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Bachari A, Nassar N, Telukutla S, Zomer R, Piva TJ, Mantri N. Evaluating the Mechanism of Cell Death in Melanoma Induced by the Cannabis Extract PHEC-66. Cells 2024; 13:268. [PMID: 38334660 PMCID: PMC10854753 DOI: 10.3390/cells13030268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024] Open
Abstract
Research suggests the potential of using cannabinoid-derived compounds to function as anticancer agents against melanoma cells. Our recent study highlighted the remarkable in vitro anticancer effects of PHEC-66, an extract from Cannabis sativa, on the MM418-C1, MM329, and MM96L melanoma cell lines. However, the complete molecular mechanism behind this action remains to be elucidated. This study aims to unravel how PHEC-66 brings about its antiproliferative impact on these cell lines, utilising diverse techniques such as real-time polymerase chain reaction (qPCR), assays to assess the inhibition of CB1 and CB2 receptors, measurement of reactive oxygen species (ROS), apoptosis assays, and fluorescence-activated cell sorting (FACS) for apoptosis and cell cycle analysis. The outcomes obtained from this study suggest that PHEC-66 triggers apoptosis in these melanoma cell lines by increasing the expression of pro-apoptotic markers (BAX mRNA) while concurrently reducing the expression of anti-apoptotic markers (Bcl-2 mRNA). Additionally, PHEC-66 induces DNA fragmentation, halting cell progression at the G1 cell cycle checkpoint and substantially elevating intracellular ROS levels. These findings imply that PHEC-66 might have potential as an adjuvant therapy in the treatment of malignant melanoma. However, it is essential to conduct further preclinical investigations to delve deeper into its potential and efficacy.
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Affiliation(s)
- Ava Bachari
- The Pangenomics Lab, School of Science, RMIT University, Bundoora, VIC 3083, Australia or (A.B.); (S.T.)
| | - Nazim Nassar
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; (N.N.); (T.J.P.)
- Faculty of Health, Charles Darwin University, Casuarina, NT 0810, Australia
| | - Srinivasareddy Telukutla
- The Pangenomics Lab, School of Science, RMIT University, Bundoora, VIC 3083, Australia or (A.B.); (S.T.)
| | - Roby Zomer
- MGC Pharmaceuticals Limited, West Perth, WA 6005, Australia;
| | - Terrence J. Piva
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia; (N.N.); (T.J.P.)
| | - Nitin Mantri
- The Pangenomics Lab, School of Science, RMIT University, Bundoora, VIC 3083, Australia or (A.B.); (S.T.)
- The UWA Institute of Agriculture, The University of Western Australia, Perth, WA 6009, Australia
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Shearn CT, Anderson AL, Miller CG, Noyd RC, Devereaux MW, Balasubramaniyan N, Orlicky DJ, Schmidt EE, Sokol RJ. Thioredoxin reductase 1 regulates hepatic inflammation and macrophage activation during acute cholestatic liver injury. Hepatol Commun 2023; 7:e0020. [PMID: 36633484 PMCID: PMC9833450 DOI: 10.1097/hc9.0000000000000020] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/27/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND AND AIMS Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by periportal inflammation with progression to hepatic fibrosis and ultimately cirrhosis. We recently reported that the thioredoxin antioxidant response is dysregulated during primary sclerosing cholangitis. The objective of this study was to examine the impact of genetic and pharmacological targeting of thioredoxin reductase 1 (TrxR1) on hepatic inflammation and liver injury during acute cholestatic injury. APPROACH AND RESULTS Primary mouse hepatocytes and intrahepatic macrophages were isolated from 3-day bile duct ligated (BDL) mice and controls. Using wildtype and mice with a liver-specific deletion of TrxR1 (TrxR1LKO), we analyzed the effect of inhibition or ablation of TrxR1 signaling on liver injury and inflammation. Immunohistochemical analysis of livers from BDL mice and human cholestatic patients revealed increased TrxR1 staining in periportal macrophages and hepatocytes surrounding fibrosis. qPCR analysis of primary hepatocytes and intrahepatic macrophages revealed increased TrxR1 mRNA expression following BDL. Compared with sham controls, BDL mice exhibited increased inflammation, necrosis, and increased mRNA expression of pro-inflammatory cytokines, fibrogenesis, the NLRP3 inflammatory complex, and increased activation of NFkB, all of which were ameliorated in TrxR1LKO mice. Importantly, following BDL, TrxR1LKO induced periportal hepatocyte expression of Nrf2-dependent antioxidant proteins and increased mRNA expression of basolateral bile acid transporters with reduced expression of bile acid synthesis genes. In the acute BDL model, the TrxR1 inhibitor auranofin (10 mg/kg/1 d preincubation, 3 d BDL) ameliorated BDL-dependent increases in Nlrp3, GsdmD, Il1β, and TNFα mRNA expression despite increasing serum alanine aminotransferase, aspartate aminotransferase, bile acids, and bilirubin. CONCLUSIONS These data implicate TrxR1-signaling as an important regulator of inflammation and bile acid homeostasis in cholestatic liver injury.
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Affiliation(s)
- Colin T. Shearn
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Aimee L. Anderson
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Colin G. Miller
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Reed C. Noyd
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Michael W. Devereaux
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Nata Balasubramaniyan
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Edward E. Schmidt
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, Montana, USA
- Laboratory of Redox Biology, Departments of Pharmacology and Physiology, University of Veterinary Medicine Budapest, Hungary
| | - Ronald J. Sokol
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, Colorado, USA
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Sobiepanek A, Milner-Krawczyk M, Musolf P, Starecki T, Kobiela T. Anandamide-Modulated Changes in Metabolism, Glycosylation Profile and Migration of Metastatic Melanoma Cells. Cancers (Basel) 2022; 14:cancers14061419. [PMID: 35326572 PMCID: PMC8946642 DOI: 10.3390/cancers14061419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Anandamide (AEA) belongs to the group of endocannabinoids and possesses various regulatory properties in physiological as well as pathological processes occurring in the organism. In this research some basic biological tests were applied to investigate AEA-induced changes in cell metabolism and motility, as well as advanced biophysical methods for the determination of the differences in the cell glycosylation profile on a highly dangerous model of melanoma skin cancer, for which an effective therapy is not yet available. Our research suggests that anandamide treatment of metastatic melanoma cells increases the cell metabolism which leads to the reduction in the metastatic potential of cells in terms of the cell glycosylation profile and cell migration. In the view of our research, it can be presumed that anandamide usage in the combined therapy of advanced melanoma would be an advantage for the patient. Abstract An effective therapy for advanced melanoma, a skin cancer with the highest mortality, has not yet been developed. The endocannabinoid system is considered to be an attractive target for cancer treatment. The use of endocannabinoids, such as anandamide (AEA), is considered to be much greater than as a palliative agent. Thus, we checked its influence on various signaling pathways in melanoma cells. Our investigation was performed on four commercial cell lines derived from different progression stages (radial WM35 and vertical WM115 growth phases, lymph node WM266-4 metastasis, solid tumor A375-P metastasis). Cell viability, glucose uptake, quantification of reactive oxygen species production, expression of selected genes encoding glycosyltransferases, quantification of glycoproteins production and changes in the glycosylation profile and migration, as well as in cell elastic properties were analyzed. The cell glycosylation profile was investigated using the biophysical profiling method—the quartz crystal microbalance with dissipation monitoring (QCM-D). Anandamide treatment of only metastatic cells resulted in: an increase in the cell metabolism, a decrease in GFAT-1 and DPM1 expression, followed by a decrease in L1-CAM glycoprotein production, which further influenced the reduction in the cell glycosylation profile and migration. Considering our results, AEA usage is highly recommended in the combined therapy of advanced melanoma.
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Affiliation(s)
- Anna Sobiepanek
- Laboratory of Biomolecular Interactions Studies, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-662 Warsaw, Poland; (M.M.-K.); (P.M.)
- Correspondence: (A.S.); (T.K.); Tel.: +48-792-350-130 (A.S.); +48-880-010-863 (T.K.)
| | - Małgorzata Milner-Krawczyk
- Laboratory of Biomolecular Interactions Studies, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-662 Warsaw, Poland; (M.M.-K.); (P.M.)
| | - Paulina Musolf
- Laboratory of Biomolecular Interactions Studies, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-662 Warsaw, Poland; (M.M.-K.); (P.M.)
| | - Tomasz Starecki
- Institute of Electronic Systems, Warsaw University of Technology, Nowowiejska 15/19, 00-665 Warsaw, Poland;
| | - Tomasz Kobiela
- Laboratory of Biomolecular Interactions Studies, Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-662 Warsaw, Poland; (M.M.-K.); (P.M.)
- Correspondence: (A.S.); (T.K.); Tel.: +48-792-350-130 (A.S.); +48-880-010-863 (T.K.)
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Helmrich N, Roderfeld M, Baier A, Windhorst A, Herebian D, Mayatepek E, Dierkes C, Ocker M, Glebe D, Christ B, Churin Y, Irungbam K, Roeb E. Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4 -/- Mice. Cell Mol Gastroenterol Hepatol 2021; 13:1041-1055. [PMID: 34954190 PMCID: PMC8873597 DOI: 10.1016/j.jcmgh.2021.12.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 11/26/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. METHODS After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. RESULTS Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. CONCLUSIONS We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.
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Affiliation(s)
| | | | - Anne Baier
- Department of Gastroenterology, Giessen, Germany
| | - Anita Windhorst
- Institute for Medical Informatics, Justus Liebig University, Giessen, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Christian Dierkes
- Medizinisches Versorgungszentrum for Pathology, Justus Liebig University Giessen, Trier, Germany
| | - Matthias Ocker
- Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University, Giessen, Germany
| | - Bruno Christ
- Applied Molecular Hepatology Laboratory, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany
| | - Yuri Churin
- Department of Gastroenterology, Giessen, Germany
| | | | - Elke Roeb
- Department of Gastroenterology, Giessen, Germany.
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The therapeutic potential of second and third generation CB1R antagonists. Pharmacol Ther 2020; 208:107477. [DOI: 10.1016/j.pharmthera.2020.107477] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/02/2020] [Indexed: 12/25/2022]
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The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures. Cells 2019; 8:cells8090995. [PMID: 31466340 PMCID: PMC6770406 DOI: 10.3390/cells8090995] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 08/22/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Cannabidiol (CBD), as the only phytocannabinoid that has no psychoactive effect, has both antioxidant and anti-inflammatory effects, and thus might be suggested as a cytoprotective compound against UV-induced metabolic changes in skin cells. Therefore, the aim of this study was to investigate the level of protective CBD activity by evaluating the proteomic profile of 2D and 3D cultured skin fibroblasts models following exposure to UVA and UVB radiation. The CBD cytoprotective effect against UV-induced damage in 2D and 3D cultured fibroblasts were different. The main alterations focus on the range of cell reaction and involved different proteins associated with various molecular functions. In the 2D cultured cells, following UV radiation, the major changes were associated with proteins involved in antioxidant response and inflammation, while, in the 3D cultured fibroblasts, CBD action against UV induced changes were mainly associated with the activation of signalling pathways. Therefore, the knowledge of the CBD action in a multilayer skin cells model allowed for the prediction of changes in cell-cell interactions and skin cell metabolism. Knowledge about the lower protective effect of CBD in 3D cultured fibroblasts should be taken into account during the design of UV light protection.
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Kassem KM, Ali M, Rhaleb NE. Interleukin 4: Its Role in Hypertension, Atherosclerosis, Valvular, and Nonvalvular Cardiovascular Diseases. J Cardiovasc Pharmacol Ther 2019; 25:7-14. [PMID: 31401864 DOI: 10.1177/1074248419868699] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hypertension is one of the major physiological risk factors for cardiovascular diseases, and it affects more than 1 billion adults worldwide, killing 9 million people every year according to World Health Organization. Also, hypertension is associated with increased risk of kidney disease and stroke. Studying the risk factors that contribute to the pathogenesis of hypertension is key to preventing and controlling hypertension. Numerous laboratories around to globe are very active pursuing research studies to delineate the factors, such as the role of immune system, which could contribute to hypertension. There are studies that were conducted on immune-deficient mice for which experimentally induced hypertension has been ameliorated. Thus, there are possibilities that immune reactivity could be associated with the development of certain type of hypertension. Furthermore, interleukin 4 has been associated with the development of pulmonary hypertension, which could lead to right ventricular remodeling. Also, the immune system is involved in valvular and nonvalvular cardiac remodeling. It has been demonstrated that there is a causative relationship between different interleukins and cardiac fibrosis.
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Affiliation(s)
- Kamal M Kassem
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
| | - Mahboob Ali
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Nour-Eddine Rhaleb
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.,Department of Physiology, Wayne State University, Detroit, MI, USA
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Petersen DR, Orlicky DJ, Roede JR, Shearn CT. Aberrant expression of redox regulatory proteins in patients with concomitant primary Sclerosing cholangitis/inflammatory bowel disease. Exp Mol Pathol 2018; 105:32-36. [PMID: 29852184 DOI: 10.1016/j.yexmp.2018.05.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/26/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Primary Sclerosing Cholangitis (PSC) is a severe cholestatic liver disease characterized by progressive peri-biliary tract inflammation, elevated oxidative stress and hepatocellular injury. A hallmark of PSC patients is the concurrent diagnosis of Inflammatory Bowel Disease occurring in approximately 70%-80% of PSC patients (PSC/IBD). We previously reported dysregulation of key anti-oxidant pathways in PSC/IBD. The objective of this study was to expand previous data by examining the abundance of thioredoxins (Trx) in PSC/IBD. METHODS Using hepatic tissue and whole cell extracts isolated from age-matched healthy humans and patients diagnosed with end stage PSC/IBD, the protein abundance of thioredoxin, thioredoxin reductase (TrxR1), and their downstream substrates peroxiredoxins was assessed. RESULTS Western blot analyses of thioredoxin and peroxiredoxin abundance revealed significant increases in abundance of Trx1 and TrxR1 whereas expression of thioredoxin-interacting protein was significantly decreased in PSC/IBD. Concurrently, abundance of cytosolic peroxiredoxins was not significantly impacted. The abundance of mitochondrial Trx2, along with peroxiredoxins 3, 5 and 6 were significantly decreased by concurrent PSC/IBD. Histological staining of Trx1/TrxR1 revealed elevated nuclear Trx1 and TrxR1 staining within cholangiocytes as well as an overall periportal increase in expression in PSC/IBD. An examination of additional anti-oxidant responses reveal suppression of gamma-glutamylcysteine synthetase and heme oxygenase (HO-1) whereas expression of the protein chaperone glucose regulated protein 78 increased suggesting elevated cellular stress in PSC/IBD. CONCLUSIONS Results herein suggest that in addition to severe dysregulation of anti-oxidant responses, cholestasis impacts both cytosolic/nuclear (Trx1) as well as mitochondrial (Trx2) redox signaling and control pathways.
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Affiliation(s)
- Dennis R Petersen
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
| | - David J Orlicky
- Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - James R Roede
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, United States
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, United States.
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McMillin M, DeMorrow S, Glaser S, Venter J, Kyritsi K, Zhou T, Grant S, Giang T, Greene JF, Wu N, Jefferson B, Meng F, Alpini G. Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats. Am J Physiol Gastrointest Liver Physiol 2017; 313:G410-G418. [PMID: 28751425 PMCID: PMC5792219 DOI: 10.1152/ajpgi.00421.2016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 06/23/2017] [Accepted: 07/05/2017] [Indexed: 01/31/2023]
Abstract
Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.
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Affiliation(s)
- Matthew McMillin
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Sharon DeMorrow
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Julie Venter
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Konstantina Kyritsi
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Tianhao Zhou
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Stephanie Grant
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Thao Giang
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - John F Greene
- Department of Pathology, Baylor Scott & White Health, Temple, Texas; and
| | - Nan Wu
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Brandi Jefferson
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, Texas
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
- Research Foundation, Baylor Scott & White Health, Temple, Texas
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, Texas;
- Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas
- Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center and Baylor Scott & White Health, Temple, Texas
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Jourdan T, Nicoloro SM, Zhou Z, Shen Y, Liu J, Coffey NJ, Cinar R, Godlewski G, Gao B, Aouadi M, Czech MP, Kunos G. Decreasing CB 1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice. Mol Metab 2017; 6:1517-1528. [PMID: 29107297 PMCID: PMC5681272 DOI: 10.1016/j.molmet.2017.08.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/24/2017] [Accepted: 08/25/2017] [Indexed: 12/15/2022] Open
Abstract
Objective Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-α, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. Methods We used intravenously administered β-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. Results We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation. Conclusion These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro-inflammatory mechanism.
CB1R signaling promotes hepatic insulin resistance by promoting hepatic steatosis and hepatic inflammation. CB1R knock-down in liver macrophages (Kupffer cells, KCs) improves global insulin resistance and glucose homeostasis. CB1R expressed in KCs play a critical role in hepatic insulin resistance independent of ectopic fat in the liver or adipose tissue inflammation.
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Affiliation(s)
- Tony Jourdan
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA.
| | - Sarah M Nicoloro
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Zhou Zhou
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA
| | - Yuefei Shen
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Jie Liu
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA
| | - Nathan J Coffey
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA
| | - Resat Cinar
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA
| | - Myriam Aouadi
- Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20852, USA.
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11
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Abstract
The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny, and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.
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MESH Headings
- Alternative Splicing/genetics
- Animals
- Humans
- Phylogeny
- Polymorphism, Genetic
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/genetics
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/genetics
- Receptor, Cannabinoid, CB2/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Allyn C Howlett
- Center for Research on Substance Use and Addiction, Wake Forest University Health Sciences, Winston-Salem, NC, United States
| | - Mary E Abood
- Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
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12
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Yang CY, Chau YP, Chen A, Lee OKS, Tarng DC, Yang AH. Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis. World J Nephrol 2017; 6:111-118. [PMID: 28540200 PMCID: PMC5424432 DOI: 10.5527/wjn.v6.i3.111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/20/2017] [Accepted: 02/20/2017] [Indexed: 02/06/2023] Open
Abstract
Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2 receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.
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13
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Dai E, Zhang L, Ye L, Wan S, Feng L, Qi Q, Yao F, Li Z. Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B. Int J Infect Dis 2017; 59:124-130. [PMID: 28315398 DOI: 10.1016/j.ijid.2017.03.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/13/2017] [Accepted: 03/08/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The endocannabinoid system is involved in the pathogenesis of liver fibrosis. However, most of the findings in this area have come from experimental studies in animal models or clinical trials on chronic hepatitis C. The roles of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) in hepatofibrosis in patients with chronic hepatitis B (CHB) have not been studied fully. This study aimed to explore the relationship between liver fibrosis and the expression of CB1 and CB2 in patients with CHB. METHODS Eighty liver biopsy specimens from patients with CHB (52 male, 28 female) were analyzed in this study. Fibrosis was staged on a scale of 1 to 4 (F1 to F4, with F4 defining cirrhosis). There were 20 samples for each fibrosis stage. The expression of hepatic alpha-smooth muscle actin (α-SMA), CB1, and CB2 was detected by immunohistochemistry. RESULTS Hepatic CB1 and CB2 were expressed in all patients with CHB. The degree of fibrosis was significantly associated with the increased expression of CB1 and CB2 in CHB. Furthermore a significant increase in cells positive for both CB1 and CB2 was detected in stage 3 and stage 4 disease compared to stage 1 and stage 2 disease. There was a strong positive association between CB1 expression and α-SMA expression. Moreover, double immunofluorescence staining for CB1 and α-SMA demonstrated that activated hepatic stellate cells (HSCs) express CB1. CONCLUSIONS The hepatic expression of CB1 and CB2 plays an important role during the progression of fibrosis induced by CHB. Endogenous activation of CB1 receptors in patients with CHB enhances fibrogenesis by direct effect on activated HSCs.
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Affiliation(s)
- Erhei Dai
- Division of Liver Diseases, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, China
| | - Lianshan Zhang
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
| | - Lihong Ye
- Division of Liver Diseases, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, China
| | - Shiqing Wan
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Lulu Feng
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Qi Qi
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Fang Yao
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Zhen Li
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
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14
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McMillin M, Frampton G, Grant S, DeMorrow S. The Neuropeptide Galanin Is Up-Regulated during Cholestasis and Contributes to Cholangiocyte Proliferation. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:819-830. [PMID: 28196718 DOI: 10.1016/j.ajpath.2016.12.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 12/07/2016] [Accepted: 12/22/2016] [Indexed: 12/18/2022]
Abstract
During the course of cholestatic liver diseases, mitotically dormant cholangiocytes proliferate and subsequently acquire a neuroendocrine phenotype. Galanin is a neuroendocrine factor responsible for regulation of physiological responses, such as feeding behavior and mood, and has been implicated in the development of fatty liver disease, although its role in biliary hyperplasia is unknown. Biliary hyperplasia was induced in rats via bile duct ligation (BDL) surgery, and galanin was increased in serum and liver homogenates from BDL rats. Treatment of sham and BDL rats with recombinant galanin increased cholangiocyte proliferation and intrahepatic biliary mass, liver damage, and inflammation, whereas blocking galanin expression with specific vivo-morpholino sequences inhibited hyperplastic cholangiocyte proliferation, liver damage, inflammation, and subsequent fibrosis. The proliferative effects of galanin were via activation of galanin receptor 1 expressed specifically on cholangiocytes and were associated with an activation of extracellular signal-regulated kinase 1/2, and ribosomal S6 kinase 1 signal transduction pathways and subsequent increase in cAMP responsive element binding protein DNA-binding activity and induction of Yes-associated protein expression. Strategies to inhibit extracellular signal-regulated kinase 1/2, ribosomal S6 kinase 1, or cAMP responsive element binding protein DNA-binding activity prevented the proliferative effects of galanin. Taken together, these data suggest that targeting galanin signaling may be effective for the maintenance of biliary mass during cholestatic liver diseases.
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Affiliation(s)
- Matthew McMillin
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Gabriel Frampton
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Stephanie Grant
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Sharon DeMorrow
- Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas.
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15
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Nizamutdinov D, DeMorrow S, McMillin M, Kain J, Mukherjee S, Zeitouni S, Frampton G, Bricker PCS, Hurst J, Shapiro LA. Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury. Sci Rep 2017; 7:40112. [PMID: 28106051 PMCID: PMC5247752 DOI: 10.1038/srep40112] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 12/02/2016] [Indexed: 12/29/2022] Open
Abstract
Annually, there are over 2 million incidents of traumatic brain injury (TBI) and treatment options are non-existent. While many TBI studies have focused on the brain, peripheral contributions involving the digestive and immune systems are emerging as factors involved in the various symptomology associated with TBI. We hypothesized that TBI would alter hepatic function, including bile acid system machinery in the liver and brain. The results show activation of the hepatic acute phase response by 2 hours after TBI, hepatic inflammation by 6 hours after TBI and a decrease in hepatic transcription factors, Gli 1, Gli 2, Gli 3 at 2 and 24 hrs after TBI. Bile acid receptors and transporters were decreased as early as 2 hrs after TBI until at least 24 hrs after TBI. Quantification of bile acid transporter, ASBT-expressing neurons in the hypothalamus, revealed a significant decrease following TBI. These results are the first to show such changes following a TBI, and are compatible with previous studies of the bile acid system in stroke models. The data support the emerging idea of a systemic influence to neurological disorders and point to the need for future studies to better define specific mechanisms of action.
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Affiliation(s)
- Damir Nizamutdinov
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA.,Department of Neurosurgery, Neuroscience Research Institute, Baylor Scott &White Health, Temple, Texas, 76504, USA
| | - Sharon DeMorrow
- Departent of Internal Medicine, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA.,Central Texas Veterans Health Care System, Temple, Texas, 76504, USA
| | - Matthew McMillin
- Departent of Internal Medicine, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA.,Central Texas Veterans Health Care System, Temple, Texas, 76504, USA
| | - Jessica Kain
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA
| | - Sanjib Mukherjee
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA
| | - Suzanne Zeitouni
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA
| | - Gabriel Frampton
- Departent of Internal Medicine, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA.,Central Texas Veterans Health Care System, Temple, Texas, 76504, USA
| | - Paul Clint S Bricker
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA
| | - Jacob Hurst
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA
| | - Lee A Shapiro
- Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, Texas, 76504, USA.,Department of Neurosurgery, Neuroscience Research Institute, Baylor Scott &White Health, Temple, Texas, 76504, USA
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16
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Biernacki M, Łuczaj W, Gęgotek A, Toczek M, Bielawska K, Skrzydlewska E. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats. Toxicol Appl Pharmacol 2016; 301:31-41. [PMID: 27086176 DOI: 10.1016/j.taap.2016.04.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 03/17/2016] [Accepted: 04/08/2016] [Indexed: 02/07/2023]
Abstract
Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis.
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Affiliation(s)
- Michał Biernacki
- Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
| | - Wojciech Łuczaj
- Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
| | - Agnieszka Gęgotek
- Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
| | - Marek Toczek
- Department of Experimental Physiology and Pathophysiology Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland
| | - Katarzyna Bielawska
- Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland
| | - Elżbieta Skrzydlewska
- Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland.
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17
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Gonadotropin-releasing hormone stimulates biliary proliferation by paracrine/autocrine mechanisms. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1061-72. [PMID: 25794706 PMCID: PMC4380841 DOI: 10.1016/j.ajpath.2014.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 12/16/2014] [Accepted: 12/30/2014] [Indexed: 11/22/2022]
Abstract
During cholestatic liver disease, there is dysregulation in the balance between biliary growth and loss in bile duct-ligated (BDL) rats modulated by neuroendocrine peptides via autocrine/paracrine pathways. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone that modulates reproductive function and proliferation in many cell types. We evaluated the autocrine role of GnRH in the regulation of cholangiocyte proliferation. The expression of GnRH receptors was assessed in a normal mouse cholangiocyte cell line (NMC), sham, and BDL rats. The effect of GnRH administration was evaluated in normal rats and in NMC. GnRH-induced biliary proliferation was evaluated by changes in intrahepatic bile duct mass and the expression of proliferation and function markers. The expression and secretion of GnRH in NMC and isolated cholangiocytes was assessed. GnRH receptor subtypes GnRHR1 and GnRHR2 were expressed in cholangiocytes. Treatment with GnRH increased intrahepatic bile duct mass as well as proliferation and function markers in cholangiocytes. Transient knockdown and pharmacologic inhibition of GnRHR1 in NMC decreased proliferation. BDL cholangiocytes had increased expression of GnRH compared with normal rats, accompanied by increased GnRH secretion. In vivo and in vitro knockdown of GnRH decreased intrahepatic bile duct mass/cholangiocyte proliferation and fibrosis. GnRH secreted by cholangiocytes promotes biliary proliferation via an autocrine pathway. Disruption of GnRH/GnRHR signaling may be important for the management of cholestatic liver diseases.
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18
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Mancinelli R, Glaser S, Francis H, Carpino G, Franchitto A, Vetuschi A, Sferra R, Pannarale L, Venter J, Meng F, Alpini G, Onori P, Gaudio E. Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors. Am J Physiol Gastrointest Liver Physiol 2015; 309:G865-73. [PMID: 26451003 PMCID: PMC4669349 DOI: 10.1152/ajpgi.00015.2015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023]
Abstract
Liver transplantation and cholangiocarcinoma induce biliary dysfunction following ischemia reperfusion (IR). The function of the intrahepatic biliary tree is regulated by both autocrine and paracrine factors. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors. Normal and bile duct ligation rats underwent 24-h sham or hepatic reperfusion after 30 min of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) before collecting liver blocks and cholangiocyte RNA or protein. We evaluated liver histology, biliary apoptosis, proliferation and expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2 in liver sections and isolated small and large cholangiocytes. Normal rat intrahepatic cholangiocyte cultures (NRICC) were maintained under standard conditions in normoxic or under a hypoxic atmosphere for 4 h and then transferred to normal conditions for selected times. Subsequently, we measured changes in biliary proliferation and apoptosis and the expression of VEGF-A/C and VEGFR-2/3. In vivo, HAIR (but not PVIR) induced damage of large bile ducts and decreased proliferation and secretin-stimulated cAMP levels. HAIR-induced damage of large bile ducts was associated with increased expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2. In vitro, under hypoxic conditions, there was increased apoptosis and reduced proliferation of NRICC concomitant with enhanced expression of VEGF-A/C and VEGFR-2/3. The functional damage of large bile ducts by HAIR and hypoxia is associated with increased expression of angiogenic factors in small cholangiocytes, presumably due to a compensatory mechanism in response to biliary damage.
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Affiliation(s)
- Romina Mancinelli
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Shannon Glaser
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Heather Francis
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Guido Carpino
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Antonio Franchitto
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy; ,6Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy
| | - Antonella Vetuschi
- 5Department of Biotechnological and Applied Clinical Sciences, University of L′Aquila, L′Aquila, Italy;
| | - Roberta Sferra
- 5Department of Biotechnological and Applied Clinical Sciences, University of L′Aquila, L′Aquila, Italy;
| | - Luigi Pannarale
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Julie Venter
- 4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Fanyin Meng
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Gianfranco Alpini
- 2Research, Central Texas Veterans Health Care System, Temple, Texas; ,3Scott & White Digestive Disease Research Center, Baylor Scott & White, Temple, Texas; ,4Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, College of Medicine, Temple, Texas;
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
| | - Eugenio Gaudio
- 1Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, Rome, Italy;
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19
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McMillin M, Frampton G, Quinn M, Divan A, Grant S, Patel N, Newell-Rogers K, DeMorrow S. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling. Mol Endocrinol 2015; 29:1720-30. [PMID: 26431088 DOI: 10.1210/me.2015-1087] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.
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Affiliation(s)
- Matthew McMillin
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Gabriel Frampton
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Matthew Quinn
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Ali Divan
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Stephanie Grant
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Nisha Patel
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Karen Newell-Rogers
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
| | - Sharon DeMorrow
- Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709
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20
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Kennedy LL, Hargrove LA, Graf AB, Francis TC, Hodges KM, Nguyen QP, Ueno Y, Greene JF, Meng F, Huynh VD, Francis HL. Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents. J Transl Med 2014; 94:1406-18. [PMID: 25365204 DOI: 10.1038/labinvest.2014.129] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/07/2014] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24 mg/kg BW/day (inhibits MC histamine release)) for 1 week. Serum, liver blocks and cholangiocytes were collected. Histidine decarboxylase (HDC) expression was measured using real-time PCR in cholangiocytes. Intrahepatic bile duct mass (IBDM) was evaluated by IHC for CK-19. MC number was determined using toluidine blue staining and correlated to IBDM. Proliferation was evaluated by PCNA expression in liver sections and purified cholangiocytes. We assessed apoptosis using real-time PCR and IHC for BAX. Expression of MC stem factor receptor, c-kit, and the proteases chymase and tryptase were measured by real-time PCR. HA levels were measured in serum by EIA. In vitro, MCs and cholangiocytes were treated with 0.1% BSA (basal) or cromolyn (25 μM) for up to 48 h prior to assessing HDC expression, HA levels and chymase and tryptase expression. Supernatants from MCs treated with or without cromolyn were added to cholangiocytes before measuring (i) proliferation by MTT assays, (ii) HDC gene expression by real-time PCR and (iii) HA release by EIA. In vivo, cromolyn treatment decreased BDL-induced: (i) IBDM, MC number, and biliary proliferation; (ii) HDC and MC marker expression; and (iii) HA levels. Cromolyn treatment increased cholangiocyte apoptosis. In vitro, cromolyn decreased HA release and chymase and tryptase expression in MCs but not in cholangiocytes. Cromolyn-treated MC supernatants decreased biliary proliferation and HA release. These studies provide evidence that MC histamine is key to biliary proliferation and may be a therapeutic target for the treatment of cholangiopathies.
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Affiliation(s)
- Lindsey L Kennedy
- Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Laura A Hargrove
- Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA
| | - Allyson B Graf
- Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Taylor C Francis
- Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | - Kyle M Hodges
- Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA
| | - Quy P Nguyen
- Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Yoshi Ueno
- CREST, Japan Science and Technology Corporation, Tokyo, Japan
| | - John F Greene
- Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA
| | - Fanyin Meng
- 1] Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA [2] Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA [3] Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | - Victoria D Huynh
- Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | - Heather L Francis
- 1] Digestive Disease Research Center, Central Texas Veterans Health Care System, Temple, TX, USA [2] Scott and White Digestive Disease Research Center, Scott and White, Temple, TX, USA [3] Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA
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21
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Graf A, Meng F, Hargrove L, Kennedy L, Han Y, Francis T, Hodges K, Ueno Y, Nguyen Q, Greene JF, Francis H. Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling. Am J Physiol Gastrointest Liver Physiol 2014; 307:G813-23. [PMID: 25169977 DOI: 10.1152/ajpgi.00188.2014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Histidine is converted to histamine by histidine decarboxylase (HDC). We have shown that cholangiocytes 1) express HDC, 2) secrete histamine, and 3) proliferate after histamine treatment via ERK1/2 signaling. In bile duct-ligated (BDL) rodents, there is enhanced biliary hyperplasia, HDC expression, and histamine secretion. This studied aimed to demonstrate that knockdown of HDC inhibits biliary proliferation via downregulation of PKA/ERK1/2 signaling. HDC(-/-) mice and matching wild-type (WT) were subjected to sham or BDL. After 1 wk, serum, liver blocks, and cholangiocytes were collected. Immunohistochemistry was performed for 1) hematoxylin and eosin, 2) intrahepatic bile duct mass (IBDM) by cytokeratin-19, and 3) HDC biliary expression. We measured serum and cholangiocyte histamine levels by enzyme immunoassay. In total liver or cholangiocytes, we studied: 1) HDC and VEGF/HIF-1α expression and 2) PCNA and PKA/ERK1/2 protein expression. In vitro, cholangiocytes were stably transfected with shRNA-HDC plasmids (or control). After transfection we evaluated pPKA, pERK1/2, and cholangiocyte proliferation by immunoblots and MTT assay. In BDL HDC(-/-) mice, there was decreased IBDM, PCNA, VEGF, and HDC expression compared with BDL WT mice. Histamine levels were decreased in BDL HDC(-/-). BDL HDC(-/-) livers were void of necrosis and inflammation compared with BDL WT. PKA/ERK1/2 protein expression (increased in WT BDL) was lower in BDL HDC(-/-) cholangiocytes. In vitro, knockdown of HDC decreased proliferation and protein expression of PKA/ERK1/2 compared with control. In conclusion, loss of HDC decreases BDL-induced biliary mass and VEGF/HIF-1α expression via PKA/ERK1/2 signaling. Our data suggest that HDC is a key regulator of biliary proliferation.
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Affiliation(s)
| | - Fanyin Meng
- Central Texas Veterans Health Care System, Temple, Texas; Scott & White Healthcare, Temple, Texas; Texas A&M Health Science Center, Temple, Texas
| | | | | | - Yuyan Han
- Texas A&M Health Science Center, Temple, Texas
| | | | | | - Yoshiyuki Ueno
- Yamagata University, Department of Gastroenterology, Yamagata, Japan; and CREST, Japan Science and Technology Corporation, Tokyo, Japan
| | | | | | - Heather Francis
- Central Texas Veterans Health Care System, Temple, Texas; Scott & White Healthcare, Temple, Texas; Texas A&M Health Science Center, Temple, Texas
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22
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Basu PP, Aloysius MM, Shah NJ, Brown RS. Review article: the endocannabinoid system in liver disease, a potential therapeutic target. Aliment Pharmacol Ther 2014; 39:790-801. [PMID: 24612021 DOI: 10.1111/apt.12673] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Revised: 12/16/2013] [Accepted: 02/03/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Endocannabinoids are a family of potent lipid-soluble molecules, acting on the cannabinoid (CB) receptors that mediate the effects of marijuana. The CB receptors, endocannabinoids and the enzymes involved in their synthesis and degradation are located in the brain and peripheral tissues, including the liver. AIMS To review the current understanding of the role of the endocannabinoid system in liver disease-associated pathophysiological conditions, and drugs targeting the endocannabinoid system as therapy for liver disease. METHODS Original articles and reviews were used to summarise the relevant pre-clinical and clinical research findings relating to this topic. RESULTS The endocannabinoid system as a whole plays an important role in liver diseases (i.e. non-alcoholic liver disease, alcoholic liver disease, hepatic encephalopathy and autoimmune hepatitis) and related pathophysiological conditions (i.e. altered hepatic haemodynamics, cirrhotic cardiomyopathy, metabolic syndrome and ischaemia/reperfusion disease). Pharmacological targeting of the endocannabinoid system has had success as treatment for patients with liver disease, but adverse events led to withdrawal of marketing approval. However, there is optimism over novel therapeutics targeting the endocannabinoid system currently in the pre-clinical stage of development. CONCLUSIONS The endocannabinoid system plays an important role in the pathophysiology of liver disease and its associated conditions. While some drugs targeting the endocannabinoid system have deleterious neurological adverse events, there is promise for a newer generation of therapies that do not cross the blood-brain barrier.
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Affiliation(s)
- P P Basu
- Division of Digestive and Liver Diseases and Center for Liver Disease and Transplantation, Columbia University Medical Center, NY, USA; King's County Hospital Medical Center, Brooklyn, NY, USA
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Han Y, Glaser S, Meng F, Francis H, Marzioni M, McDaniel K, Alvaro D, Venter J, Carpino G, Onori P, Gaudio E, Alpini G, Franchitto A. Recent advances in the morphological and functional heterogeneity of the biliary epithelium. Exp Biol Med (Maywood) 2013; 238:549-65. [PMID: 23856906 DOI: 10.1177/1535370213489926] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This review focuses on the recent advances related to the heterogeneity of different-sized bile ducts with regard to the morphological and phenotypical characteristics, and the differential secretory, apoptotic and proliferative responses of small and large cholangiocytes to gastrointestinal hormones/peptides, neuropeptides and toxins. We describe several in vivo and in vitro models used for evaluating biliary heterogeneity. Subsequently, we discuss the heterogeneous proliferative and apoptotic responses of small and large cholangiocytes to liver injury and the mechanisms regulating the differentiation of small into large (more differentiated) cholangiocytes. Following a discussion on the heterogeneity of stem/progenitor cells in the biliary epithelium, we outline the heterogeneity of bile ducts in human cholangiopathies. After a summary section, we discuss the future perspectives that will further advance the field of the functional heterogeneity of the biliary epithelium.
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Affiliation(s)
- Yuyan Han
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, TX, USA
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Frampton G, Ueno Y, Quinn M, McMillin M, Pae HY, Galindo C, Leyva-Illades D, DeMorrow S. The novel growth factor, progranulin, stimulates mouse cholangiocyte proliferation via sirtuin-1-mediated inactivation of FOXO1. Am J Physiol Gastrointest Liver Physiol 2012; 303:G1202-11. [PMID: 23086914 PMCID: PMC3532458 DOI: 10.1152/ajpgi.00104.2012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Progranulin (PGRN), a secreted growth factor, regulates the proliferation of various epithelial cells. Its mechanism of action is largely unknown. Sirtuin 1 (Sirt1) is a protein deacetylase that is known to regulate the transcriptional activity of the forkhead receptor FOXO1, thereby modulating the balance between proapoptotic and cell cycle-arresting genes. We have shown that PGRN is overexpressed in cholangiocarcinoma and stimulates proliferation. However, its effects on hyperplastic cholangiocyte proliferation are unknown. In the present study, the expression of PGRN and its downstream targets was determined after bile duct ligation (BDL) in mice and in a mouse cholangiocyte cell line after stimulation with PGRN. The effects of PGRN on cholangiocyte proliferation were assessed in sham-operated (sham) and BDL mice treated with PGRN or by specifically knocking down endogenous PGRN expression using Vivo-Morpholinos or short hairpin RNA. PGRN expression and secretion were upregulated in proliferating cholangiocytes isolated after BDL. Treatment of mice with PGRN increased biliary mass and cholangiocyte proliferation in vivo and in vitro and enhanced cholangiocyte proliferation observed after BDL. PGRN treatment decreased Sirt1 expression and increased the acetylation of FOXO1, resulting in the cytoplasmic accumulation of FOXO1 in cholangiocytes. Overexpression of Sirt1 in vitro prevented the proliferative effects of PGRN. Conversely, knocking down PGRN expression in vitro or in vivo inhibited cholangiocyte proliferation. In conclusion, these data suggest that the upregulation of PGRN may be a key feature stimulating cholangiocyte proliferation. Modulating PGRN levels may be a viable technique for regulating the balance between ductal proliferation and ductopenia observed in a variety of cholangiopathies.
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Affiliation(s)
- Gabriel Frampton
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
| | - Yoshiyuki Ueno
- 4Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Matthew Quinn
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
| | - Matthew McMillin
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
| | - Hae Yong Pae
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
| | - Cheryl Galindo
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
| | - Dinorah Leyva-Illades
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
| | - Sharon DeMorrow
- 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; ,2Digestive Disease Research Center, Scott & White Hospital, Temple, Texas; ,3Central Texas Veterans Health Care System, Temple, Texas; and
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Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events. J Transl Med 2012; 92:1451-60. [PMID: 22906985 PMCID: PMC3959781 DOI: 10.1038/labinvest.2012.110] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. MAOA expression was assessed in cholangiocarcinoma and nonmalignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of interleukin-6 (IL-6) signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.
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Downer EJ, Clifford E, Amu S, Fallon PG, Moynagh PN. The synthetic cannabinoid R(+)WIN55,212-2 augments interferon-β expression via peroxisome proliferator-activated receptor-α. J Biol Chem 2012; 287:25440-53. [PMID: 22654113 DOI: 10.1074/jbc.m112.371757] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We have demonstrated that R(+)WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN-β expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor-α (PPARα) in mediating the effects of R(+)WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN-β expression and R(+)WIN55,212-2 enhances TLR3-induced IFN-β expression in a stereoselective manner via PPARα. R(+)WIN55,212-2 promotes increased transactivation and expression of PPARα. Using the PPARα antagonist GW6471, we demonstrate that R(+)WIN55,212-2 acts via PPARα to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN-β promoter. Furthermore, GW6471 ameliorated the protective effects of R(+)WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPARα as an important mediator in manifesting the effects of R(+)WIN55,212-2 on the signaling cascade regulating IFN-β expression. The study adds to our molecular appreciation of potential therapeutic effects of R(+)WIN55,212-2 in multiple sclerosis.
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Affiliation(s)
- Eric J Downer
- Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland
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Abstract
BACKGROUND AND OBJECTIVES Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth. METHODS The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined. RESULTS Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo. CONCLUSIONS Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies.
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Floreani A, Pizzuti D, Bergasa NV, Petrosino S. The endocannabinoid system in cholestasis. Dig Liver Dis 2011; 43:1026-7. [PMID: 21816694 DOI: 10.1016/j.dld.2011.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Revised: 04/18/2011] [Accepted: 05/05/2011] [Indexed: 12/11/2022]
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Yang F, Priester S, Onori P, Venter J, Renzi A, Franchitto A, Munshi MK, Wise C, Dostal DE, Marzioni M, Saccomanno S, Ueno Y, Gaudio E, Glaser S. Castration inhibits biliary proliferation induced by bile duct obstruction: novel role for the autocrine trophic effect of testosterone. Am J Physiol Gastrointest Liver Physiol 2011; 301:G981-91. [PMID: 21903763 PMCID: PMC3233786 DOI: 10.1152/ajpgi.00061.2011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Increased cholangiocyte growth is critical for the maintenance of biliary mass during liver injury by bile duct ligation (BDL). Circulating levels of testosterone decline following castration and during cholestasis. Cholangiocytes secrete sex hormones sustaining cholangiocyte growth by autocrine mechanisms. We tested the hypothesis that testosterone is an autocrine trophic factor stimulating biliary growth. The expression of androgen receptor (AR) was determined in liver sections, male cholangiocytes, and cholangiocyte cultures [normal rat intrahepatic cholangiocyte cultures (NRICC)]. Normal or BDL (immediately after surgery) rats were treated with testosterone or antitestosterone antibody or underwent surgical castration (followed by administration of testosterone) for 1 wk. We evaluated testosterone serum levels; intrahepatic bile duct mass (IBDM) in liver sections of female and male rats following the administration of testosterone; and secretin-stimulated cAMP levels and bile secretion. We evaluated the expression of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3, the enzyme regulating testosterone synthesis) in cholangiocytes. We evaluated the effect of testosterone on the proliferation of NRICC in the absence/presence of flutamide (AR antagonist) and antitestosterone antibody and the expression of 17β-HSD3. Proliferation of NRICC was evaluated following stable knock down of 17β-HSD3. We found that cholangiocytes and NRICC expressed AR. Testosterone serum levels decreased in castrated rats (prevented by the administration of testosterone) and rats receiving antitestosterone antibody. Castration decreased IBDM and secretin-stimulated cAMP levels and ductal secretion of BDL rats. Testosterone increased 17β-HSD3 expression and proliferation in NRICC that was blocked by flutamide and antitestosterone antibody. Knock down of 17β-HSD3 blocks the proliferation of NRICC. Drug targeting of 17β-HSD3 may be important for managing cholangiopathies.
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Affiliation(s)
- Fuquan Yang
- Department of Medicine, Division of 1Gastroenterology and ,6Department of Hepatobiliary Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, China;
| | - Sally Priester
- Department of Medicine, Division of 1Gastroenterology and ,3Research & Education, Scott & White,
| | - Paolo Onori
- 7Experimental Medicine, University of L'Aquila, L'Aquila;
| | - Julie Venter
- Department of Medicine, Division of 1Gastroenterology and
| | - Anastasia Renzi
- Department of Medicine, Division of 1Gastroenterology and ,10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome;
| | - Antonio Franchitto
- 10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome; ,11Institute of Food and Radiation Safety, Dhaka, Bangladesh
| | - Md Kamruzzaman Munshi
- Department of Medicine, Division of 1Gastroenterology and ,11Institute of Food and Radiation Safety, Dhaka, Bangladesh
| | - Candace Wise
- Department of Medicine, Division of 1Gastroenterology and
| | - David E. Dostal
- 2Molecular Cardiology, Scott & White and Texas A&M Health Science Center, College of Medicine, ,5Central Texas Veterans Health Care System, Temple, Texas;
| | - Marco Marzioni
- 8Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,
| | - Stefania Saccomanno
- 8Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,
| | - Yoshiyuki Ueno
- 9Division of Gastroenterology, Tohoku Graduate University School of Medicine, Sendai, Japan; and
| | - Eugenio Gaudio
- 10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome;
| | - Shannon Glaser
- Department of Medicine, Division of 1Gastroenterology and ,4Scott & White Digestive Disease Research Center, and ,5Central Texas Veterans Health Care System, Temple, Texas;
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Wu C, Parrott AM, Fu C, Liu T, Marino SM, Gladyshev VN, Jain MR, Baykal AT, Li Q, Oka S, Sadoshima J, Beuve A, Simmons WJ, Li H. Thioredoxin 1-mediated post-translational modifications: reduction, transnitrosylation, denitrosylation, and related proteomics methodologies. Antioxid Redox Signal 2011; 15:2565-604. [PMID: 21453190 PMCID: PMC3176348 DOI: 10.1089/ars.2010.3831] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Despite the significance of redox post-translational modifications (PTMs) in regulating diverse signal transduction pathways, the enzymatic systems that catalyze reversible and specific oxidative or reductive modifications have yet to be firmly established. Thioredoxin 1 (Trx1) is a conserved antioxidant protein that is well known for its disulfide reductase activity. Interestingly, Trx1 is also able to transnitrosylate or denitrosylate (defined as processes to transfer or remove a nitric oxide entity to/from substrates) specific proteins. An intricate redox regulatory mechanism has recently been uncovered that accounts for the ability of Trx1 to catalyze these different redox PTMs. In this review, we will summarize the available evidence in support of Trx1 as a specific disulfide reductase, and denitrosylation and transnitrosylation agent, as well as the biological significance of the diverse array of Trx1-regulated pathways and processes under different physiological contexts. The dramatic progress in redox proteomics techniques has enabled the identification of an increasing number of proteins, including peroxiredoxin 1, whose disulfide bond formation and nitrosylation status are regulated by Trx1. This review will also summarize the advancements of redox proteomics techniques for the identification of the protein targets of Trx1-mediated PTMs. Collectively, these studies have shed light on the mechanisms that regulate Trx1-mediated reduction, transnitrosylation, and denitrosylation of specific target proteins, solidifying the role of Trx1 as a master regulator of redox signal transduction.
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Affiliation(s)
- Changgong Wu
- Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School Cancer Center, Newark, 07103, USA
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Huang L, Quinn MA, Frampton GA, Golden LE, DeMorrow S. Recent advances in the understanding of the role of the endocannabinoid system in liver diseases. Dig Liver Dis 2011; 43:188-93. [PMID: 20934397 PMCID: PMC3033442 DOI: 10.1016/j.dld.2010.08.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 08/29/2010] [Indexed: 12/11/2022]
Abstract
Endocannabinoids are ubiquitous signalling molecules that exert their effects through a number of specific cannabinoid receptors. Recent studies have indicated that this endocannabinoid system is involved in the pathophysiological processes associated with both acute and chronic liver diseases as well as in the complications that arise from these diseases such as hepatic encephalopathy and cardiac problems. Targeting this signalling system has been useful in ameliorating some of the symptoms and consequences in experimental models of these liver diseases. This review summarises the recent advances into our knowledge and understanding of endocannabinoids in liver diseases and highlights potential novel therapeutic strategies that may prove useful to treat these diseases.
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Affiliation(s)
- Li Huang
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple Texas
- Digestive Disease Research Center, Scott & White Hospital, Temple Texas
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Matthew A. Quinn
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple Texas
- Digestive Disease Research Center, Scott & White Hospital, Temple Texas
| | - Gabriel A. Frampton
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple Texas
| | - L. Eric. Golden
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple Texas
| | - Sharon DeMorrow
- Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple Texas
- Digestive Disease Research Center, Scott & White Hospital, Temple Texas
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Munshi MK, Priester S, Gaudio E, Yang F, Alpini G, Mancinelli R, Wise C, Meng F, Franchitto A, Onori P, Glaser SS. Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:472-84. [PMID: 21281779 PMCID: PMC3069818 DOI: 10.1016/j.ajpath.2010.09.043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Revised: 08/23/2010] [Accepted: 09/02/2010] [Indexed: 12/15/2022]
Abstract
The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction.
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Affiliation(s)
- Md Kamruzzaman Munshi
- Department of Medicine, College of Medicine, Temple, Texas
- Texas A&M Health Science Center,, College of Medicine, Temple, Texas
| | - Sally Priester
- Scott & White Digestive Disease Research Center, College of Medicine, Temple, Texas
| | - Eugenio Gaudio
- Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy
| | - Fuquan Yang
- Shengjing Hospital, China Medical University, Shenyang City, China
| | - Gianfranco Alpini
- Department of Medicine, College of Medicine, Temple, Texas
- Texas A&M Health Science Center,, College of Medicine, Temple, Texas
- Scott & White Digestive Disease Research Center, College of Medicine, Temple, Texas
- Central Texas Veterans Health Care System, Temple, Texas
| | - Romina Mancinelli
- Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy
| | - Candace Wise
- Department of Medicine, College of Medicine, Temple, Texas
| | - Fanyn Meng
- Department of Medicine, College of Medicine, Temple, Texas
- Texas A&M Health Science Center,, College of Medicine, Temple, Texas
- Scott & White Digestive Disease Research Center, College of Medicine, Temple, Texas
| | - Antonio Franchitto
- Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy
| | - Paolo Onori
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
| | - Shannon S. Glaser
- Department of Medicine, College of Medicine, Temple, Texas
- Texas A&M Health Science Center,, College of Medicine, Temple, Texas
- Scott & White Digestive Disease Research Center, College of Medicine, Temple, Texas
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Alpini G, Franchitto A, DeMorrow S, Onori P, Gaudio E, Wise C, Francis H, Venter J, Kopriva S, Mancinelli R, Carpino G, Stagnitti F, Ueno Y, Han Y, Meng F, Glaser S. Activation of alpha(1) -adrenergic receptors stimulate the growth of small mouse cholangiocytes via calcium-dependent activation of nuclear factor of activated T cells 2 and specificity protein 1. Hepatology 2011; 53:628-39. [PMID: 21274883 PMCID: PMC3522188 DOI: 10.1002/hep.24041] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2010] [Accepted: 10/01/2010] [Indexed: 01/08/2023]
Abstract
UNLABELLED Small cholangiocytes proliferate via activation of calcium (Ca(2+) )-dependent signaling in response to pathological conditions that trigger the damage of large cyclic adenosine monophosphate-dependent cholangiocytes. Although our previous studies suggest that small cholangiocyte proliferation is regulated by the activation of Ca(2+) -dependent signaling, the intracellular mechanisms regulating small cholangiocyte proliferation are undefined. Therefore, we sought to address the role and mechanisms of action by which phenylephrine, an α(1) -adrenergic agonist stimulating intracellular D-myo-inositol-1,4,5-triphosphate (IP(3) )/Ca(2+) levels, regulates small cholangiocyte proliferation. Small and large bile ducts and cholangiocytes expressed all AR receptor subtypes. Small (but not large) cholangiocytes respond to phenylephrine with increased proliferation via the activation of IP(3) /Ca(2+) -dependent signaling. Phenylephrine stimulated the production of intracellular IP(3) . The Ca(2+) -dependent transcription factors, nuclear factor of activated T cells 2 (NFAT2) and NFAT4, were predominantly expressed by small bile ducts and small cholangiocytes. Phenylephrine stimulated the Ca(2+) -dependent DNA-binding activities of NFAT2, NFAT4, and Sp1 (but not Sp3) and the nuclear translocation of NFAT2 and NFAT4 in small cholangiocytes. To determine the relative roles of NFAT2, NFAT4, or Sp1, we knocked down the expression of these transcription factors with small hairpin RNA. We observed an inhibition of phenylephrine-induced proliferation in small cholangiocytes lacking the expression of NFAT2 or Sp1. Phenylephrine stimulated small cholangiocyte proliferation is regulated by Ca(2+) -dependent activation of NFAT2 and Sp1. CONCLUSION Selective stimulation of Ca(2+) -dependent small cholangiocyte proliferation may be key to promote the repopulation of the biliary epithelium when large bile ducts are damaged during cholestasis or by toxins.
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Affiliation(s)
| | | | - Sharon DeMorrow
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
| | - Paolo Onori
- Dept. of Experimental Medicine, University of L’Aquila, L’Aquila, Italy
| | - Eugenio Gaudio
- Dept. Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - Candace Wise
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
| | - Heather Francis
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
,Division of Research and Education at Scott & White, Temple, Texas 76504
| | - Julie Venter
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
| | - Shelley Kopriva
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
| | - Romina Mancinelli
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
,Dept. Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - Guido Carpino
- Dept. of Health Science, “Foro Italico” University of Rome, Italy
| | - Franco Stagnitti
- Dept. Surgery, University of Rome “La Sapienza”, Rome, Polo Pontino, Italy
| | - Yoshiyuki Ueno
- Division of Gastroenterology, Tohoku University School of Medicine, Sendai, Japan
| | - Yuyan Han
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
| | - Fanyin Meng
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
,Division of Research and Education at Scott & White, Temple, Texas 76504
| | - Shannon Glaser
- Scott & White Digestive Disease Research Center, Temple, Texas 76504
,Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504
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Abstract
Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB(1) receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB(1) blockade. In mouse models of liver fibrosis, the activation of CB(1) receptors on hepatic stellate cells is fibrogenic, and CB(1) blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB(1) receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB(1) blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB(1) antagonists.
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Affiliation(s)
- Joseph Tam
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Jie Liu
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Bani Mukhopadhyay
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Resat Cinar
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Grzegorz Godlewski
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - George Kunos
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
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Glaser S, Lam IP, Franchitto A, Gaudio E, Onori P, Chow BK, Wise C, Kopriva S, Venter J, White M, Ueno Y, Dostal D, Carpino G, Mancinelli R, Butler W, Chiasson V, DeMorrow S, Francis H, Alpini G. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation. Hepatology 2010; 52:204-14. [PMID: 20578263 PMCID: PMC3049759 DOI: 10.1002/hep.23657] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
UNLABELLED During bile duct ligation (BDL), the growth of large cholangiocytes is regulated by the cyclic adenosine monophosphate (cAMP)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and is closely associated with increased secretin receptor (SR) expression. Although it has been suggested that SR modulates cholangiocyte growth, direct evidence for secretin-dependent proliferation is lacking. SR wild-type (WT) (SR(+/+)) or SR knockout (SR(-/-)) mice underwent sham surgery or BDL for 3 or 7 days. We evaluated SR expression, cholangiocyte proliferation, and apoptosis in liver sections and proliferating cell nuclear antigen (PCNA) protein expression and ERK1/2 phosphorylation in purified large cholangiocytes from WT and SR(-/-) BDL mice. Normal WT mice were treated with secretin (2.5 nmoles/kg/day by way of osmotic minipumps for 1 week), and biliary mass was evaluated. Small and large cholangiocytes were used to evaluate the in vitro effect of secretin (100 nM) on proliferation, protein kinase A (PKA) activity, and ERK1/2 phosphorylation. SR expression was also stably knocked down by short hairpin RNA, and basal and secretin-stimulated cAMP levels (a functional index of biliary growth) and proliferation were determined. SR was expressed by large cholangiocytes. Knockout of SR significantly decreased large cholangiocyte growth induced by BDL, which was associated with enhanced apoptosis. PCNA expression and ERK1/2 phosphorylation were decreased in large cholangiocytes from SR(-/-) BDL compared with WT BDL mice. In vivo administration of secretin to normal WT mice increased ductal mass. In vitro, secretin increased proliferation, PKA activity, and ERK1/2 phosphorylation of large cholangiocytes that was blocked by PKA and mitogen-activated protein kinase kinase inhibitors. Stable knockdown of SR expression reduced basal cholangiocyte proliferation. SR is an important trophic regulator sustaining biliary growth. CONCLUSION The current study provides strong support for the potential use of secretin as a therapy for ductopenic liver diseases.
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Affiliation(s)
- Shannon Glaser
- Scott & White Digestive Disease Research Center, College of Medicine, Temple, TX, USA.
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Mendoza-Villanueva D, Deng W, Lopez-Camacho C, Shore P. The Runx transcriptional co-activator, CBFbeta, is essential for invasion of breast cancer cells. Mol Cancer 2010; 9:171. [PMID: 20591170 PMCID: PMC2905338 DOI: 10.1186/1476-4598-9-171] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Accepted: 06/30/2010] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND The transcription factor Runx2 has an established role in cancers that metastasize to bone. In metastatic breast cancer cells Runx2 is overexpressed and contributes to the invasive capacity of the cells by regulating the expression of several invasion genes. CBFbeta is a transcriptional co-activator that is recruited to promoters by Runx transcription factors and there is considerable evidence that CBFbeta is essential for the function of Runx factors. However, overexpression of Runx1 can partially rescue the lethal phenotype in CBFbeta-deficient mice, indicating that increased levels of Runx factors can, in some situations, overcome the requirement for CBFbeta. Since Runx2 is overexpressed in metastatic breast cancer cells, and there are no reports of CBFbeta expression in breast cells, we sought to determine whether Runx2 function in these cells was dependent on CBFbeta. Such an interaction might represent a viable target for therapeutic intervention to inhibit bone metastasis. RESULTS We show that CBFbeta is expressed in the metastatic breast cancer cells, MDA-MB-231, and that it associates with Runx2. Matrigel invasion assays and RNA interference were used to demonstrate that CBFbeta contributes to the invasive capacity of these cells. Subsequent analysis of Runx2 target genes in MDA-MB-231 cells revealed that CBFbeta is essential for the expression of Osteopontin, Matrixmetalloproteinase-13, Matrixmetalloproteinase-9, and Osteocalcin but not for Galectin-3. Chromatin immunoprecipitation analysis showed that CBFbeta is recruited to both the Osteopontin and the Galectin-3 promoters. CONCLUSIONS CBFbeta is expressed in metastatic breast cancer cells and is essential for cell invasion. CBFbeta is required for expression of several Runx2-target genes known to be involved in cell invasion. However, whilst CBFbeta is essential for invasion, not all Runx2-target genes require CBFbeta. We conclude that CBFbeta is required for a subset of Runx2-target genes that are sufficient to maintain the invasive phenotype of the cells. These findings suggest that the interaction between Runx2 and CBFbeta might represent a viable target for therapeutic intervention to inhibit bone metastasis.
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Affiliation(s)
- Daniel Mendoza-Villanueva
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK
| | - Wensheng Deng
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK
| | - Cesar Lopez-Camacho
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK
| | - Paul Shore
- Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK
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Onori P, Gaudio E, Franchitto A, Alpini G, Francis H. Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes. World J Gastrointest Pathophysiol 2010; 1:38-49. [PMID: 21607141 PMCID: PMC3097946 DOI: 10.4291/wjgp.v1.i2.38] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 04/03/2010] [Accepted: 04/10/2010] [Indexed: 02/06/2023] Open
Abstract
Histamine has long been known to be involved in inflammatory events. The discovery of antihistamines dates back to the first half of the 20th century when a Swiss-Italian pharmacologist, Daniel Bovet began his work. In 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy relief. Since that time, histamine has been found to play a role in other events besides allergic reaction. Possibly unbelievable to Bovet and his peers, histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases.
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Glaser S, Onori P, Wise C, Yang F, Marzioni M, Alvaro D, Franchitto A, Mancinelli R, Alpini G, Munshi MK, Gaudio E. Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasis. Dig Liver Dis 2010; 42:245-52. [PMID: 20153989 PMCID: PMC2836402 DOI: 10.1016/j.dld.2010.01.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 01/08/2010] [Indexed: 12/11/2022]
Abstract
Bile duct epithelial cells (i.e., cholangiocytes), which line the intrahepatic biliary epithelium, are the target cells in a number of human cholestatic liver diseases (termed cholangiopathies). Cholangiocyte proliferation and death is present in virtually all human cholangiopathies. A number of recent studies have provided insights into the key mechanisms that regulate the proliferation and function of cholangiocytes during the pathogenesis of cholestatic liver diseases. In our review, we have summarised the most important of these recent studies over the past 3 years with a focus on those performed in the animal model of extrahepatic bile duct ligation. In the first part of the review, we provide relevant background on the biliary ductal system. We then proceed with a general discussion of the factors regulating biliary proliferation performed in the cholestatic animal model of bile duct ligation. Further characterisation of the factors that regulate cholangiocyte proliferation and function will help in elucidating the mechanisms regulating the pathogenesis of biliary tract diseases in humans and in devising new treatment approaches for these devastating diseases.
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Affiliation(s)
- S.S. Glaser
- Digestive Disease Research Center, Scott & White, TX, United States
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - P. Onori
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
| | - C. Wise
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - F. Yang
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
- Shengjing Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - M. Marzioni
- Department of Gastroenterology, Universita' Politecnica delle Marche, Ancona, Italy
| | - D. Alvaro
- Gastroenterology, University of Rome “La Sapienza”, Rome, Italy
| | - A. Franchitto
- Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - R. Mancinelli
- Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
| | - G. Alpini
- Digestive Disease Research Center, Scott & White, TX, United States
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
- Central Texas Veterans Health Care System, Temple, TX, United States
| | - Md. K. Munshi
- Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX, United States
| | - E. Gaudio
- Department of Human Anatomy, University of Rome “La Sapienza”, Rome, Italy
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Mancinelli R, Franchitto A, Gaudio E, Onori P, Glaser S, Francis H, Venter J, Demorrow S, Carpino G, Kopriva S, White M, Fava G, Alvaro D, Alpini G. After damage of large bile ducts by gamma-aminobutyric acid, small ducts replenish the biliary tree by amplification of calcium-dependent signaling and de novo acquisition of large cholangiocyte phenotypes. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 176:1790-1800. [PMID: 20185575 PMCID: PMC2843470 DOI: 10.2353/ajpath.2010.090677] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/07/2009] [Indexed: 01/06/2023]
Abstract
Large cholangiocytes secrete bicarbonate in response to secretin and proliferate after bile duct ligation by activation of cyclic adenosine 3', 5'-monophosphate signaling. The Ca(2+)-dependent adenylyl cyclase 8 (AC8, expressed by large cholangiocytes) regulates secretin-induced choleresis. Ca(2+)-dependent protein kinase C (PKC) regulates small cholangiocyte function. Because gamma-aminobutyric acid (GABA) affects cell functions by activation of both Ca(2+) signaling and inhibition of AC, we sought to develop an in vivo model characterized by large cholangiocyte damage and proliferation of small ducts. Bile duct ligation rats were treated with GABA for one week, and we evaluated: GABA(A), GABA(B), and GABA(C) receptor expression; intrahepatic bile duct mass (IBDM) and the percentage of apoptotic cholangiocytes; secretin-stimulated choleresis; and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation and activation of Ca(2+-)dependent PKC isoforms and AC8 expression. We found that both small and large cholangiocytes expressed GABA receptors. GABA: (i) induced apoptosis of large cholangiocytes and reduced large IBDM; (ii) decreased secretin-stimulated choleresis; and (iii) reduced ERK1/2 phosphorylation and AC8 expression in large cholangiocytes. Small cholangiocytes: (i) proliferated leading to increased IBDM; (ii) displayed activation of PKCbetaII; and (iii) de novo expressed secretin receptor, cystic fibrosis transmembrane regulator, Cl(-)/HCO(3)(-) anion exchanger 2 and AC8, and responded to secretin. Therefore, in pathologies of large ducts, small ducts replenish the biliary epithelium by amplification of Ca(2+)-dependent signaling and acquisition of large cholangiocyte phenotypes.
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Affiliation(s)
- Romina Mancinelli
- Texas A & M Health Science Center, Medical Research Building, Temple, TX 76504, USA
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Fava G, DeMorrow S, Gaudio E, Franchitto A, Onori P, Carpino G, Glaser S, Francis H, Coufal M, Marucci L, Alvaro D, Marzioni M, Horst T, Mancinelli R, Benedetti A, Alpini G. Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression. Liver Int 2009; 29:1031-42. [PMID: 19291182 PMCID: PMC2706939 DOI: 10.1111/j.1478-3231.2009.01997.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Endothelins (ET-1, ET-2, ET-3) are peptides with vasoactive properties interacting with ET(A) and ET(B) receptors. ET-1 inhibits secretin-stimulated ductal secretion (hallmark of cholangiocyte growth) of cholestatic rats by interaction with ET receptors. AIM The aims of the studies were to evaluate (i) the effect of ET-1 on cholangiocarcinoma growth in Mz-ChA-1 cells and nude mice and (ii) whether ET-1 regulation of cholangiocarcinoma growth is associated with changes in the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-2 (VEGFR-2) and VEGFR-3. METHODS We determined the expression of ET(A) and ET(B) receptors on normal and malignant (Mz-ChA-1) cholangiocytes and human cholangiocarcinoma tissue and the effect of ET-1 on the proliferation and expression of VEGF-A, VEGF-C (regulators of tumour angiogenesis) and its receptors, VEGFR-2 and VEGFR-3, in Mz-ChA-1 cells. In vivo, Mz-ChA-1 cells were injected into the flanks of athymic mice and injections of ET-1 or saline into the tumours were performed daily. The effect of ET-1 on tumour size, cell proliferation, apoptosis, collagen quantity and the expression of VEGF-A and VEGF-C and VEGFR-2 and VEGFR-3 were measured after 73 days. RESULTS Higher expression of ET(A) and ET(B) was observed in malignant compared with normal cholangiocytes. ET-1 inhibited proliferation and VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression of Mz-ChA-1 cells. Chronic ET-1 treatment decreased tumour volume, tumour cell proliferation and VEGF-A and VEGF-C expression but increased apoptosis and collagen tissue deposition compared with controls. CONCLUSIONS Modulation of VEGF-A and VEGF-C (by ET-1) may be important for managing cholangiocarcinoma growth.
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Affiliation(s)
- Giammarco Fava
- Department of Gastroenterology, Universita' Politecnica delle Marche, Ancona, Italy
| | - Sharon DeMorrow
- Scott & White Digestive Disease Research Center, Scott & White, Temple, TX, USA
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
| | - Eugenio Gaudio
- Department of Human Anatomy, Università of Rome ‘La Sapienza’, Rome, Italy
| | - Antonio Franchitto
- Department of Human Anatomy, Università of Rome ‘La Sapienza’, Rome, Italy
| | - Paolo Onori
- Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy
| | - Guido Carpino
- Department of Health Science, IUSM University of Rome, Rome, Italy
| | - Shannon Glaser
- Scott & White Digestive Disease Research Center, Scott & White, Temple, TX, USA
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
| | - Heather Francis
- Scott & White Digestive Disease Research Center, Scott & White, Temple, TX, USA
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
- Division of Research and Education, Scott & White, Temple, TX, USA
| | - Monique Coufal
- Division of Research and Education, Scott & White, Temple, TX, USA
| | - Luca Marucci
- Department of Gastroenterology, Universita' Politecnica delle Marche, Ancona, Italy
| | - Domenico Alvaro
- Department of Gastroenterology, Polo Pontino, University of Rome ‘La Sapienza’, Rome, Italy
| | - Marco Marzioni
- Department of Gastroenterology, Universita' Politecnica delle Marche, Ancona, Italy
| | - Trenton Horst
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
| | - Romina Mancinelli
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
- Department of Human Anatomy, Università of Rome ‘La Sapienza’, Rome, Italy
| | - Antonio Benedetti
- Department of Gastroenterology, Universita' Politecnica delle Marche, Ancona, Italy
| | - Gianfranco Alpini
- Scott & White Digestive Disease Research Center, Scott & White, Temple, TX, USA
- Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
- Central Texas Veterans Health Care System, Temple, TX, USA
- Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
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Mancinelli R, Onori P, Gaudio E, DeMorrow S, Franchitto A, Francis H, Glaser S, Carpino G, Venter J, Alvaro D, Kopriva S, White M, Kossie A, Savage J, Alpini G. Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1. Am J Physiol Gastrointest Liver Physiol 2009; 297:G11-26. [PMID: 19389804 PMCID: PMC2711748 DOI: 10.1152/ajpgi.00025.2009] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Sex hormones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP(3) levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. The supernatant of cholangiocytes increased NRICC proliferation, inhibited by preincubation with anti-FSH antibody. Silencing of FSH gene decreases cholangiocyte proliferation and ERK1/2 and Elk-1 phosphorylation. Modulation of cholangiocyte FSH expression may be important for the management of cholangiopathies.
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Affiliation(s)
- Romina Mancinelli
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Paolo Onori
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Eugenio Gaudio
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Sharon DeMorrow
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Antonio Franchitto
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Guido Carpino
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Julie Venter
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Domenico Alvaro
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Shelley Kopriva
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Mellanie White
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Ashley Kossie
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Jennifer Savage
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Digestive Disease Research Center, Scott & White, Department of Medicine, Division Gastroenterology, and Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Division of Research and Education, Scott & White, Temple, Texas; Department of Human Anatomy, University of Rome “La Sapienza,” Rome, Italy; Experimental Medicine, University of L'Aquila, L'Aquila, Italy, Department of Gastroenterology, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy; and Department of Health Science, Istituto Universitario di Scienze Motorie, University of Rome, Italy
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Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression. Liver Int 2009. [PMID: 19291182 DOI: 10.1111/j.1478-3231.2009.01997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
BACKGROUND Endothelins (ET-1, ET-2, ET-3) are peptides with vasoactive properties interacting with ET(A) and ET(B) receptors. ET-1 inhibits secretin-stimulated ductal secretion (hallmark of cholangiocyte growth) of cholestatic rats by interaction with ET receptors. AIM The aims of the studies were to evaluate (i) the effect of ET-1 on cholangiocarcinoma growth in Mz-ChA-1 cells and nude mice and (ii) whether ET-1 regulation of cholangiocarcinoma growth is associated with changes in the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-2 (VEGFR-2) and VEGFR-3. METHODS We determined the expression of ET(A) and ET(B) receptors on normal and malignant (Mz-ChA-1) cholangiocytes and human cholangiocarcinoma tissue and the effect of ET-1 on the proliferation and expression of VEGF-A, VEGF-C (regulators of tumour angiogenesis) and its receptors, VEGFR-2 and VEGFR-3, in Mz-ChA-1 cells. In vivo, Mz-ChA-1 cells were injected into the flanks of athymic mice and injections of ET-1 or saline into the tumours were performed daily. The effect of ET-1 on tumour size, cell proliferation, apoptosis, collagen quantity and the expression of VEGF-A and VEGF-C and VEGFR-2 and VEGFR-3 were measured after 73 days. RESULTS Higher expression of ET(A) and ET(B) was observed in malignant compared with normal cholangiocytes. ET-1 inhibited proliferation and VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression of Mz-ChA-1 cells. Chronic ET-1 treatment decreased tumour volume, tumour cell proliferation and VEGF-A and VEGF-C expression but increased apoptosis and collagen tissue deposition compared with controls. CONCLUSIONS Modulation of VEGF-A and VEGF-C (by ET-1) may be important for managing cholangiocarcinoma growth.
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DeMorrow S, Francis H, Gaudio E, Venter J, Franchitto A, Kopriva S, Onori P, Mancinelli R, Frampton G, Coufal M, Mitchell B, Vaculin B, Alpini G. The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol 2008; 295:G1150-8. [PMID: 18832445 PMCID: PMC2604798 DOI: 10.1152/ajpgi.90455.2008] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca(2+)-dependent pathway involving protein kinase C, or a Ca(2+)-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH(2)-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.
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Affiliation(s)
- Sharon DeMorrow
- Department of Medicine, Texas A & M Health Science Center, College of Medicine, Temple, TX 76504, USA.
| | - Heather Francis
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Eugenio Gaudio
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Julie Venter
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Antonio Franchitto
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Shelley Kopriva
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Paolo Onori
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Romina Mancinelli
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Gabriel Frampton
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Monique Coufal
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Brett Mitchell
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Bradley Vaculin
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
| | - Gianfranco Alpini
- Department of Medicine and Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; Digestive Disease Research Center and Division of Research and Education, Scott & White Hospital, Temple, Texas; Division of Anatomy, University “La Sapienza”, Rome, Italy; Division of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Texas Biosciences Institute, Temple College, Temple, Texas
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Kunos G, Osei-Hyiaman D, Liu J, Godlewski G, Bátkai S. Endocannabinoids and the control of energy homeostasis. J Biol Chem 2008; 283:33021-5. [PMID: 18694938 DOI: 10.1074/jbc.r800012200] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Endocannabinoids (ECBs) are ubiquitous lipid mediators that act through the same G protein-coupled receptors (CB1 and CB2) that recognize plant-derived cannabinoids. As regulators of metabolism, ECBs are anabolic: they increase the intake, promote the storage, and decrease the expenditure of energy. Recent work indicates that activation of peripheral CB1 receptors by ECBs plays a key role in the hormonal/metabolic changes associated with obesity/metabolic syndrome and may be targeted for its pharmacotherapy.
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Affiliation(s)
- George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9413, USA.
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