-threatening effects of some ENS neuropathies. By contrast, removal of vagal or sympathetic connections with the gastrointestinal tract has minor effects on GI function. Voluntary control of defecation is exerted through pelvic connections, but cutting these connections is not life-threatening and other functions are little affected.
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22
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Giustina A, Mazziotti G, Maffezzoni F, Amoroso V, Berruti A. Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors. Expert Opin Investig Drugs 2014; 23:1619-35. [DOI: 10.1517/13543784.2014.942728] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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23
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Baldassano S, Wang GD, Mulè F, Wood JD. Glucagon-like peptide-1 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro. Am J Physiol Gastrointest Liver Physiol 2012; 302:G352-8. [PMID: 22075777 PMCID: PMC3287398 DOI: 10.1152/ajpgi.00333.2011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLP-1R effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current (I(sc)), which served as a marker for chloride secretion. Transmural EFS evoked neurally mediated biphasic increases in I(sc) that had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-1 receptor antagonist exendin-(9-39) suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic or vasoactive intestinal peptide receptor antagonists but not in the presence of a muscarinic receptor antagonist. GLP-1 significantly reduced EFS-evoked ACh release. In the submucosal plexus, GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons, and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and that its activation leads to a decrease in neurally evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions in the enteric neural networks that control secretomotor functions.
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Affiliation(s)
- Sara Baldassano
- 1Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio; and ,2Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, University of Palermo, Palermo, Italy
| | - Guo-Du Wang
- 1Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio; and
| | - Flavia Mulè
- 2Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, University of Palermo, Palermo, Italy
| | - Jackie D. Wood
- 1Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio; and
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Hermann RJ, Van der Steen T, Vomhof-Dekrey EE, Al-Badrani S, Wanjara SB, Failing JJ, Haring JS, Dorsam GP. Characterization and use of a rabbit-anti-mouse VPAC1 antibody by flow cytometry. J Immunol Methods 2011; 376:20-31. [PMID: 22079255 DOI: 10.1016/j.jim.2011.10.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 10/05/2011] [Accepted: 10/13/2011] [Indexed: 12/19/2022]
Abstract
Vasoactive intestinal peptide receptor-1 signaling in lymphocytes has been shown to regulate chemotaxis, proliferation, apoptosis and differentiation. During T cell activation, VPAC1 mRNA is downregulated, but the effect on its protein levels is less clear. A small number of studies have reported measurement of human VPAC1 by flow cytometry, but murine VPAC1 reagents are unavailable. Therefore, we set out to generate a reliable and highly specific α-mouse VPAC1 polyclonal antibody for use with flow cytometry. After successfully generating a rabbit α-VPAC1 polyclonal antibody (α-mVPAC1 pAb), we characterized its cross-reactivity and showed that it does not recognize other family receptors (mouse VPAC2 and PAC1, and human VPAC1, VPAC2 and PAC1) by flow cytometry. Partial purification of the rabbit α-VPAC1 sera increased the specific-activity of the α-mVPAC1 pAb by 20-fold, and immunofluorescence microscopy (IF) confirmed a plasma membrane subcellular localization for mouse VPAC1 protein. To test the usefulness of this specific α-mVPAC1 pAb, we showed that primary, resting mouse T cells express detectable levels of VPAC1 protein, with little detectable signal from activated T cells, or CD19 B cells. These data support our previously published data showing a downregulation of VPAC1 mRNA during T cell activation. Collectively, we have established a well-characterized, and highly species specific α-mVPAC1 pAb for VPAC1 surface measurement by IF and flow cytometry.
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Affiliation(s)
- Rebecca J Hermann
- Department of Chemistry and Molecular Biology and the Center for Protease Research, North Dakota State University, Fargo, ND 58108-6050, United States
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Brown DR, Miller RJ. Neurohormonal Control of Fluid and Electrolyte Transport in Intestinal Mucosa. Compr Physiol 2011. [DOI: 10.1002/cphy.cp060424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Leleiko NS, Gee MS, Sadow PM. Case records of the Massachusetts General Hospital. Case 13-2010. An 18.5-month-old girl with watery diarrhea and poor weight gain. N Engl J Med 2010; 362:1619-26. [PMID: 20427811 DOI: 10.1056/nejmcpc0910932] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Neal S Leleiko
- Department of Pediatrics, Alpert School of Medicine, Brown University, and the Division of Pediatric Gastroenterology, Nutrition, and Liver Diseases, Hasbro Children's Hospital-Rhode Island Hospital, Providence, USA
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Fei G, Wang YZ, Liu S, Hu HZ, Wang GD, Qu MH, Wang XY, Xia Y, Sun X, Bohn LM, Cooke HJ, Wood JD. Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon. Am J Physiol Gastrointest Liver Physiol 2009; 296:G823-32. [PMID: 19179625 PMCID: PMC2670663 DOI: 10.1152/ajpgi.90447.2008] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Actions of lubiprostone, a selective type-2 chloride channel activator, on mucosal secretion were investigated in guinea pig small intestine and colon. Flat-sheet preparations were mounted in Ussing flux chambers for recording short-circuit current (Isc) as a marker for electrogenic chloride secretion. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1-3000 nM, evoked increases in Isc in a concentration-dependent manner with an EC50 of 42.5 nM. Lubiprostone applied to the mucosa of the colon in eight concentrations ranging from 1-3000 nM evoked increases in Isc in a concentration-dependent manner with an EC50 of 31.7 nM. Blockade of enteric nerves by tetrodotoxin did not influence stimulation of Isc by lubiprostone. Antagonists acting at prostaglandin (PG)E2, EP1-3, or EP4 receptors did not suppress stimulation of Isc by lubiprostone but suppressed or abolished PGE2-evoked responses. Substitution of gluconate for chloride abolished all responses to lubiprostone. The selective CFTR channel blocker, CFTR(inh)-172, did not suppress lubiprostone-evoked Isc. The broadly acting blocker, glibenclamide, suppressed (P<0.001) lubiprostone-evoked Isc. Lubiprostone, in the presence of tetrodotoxin, enhanced carbachol-evoked Isc. The cholinergic component, but not the putative vasoactive intestinal peptide component, of neural responses to electrical field stimulation was enhanced by lubiprostone. Application of any of the prostaglandins, E2, F2, or I2, evoked depolarization of the resting membrane potential in enteric neurons. Unlike the prostaglandins, lubiprostone did not alter the electrical behavior of enteric neurons. Exposure to the histamine H2 receptor agonists increased basal Isc followed by persistent cyclical increases in Isc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.
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Affiliation(s)
- Guijun Fei
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Yu-Zhong Wang
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Sumei Liu
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Hong-Zhen Hu
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Guo-Du Wang
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Mei-Hua Qu
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Xi-Yu Wang
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Yun Xia
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Xiaohong Sun
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Laura M. Bohn
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Helen J. Cooke
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
| | - Jackie D. Wood
- Departments of Physiology and Cell Biology, Pharmacology, Internal Medicine, Neuroscience, and Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio
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Dickson L, Finlayson K. VPAC and PAC receptors: From ligands to function. Pharmacol Ther 2008; 121:294-316. [PMID: 19109992 DOI: 10.1016/j.pharmthera.2008.11.006] [Citation(s) in RCA: 287] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Accepted: 11/18/2008] [Indexed: 02/03/2023]
Abstract
Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptides (PACAPs) share 68% identity at the amino acid level and belong to the secretin peptide family. Following the initial discovery of VIP almost four decades ago a substantial amount of knowledge has been presented describing the mechanisms of action, distribution and pleiotropic functions of these related peptides. It is now known that the physiological actions of these widely distributed peptides are produced through activation of three common G-protein coupled receptors (VPAC(1), VPAC(2) and PAC(1)R) which preferentially stimulate adenylate cyclase and increase intracellular cAMP, although stimulation of other intracellular messengers, including calcium and phospholipase D, has been reported. Using a range of in vitro and in vivo approaches, including cell-based functional assays, transgenic animals and rodent models of disease, VPAC/PAC receptor activation has been associated with numerous physiological processes (e.g. control of circadian rhythms) and clinical conditions (e.g. pulmonary hypertension), which underlies on-going research efforts and makes these peptides and their cognate receptors attractive targets for the pharmaceutical industry. However, despite the considerable interest in VPAC/PAC receptors and the processes which they mediate, there is still a paucity of selective and available, non-peptide ligands, which has hindered further advances in this field both at the basic research and clinical level. This review summarises the current knowledge of VIP/PACAP and the VPAC/PAC receptors with regard to their distribution, pharmacology, signalling pathways, splice variants and finally, the utility of animal models in exploring their physiological roles.
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Affiliation(s)
- Louise Dickson
- Centre for Integrative Physiology, University of Edinburgh, EH8 9XD, UK
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Abstract
The epithelium of the small intestine can both actively absorb and actively secrete electrolytes and water. Secretion can be elicited in vitro by adding cyclic AMP or a stimulator of intestinal mucosal adenylate cyclase (cholera and Escherichia coli enterotoxins, prostaglandins, vasoactive intestinal peptide) or an inhibitor of cyclic AMP phosphodiesterase (theophylline). Cyclic AMP appears to alter intestinal ion transport at two different loci: it inhibits a coupled influx process for Na+ and Cl- at the luminal border, thereby reducing active absorption of NaCl, and it also stimulates the active secretion of anion (or Na+ and anion). A variety of evidence suggests that these two effects of cyclic AMP reside in different types of cells, the former in villus cells and the latter in crypt cells. The latter process is Na+-dependent and is inhibited by low concentrations of ouabain and ethacrynic acid. Active ion absorption in vitro can be enhanced by (1) stimulating Na+-coupled organic solute absorption with glucose, amino acids and possibly also oligo peptides; (2) reducing the HCO3- concentration and/or pH of the serosal bathing solution; and (3) introducing an alpha-adrenergic agonist. Cholera toxin-induced fluid production in vivo can be diminished by the first of these manoeuvres. The in vivo efficacies of the other two have not been evaluated.
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Said SI, Mutt V, Erdös EG. The lung in relation to vasoactive polypeptides. CIBA FOUNDATION SYMPOSIUM 2008; 78:217-37. [PMID: 6162626 DOI: 10.1002/9780470720615.ch12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Among the metabolic functions of the lungs are the formation, release, activation and inactivation of biologically active peptides. The following peptides may be present or formed in normal lung: vasoactive intestinal peptide or a peptide closely related to it, a spasmogenic peptide not yet fully identified, bradykinin, substance P, a bombesin-like peptide (especially in fetal and neonatal lung), and eosinophil-chemotactic peptides. These peptides are found in special neuroendocrine cells, in neurons, or in mast cells. Normal lung also inactivates bradykinin and activates angiotensin; both processes are catalysed by the same enzyme (kininase II or angiotensin-converting enzyme), located in pulmonary vascular endothelium. Pulmonary tumours and certain non-tumorous lesions can produce and release a variety of peptide hormones that are not normally generated by the lung in substantial amounts. This 'ectopic' secretion of hormones may be detectable only by sensitive assays or may result in specific clinical syndromes.
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Grozinsky-Glasberg S, Grossman AB, Korbonits M. The role of somatostatin analogues in the treatment of neuroendocrine tumours. Mol Cell Endocrinol 2008; 286:238-50. [PMID: 18037561 DOI: 10.1016/j.mce.2007.10.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2007] [Revised: 09/30/2007] [Accepted: 10/10/2007] [Indexed: 02/08/2023]
Abstract
Neuroendocrine tumours belong to a heterogeneous family of neoplasms, originating in endocrine glands (such as the pituitary, parathyroid or the neuroendocrine adrenal glands), in endocrine islets (within the thyroid or pancreas) as well as in endocrine cells dispersed between exocrine cells throughout the digestive or respiratory tracts. The clinical behaviour of neuroendocrine tumours is variable; they may be functioning or not functioning, ranging from well-differentiated slow growing neuroendocrine tumours to poorly differentiated neuroendocrine tumours, which are highly aggressive malignant tumours. The development of somatostatin analogues as important diagnostic and treatment tools have revolutionised the clinical management of patients with neuroendocrine tumours. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with somatostatin analogues, tumour regression is rare. Development of new somatostatin analogues and new drug combination therapies should further improve the clinical management of these patients.
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Affiliation(s)
- Simona Grozinsky-Glasberg
- Department of Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary School of Medicine, University of London, London, UK
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Shibata M, Hisajima T, Nakano M, Goris RC, Funakoshi K. Morphological relationships between peptidergic nerve fibers and immunoglobulin A-producing lymphocytes in the mouse intestine. Brain Behav Immun 2008; 22:158-66. [PMID: 17931829 DOI: 10.1016/j.bbi.2007.08.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Revised: 08/10/2007] [Accepted: 08/17/2007] [Indexed: 12/11/2022] Open
Abstract
Immunoglobulin A (IgA) lymphocytes are present close to the nerve fibers in the lamina propria of the small intestine, and the administration of lipopolysaccharides (LPSs) increases the number of these cells and IgA secretion to the lumen. In the present study, we demonstrated that the nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) were close to the IgA lymphocytes in the mouse ileum lamina propria. Three hours after intraperitoneal administration of LPSs, IgA lymphocytes close to VIP nerve fibers, those close to basement membrane, and those close to both VIP nerve fibers and basement membrane were increased in number. Further, all IgA lymphocytes seen in the ileum lamina propria expressed the receptors for VIP, VIPR1, and VIPR2. Electron microscopy revealed that varicosities were in close apposition to the lymphocyte plasma membrane. The present study suggests that VIP/NPY/CGRP neurons in the submucosal plexus have a close anatomical relationship to IgA lymphocytes, playing a role in the secretion of IgA and intestinal fluid in response to stimulation by lipopolysaccharides, pathogens, or toxins.
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Affiliation(s)
- Maiko Shibata
- Department of Neuroanatomy, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
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Ikuta SI, Yasui C, Kawanaka M, Aihara T, Yoshie H, Yanagi H, Mitsunobu M, Sugihara A, Yamanaka N. Watery diarrhea, hypokalemia and achlorhydria syndrome due to an adrenal pheochromocytoma. World J Gastroenterol 2007; 13:4649-52. [PMID: 17729424 PMCID: PMC4611845 DOI: 10.3748/wjg.v13.i34.4649] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP) -producing tumor only rarely occurs in patients with nonpancreatic disease. A 49-year-old woman was referred for evaluation of a right adrenal tumor incidentally diagnosed by abdominal ultrasound during the investigation of chronic watery diarrhea. Laboratory findings showed hypokalemia and excessive production of VIP and catecholamines. After surgical resection of the tumor, diarrhea subsided and both electrolytes and affected hormone levels normalized. Immunohistochemical examination confirmed a diagnosis of pheochromocytoma, which contained VIP-positive ganglion-like cells. We herein present the clinical and histogenetic implications of this rare clinical entity, with literature review.
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Affiliation(s)
- Shin-ichi Ikuta
- Department of Surgery, Meiwa General Hospital, Agenaruo 4-31, Nishinomiya, Hyogo, Japan.
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Burleigh DE, Banks MR. Stimulation of intestinal secretion by vasoactive intestinal peptide and cholera toxin. Auton Neurosci 2007; 133:64-75. [PMID: 17023221 DOI: 10.1016/j.autneu.2006.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2006] [Accepted: 08/01/2006] [Indexed: 10/24/2022]
Affiliation(s)
- David E Burleigh
- Department of Adult and Paediatric Gastroenterology, The Wingate Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London E1 2AJ, United Kingdom.
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Anderson CMH, Thwaites DT. Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1). J Cell Physiol 2005; 204:604-13. [PMID: 15754324 DOI: 10.1002/jcp.20337] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
A H(+)-coupled amino acid transporter has been characterised functionally at the brush border membrane of the human intestinal cell line Caco-2. This carrier, hPAT1 (human Proton-coupled Amino acid Transporter 1) or SLC36A1, has been identified recently at the molecular level and hPAT1 protein is localised to the brush border membrane of human small intestine. hPAT1 transports both amino acids (e.g., beta-alanine) and therapeutic agents (e.g., D-cycloserine). In human Caco-2 cells, hPAT1 function (H(+)/amino acid symport) is associated with a decrease in intracellular pH (pH(i)), which selectively activates the Na(+)/H(+) exchanger NHE3, and thus maintains pH(i) and the driving force for hPAT1 function (the H(+) electrochemical gradient). This study provides the first evidence for regulation of hPAT1 function. Activation of the cAMP/protein kinase A pathway in Caco-2 cell monolayers either using pharmacological tools (forskolin, 8-br-cAMP, [(11,22,28)Ala]VIP) or physiological activators (the neuropeptides VIP and PACAP) inhibited hPAT1 function (beta-alanine uptake) at the apical membrane. Under conditions where NHE3 is inactive (the absence of Na(+), apical pH 5.5, the presence of the NHE3 inhibitor S1611) no regulation of beta-alanine uptake is observed. Forskolin and VIP inhibit pH(i) recovery (NHE3 function) from beta-alanine-induced intracellular acidification. Immunocytochemistry localises NHERF1 (NHE3 regulatory factor 1) to the apical portion of Caco-2 cells where it will interact with NHE3 and allow PKA-mediated phosphorylation of NHE3. In conclusion, we have shown that amino acid uptake via hPAT1 is inhibited by activators of the cAMP pathway indirectly through inhibition of NHE3 activity.
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Affiliation(s)
- Catriona M H Anderson
- Faculty of Medical Sciences, Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
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Karaki SI, Kuwahara A. Regulation of intestinal secretion involved in the interaction between neurotransmitters and prostaglandin E2. Neurogastroenterol Motil 2004; 16 Suppl 1:96-9. [PMID: 15066012 DOI: 10.1111/j.1743-3150.2004.00482.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In this short review, it will be described that neurotransmitter-induced secretion in the intestine may be influenced by the tissue level of prostaglandin E2 (PGE2). In the normal condition, vasoactive intestinal polypeptide (VIP) and acetylcholine (ACh) are the predominant neurotransmitters of secretomotor neurones. VIP and ACh activate distinct second messenger systems in epithelial cells, i.e. adenosine 3', 5'-cyclic monophosphate (cAMP) and calcium ion (Ca2+), respectively. An increase in intracellular cAMP induces a small amount of chloride (Cl-) secretion in epithelial cells, while simultaneous increases in intracellular Ca2+ and cAMP greatly enhances the cAMP-induced Cl- secretion. When the concentration of prostaglandins reaches a high level in the intestinal tissue substance P, which is a neurotransmitter of sensory neurones, can also induce a massive Cl- secretion by cross-potentiation of cAMP and Ca2+ in epithelial cells. In conclusion, it is considered that the concentration of tissue PGE2 may indicate tissue alert level, and when this level elevates, PGE2 enhances ACh and SP-induced Cl- secretion, thus mediating massive fluid secretion for host defence.
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Affiliation(s)
- S-I Karaki
- Laboratory of Physiology, Institute for Environmental Sciences, University of Shizuoka, Shizuoka, Japan
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Anderson CMH, Mendoza ME, Kennedy DJ, Raldua D, Thwaites DT. Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti-absorptive effect via the VPAC1 receptor in a human enterocyte-like cell line (Caco-2). Br J Pharmacol 2003; 138:564-73. [PMID: 12598410 PMCID: PMC1573691 DOI: 10.1038/sj.bjp.0705049] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
1. Optimal dipeptide and peptidomimetic drug transport across the intestinal mucosal surface is dependent upon the co-operative functional activity of the di/tripeptide transporter hPepT1 and the Na(+)/H(+) exchanger NHE3. The ability of the anti-absorptive enteric neuropeptide VIP (vasoactive intestinal peptide) to modulate dipeptide uptake was determined using human intestinal (Caco-2) epithelial cell monolayers. 2. Uptake of glycylsarcosine (Gly-Sar) across the apical membrane of Caco-2 cell monolayers is inhibited by basolateral exposure to either VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), or the VPAC(1) receptor agonist [(11,22,28)Ala]-VIP. Inhibition of Gly-Sar uptake is observed only in the presence of extracellular Na(+). Reverse-transcription polymerase chain reaction (RT-PCR) demonstrates that VPAC(1) mRNA is expressed in Caco-2 cells whereas VPAC(2) mRNA is not detected. 3. The VIP-induced inhibition of Gly-Sar uptake is abolished in the presence of the protein kinase A (PKA) inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl). 4. (22)Na(+) uptake across the apical membrane is inhibited by the selective NHE3 inhibitor S1611. Experiments with BCECF [2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein]-loaded Caco-2 cells demonstrate that VIP reduces the NHE3-dependent recovery of intracellular pH (pH(i)) after dipeptide-induced acidification. Western blot of Caco-2 cell protein demonstrates expression of the NHE regulatory factor NHERF1 (expression of which is thought to be required for PKA-mediated inhibition of NHE3). 5. VIP has no effect on Gly-Sar uptake in the presence of S1611 suggesting that VIP and S1611 both modulate dipeptide uptake via the same mechanism. 6. These observations demonstrate that VIP (and PACAP) modulate activity of the H(+)/dipeptide transporter hPepT1 in a Na(+)-dependent manner consistent with the modulation being indirect through inhibition of NHE3.
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Affiliation(s)
- Catriona M H Anderson
- School of Cell & Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH
| | - Maria E Mendoza
- School of Cell & Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH
| | - David J Kennedy
- School of Cell & Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH
| | - Demetrio Raldua
- School of Cell & Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH
| | - David T Thwaites
- School of Cell & Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH
- Author for correspondence:
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Matta MK, Prorok JJ, Trimpi HD, Sheets JA, Stasik JJ, Khubchandani IT. WDHA syndrome caused by pheochromocytoma: report of a case. Dis Colon Rectum 2001; 21:297-301. [PMID: 657943 DOI: 10.1007/bf02586708] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A case in which a pheochromocytoma secreted vasoactive intestinal peptide, causing WDHA syndrome, is reported. The patient, a 43-year-old woman, was seen because of intractable watery diarrhea, hypokalemia and weight loss. She was found to have a mass in the right adrenal area. Preoperatively, vasoactive intestinal peptide levels were elevated, and the diagnosis of WDHA syndrome was entertained. Exploratory laparotomy revealed a tumor of the right adrenal gland, measuring 15 x 15 cm, which was resected. Histologic examination revealed it to be a pheochromocytoma. Postoperatively, vasoactive intestinal peptide returned to normal. The patient had complete remission of symptoms, and has remained well since.
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Murphy MS, Sibal A, Mann JR. Persistent diarrhoea and occult vipomas in children. BMJ (CLINICAL RESEARCH ED.) 2000; 320:1524-6. [PMID: 10834901 PMCID: PMC1118108 DOI: 10.1136/bmj.320.7248.1524] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- M S Murphy
- Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham B4 6NH.
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Läuffer JM, Modlin IM, Hinoue T, Kidd M, Zhang T, Schmid SW, Tang LH. Pituitary adenylate cyclase-activating polypeptide modulates gastric enterochromaffin-like cell proliferation in rats. Gastroenterology 1999; 116:623-35. [PMID: 10029621 DOI: 10.1016/s0016-5085(99)70184-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Gastric carcinoids (types I and II) involve the transformation of naive enterochromaffin-like (ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia. In this study, we evaluated the effects of two related neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), on ECL cell proliferation and characterized the receptor subtype(s) and signal transduction pathways that mediate this effect. METHODS Purified rat ECL cells were analyzed in culture for DNA synthesis as measured by 24-hour 5-bromo-2-deoxyuridine (BrdU) uptake. Reverse-transcription polymerase chain reaction (RT-PCR) with gene-specific oligonucleotide primers was performed to characterize the PACAP/VIP receptor subtype(s). RESULTS PACAP/VIP neuropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold greater than control) than that at the maximal dose of gastrin (2.2-fold greater than control). PACAP-stimulated ECL cell proliferation (EC50, approximately 3 x 10(-)14 mol/L) was approximately 100-fold more potent than VIP (EC50, approximately 3x 10(-)12 mol/L). The stimulated BrdU uptake by both PACAP and VIP was competitively inhibited by PACAP-receptor antagonist (IC50, 10(-)9 mol/L, 3 x 10(-)9 mol/L, respectively) and VIP-receptor antagonist (IC50, 3 x 10(-)7 mol/L, 5 x 10(-)7 mol/L, respectively). RT-PCR identified the presence of the PACAP-specific but not PACAP/VIP receptor subtypes. The PACAP-stimulated BrdU uptake was inhibited (70%-80%) by inhibitors of adenosine 3',5'-cyclic monophosphate, phosphatidylinositol 3 kinase, and protein tyrosine kinase as well as mitogen-activated protein kinase. CONCLUSIONS PACAP/VIP-related peptides are more potent modulators of ECL cell proliferation than gastrin, and their effect is mediated by a PACAP-specific receptor whose activation is transduced by multiple intracellular messenger systems.
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Affiliation(s)
- J M Läuffer
- Gastric Pathobiology Research Group, Department of Surgery, Yale University School of Medicine and West Haven Veterans Administration Medical Center, New Haven, Connecticut, USA
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Newton M, Kamm MA, Soediono PO, Milner P, Burnham WR, Burnstock G. Oesophageal epithelial innervation in health and reflux oesophagitis. Gut 1999; 44:317-22. [PMID: 10026314 PMCID: PMC1727420 DOI: 10.1136/gut.44.3.317] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND The response of the oesophagus to refluxed gastric contents is likely to depend on intact neural mechanisms in the oesophageal mucosa. The epithelial innervation has not been systematically evaluated in health or reflux disease. AIMS To study oesophageal epithelial innervation in controls, and also inflamed and non-inflamed mucosa in patients with reflux oesophagitis and healed oesophagitis. PATIENTS Ten controls, nine patients with reflux oesophagitis, and five patients with healed oesophagitis. METHODS Oesophageal epithelial biopsy specimens were obtained at endoscopy. The distribution of the neuronal marker protein gene product 9.5 (PGP), and the neuropeptides calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), substance P (SP), and vasoactive intestinal peptide (VIP) were investigated by immunohistochemistry. Density of innervation was assessed by the proportion of papillae in each oesophageal epithelial biopsy specimen containing immunoreactive fibres (found in the subepithelium and epithelial papillae, but not penetrating the epithelium). RESULTS The proportion of papillae positive for PGP immunoreactive nerve fibres was significantly increased in inflamed tissue when compared with controls, and non-inflamed and healed tissue. There was also a significant increase in VIP immunoreactive fibres within epithelial papillae. Other neuropeptides showed no proportional changes in inflammation. CONCLUSIONS Epithelial biopsy specimens can be used to assess innervation in the oesophagus. The innervation of the oesophageal mucosa is not altered in non-inflamed tissue of patients with oesophagitis but alters in response to inflammation, where there is a selective increase (about three- to fourfold) in VIP containing nerves.
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Affiliation(s)
- M Newton
- Department of Physiology, St Mark's Hospital, Northwick Park, Watford Road, Harrow, Middlesex HA1 3UJ, UK
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Holliday ND, Cox HM. Modulation of chloride, potassium and bicarbonate transport by muscarinic receptors in a human adenocarcinoma cell line. Br J Pharmacol 1999; 126:269-79. [PMID: 10051145 PMCID: PMC1565781 DOI: 10.1038/sj.bjp.0702270] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1. Short-circuit current (I(SC)) responses to carbachol (CCh) were investigated in Colony 1 epithelia, a subpopulation of the HCA-7 adenocarcinoma cell line. In Krebs-Henseleit (KH) buffer, CCh responses consisted of three I(SC) components: an unusual rapid decrease (the 10 s spike) followed by an upward spike at 30 s and a slower transient increase (the 2 min peak). This response was not potentiated by forskolin; rather, CCh inhibited cyclic AMP-stimulated I(SC). 2. In HCO3- free buffer, the decrease in forskolin-elevated I(SC) after CCh was reduced, although the interactions between CCh and forskolin remained at best additive rather than synergistic. When Cl- anions were replaced by gluconate, both Ca2+- and cyclic AMP-mediated electrogenic responses were significantly inhibited. 3. Basolateral Ba2+ (1-10 mM) and 293B (10 microM) selectively inhibited forskolin stimulation of I(SC), without altering the effects of CCh. Under Ba2+- or 293B-treated conditions, CCh responses were potentiated by pretreatment with forskolin. 4. Basolateral charybdotoxin (50 nM) significantly increased the size of the 10 s spike of CCh responses in both KH and HCO3- free medium, without affecting the 2 min peak. The enhanced 10 s spike was inhibited by prior addition of 5 mM apical Ba2+. Charybdotoxin did not affect forskolin responses. 5. In epithelial layers prestimulated with forskolin, the muscarinic antagonists atropine and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, both at 100 nM) abolished subsequent 10 microM CCh responses. Following addition of p-fluoro hexahydro-sila-difenidol (pF-HHSiD, 10 microM) or pirenzepine (1 microM), qualitative changes in the CCh response time-profile also indicated a rightward shift of the agonist concentration-response curve; however, 1 microM gallamine had no effect. These results suggest that a single M3-like receptor subtype mediates the secretory response to CCh. 6. It is concluded that CCh and forskolin activate discrete populations of basolateral K+ channels gated by either Ca2+ or cyclic AMP, but that the Cl- permeability of the apical membrane may limit their combined effects on electrogenic Cl- secretion. In addition, CCh activates a Ba2+-sensitive apical K+ conductance leading to electrogenic K+ transport. Both agents may also modulate HCO3- secretion through a mechanism at least partially dependent on carbonic anhydrase.
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Affiliation(s)
- Nicholas D Holliday
- Division of Pharmacology & Therapeutics, GKT, St. Thomas's Medical School, Lambeth Palace Road, London SE1 7EH
| | - Helen M Cox
- Division of Pharmacology & Therapeutics, GKT, St. Thomas's Medical School, Lambeth Palace Road, London SE1 7EH
- Author for correspondence:
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Höckerfelt U, Hansson M, Gulbenkian S, Franzén L, Henriksson R, Forsgren S. Binding sites for VIP in the reorganizing mucosa of the irradiated bowel. Ann N Y Acad Sci 1998; 865:344-52. [PMID: 9928028 DOI: 10.1111/j.1749-6632.1998.tb11194.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Rats were given radiotherapy (total dose 30 Gy) over the abdomen. Seven days later specimens of the duodenum were prepared for in vitro receptor autoradiography using the radioligand [125I]VIP. The autoradiograms were quantitatively analyzed using a computer system. Histological examination revealed that a very marked reorganization of the mucosa had occurred in response to irradiation. Using receptor autoradiography, we found [125I]VIP-specific binding sites in the reorganizing mucosa, except where denudation had occurred. Such binding sites also occurred in the smooth muscle layer of the duodenal wall. The observations suggest that VIP has profound effects in radiation-induced enteropathy.
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Affiliation(s)
- T E Bowling
- Department of Gastroenterology and Nutrition, Central Middlesex Hospital, London, UK
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Affiliation(s)
- S C Martin
- Department of Physiology, University of Rochester, School of Medicine and Dentistry, New York 14642, USA
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Bowling TE, Silk DB. Hormonal response to enteral feeding and the possiblerole of peptide YY in pathogenesis of enteral feeding-related diarrhoea. Clin Nutr 1996; 15:307-10. [PMID: 16844062 DOI: 10.1016/s0261-5614(96)80005-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Diarrhoea is a common complication of enteral feeding. Previous studies have demonstrated a secretion of water and electrolytes in the ascending colon during intragastric but not intraduodenal enteral feeding. The cause of this secretion is likely to be neurohumoral in origin. This study was designed to examine the hormonal responses to enteral feeding. In vivo segmental colonic perfusion studies were undertaken. Before and at hourly intervals during these studies serum was taken for estimations of neurotensin (NT), pancreatic glucagon (PG), peptide YY (PYY) and vasoactive intestinal polypeptide (VIP). During fasting there was a median ascending colonic absorption of water in all groups. During feeding there was a net secretion in the ascending colon in both gastric groups and in the high load duodenal group, but not in the low load duodenal group. During these studies the PYY levels remained unchanged from fasting in the low and high load gastric groups. In the low and high load duodenal groups the PYY levels increased. The NT levels increased only in the high load duodenal group. There were no other changes in NT or in PG or VIP levels either between fasting and feeding, or between the gastric and duodenal groups. PYY is known to stimulate intestinal absorption. The absence of a rise during intragastric feeding may be important in the underlying mechanisms of enteral feeding-induced colonic secretion and hence enteral feeding-related diarrhoea.
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Affiliation(s)
- T E Bowling
- Department of Gastroenterology and Nutrition, Central Middlesex Hospital NHS Trust, London NW10 7NS, UK
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Hyun HS, Onaga T, Mineo H, Kato S. Comparison of the effects of secretagogues on the net movement of electrolyte and glucose absorption in the proximal and middle small intestine of sheep. J Anim Physiol Anim Nutr (Berl) 1996. [DOI: 10.1111/j.1439-0396.1996.tb00686.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Trischitta F, Denaro MG, Faggio C, Mandolfino M, Schettino T. Different effects of cGMP and cAMP in the intestine of the European eel, Anguilla anguilla. J Comp Physiol B 1996; 166:30-6. [PMID: 8621839 DOI: 10.1007/bf00264636] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The regulation of salt absorption in the sea water eel intestine was studied by evaluating the effects of theophylline, 8 Br cyclic adenosine monophosphate, 8 Br cyclic guanosine monophosphate, atriopeptin III, porcine vasoactive intestinal peptide and prostaglandin E1 on the short-circuit current, the transepithelial voltage difference and conductance and on the dilution potentials. It was shown that theophylline increased the transepithelial conductance and reduced the magnitude of the dilution potentials, indicating that the drug increases the anion conductance of the tight junctions. In addition its inhibitory effect on short-circuit current and transepithelial voltage difference suggests that theophylline also affects the transcellular transport mechanisms. It was shown that 8 Br cyclic guanosine monophosphate and 8 Br cyclic adenosine monophosphate affect transcellular mechanisms underlying C1- transport since both compounds reduced short-circuit current and transepithelial voltage difference; however, cyclic adenosine monophosphate is less effective since unlike cyclic guanosine monophosphate, even at maximal concentration, it was not able to completely abolish transepithelial voltage difference and short-circuit current. The effects of cyclic guanosine monophosphate and cyclic adenosine monophosphate were not additive even if cyclic guanosine monophosphate may produce further inhibition of ion transport in 8 Br cyclic adenosine monophosphate-treated tissues. In addition, cyclic guanosine monophosphate but not cyclic adenosine monophosphate reduced the magnitude of the dilution potentials, suggesting that cyclic guanosine monophosphate acts also on the paracellular pathway. Rat atriopeptin III, a peptide known to increase cyclic guanosine monophosphate cellular levels, behaved like 8 Br cyclic guanosine monophosphate since it lowered the dilution potentials and reduced short-circuit current and transepithelial voltage difference to near zero values, suggesting that the hormone modulates both paracellular and transcellular transport mechanisms, probably acting on the Na-K-2Cl cotransport. Agents acting via cyclic adenosine monophosphate, like porcine Basoactive intenstinal peptide and prostaglandin, behaved like 8 Br cyclic adenosine monophosphate. They were less effective in inhibiting ion transport and did not interfere with the paracellular pathway.
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Affiliation(s)
- F Trischitta
- Instituto di Fisiologia Generale, Università di Messina, Italy
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