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Modares NF, Hendrikse LD, Smith LK, Paul MS, Haight J, Luo P, Liu S, Fortin J, Tong FK, Wakeham AC, Jafari SM, Zheng C, Buckland M, Flick R, Silvester J, Berger T, Ketela T, Helke S, Foffi E, Niavarani R, Mcwilliam R, Saunders ME, Colonna I, David BA, Rastogi T, Lee WY, Kubes P, Mak TW. B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8 + T cell function. Immunity 2025; 58:1201-1216.e7. [PMID: 40286791 DOI: 10.1016/j.immuni.2025.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/20/2024] [Accepted: 04/02/2025] [Indexed: 04/29/2025]
Abstract
Liver regeneration (LR) is essential for recovery from acute trauma, cancer surgery, or transplantation. Neurotransmitters such as acetylcholine (ACh) play a role in LR by stimulating immune cells and augmenting hepatocyte proliferation, but the source of this ACh remains unclear. Here, we demonstrated that B cells expressing choline acetyltransferase (ChAT), which synthesizes ACh, were required for LR. Mice lacking ChAT+ B cells subjected to partial hepatectomy (PHX) displayed greater mortality due to failed LR. Kupffer cells and hepatic CD8+ T cells expressed the α7 nicotinic ACh receptor (nAChR), and LR was disrupted in mice lacking α7 nAChR. Mechanistically, B cell-derived ACh signaled through α7 nAChR to positively regulate the function of regenerative Kupffer cells and to control the activation of hepatic CD8+ T cells to curtail harmful interferon-gamma (IFNγ) production. Our work offers insights into LR mechanisms that may point to therapies for liver damage.
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Affiliation(s)
| | - Liam D Hendrikse
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Logan K Smith
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Michael St Paul
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Jillian Haight
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ping Luo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Shaofeng Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Jerome Fortin
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Frances K Tong
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Andrew C Wakeham
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | - Chunxing Zheng
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
| | - Mackenzie Buckland
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Robert Flick
- Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Jennifer Silvester
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Thorsten Berger
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Troy Ketela
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Simone Helke
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Erica Foffi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Raheleh Niavarani
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ryan Mcwilliam
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Mary E Saunders
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Isabelle Colonna
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Bruna Araujo David
- Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Tashi Rastogi
- Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Woo-Yong Lee
- Department of Biomedical and Molecular Science, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Paul Kubes
- Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biomedical and Molecular Science, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Tak W Mak
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China; Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
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2
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Mravec B, Szantova M. Liver Neurobiology: Regulation of Liver Functions by the Nervous System. Semin Liver Dis 2025. [PMID: 40239709 DOI: 10.1055/a-2562-2000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
The nervous system plays an important role in the regulation of liver functions during physiological as well as pathological conditions. This regulatory effect is based on the processing of signals transmitted to the brain by sensory nerves innervating the liver tissue and other visceral organs and by humoral pathways transmitting signals from peripheral tissues and organs. Based on these signals, the brain modulates metabolism, detoxification, regeneration, repair, inflammation, and other processes occurring in the liver. The nervous system thus determines the functional and morphological characteristics of the liver. Liver innervation also mediates the influence of psychosocial factors on liver functions. The aim of this review is to describe complexity of bidirectional interactions between the brain and liver and to characterize the mechanisms and pathways through which the nervous system influences liver function during physiological conditions and maintains liver and systemic homeostasis.
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Affiliation(s)
- Boris Mravec
- Department of Physiology Faculty of Medicine, Comenius University, Bratislava, Slovakia
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maria Szantova
- 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
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Haider SA, Sharif R, Sharif F. Multi-Organ Denervation: The Past, Present and Future. J Clin Med 2025; 14:2746. [PMID: 40283576 PMCID: PMC12027612 DOI: 10.3390/jcm14082746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/04/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025] Open
Abstract
The sympathetic division of the autonomic nervous system plays a crucial role in maintaining homeostasis, but its overactivity is implicated in various pathological conditions, including hypertension, hyperglycaemia, heart failure, and rheumatoid arthritis. Traditional pharmacotherapies often face limitations such as side effects and poor patient adherence, thus prompting the exploration of device-based multi-organ denervation as a therapeutic strategy. Crucially, this procedure can potentially offer therapeutic benefits throughout the 24 h circadian cycle, described as an "always-on" effect independent of medication compliance and pharmacokinetics. In this comprehensive review, we evaluate the evidence behind targeted multi-organ sympathetic denervation by considering the anatomy and function of the autonomic nervous system, examining the evidence linking sympathetic nervous system overactivity to various cardiometabolic and inflammatory conditions and exploring denervation studies within the literature. So far, renal denervation, developed in 2010, has shown promise in reducing blood pressure and may have broader applications for conditions including arrhythmias, glucose metabolism disorders, heart failure, chronic kidney disease and obstructive sleep apnoea. We review the existing literature surrounding the denervation of other organ systems including the hepatic and splenic arteries, as well as the pulmonary artery and carotid body, which may provide additional physiological benefits and enhance therapeutic effects if carried out simultaneously. Furthermore, we highlight the challenges and future directions for implementing multi-organ sympathetic ablation, emphasising the need for further clinical trials to establish optimal procedural technique, efficacy and safety.
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Affiliation(s)
- Syedah Aleena Haider
- Department of Medicine, University of Galway, H91 TK33 Galway, Ireland
- Department of Cardiology, University Hospital Galway, H91 YR71 Galway, Ireland;
| | - Ruth Sharif
- Department of Cardiology, University Hospital Galway, H91 YR71 Galway, Ireland;
| | - Faisal Sharif
- Department of Medicine, University of Galway, H91 TK33 Galway, Ireland
- Department of Cardiology, University Hospital Galway, H91 YR71 Galway, Ireland;
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Kawana Y, Imai J, Morizawa YM, Ikoma Y, Kohata M, Komamura H, Sato T, Izumi T, Yamamoto J, Endo A, Sugawara H, Kubo H, Hosaka S, Munakata Y, Asai Y, Kodama S, Takahashi K, Kaneko K, Sawada S, Yamada T, Ito A, Niizuma K, Tominaga T, Yamanaka A, Matsui K, Katagiri H. Optogenetic stimulation of vagal nerves for enhanced glucose-stimulated insulin secretion and β cell proliferation. Nat Biomed Eng 2024; 8:808-822. [PMID: 37945752 PMCID: PMC11310082 DOI: 10.1038/s41551-023-01113-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 09/26/2023] [Indexed: 11/12/2023]
Abstract
The enhancement of insulin secretion and of the proliferation of pancreatic β cells are promising therapeutic options for diabetes. Signals from the vagal nerve regulate both processes, yet the effectiveness of stimulating the nerve is unclear, owing to a lack of techniques for doing it so selectively and prolongedly. Here we report two optogenetic methods for vagal-nerve stimulation that led to enhanced glucose-stimulated insulin secretion and to β cell proliferation in mice expressing choline acetyltransferase-channelrhodopsin 2. One method involves subdiaphragmatic implantation of an optical fibre for the photostimulation of cholinergic neurons expressing a blue-light-sensitive opsin. The other method, which suppressed streptozotocin-induced hyperglycaemia in the mice, involves the selective activation of vagal fibres by placing blue-light-emitting lanthanide microparticles in the pancreatic ducts of opsin-expressing mice, followed by near-infrared illumination. The two methods show that signals from the vagal nerve, especially from nerve fibres innervating the pancreas, are sufficient to regulate insulin secretion and β cell proliferation.
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Affiliation(s)
- Yohei Kawana
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Yosuke M Morizawa
- Super-network Brain Physiology, Tohoku University Graduate School of Life Sciences, Sendai, Japan
| | - Yoko Ikoma
- Super-network Brain Physiology, Tohoku University Graduate School of Life Sciences, Sendai, Japan
| | - Masato Kohata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroshi Komamura
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshihiro Sato
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junpei Yamamoto
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Endo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroto Sugawara
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Haremaru Kubo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | - Yuichiro Munakata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shojiro Sawada
- Division of Metabolism and Diabetes, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akira Ito
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kuniyasu Niizuma
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Neurosurgical Engineering and Translational Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Neurosurgical Engineering and Translational Neuroscience, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Teiji Tominaga
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akihiro Yamanaka
- Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Ko Matsui
- Super-network Brain Physiology, Tohoku University Graduate School of Life Sciences, Sendai, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
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Chicherova I, Hernandez C, Mann F, Zoulim F, Parent R. Axon guidance molecules in liver pathology: Journeys on a damaged passport. Liver Int 2023; 43:1850-1864. [PMID: 37402699 DOI: 10.1111/liv.15662] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/09/2023] [Accepted: 06/18/2023] [Indexed: 07/06/2023]
Abstract
BACKGROUND AND AIMS The liver is an innervated organ that develops a variety of chronic liver disease (CLD). Axon guidance cues (AGCs), of which ephrins, netrins, semaphorins and slits are the main representative, are secreted or membrane-bound proteins that can attract or repel axons through interactions with their growth cones that contain receptors recognizing these messengers. While fundamentally implicated in the physiological development of the nervous system, the expression of AGCs can also be reinduced under acute or chronic conditions, such as CLD, that necessitate redeployment of neural networks. METHODS This review considers the ad hoc literature through the neglected canonical neural function of these proteins that is also applicable to the diseased liver (and not solely their observed parenchymal impact). RESULTS AGCs impact fibrosis regulation, immune functions, viral/host interactions, angiogenesis, and cell growth, both at the CLD and HCC levels. Special attention has been paid to distinguishing correlative and causal data in such datasets in order to streamline data interpretation. While hepatic mechanistic insights are to date limited, bioinformatic evidence for the identification of AGCs mRNAs positive cells, protein expression, quantitative regulation, and prognostic data have been provided. Liver-pertinent clinical studies based on the US Clinical Trials database are listed. Future research directions derived from AGC targeting are proposed. CONCLUSION This review highlights frequent implication of AGCs in CLD, linking traits of liver disorders and the local autonomic nervous system. Such data should contribute to diversifying current parameters of patient stratification and our understanding of CLD.
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Affiliation(s)
- Ievgeniia Chicherova
- Cancer Research Centre of Lyon, Inserm Unit 1052, CNRS UMR 5286, University of Lyon, Léon Bérard Anticancer Centre, Lyon, France
| | - Charlotte Hernandez
- Cancer Research Centre of Lyon, Inserm Unit 1052, CNRS UMR 5286, University of Lyon, Léon Bérard Anticancer Centre, Lyon, France
| | - Fanny Mann
- Aix-Marseille University, CNRS, IBDM, Marseille, France
| | - Fabien Zoulim
- Cancer Research Centre of Lyon, Inserm Unit 1052, CNRS UMR 5286, University of Lyon, Léon Bérard Anticancer Centre, Lyon, France
- Hepatogastroenterology Service, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France
| | - Romain Parent
- Cancer Research Centre of Lyon, Inserm Unit 1052, CNRS UMR 5286, University of Lyon, Léon Bérard Anticancer Centre, Lyon, France
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Huang Y, He Z, Manyande A, Feng M, Xiang H. Nerve regeneration in transplanted organs and tracer imaging studies: A review. Front Bioeng Biotechnol 2022; 10:966138. [PMID: 36051591 PMCID: PMC9424764 DOI: 10.3389/fbioe.2022.966138] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
The technique of organ transplantation is well established and after transplantation the patient might be faced with the problem of nerve regeneration of the transplanted organ. Transplanted organs are innervated by the sympathetic, parasympathetic, and visceral sensory plexuses, but there is a lack of clarity regarding the neural influences on the heart, liver and kidneys and the mechanisms of their innervation. Although there has been considerable recent work exploring the potential mechanisms of nerve regeneration in organ transplantation, there remains much that is unknown about the heterogeneity and individual variability in the reinnervation of organ transplantation. The widespread availability of radioactive nerve tracers has also made a significant contribution to organ transplantation and has helped to investigate nerve recovery after transplantation, as well as providing a direction for future organ transplantation research. In this review we focused on neural tracer imaging techniques in humans and provide some conceptual insights into theories that can effectively support our choice of radionuclide tracers. This also facilitates the development of nuclear medicine techniques and promotes the development of modern medical technologies and computer tools. We described the knowledge of neural regeneration after heart transplantation, liver transplantation and kidney transplantation and apply them to various imaging techniques to quantify the uptake of radionuclide tracers to assess the prognosis of organ transplantation. We noted that the aim of this review is both to provide clinicians and nuclear medicine researchers with theories and insights into nerve regeneration in organ transplantation and to advance imaging techniques and radiotracers as a major step forward in clinical research. Moreover, we aimed to further promote the clinical and research applications of imaging techniques and provide clinicians and research technology developers with the theory and knowledge of the nerve.
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Affiliation(s)
- Yan Huang
- Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Interventional Therapy, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zhigang He
- Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Anne Manyande
- School of Human and Social Sciences, University of West London, London, United Kingdom
| | - Maohui Feng
- Department of Gastrointestinal Surgery, Wuhan Peritoneal Cancer Clinical Medical Research Center, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
- *Correspondence: Maohui Feng, ; Hongbing Xiang,
| | - Hongbing Xiang
- Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Maohui Feng, ; Hongbing Xiang,
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Gama JFG, Cardoso LMDF, Bisaggio RDC, Lagrota-Candido J, Henriques-Pons A, Alves LA. Immunological Tolerance in Liver Transplant Recipients: Putative Involvement of Neuroendocrine-Immune Interactions. Cells 2022; 11:cells11152327. [PMID: 35954171 PMCID: PMC9367574 DOI: 10.3390/cells11152327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/20/2022] [Accepted: 06/29/2022] [Indexed: 02/04/2023] Open
Abstract
The transplantation world changed significantly following the introduction of immunosuppressants, with millions of people saved. Several physicians have noted that liver recipients that do not take their medication for different reasons became tolerant regarding kidney, heart, and lung transplantations at higher frequencies. Most studies have attempted to explain this phenomenon through unique immunological mechanisms and the fact that the hepatic environment is continuously exposed to high levels of pathogen-associated molecular patterns (PAMPs) or non-pathogenic microorganism-associated molecular patterns (MAMPs) from commensal flora. These components are highly inflammatory in the periphery but tolerated in the liver as part of the normal components that arrive via the hepatic portal vein. These immunological mechanisms are discussed herein based on current evidence, although we hypothesize the participation of neuroendocrine-immune pathways, which have played a relevant role in autoimmune diseases. Cells found in the liver present receptors for several cytokines, hormones, peptides, and neurotransmitters that would allow for system crosstalk. Furthermore, the liver is innervated by the autonomic system and may, thus, be influenced by the parasympathetic and sympathetic systems. This review therefore seeks to discuss classical immunological hepatic tolerance mechanisms and hypothesizes the possible participation of the neuroendocrine-immune system based on the current literature.
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Affiliation(s)
- Jaciara Fernanda Gomes Gama
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazil Avenue, 4365-Manguinhos, Rio de Janeiro 21045-900, Brazil; (J.F.G.G.); (L.M.d.F.C.)
- Laboratory of Immunopathology, Department of Immunobiology, Biology Institute, Federal Fluminense University (UFF), Gragoatá Bl-M Campus, Niterói 24210-200, Brazil;
| | - Liana Monteiro da Fonseca Cardoso
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazil Avenue, 4365-Manguinhos, Rio de Janeiro 21045-900, Brazil; (J.F.G.G.); (L.M.d.F.C.)
| | - Rodrigo da Cunha Bisaggio
- Department of Biotechnology, Federal Institute of Rio de Janeiro (IFRJ), Maracanã, Rio de Janeiro 20270-021, Brazil;
| | - Jussara Lagrota-Candido
- Laboratory of Immunopathology, Department of Immunobiology, Biology Institute, Federal Fluminense University (UFF), Gragoatá Bl-M Campus, Niterói 24210-200, Brazil;
| | - Andrea Henriques-Pons
- Laboratory of Innovations in Therapies, Education, and Bioproducts, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-361, Brazil;
| | - Luiz A. Alves
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazil Avenue, 4365-Manguinhos, Rio de Janeiro 21045-900, Brazil; (J.F.G.G.); (L.M.d.F.C.)
- Correspondence: or ; Tel.: +55-(21)-2562-1816 (ext. 1841)
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Miller BM, Oderberg IM, Goessling W. Hepatic Nervous System in Development, Regeneration, and Disease. Hepatology 2021; 74:3513-3522. [PMID: 34256416 PMCID: PMC8639644 DOI: 10.1002/hep.32055] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/10/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022]
Abstract
The liver is innervated by autonomic and sensory fibers of the sympathetic and parasympathetic nervous systems that regulate liver function, regeneration, and disease. Although the importance of the hepatic nervous system in maintaining and restoring liver homeostasis is increasingly appreciated, much remains unknown about the specific mechanisms by which hepatic nerves both influence and are influenced by liver diseases. While recent work has begun to illuminate the developmental mechanisms underlying recruitment of nerves to the liver, evolutionary differences contributing to species-specific patterns of hepatic innervation remain elusive. In this review, we summarize current knowledge on the development of the hepatic nervous system and its role in liver regeneration and disease. We also highlight areas in which further investigation would greatly enhance our understanding of the evolution and function of liver innervation.
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Affiliation(s)
- Bess M. Miller
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Isaac M. Oderberg
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Wolfram Goessling
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.,Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.,Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, 02139, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, 02114, USA.,corresponding author: Contact Information: Wolfram Goessling, MD, PhD, Wang 539B, 55 Fruit Street, Boston, MA 02114,
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9
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Colonna CH, Henriquez AR, House JS, Motsinger-Reif AA, Alewel DI, Fisher A, Ren H, Snow SJ, Schladweiler MC, Miller DB, Miller CN, Kodavanti PRS, Kodavanti UP. The Role of Hepatic Vagal Tone in Ozone-Induced Metabolic Dysfunction in the Liver. Toxicol Sci 2021; 181:229-245. [PMID: 33662111 DOI: 10.1093/toxsci/kfab025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Air pollution has been associated with metabolic diseases and hepatic steatosis-like changes. We have shown that ozone alters liver gene expression for metabolic processes through neuroendocrine activation. This study aimed to further characterize ozone-induced changes and to determine the impact of hepatic vagotomy (HV) which reduces parasympathetic influence. Twelve-week-old male Wistar-Kyoto rats underwent HV or sham surgery 5-6 days before air or ozone exposure (0 or 1 ppm; 4 h/day for 1 or 2 days). Ozone-induced lung injury, hyperglycemia, glucose intolerance, and increases in circulating cholesterol, triglycerides, and leptin were similar in rats with HV and sham surgery. However, decreases in circulating insulin and increased HDL and LDL were observed only in ozone-exposed HV rats. Ozone exposure resulted in changed liver gene expression in both sham and HV rats (sham > HV), however, HV did not change expression in air-exposed rats. Upstream target analysis revealed that ozone-induced transcriptomic changes were similar to responses induced by glucocorticoid-mediated processes in both sham and HV rats. The directionality of ozone-induced changes reflecting cellular response to stress, metabolic pathways, and immune surveillance was similar in sham and HV rats. However, pathways regulating cell-cycle, regeneration, proliferation, cell growth, and survival were enriched by ozone in a directionally opposing manner between sham and HV rats. In conclusion, parasympathetic innervation modulated ozone-induced liver transcriptional responses for cell growth and regeneration without affecting stress-mediated metabolic changes. Thus, impaired neuroendocrine axes and parasympathetic innervation could collectively contribute to adverse effects of air pollutants on the liver.
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Affiliation(s)
- Catherine H Colonna
- Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711
| | - Andres R Henriquez
- Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711
| | - John S House
- Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - Alison A Motsinger-Reif
- Division of Intramural Research, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - Devin I Alewel
- Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711
| | - Anna Fisher
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
| | - Hongzu Ren
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
| | - Samantha J Snow
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
| | - Mette C Schladweiler
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
| | - Desinia B Miller
- Curriculum in Toxicology and Environmental Medicine, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Colette N Miller
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
| | - Prasada Rao S Kodavanti
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
| | - Urmila P Kodavanti
- Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
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10
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Imai J, Katagiri H. Regulation of systemic metabolism by the autonomic nervous system consisting of afferent and efferent innervation. Int Immunol 2021; 34:67-79. [PMID: 33982088 DOI: 10.1093/intimm/dxab023] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/10/2021] [Indexed: 12/18/2022] Open
Abstract
Autonomic nerves, sympathetic and parasympathetic, innervate organs and modulate their functions. It has become evident that afferent and efferent signals of the autonomic nervous system play important roles in regulating systemic metabolism, thereby maintaining homeostasis at the whole-body level. Vagal afferent nerves receive signals, such as nutrients and hormones, from the peripheral organs/tissues including the gastrointestinal tract and adipose tissue then transmit these signals to the hypothalamus, thereby regulating feeding behavior. In addition to roles in controlling appetite, areas in the hypothalamus serves as regulatory centers of both sympathetic and parasympathetic efferent fibers. These efferent innervations regulate the functions of peripheral organs/tissues, such as pancreatic islets, adipose tissues and the liver, which play roles in metabolic regulation. Furthermore, recent evidence has unraveled the metabolic regulatory systems governed by autonomic nerve circuits. In these systems, afferent nerves transmit metabolic information from peripheral organs to the central nervous system (CNS) and the CNS thereby regulates the organ functions through the efferent fibers of autonomic nerves. Thus, the autonomic nervous system regulates the homeostasis of systemic metabolism, and both afferent and efferent fibers play critical roles in its regulation. In addition, several lines of evidence demonstrate the roles of the autonomic nervous system in regulating and dysregulating the immune system. This review introduces variety of neuron-mediated inter-organ cross-talk systems and organizes the current knowledge of autonomic control/coordination of systemic metabolism, focusing especially on a liver-brain-pancreatic β-cell autonomic nerve circuit, as well as highlighting the potential importance of connections with the neuronal and immune systems.
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Affiliation(s)
- Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
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11
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Carnagarin R, Tan K, Adams L, Matthews VB, Kiuchi MG, Marisol Lugo Gavidia L, Lambert GW, Lambert EA, Herat LY, Schlaich MP. Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)-A Condition Associated with Heightened Sympathetic Activation. Int J Mol Sci 2021; 22:ijms22084241. [PMID: 33921881 PMCID: PMC8073135 DOI: 10.3390/ijms22084241] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.
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Affiliation(s)
- Revathy Carnagarin
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Kearney Tan
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Leon Adams
- Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6009, Australia;
| | - Vance B. Matthews
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Marcio G. Kiuchi
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Leslie Marisol Lugo Gavidia
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Gavin W. Lambert
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (G.W.L.); (E.A.L.)
- Human Neurotransmitter Lab, Melbourne, VIC 3004, Australia
| | - Elisabeth A. Lambert
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (G.W.L.); (E.A.L.)
- Human Neurotransmitter Lab, Melbourne, VIC 3004, Australia
| | - Lakshini Y. Herat
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Markus P. Schlaich
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
- Neurovascular Hypertension and Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA 6000, Australia
- Correspondence: ; Tel.: +61-8-9224-0382; Fax: +61-8-9224-0374
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12
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Pattanayak S, Acharya R, Mishra N, Kumar A, Bose P, Pattnaik A, Mukhopadhyay K, Sunita P. Naringin, a natural flavonone glycoside attenuates N-nitrosodiethylamine- induced hepatocellular carcinoma in sprague-dawley rats. Pharmacogn Mag 2021. [DOI: 10.4103/pm.pm_94_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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13
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Imai J. Regulation of Adaptive Cell Proliferation by Vagal Nerve Signals for Maintenance of Whole-Body Homeostasis: Potential Therapeutic Target for Insulin-Deficient Diabetes. TOHOKU J EXP MED 2021; 254:245-252. [PMID: 34373421 DOI: 10.1620/tjem.254.245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In insulin-resistant states such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. Failure of this β-cells proliferative response leads to the development of diabetes. On the other hand, when organs are damaged, cells proliferate to repair the organs. Therefore, these proliferations are compensatory mechanisms aimed at maintaining whole-body homeostasis. We previously discovered vagal signal-mediated systems regulating adaptive proliferation of β-cells and hepatocytes. Neuron-mediated liver-β-cell inter-organ crosstalk is involved in promotion of β-cell proliferation during obesity, and in this system, vagal signals directly stimulate β-cell proliferation. Meanwhile, in the liver, the multi-step mechanisms whereby vagal nerve signals activate hepatic resident macrophages are involved in hepatocyte proliferation after severe injury. Diabetes mellitus develops on the pathological basis of insufficient insulin action. Insulin action insufficiency is attributable to insulin resistance, i.e., the failure of insulin to exert sufficient effects, and/or to impairment of insulin secretion. Impairment of insulin secretion is attributable not only to the β-cell dysfunction but also to functional β-cell mass reduction. In this regard, there are already therapeutic options to increase insulin secretion from residual β-cells, such as sulfonyl urea and incretin-related drugs. In contrast, there are as yet no applicable therapeutic strategies to increase functional β-cell mass in vivo. Therefore, we have conducted the basic investigations to tackle this issue based on the discovery of neuron-mediated liver-β-cell inter-organ crosstalk. This review introduces vagal signal-mediated regulatory systems of adaptive cell proliferation in vivo and efforts to develop cell-increasing therapies based on vagal nerve-mediated cell proliferation.
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Affiliation(s)
- Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine
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14
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Chen X, Zhao C, Zhang C, Li Q, Chen J, Cheng L, Zhou J, Su X, Song Y. Vagal-α7nAChR signaling promotes lung stem cells regeneration via fibroblast growth factor 10 during lung injury repair. Stem Cell Res Ther 2020; 11:230. [PMID: 32522255 PMCID: PMC7288553 DOI: 10.1186/s13287-020-01757-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/19/2020] [Accepted: 06/01/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Proliferation and transdifferentiation of lung stem cells (LSCs) could promote lung injury repair. The distal airways of the lung are innervated by the vagus nerve. Vagal-alpha7 nicotinic acetylcholine receptor (α7nAChR) signaling plays a key role in regulating lung infection and inflammation; however, whether this pathway could regulate LSCs remains unknown. METHODS LSCs (Sca1+CD45-CD31- cells) were isolated and characterized according to a previously published protocol. α7nAChR knockout mice and wild-type littermates were intratracheally challenged with lipopolysaccharide (LPS) to induce lung injury. A cervical vagotomy was performed to study the regulatory effect of the vagus nerve on LSCs-mediated lung repair. α7nAChR agonist or fibroblast growth factor 10 (FGF10) was intratracheally delivered to mice. A single-cell suspension of lung cells was analyzed by flow cytometry. Lung tissues were collected for histology, quantitative real-time polymerase chain reaction (RT-PCR), and immunohistochemistry. RESULTS We found that LSCs maintained multilineage differentiation ability and transdifferentiated into alveolar epithelial type II cells (AEC2) following FGF10 stimulation in vitro. Vagotomy or α7nAChR deficiency reduced lung Ki67+ LSCs expansion and hampered the resolution of LPS-induced lung injury. Vagotomy or α7nAChR deficiency decreased lung FGF10 expression and the number of AEC2. The α7nAChR agonist-GTS-21 reversed the reduction of FGF10 expression in the lungs, as well as the number of Ki67+ cells, LSCs, Ki67+ LSCs, and AEC2 in LPS-challenged vagotomized mice. Supplementation with FGF10 counteracted the loss of Ki67+ LSCs and AEC2 in LPS-challenged α7nAChR knockout mice. CONCLUSIONS The vagus nerve deploys α7nAChR to enhance LSCs proliferation and transdifferentiation and promote lung repair in an FGF10-dependent manner during LPS-induced lung injury.
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Affiliation(s)
- Xiaoyan Chen
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University and Shanghai Respiratory Research Institute, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Caiqi Zhao
- Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China
| | - Cuiping Zhang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University and Shanghai Respiratory Research Institute, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Qingmei Li
- Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China
| | - Jie Chen
- Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China
| | - Lianping Cheng
- Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China
| | - Jian Zhou
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University and Shanghai Respiratory Research Institute, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xiao Su
- Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China.
| | - Yuanlin Song
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University and Shanghai Respiratory Research Institute, 180 Fenglin Road, Shanghai, 200032, People's Republic of China. .,Department of Pulmonary Medicine, Zhongshan Hospital, Qingpu Branch, Fudan University, Shanghai, People's Republic of China. .,National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
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15
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Bose P, Siddique MUM, Acharya R, Jayaprakash V, Sinha BN, Lapenna A, Pattanayak SP. Quinazolinone derivative BNUA-3 ameliorated [NDEA+2-AAF]-induced liver carcinogenesis in SD rats by modulating AhR-CYP1B1-Nrf2-Keap1 pathway. Clin Exp Pharmacol Physiol 2019; 47:143-157. [PMID: 31563143 DOI: 10.1111/1440-1681.13184] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/23/2019] [Accepted: 09/23/2019] [Indexed: 12/13/2022]
Abstract
Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species-mediated stress alter different molecular signalling pathways and gene expressions. Quinazoline derivatives are recognized for their diversified biological activities including anticancer properties. The current study was designed for evaluation of chemotherapeutic efficacy of a synthetic quinazolinone derivative BNUA-3 against hepatocellular cancer in Sprague-Dawley (SD) rats. A detailed in vivo analysis was performed by administrating BNUA-3 (15, 30 mg/kg b.w. for 28 days, i.p.) in N-Nitrosodiethylamine + 2-Acetylaminofluorene induced partially hepatectomized liver cancer in SD rats. This was followed by morphological evaluations, biochemical estimations and analysis of different mRNA and protein expressions. The results demonstrated the potency of BNUA-3 in efficient restoration of the altered morphology of liver, its protective effect against lipid peroxidation, enzymic and non-enzymic antioxidants levels in liver tissue which was disrupted after cancer induction. The study also demonstrated downregulation of AhR, CYP1B1 and Keap1 expressions with subsequent augmentation of protective Nrf2, HO-1, NQO1 and GSTA1 expressions thus, revealing the chemotherapeutic potency of BNUA-3 in inhibiting liver carcinogenesis through AhR/CYP1B1/Nrf2/Keap1 pathway.
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Affiliation(s)
- Pritha Bose
- Division of Advanced Pharmacology, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology Mesra, Ranchi, India
| | - Mohd Usman M Siddique
- Division of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology Mesra, Ranchi, India
| | - Reetuparna Acharya
- Division of Advanced Pharmacology, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology Mesra, Ranchi, India
| | - Venkatesan Jayaprakash
- Division of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology Mesra, Ranchi, India
| | - Barij Nayan Sinha
- Division of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology Mesra, Ranchi, India
| | - Antonio Lapenna
- Department of Oncology & Metabolism, Medical School, University of Sheffield, Sheffield, UK
| | - Shakti P Pattanayak
- Division of Advanced Pharmacology, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology Mesra, Ranchi, India
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16
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Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells 2019; 8:670. [PMID: 31269754 PMCID: PMC6679154 DOI: 10.3390/cells8070670] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.
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Affiliation(s)
- David J Brinkman
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Anne S Ten Hove
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
| | - Margriet J Vervoordeldonk
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Galvani Bioelectronics, Stevenage SG1 2NY, UK
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands.
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany.
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Parent R, Gidron Y, Lebossé F, Decaens T, Zoulim F. The Potential Implication of the Autonomic Nervous System in Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol 2019; 8:145-148. [PMID: 30981632 PMCID: PMC6599107 DOI: 10.1016/j.jcmgh.2019.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/05/2019] [Accepted: 03/13/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Romain Parent
- UMR5286, CNRS, INSERM U1052, Lyon Cancer Research Center, Lyon, France; Department of Immunology and Virology, University of Lyon, Lyon, France; DevWeCan Laboratories of Excellence Network (Labex), Lyon, France.
| | - Yori Gidron
- SCALAB UMR CNRS 9193, University of Lille, Villeneuve d'Ascq, France
| | - Fanny Lebossé
- UMR5286, CNRS, INSERM U1052, Cancer Research Centre of Lyon, Lyon, France; Department of Immunology and Virology, University of Lyon, Lyon, France; Hepatogastroenterology Service, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Thomas Decaens
- University of Grenoble-Alpes, Grenoble, France; Department of Hepatogastroenterology, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France; Institute for Advanced Biosciences, CNRS UMR 5309, INSERM U1209, University of Grenoble-Alpes, Grenoble, France
| | - Fabien Zoulim
- UMR5286, CNRS, INSERM U1052, Cancer Research Centre of Lyon, Lyon, France; Department of Immunology and Virology, University of Lyon, Lyon, France; DevWeCan Laboratories of Excellence Network (Labex), Lyon, France; Hepatogastroenterology Service, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
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18
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Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation. Nat Commun 2018; 9:5300. [PMID: 30546054 PMCID: PMC6294142 DOI: 10.1038/s41467-018-07747-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 11/23/2018] [Indexed: 12/18/2022] Open
Abstract
The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival. The mechanisms underlying the regenerative capacity of the liver are not fully understood. Here, the authors show that the acute regenerative response to liver injury in mice is regulated by the communication involving the vagus nerve, macrophages, and hepatocytes, leading to hepatic FoxM1 activation and promotion of overall survival.
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19
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Pattanayak SP, Bose P, Sunita P, Siddique MUM, Lapenna A. Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways. Biomed Pharmacother 2018; 108:297-308. [DOI: 10.1016/j.biopha.2018.08.145] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 08/27/2018] [Accepted: 08/28/2018] [Indexed: 11/30/2022] Open
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20
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Davis EA, Dailey MJ. A direct effect of the autonomic nervous system on somatic stem cell proliferation? Am J Physiol Regul Integr Comp Physiol 2018; 316:R1-R5. [PMID: 30303708 DOI: 10.1152/ajpregu.00266.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Regulation of somatic stem cell proliferation is critical for the maintenance of tissue and organ function throughout the body. Modulators of this process include nutrients and peptides, but the role of an autonomic neural influence on stem cell proliferation has been neglected. This article describes the literature in support of autonomic nervous system (ANS) influence on somatic stem cells, with emphasis on intestinal epithelial stem cells (IESCs) as a representative somatic stem cell. Based on the current available data, models for the direct influence of both branches of the ANS (the sympathetic and parasympathetic nervous systems) on IESCs are outlined. Finally, the prospect of treatments derived from ANS influence on somatic stem cells is explored.
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Affiliation(s)
- Elizabeth A Davis
- Neuroscience Program, University of Illinois at Urbana-Champaign , Urbana, Illinois
| | - Megan J Dailey
- Neuroscience Program, University of Illinois at Urbana-Champaign , Urbana, Illinois.,Department of Animal Sciences, University of Illinois at Urbana-Champaign , Urbana, Illinois
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21
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Imai J. Regulation of compensatory β-cell proliferation by inter-organ networks from the liver to pancreatic β-cells. Endocr J 2018; 65:677-684. [PMID: 29973428 DOI: 10.1507/endocrj.ej18-0241] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
In insulin-resistant states such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. However, the mechanism(s) by which obesity induces compensatory β-cell responses is not fully understood. Recently, several studies have shown that signals from the liver, such as neuronal signals or humoral factors, regulate β-cell proliferation during obesity development. We previously reported a liver-brain-pancreas neuronal relay, consisting of afferent splanchnic nerves, the central nervous system and efferent vagal nerves, to promote this compensatory β-cell proliferation. Furthermore, we recently clarified the molecular mechanisms by which efferent vagal signals induce β-cell proliferation in this inter-organ neuronal network system. Herein, these liver-β-cell inter-organ networks are reviewed, focusing mainly on the neuronal network. The significance of the neuronal network system in the maintenance of glucose homeostasis is also discussed with reference to the relevant literature.
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Affiliation(s)
- Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine
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22
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Tanimizu N, Ichinohe N, Mitaka T. Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver. Development 2018; 145:dev.159095. [PMID: 29615468 DOI: 10.1242/dev.159095] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 03/23/2018] [Indexed: 01/03/2023]
Abstract
Epithelial organs consist of multiple tissue structures, such as epithelial sheets, blood vessels and nerves, which are spatially organized to achieve optimal physiological functions. The hepatic nervous system has been implicated in physiological functions and regeneration of the liver. However, the processes of development and reconstruction of the intrahepatic nerve network and its underlying mechanisms remain unknown. Here, we demonstrate that neural class III β-tubulin (TUBB3)+ nerve fibers are not distributed in intrahepatic tissue at embryonic day 17.5; instead, they gradually extend along the periportal tissue, including intrahepatic bile ducts (IHBDs), after birth. Nerve growth factor (Ngf) expression increased in biliary epithelial cells (BECs) and mesenchymal cells next to BECs before nerve fiber extension, and Ngf was upregulated by hairy enhancer of slit 1 (Hes family bHLH transcription factor 1; Hes1). Ectopic NGF expression in mature hepatocytes induced nerve fiber extension into the parenchymal region, from where these fibers are normally excluded. Furthermore, after BECs were damaged by the administration of 4,4-diaminodiphenylmethane, the nerve network appeared shrunken; however, it was reconstructed after IHBD regeneration, which depended on the NGF signal. These results suggest that IHBDs guide the extension of nerve fibers by secreting NGF during nerve fiber development and regeneration.
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Affiliation(s)
- Naoki Tanimizu
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan
| | - Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan
| | - Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan
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23
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Yamamoto J, Imai J, Izumi T, Takahashi H, Kawana Y, Takahashi K, Kodama S, Kaneko K, Gao J, Uno K, Sawada S, Asano T, Kalinichenko VV, Susaki EA, Kanzaki M, Ueda HR, Ishigaki Y, Yamada T, Katagiri H. Neuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism. Nat Commun 2017; 8:1930. [PMID: 29208957 PMCID: PMC5717276 DOI: 10.1038/s41467-017-01869-7] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 10/23/2017] [Indexed: 12/17/2022] Open
Abstract
Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver–brain–pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the β-cell FoxM1 pathway and suppresses β-cell expansion. Inducible β-cell-specific FoxM1 deficiency also blocks compensatory β-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote β-cell proliferation through a FoxM1-dependent mechanism. These findings indicate that vagal nerves that release several neurotransmitters may allow simultaneous activation of multiple pathways in β-cells selectively, thereby efficiently promoting β-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic β-cells. Neuronal signals, in particular those transmitted via the vagal nerve, regulate both β-cell function and proliferation. Here, Yamamoto et al. show that the forkhead box M1 pathway is required for vagal signal-mediated induction of β-cell proliferation during obesity.
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Affiliation(s)
- Junpei Yamamoto
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Hironori Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Yohei Kawana
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Junhong Gao
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Kenji Uno
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Shojiro Sawada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Tomoichiro Asano
- Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Hiroshima, 734-8553, Japan
| | - Vladimir V Kalinichenko
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Etsuo A Susaki
- Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, Osaka, 565-0871, Japan.,PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan
| | - Makoto Kanzaki
- Tohoku University Graduate School of Biomedical Engineering, Sendai, 980-8579, Japan
| | - Hiroki R Ueda
- Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.,Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, Osaka, 565-0871, Japan
| | - Yasushi Ishigaki
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.,Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Morioka, 020-8505, Japan
| | - Tetsuya Yamada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.,Japan Agency for Medical Research and Development, Project for Elucidating and Controlling Mechanisms of Aging and Longevity, Tokyo, 100-0004, Japan.,Japan Agency for Medical Research and Development, CREST, Tokyo, 100-1004, Japan
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24
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Davis EA, Washington MC, Yaniz ER, Phillips H, Sayegh AI, Dailey MJ. Long-term effect of parasympathetic or sympathetic denervation on intestinal epithelial cell proliferation and apoptosis. Exp Biol Med (Maywood) 2017; 242:1499-1507. [PMID: 28766984 DOI: 10.1177/1535370217724790] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Intestinal epithelial tissue is constantly regenerated as a means to maintain proper tissue function. Previous studies have demonstrated that denervation of the parasympathetic or sympathetic nervous system to the intestine alters this process. However, results are inconsistent between studies, showing both increases and decreases in proliferation after denervation of the parasympathetic or sympathetic. The effect appears to correlate with (1) the timing post-denervation, (2) denervation-induced changes in food intake, (3) the denervation technique used, and (4) which intestinal segment is investigated. Thus, we proposed that parasympathetic or sympathetic denervation does not have an effect on intestinal epithelial regeneration when you (1) evaluate denervation after long-term denervation, (2) control for post-surgical changes in food intake, (3) use minimally invasive surgical techniques and (4) include a segmental analysis. To test this, adult male Sprague Dawley rats underwent parasympathetic denervation via subdiaphragmatic vagotomy, sympathetic denervation via celiacomesenteric ganglionectomy, a parasympathetic denervation sham surgery, or a sympathetic denervation sham surgery. Sham surgery ad libitum-fed groups and sham surgery pair-fed groups were used to control for surgically induced changes in food intake. Three weeks post-surgery, animals were sacrificed and tissue from the duodenum, jejunum, and ileum was excised and immunohistochemically processed to visualize indicators of proliferation (bromodeoxyuridine-positive cells) and apoptosis (caspase-3-positive cells). Results showed no differences between groups in proliferation, apoptosis, or total cell number in any intestinal segment. These results suggest that parasympathetic or sympathetic denervation does not have a significant long-term effect on intestinal epithelial turnover. Thus, intestinal epithelial regeneration is able to recover after autonomic nervous system injury. Impact statement This study investigates the long-term effect of autonomic denervation on intestinal epithelial cell turnover, as measured by proliferation, apoptosis, and total cell number. Although previous research has established that autonomic denervation can alter intestinal epithelial turnover under short-term conditions, here we establish for the first time that these changes do not persist long-term when you control for surgical-induced changes in food intake and use targeted denervation procedures. These findings add to the base of knowledge on autonomic control of tissue turnover, highlight the ability of the intestinal epithelium to recover after autonomic injury and reveal possible implications of the use of ANS denervation for disease treatment in humans.
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Affiliation(s)
- Elizabeth A Davis
- 1 Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, IL, 61801, USA
| | - Martha C Washington
- 2 Department of Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, 36088, USA
| | - Emily R Yaniz
- 1 Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, IL, 61801, USA
| | - Heidi Phillips
- 3 Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, 61802, USA
| | - Ayman I Sayegh
- 2 Department of Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, 36088, USA
| | - Megan J Dailey
- 1 Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, IL, 61801, USA.,4 Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, 61801, USA
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25
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Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:3190617. [PMID: 26798417 PMCID: PMC4699022 DOI: 10.1155/2016/3190617] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 08/17/2015] [Accepted: 09/29/2015] [Indexed: 12/14/2022]
Abstract
In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.
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Abstract
The liver has a nervous system containing both afferent and efferent neurons that are involved in a number of processes. The afferent arm includes the sensation of lipids, glucose, and metabolites (after eating and drinking) and triggers the nervous system to make appropriate physiological changes. The efferent arm is essential for metabolic regulation, modulation of fibrosis and biliary function and the control of a number of other processes. Experimental models have helped us to establish how: (i) the liver is innervated by the autonomic nervous system; and (ii) the cell types that are involved in these processes. Thus, the liver acts as both a sensor and effector that is influenced by neurological signals and ablation. Understanding these processes hold significant implications in disease processes such as diabetes and obesity, which are influenced by appetite and hormonal signals.
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Affiliation(s)
- Kendal Jay Jensen
- Department of Medicine, Division of Gastroenterology, and Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
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27
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Coelho WS, Da Silva D, Marinho-Carvalho MM, Sola-Penna M. Serotonin modulates hepatic 6-phosphofructo-1-kinase in an insulin synergistic manner. Int J Biochem Cell Biol 2012; 44:150-7. [DOI: 10.1016/j.biocel.2011.10.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 09/24/2011] [Accepted: 10/14/2011] [Indexed: 01/20/2023]
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28
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Abstract
Serotonin or 5-hydroxytryptamine (5-HT) is known to regulate several key aspects of liver biology and these functions include hepatic blood flow, innervation and wound healing. Given the importance of these functions it is surprising that relatively little time has been dedicated to studying the precise function and mechanisms of serotonin within the liver. Here we describe what is known about serotonin and the liver and those receptor types that mediate the observed effects with an aim to stimulating new interest in the field of serotonin and liver biology.
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29
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Ikeda O, Ozaki M, Murata S, Matsuo R, Nakano Y, Watanabe M, Hisakura K, Myronovych A, Kawasaki T, Kohno K, Ohkohchi N. Autonomic regulation of liver regeneration after partial hepatectomy in mice. J Surg Res 2008; 152:218-23. [PMID: 18621395 DOI: 10.1016/j.jss.2008.02.059] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2007] [Revised: 02/21/2008] [Accepted: 02/25/2008] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIMS The autonomic vagus nerve is thought to play an essential role in liver regeneration since hepatic vagotomy delays hepatic DNA synthesis. However, how the parasympathetic vagus nerve is involved in liver regeneration remains obscure. Kupffer cells are located in liver sinusoids adjacent to hepatocytes and might regulate liver regeneration by releasing interleukin-6 (IL-6). The present study examines the role of the vagus nerve and how Kupffer cells are involved in parasympathetic nerve-mediated liver regeneration in mice. METHODS We performed surgical vagotomy of the hepatic branch and then partial hepatectomy (PH); some mice received acetylcholine (ACh) agonist/antagonist before PH. We then evaluated liver regeneration and signal transducer and activator of transcription-3 (STAT3) activation. We also investigated whether ACh stimulates IL-6 release from Kupffer cells. RESULTS Surgical vagotomy impaired liver regeneration. STAT3, which is activated by IL-6 after hepatectomy and plays a pivotal role in liver regeneration, was less activated in vagotomized mice after PH. Post-PH STAT3 activation was recovered by administering vagotomized mice with an ACh agonist. Furthermore, ACh stimulated IL-6 release in Kupffer cells in vitro. CONCLUSION The parasympathetic system (vagus nerve) contributes to liver regeneration after hepatectomy by stimulating IL-6 release from Kupffer cells followed by STAT3 activation in hepatocytes.
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Affiliation(s)
- Osamu Ikeda
- Department of Surgery, Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
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30
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Fava G, Marzioni M, Francis H, Glaser S, Demorrrow S, Ueno Y, Benedetti A, Alpini G. Novel interaction of bile acid and neural signaling in the regulation of cholangiocyte function. Hepatol Res 2007; 37 Suppl 3:S420-S429. [PMID: 17931197 DOI: 10.1111/j.1872-034x.2007.00228.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cholangiocytes, the epithelial cells that line the intrahepatic biliary tree, are the target of cholangiopathies, a wide array of chronic disorders that are characterized by the progressive vanishing of bile ducts, leading to ductopenia and liver failure. The loss of bile ducts is a consequence of cholangiocyte death by apoptosis and impaired proliferative response of these cells to injury. The factors that regulate cholangiocyte proliferation and survival are poorly understood. In this regard, a major role is played by the interaction between bile acids and the autonomic nervous system. It has been shown that adrenergic and cholinergic denervation of the liver results in the induction of cell death and impaired proliferative responses of the biliary epithelium to cholestasis. In addition,bile acids have been shown to enter cholangiocytes through the apical, Na(+)-dependent bile acid transporter, ASBT, which has a marked impact on cholangiocyte pathobiology. Recent evidence shows that bile acids and autonomic innervation interact in modulating cholangiocyte response to liver injury. In this review, we describe the recent advances in understanding the molecular mechanisms by which such events occur.
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Affiliation(s)
- Giammarco Fava
- Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
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31
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Hamada T, Eguchi S, Yanaga K, Inuo H, Yamanouchi K, Kamohara Y, Okudaira S, Tajima Y, Kanematsu T. The effect of denervation on liver regeneration in partially hepatectomized rats. J Surg Res 2007; 142:170-4. [PMID: 17574578 DOI: 10.1016/j.jss.2007.01.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Revised: 01/03/2007] [Accepted: 01/16/2007] [Indexed: 01/03/2023]
Abstract
BACKGROUND/AIM In a partial liver transplantation, the dissected hepatic nerves are left unrepaired during active liver regeneration. In fact, the pathophysiological influence of such hepatic denervation on liver regeneration has not yet been fully clarified. The aim of the present study is to elucidate the effect of total hepatic denervation on liver regeneration. METHODS Experiment 1: To confirm the effect of hepatic denervation, the hepatic contents of norepinephrine were measured in both denervated (n = 5) and sham (n = 5) rats. The changes in the hepatic microcirculation were also measured in both denervated (n = 5) and sham (n = 5) rats. Experiment 2: The rats (n = 80) were randomly assigned to two groups: DN group (n = 40); hepatic denervation followed by a partial hepatectomy (PH). Control group (n = 40); sham hepatic denervation followed by PH. In both groups, the animals were killed at 12, 24, 36, 48, 72, 120, and 168 h after PH, respectively. The liver to body weight ratio and the proliferating cell nuclear antigen (PCNA) labeling index were measured at each time point. RESULTS Experiment 1: Nearly a total depletion of norepinephrine (<99%) was observed in the DN rats. In addition, the hepatic tissue blood flow significantly increased in the DN rats. Experiment 2: The liver to body weight ratio of the DN group was also significantly higher than that of the control group at 168 h (P < 0.05). The PCNA labeling index peaked between 24 and 36 h in the control group, while that in the DN group showed a delayed peak. At 72 and 120 h, the PCNA labeling index was significantly higher in the DN group than in the control group (P < 0.05). CONCLUSION Total hepatic denervation was thus found to enhance liver regeneration after a partial hepatectomy. This phenomenon is partially triggered by the increased hepatic blood flow to the remnant liver.
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Affiliation(s)
- Takayuki Hamada
- Department of Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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32
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Marzioni M, Ueno Y, Glaser S, Francis H, Benedetti A, Alvaro D, Venter J, Fava G, Alpini G. Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver. Liver Int 2007; 27:558-568. [PMID: 17403196 DOI: 10.1111/j.1478-3231.2007.01443.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Cholangiopathies impair the balance between proliferation and apoptosis of cholangiocytes leading to the disappearance of bile ducts and liver failure. Taurocholic acid (TC) is essential for cholangiocyte proliferative and functional response to cholestasis. Bile acids and neurotransmitters co-operatively regulate the biological response of the biliary epithelium to cholestasis. Adrenergic denervation of the liver during cholestasis results in the damage of bile ducts. AIM To verify whether TC feeding prevents the damage of the biliary tree induced by adrenergic denervation in the course of cholestasis. METHODS Rats subjected to bile duct ligation (BDL) and to adrenergic denervation were fed a TC-enriched diet, in the absence or presence of daily administration of the phosphatidyl-inositol-3-kinase (PI3K) inhibitor wortmannin for 1 week. RESULTS TC prevented the induction of cholangiocyte apoptosis induced by adrenergic denervation. TC also restored cholangiocyte proliferation and functional activity, reduced after adrenergic denervation. TC prevented AKT dephosphorylation induced by adrenergic denervation. The cytoprotective effects of TC were abolished by the simultaneous administration of wortmannin. SUMMARY/CONCLUSIONS TC administration prevents the damage of the biliary tree induced by the adrenergic denervation of the liver. These novel findings open novel perspectives in the understanding of the potential of bile acids especially in post-transplant liver disease.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
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Yoshimura R, Somekawa S, Omori H, Endo Y. Carbachol induces hepatocyte proliferation, but only in the presence of hepatic nonparenchymal cells. J Physiol Sci 2007; 57:139-45. [PMID: 17442131 DOI: 10.2170/physiolsci.rp003707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Accepted: 04/17/2007] [Indexed: 11/05/2022]
Abstract
Vagal hyperactivity correlates with enhanced DNA synthesis and cell proliferation in the peripheral tissues of ventromedial hypothalamic (VMH)-lesioned rats. The infusion of an ACh receptor agonist, carbachol (Cch), induces rat duodenal and pancreatic cell proliferation to a degree comparable to the VMH lesions. Whereas the VMH lesions also induce the proliferation of hepatic cells, it is unclear whether Cch can also do this. Here we attempted to clarify the mechanism of hepatic cell proliferation induction by cholinergic stimulation. First, hepatic cell proliferation was examined in rats previously vagotomized and intraperitoneally administered with Cch via an osmotic minipump. Second, the sera from the Cch-infused rats were examined for a proliferative effect on isolated hepatic cells. And last, the effect of the presence of hepatic nonparenchymal cells (NPCs) on the proliferation of the cultured hepatocytes treated with Cch was investigated. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that the 3-day Cch infusion significantly increased the number of PCNA-immunoreactive cells in the liver. Moreover, the sera from the Cch-infused rats increased the number of PCNA-immunoreactive hepatocytes in culture. However, Cch alone did not induce proliferation in monocultured hepatocytes. When compared with the monoculture of hepatocytes, the coculture of those with hepatic NPCs resulted in enhanced PCNA immunoreactivity after a 4-day treatment with 3 mM Cch. These findings suggest that ACh induces hepatocyte proliferation, which is mediated by unidentified humoral factor(s) possibly secreted from hepatic NPCs, and that it also participates in liver hypertrophy in the VMH-lesioned animals.
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Affiliation(s)
- Ryoichi Yoshimura
- Division of Applied Biology, Kyoto Institute of Technology Graduate School of Science and Technology, Matsugasaki, Kyoto, Japan.
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34
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Marzioni M, Francis H, Benedetti A, Ueno Y, Fava G, Venter J, Reichenbach R, Mancino MG, Summers R, Alpini G, Glaser S. Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:398-409. [PMID: 16436655 PMCID: PMC1606491 DOI: 10.2353/ajpath.2006.050126] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/27/2005] [Indexed: 01/08/2023]
Abstract
Chronic cholestatic liver diseases are characterized by impaired balance between proliferation and death of cholangiocytes, as well as vanishing of bile ducts and liver failure. Ursodeoxycholic acid (UDCA) is a bile acid widely used for the therapy of cholangiopathies. However, little is known of the cytoprotective effects of UDCA on cholangiocytes. Therefore, UDCA and its taurine conjugate tauroursodeoxycholic acid (TUDCA) were administered in vivo to rats simultaneously subjected to bile duct ligation and vagotomy, a model that induces cholestasis and loss of bile ducts by apoptosis of cholangiocytes. Because these two bile acids act through Ca2+ signaling, animals were also treated with BAPTA/AM (an intracellular Ca2+ chelator) or Gö6976 (a Ca2+-dependent protein kinase C-alpha inhibitor). The administration of UDCA or TUDCA prevented the induction of apoptosis and the loss of proliferative and functional responses observed in the bile duct ligation-vagotomized rats. These effects were neutralized by the simultaneous administration of BAPTA/AM or Gö6976. UDCA and TUDCA enhanced intracellular Ca2+ and IP3 levels, together with increased phosphorylation of protein kinase C-alpha. Parallel changes were observed regarding the activation of the MAPK and PI3K pathways, changes that were abolished by addition of BAPTA/AM or Gö6976. These studies provide information that may improve the response of cholangiopathies to medical therapy.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Universitá Politecnica delle Marche, Italy
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35
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Oben JA, Diehl AM. Sympathetic nervous system regulation of liver repair. ACTA ACUST UNITED AC 2005; 280:874-83. [PMID: 15382023 DOI: 10.1002/ar.a.20081] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
This chapter reviews recent evidence that the sympathetic nervous system (SNS) regulates liver repair by modulating the phenotypes of hepatic stellate cells (HSCs), the liver's principal fibrogenic cells, and hepatic epithelial progenitors, i.e., oval cells. SNS nerve fibers touch HSCs and these cells express adrenoceptors, suggesting that HSCs may be targets for SNS neurotransmitters. HSCs also contain catecholamine biosynthetic enzymes, release norepinephrine (NE), and are growth-inhibited by adrenoceptor antagonists. In addition, HSCs from mice with reduced levels of NE grow poorly in culture and exhibit inhibited activation during liver injury. Finally, growth and injury-related fibrogenic responses are rescued by adrenoceptor agonists. Thus, certain SNS inhibitors (SNSIs) protect experimental animals from cirrhosis. Conversely, SNSIs enhance the hepatic accumulation of oval cells (OCs) in injured livers. This response is associated with improved liver injury. Because SNSIs do not affect the expression of cytokines, growth factors, or growth factor receptors that are known to regulate OCs, and OCs express adrenoceptors, it is conceivable that catecholamines influence OCs by direct interaction with OC adrenoceptors. Given evidence that the SNS regulates the viability and activation of HSCs and OCs differentially, SNSIs may be novel therapies to improve the repair of damaged livers.
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Affiliation(s)
- Jude A Oben
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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36
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Colle I, Van Vlierberghe H, Troisi R, De Hemptinne B. Transplanted liver: consequences of denervation for liver functions. ACTA ACUST UNITED AC 2005; 280:924-31. [PMID: 15382009 DOI: 10.1002/ar.a.20097] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Following liver transplantation, all hepatic nerves are transected; thus, liver allografts are completely isolated from neural control of their hosts. Despite this absolute denervation, liver allograft function does not appear to be significantly impaired after successful transplantation. In experimental animal models, hepatic denervation has no major effects on bile acid production and biotransformation, while it increases blood pressure and salt retention; decreases the number of hepatic progenitor cells, cholangiocyte proliferation, and liver regeneration; and influences the hepatic microcirculation, diet behavior, and glycemic control. In humans, hepatic denervation after liver transplantation has no major deleterious effects on bile secretion, liver regeneration, and hepatic blood flow. Insulin resistance and postprandial hyperglycemia, changes in ingestion behavior, and reduced stimulation of hepatic progenitor cells in the canals of Hering are the major side effects of absent liver innervation. Despite these abnormalities, patients can lead a new life with improved quality of life.
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Affiliation(s)
- Isabelle Colle
- Department of Hepato-Gastroenterology, Ghent University Hospital, Belgium.
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37
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Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Li Z, Torbenson M, Huang J, Guarino P, Kafrouni M, Diehl AM. Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury. Hepatology 2003; 38:664-73. [PMID: 12939593 DOI: 10.1053/jhep.2003.50371] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Recovery from liver damage might be enhanced by encouraging repopulation of the liver by endogenous hepatic progenitor cells. Oval cells are resident hepatic stem cells that promote liver regeneration and repair. Little is known about the mediators that regulate the accumulation of these cells in the liver. Parasympathetic nervous system inhibition reduces the number of oval cells in injured livers. The effect of sympathetic nervous system (SNS) inhibition on oval cell number is not known. Adrenergic inhibition mobilizes hematopoietic precursors into the circulation and has also been shown to promote liver regeneration. Thus, we hypothesized that SNS inhibition would promote hepatic accumulation of oval cells and reduce liver damage in mice fed antioxidant-depleted diets to induce liver injury. Our results confirm this hypothesis. Compared with control mice that were fed only the antioxidant-depleted diets, mice fed the same diets with prazosin (PRZ, an alpha-1 adrenoceptor antagonist) or 6-hydroxydopamine (6-OHDA, an agent that induces chemical sympathectomy) had significantly increased numbers of oval cells. Increased oval cell accumulation was accompanied by less hepatic necrosis and steatosis, lower serum aminotransferases, and greater liver and whole body weights. Neither PRZ nor 6-OHDA affected the expression of cytokines, growth factors, or growth factor receptors that are known to regulate progenitor cells. In conclusion, stress-related sympathetic activity modulates progenitor cell accumulation in damaged livers and SNS blockade with alpha-adrenoceptor antagonists enhances hepatic progenitor cell accumulation.
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Affiliation(s)
- Jude A Oben
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Sakamoto I, Takahashi T, Kakita A, Hayashi I, Majima M, Yamashina S. Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats. J Hepatol 2002; 37:814-23. [PMID: 12445423 DOI: 10.1016/s0168-8278(02)00283-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The present study examined whether extrinsic hepatic reinnervation occurred after orthotopic liver transplantation (OLT) in rats. METHODS Inbred male Lewis rats were the recipients and females the donors. Tissue specimens were obtained postoperatively from the stump of a recipient's hepatoduodenal ligament (A), and the hepatic hilus (B) and peripheral parenchyma (C) of liver allografts, up to 6 months post-operation. Specimens were subjected to immunohistochemical examination using growth-associated protein (GAP)-43 as an axonal marker and transmission electron microscopy (TEM) for observing regenerating axons, as well as the polymerase chain reaction assay to detect the rat sex-determining region Y (SRY) protein gene of the regenerating nerves. RESULTS At site A, GAP-43-positive nerve axons were identified from day 1 to 1 month post-OLT and SRY protein genes were expressed at and after 3 days post-OLT. At site B, GAP-43-positive axons were observed between 3 days and 1 month, and SRY protein genes were detected at 1 month post-OLT and thereafter. TEM confirmed the presence of regenerating axons at and after 3 days post-OLT. CONCLUSIONS The results demonstrated that regenerating nerve fibers originating from the recipients reinnervated liver allografts. This extrinsic innervation occurred shortly after OLT, and most likely terminated after about 3 months.
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Affiliation(s)
- Izumi Sakamoto
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
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Yoneda M, Kurosawa M, Watanobe H, Shimada T, Terano A. Brain-gut axis of the liver: the role of central neuropeptides. J Gastroenterol 2002; 37 Suppl 14:151-6. [PMID: 12572884 DOI: 10.1007/bf03326435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Masashi Yoneda
- Department of Gastroenterology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
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Sakaguchi T, Liu L. Hepatic branch vagotomy can block liver regeneration enhanced by ursodesoxycholic acid in 66% hepatectomized rats. Auton Neurosci 2002; 99:54-7. [PMID: 12171257 DOI: 10.1016/s1566-0702(02)00060-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The effect of hepatic branch vagotomy on liver regeneration induced by ursodesoxycholic acid was examined in 66% hepatectomized rats. A standard feeding was obtained from animals with hepatic branch vagotomy, and all rats examined received pair food intake. Liver regeneration was evaluated by the hepatocyte mitotic index. When ursodesoxycholic acid 12.5 mg kg(-1) day(-1) was administered orally, a significant increase in the mitotic index was observed 2 and 3 days after hepatectomy, and the mitotic index response 2 days after hepatectomy was dose-dependent in the range of 0-25 mg kg(-1) day(-1). Hepatic branch vagotomy suppressed the mitotic index 2 days after hepatectomy, and the mitotic index increase due to ursodesoxycholic acid was blocked by hepatic branch vagotomy, but not by gastric branch vagotomy. It was also noted that hepatic branch vagotomy or ursodesoxycholic acid or both did not affect serum parameters indicating liver and kidney function. Because ursodesoxycholic acid exists in the bile juice, these results suggest that the hepatic vagus nerve is specifically active with endogenous bile acids in the control of liver regeneration.
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Affiliation(s)
- Takeo Sakaguchi
- Department of Sensory and Integrative Medicine, Niigata University, Japan.
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Kiba T, Saito S, Numata K, Kon Y, Mizutani T, Sekihara H. Expression of apoptosis on rat liver by hepatic vagus hyperactivity after ventromedial hypothalamic lesioning. Am J Physiol Gastrointest Liver Physiol 2001; 280:G958-67. [PMID: 11292605 DOI: 10.1152/ajpgi.2001.280.5.g958] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We examined whether the Fas (APO-1/CD95)/Fas ligand system mediates apoptosis in rats with ventromedial hypothalamus (VMH) lesions. Northern and Western blotting indicated that VMH lesions lead to a significant increase in Fas mRNA and protein expression from day 1 to day 7 and in Fas ligand mRNA and protein expression from day 2 to day 7. Immunohistochemistry indicated that the region of strongest Fas expression shifted from acinar zone 1 to zones 2 and 3 by day 7 after VMH lesioning and that at days 2-7 Fas-ligand-positive hepatocyte cell membranes and cytoplasm were randomly distributed in acinar zones 1-3. We also analyzed activation of caspase 3-like proteases in hepatocytes, Kupffer cells, and sinusoidal endothelial cells. Spectrofluorometric assay demonstrated that caspase 3-like activity significantly increased only in hepatocytes after VMH lesioning. Moreover, electron microscopy and TUNEL assay showed that VMH lesions induced apoptosis. All of these effects were completely inhibited by hepatic vagotomy and administration of atropine. Vagal firing after VMH lesioning may stimulate Fas/Fas ligand system-mediated apoptosis through the cholinergic system in the rat liver.
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Affiliation(s)
- T Kiba
- Third Department of Internal Medicine, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004.
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Cassiman D, van Pelt J, De Vos R, Van Lommel F, Desmet V, Yap SH, Roskams T. Synaptophysin: A novel marker for human and rat hepatic stellate cells. THE AMERICAN JOURNAL OF PATHOLOGY 1999; 155:1831-9. [PMID: 10595912 PMCID: PMC1866940 DOI: 10.1016/s0002-9440(10)65501-0] [Citation(s) in RCA: 114] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Synaptophysin is a protein involved in neurotransmitter exocytosis and is a neuroendocrine marker. We studied synaptophysin immunohistochemical expression in 35 human liver specimens (normal and different pathological conditions), in rat models of galactosamine hepatitis and carbon tetrachloride-induced cirrhosis, and in freshly isolated rat stellate cells. Synaptophysin reactivity was present in perisinusoidal stellate cells in both human and rat normal liver biopsies. The number of synaptophysin-reactive perisinusoidal cells increased in pathological conditions. Double staining for alpha-smooth muscle actin and synaptophysin, detected by confocal laser scanning microscopy, unequivocally demonstrated colocalization of both markers in lobular stellate cells. In addition, freshly isolated rat stellate cells expressed synaptophysin mRNA (detected by polymerase chain reaction) and protein. Finally, electron microscopy showed the presence of small electron translucent vesicles, comparable to the synaptophysin-reactive synaptic vesicles in neurons, in stellate cell projections. We conclude that synaptophysin is a novel marker for quiescent as well as activated hepatic stellate cells. Together with the stellate cell's expression of neural cell adhesion molecule, glial fibrillary acidic protein, and nestin, this finding raises questions about its embryonic origin and its differentiation. In addition, the presence of synaptic vesicles in stellate cell processes suggests a hitherto unknown mechanism of interaction with neighboring cells.
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Affiliation(s)
- D Cassiman
- Laboratory of Liver and Pancreatic Diseases, Leuven University, Leuven, Belgium
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LeSagE G, Alvaro D, Benedetti A, Glaser S, Marucci L, Baiocchi L, Eisel W, Caligiuri A, Phinizy JL, Rodgers R, Francis H, Alpini G. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats. Gastroenterology 1999; 117:191-199. [PMID: 10381927 DOI: 10.1016/s0016-5085(99)70567-6] [Citation(s) in RCA: 129] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS To investigate the role of the cholinergic system in regulation of cholangiocyte functions, we evaluated the effects of vagotomy on cholangiocyte proliferation and secretion in rats that underwent bile duct ligation (BDL rats). METHODS After bile duct ligation (BDL), the vagus nerve was resected; 7 days later, expression of M3 acetylcholine receptor was evaluated. Cholangiocyte proliferation was assessed by morphometry and measurement of DNA synthesis. Apoptosis was evaluated by light microscopy and annexin-V staining. Ductal secretion was evaluated by measurement of secretin-induced choleresis, secretin receptor (SR) gene expression, and cyclic adenosine 3',5'-monophosphate (cAMP) levels. RESULTS Vagotomy decreased the expression of M3 acetylcholine receptors in cholangiocytes. DNA synthesis and ductal mass were markedly decreased, whereas cholangiocyte apoptosis was increased by vagotomy. Vagotomy decreased ductal secretion. Forskolin treatment prevented the decrease in cAMP levels induced by vagotomy, maintained cholangiocyte proliferation, and decreased cholangiocyte apoptosis caused by vagotomy in BDL rats. Cholangiocyte secretion was also maintained by forskolin. CONCLUSIONS Vagotomy impairs cholangiocyte proliferation and enhances apoptosis, leading to decreased ductal mass in response to BDL. Secretin-induced choleresis of BDL rats was virtually eliminated by vagotomy in association with decreased cholangiocyte cAMP levels. Maintenance of cAMP levels by forskolin administration prevents the effects of vagotomy on cholangiocyte proliferation, apoptosis, and secretion.
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Affiliation(s)
- G LeSagE
- Department of Internal Medicine, Scott & White Hospital, and Texas A&M University System Health Science Center College of Medicine, Temple, Texas, USA
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Yoneda M. Regulation of hepatic function by brain neuropeptides. World J Gastroenterol 1998; 4:192-196. [PMID: 11819273 PMCID: PMC4723454 DOI: 10.3748/wjg.v4.i3.192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/1998] [Revised: 05/15/1998] [Accepted: 06/02/1998] [Indexed: 02/06/2023] Open
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45
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Barbaro G, Di Lorenzo G, Soldini M, Bellomo G, Belloni G, Grisorio B, Barbarini G. Vagal system impairment in human immunodeficiency virus-positive patients with chronic hepatitis C: does hepatic glutathione deficiency have a pathogenetic role? Scand J Gastroenterol 1997; 32:1261-6. [PMID: 9438326 DOI: 10.3109/00365529709028157] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Both an autonomic impairment and a systemic depletion of reduced glutathione (GSH) may be documented in patients with chronic liver diseases and in human immunodeficiency virus (HIV)-positive patients. METHODS The coefficients of electrocardiographic R-R interval variation (CVc) were assessed in 125 patients with chronic hepatitis C (CHC) (65 HIV-positive and 60 HIV-negative) and in 61 healthy controls. The CVc values were correlated with hepatic (H-GSH), plasmatic (P-GSH), lymphocyte (L-GSH), and erythrocyte (E-GSH) concentrations of GSH and with erythrocyte malonyldialdehyde (MDA) levels. RESULTS Compared with healthy controls, in CHC patients the concentrations of H-GSH, P-GSH, L-GSH, and E-GSH were reduced, whereas MDA levels were increased with a statistically significant difference (P < 0.001). CVc was significantly reduced in patients with CHC (especially in those who were HIV-positive) and correlated significantly with the values of H-GSH, P-GSH, L-GSH, E-GSH, and MDA (P < 0.001). CONCLUSIONS A dysfunction of the cardiac vagal system may be detected in patients with CHC (especially in those who are HIV-positive); this abnormality may be related to a reduced response to oxidative stress because of a systemic depletion of GSH.
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Affiliation(s)
- G Barbaro
- Dept. of Emergency Medicine, La Sapienza University, Rome, Italy
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46
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Hsu CT. The role of the autonomic nervous system in chemically-induced liver damage and repair--using the essential hypertensive animal model (SHR). JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1995; 51:135-42. [PMID: 7738287 DOI: 10.1016/0165-1838(94)00124-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The effects of autonomic nervous system on liver damage induced by carbon tetrachloride (CCl4) and repair were investigated morphologically and biochemically in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). After repetition of CCl4 treatment twice a week for 4 weeks, the SHR showed liver cirrhosis histologically. In WKY, however, only fibrosis was observed. Biochemically, the serum glutamate-pyruvate transaminase (GPT), liver lipid peroxidation (LPO) and superoxide dismutase (SOD) activities were measured. CCl4 increased the activities of GPT and LPO but decreased that of SOD in SHR more than in WKY. These findings indicate that liver damage induced by CCl4 was more severe in the sympathetic hyperactive SHR than in the normally active WKY. In induced cirrhotic liver of SHR and fibrotic liver of WKY, diffuse serotonin particles and numerous mast cells were observed in the fibrotic matrix, and some neovascular adrenergic fibers were found in these areas. These results indicate that the sympathetic nerve can exacerbate the liver damage, and both mast cells or serotonin particles and sympathetic nerve participate at some stages in the repair of liver damage.
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Affiliation(s)
- C T Hsu
- Department of Pathology, School of Medicine, China Medical College, Taichung, Taiwan ROC
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47
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Isobe H, Sakai H, Sakamoto S, Nawata H. Decreased variation of electrocardiographic R-R interval in patients with liver cirrhosis. J Gastroenterol Hepatol 1994; 9:232-5. [PMID: 8054521 DOI: 10.1111/j.1440-1746.1994.tb01715.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Electrocardiographic R-R interval variations were assessed to determine the functional integrity of the cardiac vagal nervous system in 20 normal controls and 71 cirrhotic patients. The ratio of the coefficient of variation to standard prediction value was used as an index. The cirrhotic patients showed significant reductions in the ratio of the coefficient compared with controls (0.71 +/- 0.27 vs 0.91 +/- 0.14; P < 0.01). There was a significant relationship between decreased R-R interval variation and the liver function tests. The ratio of the coefficient increased with improvement in encephalopathy, and decreased with the development of encephalopathy. These results show that there is dysfunction of the cardiac vagal nervous system in patients with liver cirrhosis, and that this abnormality is partially reversible and might be related to liver dysfunction.
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Affiliation(s)
- H Isobe
- Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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Kikuchi N, Yamaguchi Y, Mori K, Takata N, Goto M, Makino Y, Hamaguchi H, Hisama N, Ogawa M. Effect of cyclosporine on liver regeneration after orthotopic reduced-size hepatic transplantation in the rat. Dig Dis Sci 1993; 38:1492-9. [PMID: 8344106 DOI: 10.1007/bf01308610] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
These experiments were undertaken to study the effects of cyclosporine A (CsA) on liver regeneration after an isogeneic orthotopic reduced-size hepatic transplantation (RSHT) in rats. Male Wistar rats were treated with or without a daily injection of CsA beginning 24 hr before surgery and were subjected to a 68% partial hepatectomy. A isogeneic orthotopic reduced-size hepatic transplantation was performed in recipient rats pretreated with or without CsA. A daily injection of CsA was continued until the recipient rats were sacrificed. Animals were sacrificed at various time points (12, 24, 36, 48, and 72 hr) postoperatively. The incorporation of bromodeoxyuridine (BrdU) into the DNA of the remnant hepatocytes was evaluated by immunohistochemical staining with a monoclonal antibody against BrdU. CsA (10 mg/kg/day) significantly augmented BrdU incorporation into hepatocytes after hepatectomy. The maximum labeling index (LI) was observed at 24 hr after hepatectomy. In contrast, the maximum LI in the recipient rats not receiving CsA was seen at 36 hr after RSHT, and 10 mg/kg/day of CsA decreased the LI at 36 hr after RSHT. A lower dose of CsA (3 mg/kg/day), however, significantly increased the LI in the recipient rats (P < 0.01), and it reached a peak at 24 hr after RSHT when compared to the transplant recipients not receiving CsA. The time course of the increase in the LI in the transplant recipient rats receiving 3 mg/kg/day of CsA was similar to that observed in the rats after hepatectomy. This dosage improved the delay in the reduced-size hepatic transplant LI reaching its peak.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- N Kikuchi
- Department of Surgery II, Kumamoto University Medical School, Japan
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Bellinger LL, Gietzen DW, Williams FE. Liver denervation, 5-HT3 receptor antagonist, and intake of imbalanced amino acid diet. Brain Res Bull 1993; 32:549-54. [PMID: 8221151 DOI: 10.1016/0361-9230(93)90306-v] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The serotonin3 receptor antagonist ICS 205-930 (ICS) may act peripherally to attenuate the anorectic response of rats given an imbalanced amino acid (IMB) diet. Rats were divided into four groups: SHAM+saline (sal); SHAM+ICS; total liver denervation (TLD) + sal; and TLD+ICS. Rats were then given a purified basal diet for 16 days. Next, the groups were injected with sal or 9 mg/kg BW of ICS at 0800 h and at 0900 h (lights out) an isoleucine IMB diet was presented. By 12 h postinjection, the food intake (FI) of TLD and SHAM rats receiving ICS was similarly higher (p < 0.02) than sal-injected counterparts whose FI was also similar; BW followed FI. By day 3, the SHAM groups had similar low FI, whereas the FI of the TLD groups was increasing. The above study was repeated with similar results. Liver innervation is not required for ICS attenuation of IMB diet-induced hypophagia. Also, while sal-injected TLD rats show a normal attenuation of consumption of the IMB diet on the first day of exposure, they subsequently consume more of the IMB diet than SHAM rats. The reason for this difference in TLD rats is not clear but may be related to metabolism of the IMB diet or possibly learning.
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Affiliation(s)
- L L Bellinger
- Department of Physiology, Baylor College of Dentistry, Dallas, TX 75246
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Iwai M, Shimazu T. Alteration in sympathetic nerve activity during liver regeneration in rats after partial hepatectomy. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1992; 41:209-14. [PMID: 1289384 DOI: 10.1016/0165-1838(92)90060-t] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
To determine if the sympathetic nerve has a role in liver regeneration, the alterations of tissue norepinephrine (NE) content and its turnover were measured in rats after partial hepatectomy. NE content per unit liver mass decreased progressively to about one-fourth of controls by the ninth day after partial hepatectomy. Since the total amount of NE in the whole liver did not change during nine days of liver regeneration, it was supposed that sympathetic innervation could make slower progress than proliferation of hepatocytes. Fractional turnover rate of NE was reduced transiently in regenerating liver 24-48 h after partial hepatectomy and recovered to normal 8-9 days after the operation. Such a transient reduction of NE turnover was observed specifically in the liver. These results suggest that sympathetic nerve activity of the liver is suppressed at the early stage of regeneration.
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Affiliation(s)
- M Iwai
- Department of Medical Biochemistry, Ehime University School of Medicine, Japan
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