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Xu C, Ezzi SHA, Zou X, Dong Y, Alhaskawi A, Zhou H, Kota VG, Abdulla MHAH, Abdalbary SA, Lu H. The role of TNF in metabolic disorders and liver diseases. Cytokine 2025; 190:156933. [PMID: 40174483 DOI: 10.1016/j.cyto.2025.156933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/23/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
Tumor necrosis factor (TNF) is identified as a pro-inflammatory cytokine critical to the pathology of liver disease. In the carbohydrate metabolism, TNF has been demonstrated to impede the insulin signaling pathway, thereby precipitating glucose intolerance and insulin resistance. In lipid metabolism, TNF upregulates genes implicated in fatty acid synthesis, resulting in increased lipid accumulation within the liver. In amino acid metabolism, TNF has shown to promote the gene expression for amino acid catabolism, leading to decreased protein synthesis. Additionally, TNF stimulates the production of other chemokines and inflammatory cytokines that can further exacerbate liver injury. Overall, TNF is crucial in developing liver diseases by disrupting various metabolic pathways in the liver, causing insulin resistance, lipid accumulation, and decreased protein synthesis. This review summarizes the present understanding of TNF's role in the regulation of carbohydrate, lipid and amino acid metabolism in liver disease together with its potential therapeutic implications.
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Affiliation(s)
- Chuze Xu
- School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | | | - Xiaodi Zou
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yanzhao Dong
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Ahmad Alhaskawi
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Haiying Zhou
- Faculty of Medicine, The Chinese University of Hong Kong School of Biomedical Science, Hong Kong, China
| | | | | | - Sahar Ahmed Abdalbary
- Department of Orthopedic Physical Therapy, Faculty of Physical Therapy, Nahda University, Beni Suef, Egypt
| | - Hui Lu
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China; Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Zhejiang University, Hangzhou, China.
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2
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Kojima H, Morinelli TA, Wang Y, Chin JL, Meyer AS, Kao YC, Kadono K, Yao S, Torgerson T, Dery KJ, Bhat A, Reed EF, Kaldas FM, van der Windt DJ, Farmer DG, Kupiec-Weglinski JW, Zhai Y. Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon gamma-mediated pathway. Am J Transplant 2024:S1600-6135(24)00793-7. [PMID: 39736469 DOI: 10.1016/j.ajt.2024.11.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/07/2024] [Accepted: 11/23/2024] [Indexed: 01/01/2025]
Abstract
As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild-type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 knockout (KO) recipients, in association with downregulation of group 1 ILCs genes, including interferon gamma. Antibody-mediated ILC depletion or interferon gamma neutralization in Rag2 KO recipients increased, while interferon gamma treatment in DKO recipients reduced, liver graft injuries. At the donor side, grafts from DKO mice or anti-NK1.1-treated WT mice suffered significantly higher IRI, while grafts treated with interferon gamma during cold preservation decreased IRI. Thus, both recipient and donor group 1 ILCs protect liver grafts from IRI. Low-dose interferon gamma upregulated c-FLIP expression in vitro and in vivo and protected hepatocytes from inflammatory cell death. In human liver graft biopsies, single-cell RNA-sequencing analysis revealed group 1 ILCs produce interferon gamma. The c-FLIP levels were positively correlated with interferon gamma in pretransplant biopsies. Grafts with higher c-FLIP were associated with lower caspase-8 activation, IRI gradings, and frequency of early allograft dysfunction post-LT. Our study reveals a novel interferon gamma-mediated cytoprotective role of group 1 ILCs in LT.
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Affiliation(s)
- Hidenobu Kojima
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Thomas A Morinelli
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yue Wang
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Jackson L Chin
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
| | - Aaron S Meyer
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
| | - Yi-Chu Kao
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Kentaro Kadono
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Siyuan Yao
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Taylor Torgerson
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Kenneth J Dery
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Adil Bhat
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Fady M Kaldas
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Dirk J van der Windt
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Douglas G Farmer
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Yuan Zhai
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
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3
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Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, et alVitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 2023; 30:1097-1154. [PMID: 37100955 PMCID: PMC10130819 DOI: 10.1038/s41418-023-01153-w] [Show More Authors] [Citation(s) in RCA: 164] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/28/2023] Open
Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
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Affiliation(s)
- Ilio Vitale
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Emma Guilbaud
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institut für Immunologie, Kiel University, Kiel, Germany
| | - Massimiliano Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patrizia Agostinis
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- BIOGEM, Avellino, Italy
| | - Ivano Amelio
- Division of Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - David W Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Rami I Aqeilan
- Hebrew University of Jerusalem, Lautenberg Center for Immunology & Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Jerusalem, Israel
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniele Bano
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Nickolai A Barlev
- Department of Biomedicine, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Jiri Bartek
- Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesca Bernassola
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Mathieu J M Bertrand
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Marco E Bianchi
- Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy and Ospedale San Raffaele IRCSS, Milan, Italy
| | | | - J Magarian Blander
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Carl D Bortner
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Pierluigi Bove
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patricia Boya
- Centro de Investigaciones Biologicas Margarita Salas, CSIC, Madrid, Spain
| | - Catherine Brenner
- Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques, Villejuif, France
| | - Petr Broz
- Department of Immunobiology, University of Lausanne, Epalinges, Vaud, Switzerland
| | - Thomas Brunner
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- UCL Consortium for Mitochondrial Research, London, UK
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Francesco Cecconi
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francis K-M Chan
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guo-Qiang Chen
- State Key Lab of Oncogene and its related gene, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quan Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Youhai H Chen
- Shenzhen Institute of Advanced Technology (SIAT), Shenzhen, Guangdong, China
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Aaron Ciechanover
- The Technion-Integrated Cancer Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Marcus Conrad
- Helmholtz Munich, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Mads Daugaard
- Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Ted M Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruggero De Maria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bart De Strooper
- VIB Centre for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
- The Francis Crick Institute, London, UK
- UK Dementia Research Institute at UCL, University College London, London, UK
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J Deberardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexei Degterev
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Giannino Del Sal
- Department of Life Sciences, University of Trieste, Trieste, Italy
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | | | - Marc Diederich
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - John W Elrod
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Kurt Engeland
- Molecular Oncology, University of Leipzig, Leipzig, Germany
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Carlo Ganini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
| | - Ana J Garcia-Saez
- CECAD, Institute of Genetics, University of Cologne, Cologne, Germany
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM, UMR, 1231, Dijon, France
- Faculty of Medicine, Université de Bourgogne Franche-Comté, Dijon, France
- Anti-cancer Center Georges-François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Motti Gerlic
- Department of Clinical Microbiology and Immunology, Sackler school of Medicine, Tel Aviv university, Tel Aviv, Israel
| | - Sourav Ghosh
- Department of Neurology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Hinrich Gronemeyer
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Departments of Molecular Microbiology and Immunology, Pharmacology, Oncology and Neurology, Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA
| | - Ygal Haupt
- VITTAIL Ltd, Melbourne, VIC, Australia
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Sudan He
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- National Cancer Center Research Institute, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ana Janic
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philipp J Jost
- Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Michael Karin
- Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA, USA
| | - Hamid Kashkar
- CECAD Research Center, Institute for Molecular Immunology, University of Cologne, Cologne, Germany
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Ruth Kluck
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Dagmar Kulms
- Department of Dermatology, Experimental Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, Dresden, Germany
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Sergio Lavandero
- Universidad de Chile, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
- Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Inna N Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - John J Lemasters
- Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Gianmaria Liccardi
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
| | - Richard A Lockshin
- Department of Biology, Queens College of the City University of New York, Flushing, NY, USA
- St. John's University, Jamaica, NY, USA
| | - Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Field of Excellence BioHealth - University of Graz, Graz, Austria
| | - Walter Malorni
- Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gwenola Manic
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - Jean-Christophe Marine
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Pier G Mastroberardino
- Department of Molecular Genetics, Rotterdam, the Netherlands
- IFOM-ETS The AIRC Institute for Molecular Oncology, Milan, Italy
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer, and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Ute M Moll
- Department of Pathology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Daniel J Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Dimitry Ofengeim
- Rare and Neuroscience Therapeutic Area, Sanofi, Cambridge, MA, USA
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine and Howard Hughes Medical Institute, New York, NY, USA
| | - Theocharis Panaretakis
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | | | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, YLL School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
- National University Cancer Institute, NUHS, Singapore, Singapore
- ISEP, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - Marcus E Peter
- Department of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Porta
- Center of Genomic Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | | | - Kodi S Ravichandran
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Cell Clearance, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Barak Rotblat
- Department of Life sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- The NIBN, Beer Sheva, Israel
| | - Carla V Rothlin
- Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Thomas Rudel
- Microbiology Biocentre, University of Würzburg, Würzburg, Germany
| | - Alessandro Rufini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- University of Leicester, Leicester Cancer Research Centre, Leicester, UK
| | - Kevin M Ryan
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA
- Department of Systems Biology, Lab of Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
- Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Akira Sawa
- Johns Hopkins Schizophrenia Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emre Sayan
- Faculty of Medicine, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, PR China
| | - Yufang Shi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Giuseppe S Sica
- Department of Surgical Science, University Tor Vergata, Rome, Italy
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Antonella Sistigu
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Brent R Stockwell
- Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
| | - Flavie Strapazzon
- IRCCS Fondazione Santa Lucia, Rome, Italy
- Univ Lyon, Univ Lyon 1, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyogène CNRS, INSERM, Lyon, France
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Liming Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Daolin Tang
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Carol M Troy
- Departments of Pathology & Cell Biology and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Boris Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicoletta Urbano
- Department of Oncohaematology, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Methusalem Program, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
- School of Forensic Medicine, China Medical University, Shenyang, China
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
- The Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences (OeAW), Vienna, Austria
- The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Daniela Vuri
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Achim Weber
- University of Zurich and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
- University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
| | - Will Wood
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Huang-Tian Yang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, Flushing, NY, USA
| | - Joanna E Zawacka-Pankau
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Biochemistry, Laboratory of Biophysics and p53 protein biology, Medical University of Warsaw, Warsaw, Poland
| | - Lin Zhang
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Wenzhao Zhou
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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Meurisse N, Mertens M, Fieuws S, Gilbo N, Jochmans I, Pirenne J, Monbaliu D. Effect of a Combined Drug Approach on the Severity of Ischemia-Reperfusion Injury During Liver Transplant: A Randomized Clinical Trial. JAMA Netw Open 2023; 6:e230819. [PMID: 36853611 PMCID: PMC9975910 DOI: 10.1001/jamanetworkopen.2023.0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
IMPORTANCE In a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant. OBJECTIVE To assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury. DESIGN, SETTING, AND PARTICIPANTS This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020. INTERVENTIONS Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase. MAIN OUTCOMES AND MEASURES The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival. RESULTS Of 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; P = .49) (to convert AST to μkat/L, multiply by 0.0167). There also were no significant differences in the secondary end points between the groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, the combined drug approach targeting the post-cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02251041.
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Affiliation(s)
- Nicolas Meurisse
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
- Department of Abdominal Surgery and Transplantation, CHU de Liège, University of Liège, Liège, Belgium
| | - Markoen Mertens
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Steffen Fieuws
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics, KU Leuven—University of Leuven, Leuven, Belgium
| | - Nicholas Gilbo
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Ina Jochmans
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
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5
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Fodor M, Salcher S, Gottschling H, Mair A, Blumer M, Sopper S, Ebner S, Pircher A, Oberhuber R, Wolf D, Schneeberger S, Hautz T. The liver-resident immune cell repertoire - A boon or a bane during machine perfusion? Front Immunol 2022; 13:982018. [PMID: 36311746 PMCID: PMC9609784 DOI: 10.3389/fimmu.2022.982018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.
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Affiliation(s)
- M. Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - H. Gottschling
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - M. Blumer
- Department of Anatomy and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - R. Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - D. Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: T. Hautz,
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6
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Li Y, Palmer A, Lupu L, Huber-Lang M. Inflammatory response to the ischaemia-reperfusion insult in the liver after major tissue trauma. Eur J Trauma Emerg Surg 2022; 48:4431-4444. [PMID: 35831749 DOI: 10.1007/s00068-022-02026-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Polytrauma is often accompanied by ischaemia-reperfusion injury to tissues and organs, and the resulting series of immune inflammatory reactions are a major cause of death in patients. The liver is one of the largest organs in the body, a characteristic that makes it the most vulnerable organ after multiple injuries. In addition, the liver is an important digestive organ that secretes a variety of inflammatory mediators involved in local as well as systemic immune inflammatory responses. Therefore, this review considers the main features of post-traumatic liver injury, focusing on the immuno-pathophysiological changes, the interactions between liver organs, and the principles of treatment deduced. METHODS We focus on the local as well as systemic immune response involving the liver after multiple injuries, with emphasis on the pathophysiological mechanisms. RESULTS An overview of the mechanisms underlying the pathophysiology of local as well as systemic immune responses involving the liver after multiple injuries, the latest research findings, and the current mainstream therapeutic approaches. CONCLUSION Cross-reactivity between various organs and cascade amplification effects are among the main causes of systemic immune inflammatory responses after multiple injuries. For the time being, the pathophysiological mechanisms underlying this interaction remain unclear. Future work will continue to focus on identifying potential signalling pathways as well as target genes and intervening at the right time points to prevent more severe immune inflammatory responses and promote better and faster recovery of the patient.
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Affiliation(s)
- Yang Li
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Annette Palmer
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Ludmila Lupu
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany.
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7
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Kawasoe J, Uchida Y, Kawamoto H, Miyauchi T, Watanabe T, Saga K, Tanaka K, Ueda S, Terajima H, Taura K, Hatano E. Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice. Front Immunol 2022; 13:862503. [PMID: 35572528 PMCID: PMC9097600 DOI: 10.3389/fimmu.2022.862503] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022] Open
Abstract
Liver ischemia and reperfusion injury (IRI) is one of the obstacles in liver surgery such as liver resection and transplantation. In this study, we investigated the preventive effect on mouse liver IRI by feeding mice with inulin, which is a heterogeneous blend of indigestible fructose polymer. Mice were fed either a control ordinary diet (CD) or an inulin diet (ID) containing 5% inulin in the CD, for 14 days before the ischemia and reperfusion (IR) maneuver. IR induced-liver damages were significantly ameliorated in the ID group, compared with those in the CD group. Feeding mice with an ID, but not a CD, elevated levels of Bacteroidetes among gut microbiota, and especially increased Bacteroides acidifaciens in mouse feces, which resulted in significant elevation of short-chain fatty acids (SCFAs) in the portal vein of mice. Among SCFAs, propionic acid (PA) was most significantly increased. The microbial gene functions related to PA biosynthesis were much higher in the fecal microbiome of the ID group compared to the CD. However, the action of PA on liver IRI has not been yet clarified. Direct intraperitoneal administration of PA alone prior to the ischemia strongly suppressed liver cell damages as well as inflammatory responses caused by liver IR. Furthermore, PA suppressed the secretion of inflammatory cytokines from peritoneal macrophages stimulated in vitro through TLR-4 with high-mobility group box 1 protein (HMGB-1), known to be released from apoptotic liver cells during the IR insult. The present study shows that PA may play a key role in the inulin-induced amelioration of mouse liver IRI.
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Affiliation(s)
- Junya Kawasoe
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Yoichiro Uchida
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
- *Correspondence: Yoichiro Uchida,
| | - Hiroshi Kawamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Tomoyuki Miyauchi
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Takeshi Watanabe
- Division of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Kenichi Saga
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Kosuke Tanaka
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Shugo Ueda
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Hiroaki Terajima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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8
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Tsai LW, Lu YH, Dubey R, Chiou JF. Reenvisioning Traditional to Regenerative Therapeutic Advances in Managing Nonalcoholic Fatty Liver Disease in Diabetes Mellitus. J Diabetes Res 2021; 2021:7692447. [PMID: 34805412 PMCID: PMC8601846 DOI: 10.1155/2021/7692447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 10/23/2021] [Indexed: 12/07/2022] Open
Abstract
Reports indicate the increasing prevalence of liver disorders in diabetes mellitus (DM) patients. Clinically, it has also been revealed that the existence of nonalcoholic fatty liver disease (NAFLD) enhances the incidence of type 2 diabetes mellitus (T2DM), while T2DM exacerbates NAFLD to extremely severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma. This implies the coexistence and bidirectional nature of NAFLD and T2DM, which function synergistically to drive adverse consequences in clinical practice. For treatment of such comorbid state, though the existing practices such as lifestyle management, traditional Chinese medicines (TCM), and pharmaceuticals have offered somewhat relief, the debate continues about the optimal therapeutic impacts. Recent developments in the field of tissue engineering have led to a renewed interest in novel biomaterial alternatives such as stem cells. This might be attributable to their differentiation potential towards hepatic and pancreatic lineage. These cellular therapies could be further complemented by platelet-derived biomaterials, TCM formulations, or any specific drug. Based on these abovementioned approaches, we aimed to comprehensively analyze various preclinical and clinical studies from traditional to regenerative therapeutic approaches in managing concomitant NAFLD and T2DM.
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Affiliation(s)
- Lung-Wen Tsai
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Department of Information Technology Office, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Hsiang Lu
- Department of Otolaryngology, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Rajni Dubey
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Jeng-Fong Chiou
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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9
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Kageyama S, Kadono K, Hirao H, Nakamura K, Ito T, Gjertson DW, Sosa RA, Reed EF, Kaldas FM, Busuttil RW, Kupiec-Weglinski JW, Zhai Y. Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury. Transplantation 2021; 105:1989-1997. [PMID: 33065722 PMCID: PMC8046839 DOI: 10.1097/tp.0000000000003488] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. METHODS In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients. RESULTS CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels. CONCLUSIONS CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.
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Affiliation(s)
- Shoichi Kageyama
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Kentaro Kadono
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Hirofumi Hirao
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Kojiro Nakamura
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Takahiro Ito
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - David W. Gjertson
- Department of Biostatistics, UCLA School of Public Health University of California, Los Angeles, CA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
| | - Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA
| | - Fady M. Kaldas
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
| | - Yuan Zhai
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, University of California, Los Angeles, CA
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10
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Liu Y, Qin X, Lei Z, Chai H, Huang Z, Wu Z. Tetramethylpyrazine inhibits neutrophil extracellular traps formation and alleviates hepatic ischemia/reperfusion injury in rat liver transplantation. Exp Cell Res 2021; 406:112719. [PMID: 34273405 DOI: 10.1016/j.yexcr.2021.112719] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 10/20/2022]
Abstract
Hepatic ischemia/reperfusion injury (IRI) is an adverse effect for liver transplantation which is characterized by immune response mediated inflammation. Recent studies report that neutrophil extracellular traps (NETs) are implicated in hepatic IRI. The aim of this study was to explore the mechanism of action of tetramethylpyrazine (TMP), the main chemical composition of Ligusticum chuanxiong in treatment of ischemic related diseases. Data showed that hepatic IRI increases the leak of alanine aminotransferase (ALT) and aspartate transaminase (AST), and stimulates formation of NETs. Extracellular DNA/NETs assay, hematoxylin-eosin (HE) staining, immunofluorescence assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Western blot assay, showed that TMP significantly reduces formation of NETs and alleviates hepatic IRI. Moreover, TMP and Diphenyleneiodonium (DPI) suppressed ROS production in neutrophils. In addition, analysis showed that activation of NADPH oxidase plays a role in formation of NETs triggered by hepatic IRI. Notably, TMP inhibited formation of NETs though inhibition of NADPH oxidase. Additionally, Combination treatment using TMP and DPI was more effective compared with monotherapy of either of the two drugs. These findings show that combination therapy using TMP and DPI is a promising method for treatment hepatic IRI.
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Affiliation(s)
- Yanyao Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoyan Qin
- Department of General Surgery of Yuzhong District, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Zilun Lei
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Chai
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zuotian Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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11
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Yang Q, Zhao ZZ, Xie J, Wang YP, Yang K, Guo Y, Wang JF, Deng XM. Senkyunolide I attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways. Int Immunopharmacol 2021; 97:107717. [PMID: 33933846 DOI: 10.1016/j.intimp.2021.107717] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 01/17/2023]
Abstract
BACKGROUND Senkyunolide I (SEI)exerts considerable protective effects in various disease models, but its effect on hepatic ischemia-reperfusion (I/R) injury remains unknown. This research aimed to investigate the effect of SEI in a murine model of hepatic I/R injury. METHODS With modified liver I/R murine model, low, medium and high doses of SEI were injected intraperitoneally after operation. After 6 h of reperfusion, the blood and liver were collected. Serum ALT and AST were detected by automatic analyzer, while liver injury was evaluated by HE staining. High-dose SEI was selected to further explore its impacts on oxidative stress, inflammatory responses and apoptosis induced by hepatic I/R. The pharmacological effect of SEI was also compared with a positive control, glutathione (GSH). We used ELISA to detect serum TNF-α, IL-1 β and IL-6, special kit to explore activities of SOD and GSH-Px, and the content of MDA, and western blotting to detect HO-1, Bax and Bcl-2 levels, and to perceive expressions and phosphorylations of NF- κB p65 and p38/ERK/JNK in liver tissues. Apoptosis in liver tissue was evaluated by TUNEL. The antioxidative effect of SEI was further investigated using the HuCCT1 cells stimulated with H2O2 and the role of SEI on regulation of Nrf-2/HO-1 was determined. RESULTS 200 mg/kg of SEI was optimal dose for treating liver I/R injury. Elevated ALT, AST and histopathological injury in I/R liver was attenuated by SEI administration, similarly to GSH. Serum TNF-α, IL-1β, and IL-6 were reduced in liver I/R mice treated with SEI, and in liver tissues, phosphorylation of p65 NF-κB and MAPK kinases (p38, ERK, JNK), were inhibited. SEI reduced the MDA content, but increased HO-1 level and enhanced SOD and GSH-Px activities. Apoptosis of liver tissues was decreased, while SEI inhibited Bax and elevated Bcl-2 expression. In in vitro experiments, H2O2 reduced the survival rate of HuCCT1 cells, which was protected by SEI administration. SEI reduced the ROS and MDA content. The transportation of Nrf-2 into the nucleus was enhanced and HO-1 expression was upregulated. CONCLUSIONS SEI attenuates hepatic I/R injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways.
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Affiliation(s)
- Qing Yang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhen-Zhen Zhao
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jian Xie
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yun-Peng Wang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Kai Yang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yu Guo
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jia-Feng Wang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.
| | - Xiao-Ming Deng
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.
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12
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Gerussi A, Natalini A, Antonangeli F, Mancuso C, Agostinetto E, Barisani D, Di Rosa F, Andrade R, Invernizzi P. Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models. Int J Mol Sci 2021; 22:4557. [PMID: 33925355 PMCID: PMC8123708 DOI: 10.3390/ijms22094557] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.
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Affiliation(s)
- Alessio Gerussi
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Ambra Natalini
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Fabrizio Antonangeli
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Clara Mancuso
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet, L’Universite’ Libre de Bruxelles (ULB), 1050 Brussels, Belgium;
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center—IRCCS, Humanitas Cancer Center, Rozzano, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
| | - Donatella Barisani
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), 00185 Rome, Italy; (A.N.); (F.A.); (F.D.R.)
| | - Raul Andrade
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), UGC Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29016 Málaga, Spain;
| | - Pietro Invernizzi
- Centre for Autoimmune Liver Diseases, Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (C.M.); (D.B.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
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13
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Nofal AE, Shatla IM, Abdelhafeez DA, Mustafa M, Aly OM. OMA1520 and OMA1774, novel 1,2,4-triazole bearing analogs of combretastatin A-4, inhibit hepatocellular carcinoma: Histological and immunohistochemical studies. Biomed Pharmacother 2021; 138:111417. [PMID: 33752057 DOI: 10.1016/j.biopha.2021.111417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 12/16/2022] Open
Abstract
Combretastatin A-4 (CA-4) received significant interest as a potential anticancer agent in recent years. Several CA-4 analogs were synthesized and investigated to enhance the activity or solve the in vivo decreased activity of CA-4. AIM The present study aims to investigate the chemotherapeutic and the antiproliferative effects of the mono and the dual therapy of the newly synthesized CA-4 analogs OMA1520 and OMA1774 against hepatocellularcarcinoma (HCC) induced in male adult rats by N-methylnitrosourea (MNU). METHODS 50 male rats were divided into 5 groups of 10 animals in each group. Group I: normal healthy control; group II: MNU treated group, group III: MNU animals treated by OMA1520, group IV: MNU animals treated by OMA1774, and group V: MNU animals treated by both OMA1520 and OMA1774. The rats were assessed for liver cancer progression or inhibition by evaluating the histopathological, immunohistochemical, biochemical, and antioxidant enzyme status. RESULTS The present work indicated that OMA1520 and OMA1774 possessed substantial chemotherapeutic efficiency against HCC. The histological and immunohistochemical examinations of liver tissues confirmed the biochemical sera data. Also, they diminished the cytotoxic effects of MNU and restored the normal histological hepatic architecture. Both analogs restored the normal levels of liver enzymes and functions and revealed potential antioxidant effects. OMA1520 and OMA1774 reduced the inflammatory and tumor markers' elevated expressions in serum. CONCLUSION Substantial evidence in our results suggests that both CA-4 analogs could be possible alternative anticancer agents, and their co-administration provides a synergistic activity.
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Affiliation(s)
- Amany E Nofal
- Department of Zoology, Faculty of Sciences, Menoufia University, Shebin El-Kom, Egypt.
| | - Ibrahim M Shatla
- Department of Physiology, Demietta Faculty of Medicine, Al-Azhar University, Egypt
| | | | - Muhamad Mustafa
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt.
| | - Omar M Aly
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
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14
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Kawasoe J, Uchida Y, Miyauchi T, Kadono K, Hirao H, Saga K, Watanabe T, Ueda S, Terajima H, Uemoto S. The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice. Am J Transplant 2021; 21:540-551. [PMID: 32805077 PMCID: PMC7891328 DOI: 10.1111/ajt.16269] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/13/2020] [Accepted: 08/03/2020] [Indexed: 01/25/2023]
Abstract
Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.
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Affiliation(s)
- Junya Kawasoe
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Yoichiro Uchida
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Tomoyuki Miyauchi
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Kentaro Kadono
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hirofumi Hirao
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kenichi Saga
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Takeshi Watanabe
- Division of Immunology, Institute for Frontier Life and Medical SciencesKyoto UniversityKyotoJapan
| | - Shugo Ueda
- Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Hiroaki Terajima
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Shinji Uemoto
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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15
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Kyriakopoulos G, Valsami G, Tsalikidis C, Pitiakoudis M, Tsaroucha AK. Use of natural anti-oxidants in experimental animal models of hepatic ischemia-reperfusion injury. Ann Med Surg (Lond) 2020; 60:592-599. [PMID: 33304570 PMCID: PMC7708685 DOI: 10.1016/j.amsu.2020.11.061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/19/2020] [Accepted: 11/24/2020] [Indexed: 11/28/2022] Open
Abstract
Background Ischemia-reperfusion injury (IRI) remains a clinical challenge in liver surgery, trauma and transplantation, contributing to morbidity and mortality worldwide. Thus, its impact, not only on the liver itself but also on remote tissues, has been studied during the last years. Different natural anti-oxidant substances have been researched in animal models, implementing different times of ischemia, aiming to test new therapeutic interventions. Objective A literature review has been conducted with two goals: (1) to identify different natural anti-oxidants studied in experimental models; and (2) to summarize the various times of ischemia employed. Methods Scientific papers published in PubMed for the period 2000–2020 were searched and reviewed. Results More than 30 natural anti-oxidants have been tested. The time of ischemia ranged from 15 to 90 min with 60 min used most frequently, followed by 45 min. No studies were found with time exceeding 90 min. Conclusions A significant number of research has been conducted on the use and protective effect of natural anti-oxidants in experimental animal models. Based on the published papers, 45–60 min seems to be the optimal duration of ischemia.
Liver IRI is a multifactorial and complex process, involving many mechanisms, cells and mediators. Even though, most of these mechanisms have not been completely understood, several substances have been tested in experimental models in order to determine their protective or destructive role. Antioxidant therapy is a promising therapeutic pathway that can ameliorate the impact of liver ischemia-reperfusion injury. Non-pharmaceutical, natural extracts are increasingly gaining their place into the therapeutic options of physicians, in an attempt to avoid various adverse effects that the chemical drugs can cause. New unexplored research areas may include different strains of rats, more studies in larger mammals of comparable anatomy to humans, experiments on different liver diseases, publishing negative results regarding toxic doses of natural antioxidants, and testing different ischemia times.
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Affiliation(s)
- Georgios Kyriakopoulos
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Georgia Valsami
- School of Health Sciences, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
| | - Christos Tsalikidis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,2Department of Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Michail Pitiakoudis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,2Department of Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Alexandra K Tsaroucha
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,Laboratory of Experimental Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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16
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Abbas NAT, Awad MM, Nafea OE. Silymarin in combination with chlorogenic acid protects against hepatotoxicity induced by doxorubicin in rats: possible role of adenosine monophosphate-activated protein kinase pathway. Toxicol Res (Camb) 2020; 9:771-777. [PMID: 33447361 DOI: 10.1093/toxres/tfaa080] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/25/2020] [Accepted: 10/05/2020] [Indexed: 12/29/2022] Open
Abstract
Many xenobiotics are known to cause hepatic damage with subsequent significant morbidity and mortality. Doxorubicin (DOX) is a broad-spectrum antineoplastic agent. DOX is reported to cause hepatocellular damage. Previous studies verified the promising role of many natural antioxidant products against various models of hepatic dysfunction. We conducted this study to evaluate the possible hepatoprotective effect of silymarin (SILY) and/or chlorogenic acid (CGA) in a rat model of DOX-induced hepatotoxicity. For this purpose, we randomly divided 30 adult male rats into five equal groups as control, DOX, co-treated DOX with SILY, co-treated DOX with GCA and co-treated DOX with SILY and CGA groups. All treatments were administered every second day for 4 weeks. Our results showed that simultaneous SILY and CGA administration caused a significant decrease in hepatic apoptosis biomarkers (hepatic caspase-3 and nuclear factor-κB levels), a significant improvement in hepatic oxidant/antioxidant status (malondialdehyde and superoxide dismutase) and significant decrease in hepatic pro-inflammatory biomarkers (tumor necrosis factor-alpha and interlukin-1β) compared with DOX treatment. We concluded that adding CGA to SILY acts as a hepatoprotective agent against DOX-induced liver injury through inhibiting apoptosis biomarkers, maintaining antioxidant enzyme levels, decreasing pro-inflammatory cytokines as well as regulating liver adenosine monophosphate-activated protein kinase signaling.
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Affiliation(s)
- Noha A T Abbas
- Faculty of Medicine, Department of Clinical Pharmacology, Zagazig University, Zagazig 44519, Egypt
| | - Mohammed M Awad
- Endocrinology Division, Faculty of Medicine, Department of Internal Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Ola E Nafea
- Faculty of Medicine, Department of Forensic Medicine and Clinical Toxicology, Zagazig University, Zagazig 44519, Egypt
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17
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Ni M, Zhou H, Zhang J, Jin D, Lu T, Busuttil RW, Kupiec-Weglinski JW, Wang X, Zhai Y. Isoform- and Cell Type-Specific Roles of Glycogen Synthase Kinase 3 N-Terminal Serine Phosphorylation in Liver Ischemia Reperfusion Injury. THE JOURNAL OF IMMUNOLOGY 2020; 205:1147-1156. [PMID: 32680958 DOI: 10.4049/jimmunol.2000397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 06/21/2020] [Indexed: 12/31/2022]
Abstract
Glycogen synthase kinase 3 (Gsk3) α and β are both constitutively active and inhibited upon stimulation by N-terminal serine phosphorylation. Although roles of active Gsk3 in liver ischemia reperfusion injury (IRI) have been well appreciated, whether Gsk3 N-terminal serine phosphorylation has any functional significance in the disease process remains unclear. In a murine liver partial warm ischemia model, we studied Gsk3 N-terminal serine mutant knock-in (KI) mice and showed that liver IRI was decreased in Gsk3αS21A but increased in Gsk3βS9A mutant KI mice. Bone marrow chimeric experiments revealed that the Gsk3α, but not β, mutation in liver parenchyma protected from IRI, and both mutations in bone marrow-derived cells exacerbated liver injuries. Mechanistically, mutant Gsk3α protected hepatocytes from inflammatory (TNF-α) cell death by the activation of HIV-1 TAT-interactive protein 60 (TIP60)-mediated autophagy pathway. The pharmacological inhibition of TIP60 or autophagy diminished the protection of the Gsk3α mutant hepatocytes from inflammatory cell death in vitro and the Gsk3α mutant KI mice from liver IRI in vivo. Thus, Gsk3 N-terminal serine phosphorylation inhibits liver innate immune activation but suppresses hepatocyte autophagy in response to inflammation. Gsk3 αS21, but not βS9, mutation is sufficient to sustain Gsk4 activities in hepatocytes and protect livers from IRI via TIP60 activation.
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Affiliation(s)
- Ming Ni
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.,Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China
| | - Haoming Zhou
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.,Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China
| | - Jing Zhang
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095
| | - Dan Jin
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.,Department of Obstetrics and Gynecology, Shanghai Jiaotong University, Shanghai 200025, China; and
| | - Tianfei Lu
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.,Liver Surgery, Renji Hospital, Shanghai Jiaotong University, Shanghai 200025, China
| | - Ronald W Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095
| | - Jerzy W Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095
| | - Xuehao Wang
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China;
| | - Yuan Zhai
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
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18
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Li S, Li H, Xu X, Saw PE, Zhang L. Nanocarrier-mediated antioxidant delivery for liver diseases. Theranostics 2020; 10:1262-1280. [PMID: 31938064 PMCID: PMC6956819 DOI: 10.7150/thno.38834] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open
Abstract
Liver is the principal detoxifying organ and metabolizes various compounds that produce free radicals (FR) constantly. To maintain the oxidative/antioxidative balance in the liver, antioxidants would scavenge FR by preventing tissue damage through FR formation, scavenging, or by enhancing their decomposition. The disruption of this balance therefore leads to oxidative stress and in turn leads to the onset of various diseases. Supplying the liver with exogeneous antioxidants is an effective way to recreate the oxidative/antioxidative balance in the liver homeostasis. Nevertheless, due to the short half-life and instability of antioxidants in circulation, the methodology for delivering antioxidants to the liver needs to be improved. Nanocarrier mediated delivery of antioxidants proved to be an ingenious way to safely and efficiently deliver a high payload of antioxidants into the liver for circumventing liver diseases. The objective of this review is to provide an overview of the role of reactive oxygen species (oxidant) and ROS scavengers (antioxidant) in liver diseases. Subsequently, current nanocarrier mediated antioxidant delivery methods for liver diseases are discussed.
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Affiliation(s)
- Senlin Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Huiru Li
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Lei Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
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19
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Jing ZT, Liu W, Xue CR, Wu SX, Chen WN, Lin XJ, Lin X. AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury. Am J Physiol Gastrointest Liver Physiol 2019; 316:G387-G396. [PMID: 30629471 DOI: 10.1152/ajpgi.00350.2018] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.
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Affiliation(s)
- Zhen-Tang Jing
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Wei Liu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University , Fuzhou , China
| | - Chao-Rong Xue
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Shu-Xiang Wu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Wan-Nan Chen
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University , Fuzhou , China
| | - Xin-Jian Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University , Fuzhou , China
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20
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Guo L, Wu X, Zhang Y, Wang F, Li J, Zhu J. Protective effects of gastrin-releasing peptide receptor antagonist RC-3095 in an animal model of hepatic ischemia/reperfusion injury. Hepatol Res 2019; 49:247-255. [PMID: 30656798 DOI: 10.1111/hepr.13315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/21/2018] [Accepted: 01/10/2019] [Indexed: 12/14/2022]
Abstract
AIM We aimed to evaluate effects of RC-3095 on mice with hepatic ischemia followed by reperfusion (I/R) injury and further explore the possible underlying mechanism. METHODS Mice were subjected to partial hepatic ischemia for 60 min followed by different durations of reperfusion. Levels of gastrin-releasing peptide (GRP) and GRP receptor (GRPR) in the blood and liver were detected by enzyme-linked immunosorbent assay (ELISA) or western blotting (WB) after 3, 6, 12, or 24 h of reperfusion. RC-3095 or normal saline (control) was given i.p. at the time of reperfusion. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in blood and liver samples were examined with ELISA. Neutrophil influx into the liver was assessed by flow cytometry and myeloperoxidase assay. Hematoxylin-eosin staining of the liver and terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling assay were used to determine hepatic injury and hepatocellular necrosis. Activation of nuclear factor (NF)-κB and p38/extracellular regulated protein kinase (ERK) mitogen activated protein kinase (MAPK) was investigated with WB. RESULTS The expression of GRP was upregulated within 3 h after reperfusion and remained elevated for up to 24 h in the liver, whereas GRPR was also upregulated after 3 or 6 h of reperfusion, but returned to baseline levels within 24 h. RC-3095 significantly reduced the inflammatory hepatic injury, liver neutrophil accumulation, and hepatocellular apoptosis, probably by inhibiting activation of NF-κB or p38/ERK MAPK. CONCLUSION These findings supported that GRP-GRPR played an important role in hepatic I/R injury, and RC-3095 ameliorated liver damage by suppressing the inflammatory response and hepatocellular necrosis.
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Affiliation(s)
- Long Guo
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinwan Wu
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Zhang
- Department of Anesthesiology, Central Hospital of Jiading District, Shanghai, China
| | - Fang Wang
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinbao Li
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiali Zhu
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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21
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Cubero FJ, Woitok MM, Zoubek ME, de Bruin A, Hatting M, Trautwein C. Disruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease. Cell Death Dis 2019; 10:115. [PMID: 30737368 PMCID: PMC6368573 DOI: 10.1038/s41419-019-1391-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/16/2019] [Accepted: 01/21/2019] [Indexed: 12/21/2022]
Abstract
Fas Ligand (FasL) and Fas (APO-1/CD95) are members of the TNFR superfamily and may trigger apoptosis. Here, we aimed to elucidate the functional role of Fas signaling in an experimental model of chronic liver disease, the hepatocyte-specific NEMO knockout (NEMOΔhepa) mice. We generated NEMOΔhepa /Faslpr mice, while NEMOΔhepa, NEMOf/f as well as Faslpranimals were used as controls, and characterized their phenotype during liver disease progression. Liver damage was evaluated by serum transaminases, histological, immunofluorescence procedures, and biochemical and molecular biology techniques. Proteins were detected by western Blot, expression of mRNA by RT-PCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Faslpr mutation in NEMOΔhepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMOΔhepa mice. Moreover, NEMOΔhepa/Faslpr animals elicited significantly decreased parameters of liver fibrosis, such as Collagen IA1, MMP2, and TIMP1, and reduced proinflammatory macrophages and cytokine expression. At 52 weeks of age, NEMOΔhepa/Faslpr exhibited less malignant growth as evidenced by reduced HCC burden associated with a significantly decreased number of nodules and LW/BW ratio and decreased myeloid populations. Deletion of TNFR1 further reduced tumor load of 52-weeks-old NEMOΔhepa/Faslpr mice. The functionality of FasL/Fas might affect inflammation-driven tumorigenesis in an experimental model of chronic liver disease. These results help to develop alternative therapeutic approaches and extend the limitations of tumor therapy against HCC.
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Affiliation(s)
- Francisco Javier Cubero
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany. .,Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain. .,12 de Octubre Health Research Institute (imas12), Madrid, Spain.
| | | | - Miguel E Zoubek
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.,Department of Toxicology, Faculty of Health Medicine and Life Sciences, School of Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Alain de Bruin
- Department of Toxicology, Faculty of Health Medicine and Life Sciences, School of Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands.,Institute of Pathology, Utrecht University, Utrecht, The Netherlands
| | - Maximilian Hatting
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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22
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NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation. Int J Mol Sci 2018; 19:ijms19092732. [PMID: 30213101 PMCID: PMC6163521 DOI: 10.3390/ijms19092732] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 12/11/2022] Open
Abstract
In sterile liver inflammation, danger signals are released in response to tissue injury to alert the immune system; e.g., by activation of the NLRP3 inflammasome. Recently, IL-33 has been identified as a novel type of danger signal or “alarmin”, which is released from damaged and necrotic cells. IL-33 is a pleiotropic cytokine that targets a broad range of immune cells and exhibits pro- and anti-inflammatory properties dependent on the disease. This review summarizes the immunomodulatory roles of the NLRP3 inflammasome and IL-33 in sterile liver inflammation and highlights potential therapeutic strategies targeting these pathways in liver disease.
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23
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Abstract
Necrosis is a hallmark of several widespread diseases or their direct complications. In the past decade, we learned that necrosis can be a regulated process that is potentially druggable. RIPK3- and MLKL-mediated necroptosis represents by far the best studied pathway of regulated necrosis. During necroptosis, the release of damage-associated molecular patterns (DAMPs) drives a phenomenon referred to as necroinflammation, a common consequence of necrosis. However, most studies of regulated necrosis investigated cell lines in vitro in a cell autonomous manner, which represents a non-physiological situation. Conclusions based on such work might not necessarily be transferrable to disease states in which synchronized, non-cell autonomous effects occur. Here, we summarize the current knowledge of the pathophysiological relevance of necroptosis in vivo, and in light of this understanding, we reassess the morphological classification of necrosis that is generally used by pathologists. Along these lines, we discuss the paucity of data implicating necroptosis in human disease. Finally, the in vivo relevance of non-necroptotic forms of necrosis, such as ferroptosis, is addressed.
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Affiliation(s)
- Wulf Tonnus
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
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24
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Schueller F, Roy S, Vucur M, Trautwein C, Luedde T, Roderburg C. The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity. Int J Mol Sci 2018; 19:ijms19010261. [PMID: 29337905 PMCID: PMC5796207 DOI: 10.3390/ijms19010261] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/12/2018] [Accepted: 01/13/2018] [Indexed: 12/12/2022] Open
Abstract
Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed. MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets”. Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases. In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes. Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology. Here, we review the function of miRNAs in the context of acute and chronic liver diseases. Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine.
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Affiliation(s)
- Florian Schueller
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Sanchari Roy
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Mihael Vucur
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
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25
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Wu L, Zhang Q, Dai W, Li S, Feng J, Li J, Liu T, Xu S, Wang W, Lu X, Yu Q, Chen K, Xia Y, Lu J, Zhou Y, Fan X, Guo C. Quercetin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy by Inhibiting ERK/NF- κB Pathway. Gastroenterol Res Pract 2017; 2017:9724217. [PMID: 29123547 PMCID: PMC5662816 DOI: 10.1155/2017/9724217] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/20/2017] [Accepted: 06/12/2017] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Hepatic ischemia reperfusion (IR) injury is a common phenomenon in transplantation or trauma. The aim of the present study was to determine the protective effect of quercetin (QE) on hepatic IR injury via the ERK/NF-κB pathway. METHODS Mice were randomized into the sham, IR, QE100 + IR, and QE200 + IR groups. Quercetin was administered intragastrically daily at two doses (100 mg/kg and 200 mg/kg) for 5 days prior to IR injury. The expression levels of liver enzymes, inflammatory cytokines, and other marker proteins were determined at 2, 8, and 24 hours after IR. And they were compared among these groups. RESULTS Compared with the IR group, the treatment of QE reduced the release of cytokines, leading to inhibition of apoptosis and autophagy via downregulation of the ERK/NF-κB pathway in this model of hepatic IR injury. CONCLUSION Apoptosis and autophagy caused by hepatic IR injury were inhibited by QE following a reduction in the release of inflammatory cytokines, and the relationship between the two may be associated with inactivation of the ERK/NF-κB pathway.
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Affiliation(s)
- Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Qinghui Zhang
- Department of Clinical Laboratory, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Shizan Xu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, China
| | - Wenwen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xiya Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xiaoming Fan
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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Bouhlel A, Ben Mosbah I, Hadj Abdallah N, Ribault C, Viel R, Mannaï S, Corlu A, Ben Abdennebi H. Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion. Biomed Pharmacother 2017; 94:964-973. [DOI: 10.1016/j.biopha.2017.08.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 08/01/2017] [Accepted: 08/02/2017] [Indexed: 01/14/2023] Open
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Yagmurdur H, Binnetoglu K, Astarci HM, Yagmurdur MC. Propofol attenuates cytokine-mediated upregulation of expression of inducible nitric oxide synthase and apoptosis during regeneration post-partial hepatectomy. Acta Cir Bras 2017; 32:396-406. [PMID: 28591369 DOI: 10.1590/s0102-865020170050000009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 04/19/2017] [Indexed: 01/28/2023] Open
Abstract
Purpose: To determine the effects of propofol and ketamine anesthesia on liver regeneration in rats after partial hepatectomy (PHT). Methods: Male Wistar albino rats were assigned randomly to four groups of 10. Anesthesia was induced and maintained with propofol in groups 1 and 2, and with ketamine in groups 3 and 4. PHT was undertaken in groups 1 and 3. Rats in groups 2 and 4 (control groups) underwent an identical surgical procedure, but without PHT. At postoperative day-5, rats were killed. Regenerated liver was removed, weighed, and evaluated (by immunohistochemical means) for expression of inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), apoptosis protease-activating factor (APAF)-1, and proliferating cell nuclear antigen (PCNA). Also, blood samples were collected for measurement of levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Results: Between groups 2 and 4, there were no differences in tissue levels of iNOS, eNOS, and APAF-1 or plasma levels of TNF-α and IL-6. eNOS expression was similar in group 1 and group 3. Expression of iNOS and APAF-1 was mild-to-moderate in group 1, but significantly higher in group 3. Groups 1 and 3 showed an increase in PCNA expression, but expression in both groups was comparable. Plasma levels of TNF-α and IL-6 increased to a lesser degree in group 1 than in group 3. Conclusion: Propofol, as an anesthetic agent, may attenuate cytokine-mediated upregulation of iNOS expression and apoptosis in an animal model of liver regeneration after partial hepatectomy.
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Affiliation(s)
- Hatice Yagmurdur
- Professor, Department of Anesthesiology and Reanimation, School of Medicine, Kafkas University, Kars, Turkey. Conception and design of the study; acquisition, analysis and interpretation of data; manuscript writing; critical revision
| | - Kenan Binnetoglu
- Assistant Professor, Department of General Surgery, School of Medicine, Kafkas University, Kars, Turkey. Design of the study, manuscript writing
| | - Hesna Muzeyyen Astarci
- MD, Department of Pathology, Ministry of Health Ankara Research and Training Hospital, Ankara, Turkey. Acquisition, analysis and interpretation of data; manuscript writing
| | - Mahmut Can Yagmurdur
- Professor, Department of General Surgery, School of Medicine, Kafkas University, Kars, Turkey. Conception of the study, analysis and interpretation of data, manuscript writing, critical revision
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Abstract
BACKGROUND Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.
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Abstract
Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver ischemia-reperfusion injury involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver ischemia-reperfusion injury in patients.
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Kadono K, Uchida Y, Hirao H, Miyauchi T, Watanabe T, Iida T, Ueda S, Kanazawa A, Mori A, Okajima H, Terajima H, Uemoto S. Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner. Am J Transplant 2017; 17:69-80. [PMID: 27467205 DOI: 10.1111/ajt.13991] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 01/25/2023]
Abstract
Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit an anti-inflammatory effect through binding to the high-mobility group box 1 protein (HMGB-1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild-type (WT) and toll-like receptor 4 (TLR-4) KO mice focusing on the HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR-4 and also HMGB-1 expression in liver cells, as well as release of HMGB-1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR-4 pathway-dependent manner.
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Affiliation(s)
- K Kadono
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - Y Uchida
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - H Hirao
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - T Miyauchi
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - T Watanabe
- Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - T Iida
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - S Ueda
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - A Kanazawa
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - A Mori
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - H Okajima
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - H Terajima
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan
| | - S Uemoto
- Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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31
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Cannistrà M, Ruggiero M, Zullo A, Gallelli G, Serafini S, Maria M, Naso A, Grande R, Serra R, Nardo B. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. Int J Surg 2016; 33 Suppl 1:S57-70. [PMID: 27255130 DOI: 10.1016/j.ijsu.2016.05.050] [Citation(s) in RCA: 243] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) is not only a pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. Hepatic IRI can seriously impair liver function, even producing irreversible damage, which causes a cascade of multiple organ dysfunction. Many factors, including anaerobic metabolism, mitochondrial damage, oxidative stress and secretion of ROS, intracellular Ca(2+) overload, cytokines and chemokines produced by KCs and neutrophils, and NO, are involved in the regulation of hepatic IRI processes. Matrix Metalloproteinases (MMPs) can be an important mediator of early leukocyte recruitment and target in acute and chronic liver injury associated to ischemia. MMPs and neutrophil gelatinase-associated lipocalin (NGAL) could be used as markers of I-R injury severity stages. This review explores the relationship between factors and inflammatory pathways that characterize hepatic IRI, MMPs and current pharmacological approaches to this disease.
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Affiliation(s)
- Marco Cannistrà
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Michele Ruggiero
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Alessandra Zullo
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Giuseppe Gallelli
- Department of Emergency, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
| | - Simone Serafini
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Mazzitelli Maria
- Department of Primary Care, Provincial Health Authority of Vibo Valentia, 89900 Vibo Valentia, Italy.
| | - Agostino Naso
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Grande
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Bruno Nardo
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy; Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
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Li S, Takahara T, Li XK, Fujino M, Sugiyama T, Tsukada K, Liu C, Kakuta Y, Nonomura N, Ito H, Takahashi K, Nakajima M, Tanaka T, Takahara S. 5-Aminolevulinic acid combined with ferrous iron ameliorate ischemia-reperfusion injury in the mouse fatty liver model. Biochem Biophys Res Commun 2016; 470:900-6. [PMID: 26820535 DOI: 10.1016/j.bbrc.2016.01.136] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 01/22/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND The fatty liver could increase the risk of serious acute ischemia reperfusion (I/R) injury, and hepatic steatosis is indeed a major risk factor for hepatic failure after grafting a fatty liver. MATERIALS & METHODS Fatty liver models of methionine- and choline-deficient high-fat mice were subjected to I/R injury with or without 5-aminolevulinic acid (5-ALA)/sodium ferrous citrate (SFC) treatment. Levels of hepatic enzymes, lipid peroxidation and apoptosis, inflammatory cytokines and heme oxygenase (HO)-1, and the carbon monoxide (CO) in the liver, and reactive oxygen species (ROS), inflammatory cytokines and members of the signaling pathway in isolated Kupffer were assessed. RESULTS Alanine aminotransferase and aspartate aminotransferase levels, the number of necrotic areas, thiobarbituric acid reactive substance content, TUNEL-positive cells, infiltrated macrophages, and the inflammatory cytokine expression after I/R injury were dramatically decreased, whereas the endogenous CO concentrations and the HO-1 expression were significantly increased by 5-ALA/SFC treatment. The expression of toll-like receptors 2 and 4, NF-κB and inflammatory cytokines and ROS production in Kupffer cells were significantly decreased with 5-ALA/SFC treatment. CONCLUSION 5-ALA/SFC significantly attenuates the injury level in the fatty liver after I/R injury.
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Affiliation(s)
- Shaowei Li
- Division of Transplantation Immunology, National Institute for Child Health and Development, Tokyo, Japan; Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan; Second Department of Surgery, University of Toyama, Toyama, Japan; Clinical Medicine Research Center of Affiliated Hospital, Inner Mongolia Medical University, Hohhot, China
| | - Terumi Takahara
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan.
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Institute for Child Health and Development, Tokyo, Japan.
| | - Masayuki Fujino
- Division of Transplantation Immunology, National Institute for Child Health and Development, Tokyo, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Toshiro Sugiyama
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Kazuhiro Tsukada
- Second Department of Surgery, University of Toyama, Toyama, Japan
| | - Chi Liu
- Division of Transplantation Immunology, National Institute for Child Health and Development, Tokyo, Japan
| | - Yoichi Kakuta
- Department of Specific Organ Regulation (Urology), Osaka University Graduate School of Medicine, Osaka, Japan
| | - Norio Nonomura
- Department of Specific Organ Regulation (Urology), Osaka University Graduate School of Medicine, Osaka, Japan
| | | | | | | | | | - Shiro Takahara
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan
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Niu C, Sheng Y, Zhu E, Ji L, Wang Z. Ferulic acid prevents liver injury induced by Diosbulbin B and its mechanism. Biosci Trends 2016; 10:386-391. [DOI: 10.5582/bst.2016.01152] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Chengwei Niu
- hanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine
| | - Yuchen Sheng
- Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine
| | - Enyuan Zhu
- hanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine
| | - Lili Ji
- hanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine
| | - Zhengtao Wang
- hanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine
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Yang P, Zhou W, Li C, Zhang M, Jiang Y, Jiang R, Ba H, Li C, Wang J, Yin B, Gong F, Li Z. Kupffer-cell-expressed transmembrane TNF-α is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury. Cell Tissue Res 2015; 363:371-83. [PMID: 26267221 DOI: 10.1007/s00441-015-2252-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Accepted: 06/11/2015] [Indexed: 12/22/2022]
Abstract
Tumor necrosis factor (TNF)-α exists in two bioactive forms, a 26-kDa transmembrane form (tmTNF-α) and a 17-kDa soluble form (sTNF-α). sTNF-α has been recognized as a key regulator of hepatitis; however, serum sTNF-α disappears in mice during the development of severe liver injury, and high levels of serum sTNF-α do not necessarily result in liver damage. Interestingly, in a mouse model of acute hepatitis, we have found that tmTNF-α expression on Kupffer cells (KCs) significantly increases when mice develop severe liver injury caused by lipopolysaccharide (LPS)/D-galactosamine (D-gal), and the level of tmTNF-α expression is positively related to the activity of serum transaminases. Therefore, we hypothesized that KC-expressed tmTNF-α constitutes a pathomechanism in hepatitis and have explored the role of tmTNF-α in this disease model. Here, we have compared the impact of KCs(tmTNFlow) and KCs(tmTNFhigh) on acute hepatitis in vivo and ex vivo and have further demonstrated that KCs(tmTNFhigh), rather than KCs(tmTNFlow), not only exhibit an imbalance in secretion of pro- and anti-inflammatory cytokines, favoring inflammatory response and exacerbating liver injury, but also induce hepatocellular apoptosis via tmTNF-α and the expression of another pro-apoptotic factor, Fas ligand. Our data suggest that KC(tmTNFhigh) is a major contributor to liver injury in LPS/D-gal-induced hepatitis.
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Affiliation(s)
- Peng Yang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Wenjing Zhou
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Chenxi Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Meng Zhang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Yaping Jiang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Rui Jiang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Hongping Ba
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Cheng Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Jing Wang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Bingjiao Yin
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Feili Gong
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China
| | - Zhuoya Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, People's Republic of China.
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Takhtfooladi HA, Asl AHK, Shahzamani M, Takhtfooladi MA, Allahverdi A, Khansari M. Tramadol alleviates myocardial injury induced by acute hindlimb ischemia reperfusion in rats. Arq Bras Cardiol 2015; 105:151-9. [PMID: 26039663 PMCID: PMC4559124 DOI: 10.5935/abc.20150059] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background Organ injury occurs not only during periods of ischemia but also during
reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ
and local injuries. Objective This study evaluated the effects of tramadol on the heart as a remote organ after
acute hindlimb IR. Methods Thirty healthy mature male Wistar rats were allocated randomly into three groups:
Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced
in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of
reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior
to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts
were harvested for histological and biochemical examination. Results The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione
peroxidase (GPx) were higher in Groups I and III than those in Group II (p <
0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in
Group II were significantly increased (p < 0.05), and this increase was
prevented by tramadol. Histopathological changes, including microscopic bleeding,
edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore
in Group III was significantly decreased (p < 0.05) compared with Group II. Conclusion From the histological and biochemical perspectives, treatment with tramadol
alleviated the myocardial injuries induced by skeletal muscle IR in this
experimental model.
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Affiliation(s)
| | | | - Mehran Shahzamani
- Department of Cardiovascular Surgery, Isfahan University of Medical Sciences, Tehran, IR
| | | | - Amin Allahverdi
- Department of Surgery, Science and Research Branch, Islamic Azad University, Tehran, IR
| | - Mohammadreza Khansari
- Department of Physiology, Science and Research Branch, Islamic Azad University, Tehran, IR
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Wang J, Cai Z, Liu J. Microarray analysis for differentially expressed genes of patients undergoing total knee arthroplasty with ischemia preconditioning. J Orthop Surg Res 2014; 9:133. [PMID: 25496472 PMCID: PMC4298116 DOI: 10.1186/s13018-014-0133-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Ischemia preconditioning (IPC) has been proved as a powerful method of protecting tissues against ischemia reperfusion insults. We aimed to elucidate the mechanism of IPC in ischemia reperfused tissues. METHODS GSE21164 containing 16 muscle biopsies taken from the operative knee of four IPC-treated patients and four control at the onset of surgery (T¿=¿0) and 1 h into surgery (T¿=¿1) undergoing primary total knee arthroplasty was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between IPC group and control were screened with Limma package in R language. KEGG pathway enrichment analysis was performed by the DAVID online tool. Meanwhile, potential regulatory microRNAs (miRNAs) for downregulated DEGs and targets of transcription factors for upregulated DEGs were screened out. Based on the above DEGs, protein-protein interaction (PPI) networks were constructed by the STRING software. RESULTS Significantly upregulated DEGs at T1 were mainly enriched in asthma and p53 signaling pathway. Meanwhile, significantly enriched transcriptional factor NOTCH1 at T1 and GABP at T0 were obtained. Moreover, miRNA analysis showed that targets of miR141/200a were enriched in downregulated DEGs both at T0 and T1. Mostly, RPA1 and JAK2 in PPI network at T1 were with higher degree. CONCLUSIONS In our study, obtained DEGs, regulatory transcriptional factors, and miRNA might play a vital role in the protection of ischemia reperfusion injury. This finding will provide a deeper understanding to the mechanism of IPC.
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Chen YL, Peng HC, Hsieh YC, Yang SC. Epidermal growth factor improved alcohol-induced inflammation in rats. Alcohol 2014; 48:701-6. [PMID: 25174268 DOI: 10.1016/j.alcohol.2014.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Revised: 04/22/2014] [Accepted: 07/24/2014] [Indexed: 12/12/2022]
Abstract
The purpose of this study was to investigate the effects of an epidermal growth factor (EGF) intervention on improving the inflammatory response of rats fed an ethanol-containing diet. Eight-week-old male Wistar rats were divided into ethanol (E) and control (C) groups. Rats in the E group were fed an ethanol liquid diet, while rats in the C group were pair-fed an isoenergetic diet without ethanol. After a 4-week ethanol-induction period, both the C and E group were respectively subdivided into 2 groups: a normal liquid diet without (C group, n = 8) or with EGF supplementation (C + EGF, n = 8), and the ethanol-containing diet without (E group, n = 8) or with EGF supplementation (E + EGF group, n = 8). The EGF (30 μg/kg body weight/day) intervention period was carried out for the following 8 weeks. At the end of the experiment, activity of aspartate transaminase (AST) and alanine transaminase (ALT) and hepatic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in group E were significantly higher than those in group C. In addition, alterations in the gut microbiota profile were found in group E. In contrast, activity of AST and ALT and levels of TNF-α, IL-1β, and IL-6 in group E + EGF were significantly lower than those in group E. Significantly lower intestinal permeability and lower numbers of Escherichia coli in the fecal microbial culture were also found in group E + EGF. These results suggest that EGF improved the intestinal integrity by decreasing E. coli colonization and lowering intestinal permeability, which then ameliorated the inflammatory response under chronic ethanol exposure.
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Ibrahim MA, Abdel-Gaber SA, Amin EF, Ibrahim SA, Mohammed RK, Abdelrahman AM. Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury. Eur J Pharmacol 2014; 741:64-73. [DOI: 10.1016/j.ejphar.2014.07.047] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Revised: 07/12/2014] [Accepted: 07/19/2014] [Indexed: 12/14/2022]
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Krishnan TR, Velusamy P, Srinivasan A, Ganesan T, Mangaiah S, Narasimhan K, Chakrapani LN, J. T, Walter CEJ, Durairajan S, Nathakattur Saravanabavan S, Periandavan K. EGCG mediated downregulation of NF-AT and macrophage infiltration in experimental hepatic steatosis. Exp Gerontol 2014; 57:96-103. [DOI: 10.1016/j.exger.2014.05.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 05/03/2014] [Accepted: 05/08/2014] [Indexed: 10/25/2022]
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Patouraux S, Rousseau D, Rubio A, Bonnafous S, Lavallard VJ, Lauron J, Saint-Paul MC, Bailly-Maitre B, Tran A, Crenesse D, Gual P. Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice. Cell Death Dis 2014; 5:e1208. [PMID: 24810044 PMCID: PMC4047890 DOI: 10.1038/cddis.2014.174] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 02/26/2014] [Accepted: 03/18/2014] [Indexed: 12/17/2022]
Abstract
Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia–reperfusion (I–R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn−/− mice compared with wild-type (Wt) mice after I–R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn−/− mice versus Wt mice after I–R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen–glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn−/− mice versus Wt mice livers after I–R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I–R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.
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Affiliation(s)
- S Patouraux
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Pôle Biologique, Hôpital Pasteur, Nice, France
| | - D Rousseau
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France
| | - A Rubio
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France
| | - S Bonnafous
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Pôle Digestif, Hôpital L'Archet, Nice, France
| | - V J Lavallard
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France
| | - J Lauron
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France
| | - M-C Saint-Paul
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Pôle Biologique, Hôpital Pasteur, Nice, France
| | - B Bailly-Maitre
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France
| | - A Tran
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Pôle Digestif, Hôpital L'Archet, Nice, France
| | - D Crenesse
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Hôpitaux Pédiatriques CHU Lenval, Nice, France
| | - P Gual
- 1] INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l'obésité», Nice, France [2] Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France
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Jiao SF, Sun K, Chen XJ, Zhao X, Cai N, Liu YJ, Xu LM, Kong XM, Wei LX. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury. J Biomed Sci 2014; 21:1. [PMID: 24397824 PMCID: PMC3902418 DOI: 10.1186/1423-0127-21-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/04/2014] [Indexed: 12/13/2022] Open
Abstract
Background Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Results Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. Conclusion These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.
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Affiliation(s)
| | | | | | | | | | | | | | - Xian-Ming Kong
- Medical Sciences Research Center, Renji hospital, School of Medicine, Shanghai Jiaotong University, 1630 Dongfang Road, Shanghai 200127, China.
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Polat B, Albayrak A, Halici Z, Karakus E, Bayir Y, Demirci E, Cadirci E, Odaci E, Yayla M, Atamanalp SS. The effect of levosimendan in rat mesenteric ischemia/reperfusion injury. J INVEST SURG 2013; 26:325-333. [PMID: 23957729 DOI: 10.3109/08941939.2013.806615] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Intestinal ischemia reperfusion (IR) is associated with morbidity and mortality. We first examined the role of levosimendan in the protection of intestine after mesenteric IR. METHODS The rats were divided into six groups: (1) Control group; (2) Levosimendan group; (3) Ischemia group (60 min of occlusion); (4) IR group (60 min of occlusion and then 60 min reperfusion); (5) IR + 1 mg/kg levosimendan group: Levosimendan was given intraperitonally 30 min prior to the ischemia; (6) IR + 2 mg/kg levosimendan group. RESULTS The levels of TNF-α, IL-6, and IL-1β were found to have increased in the IR group. The serum levels of TNF-α, IL-6, and IL-1β were found to have decreased as a result of the administration of both doses of levosimendan in the IR. Relative TNF-α and NFκB mRNA levels was decreased by administration of both doses of levosimendan in the IR. SOD activity and GSH levels for IR group were lower than, and 8-ISO levels were higher than, those of the sham-operated rat and ischemia alone group. CONCLUSIONS Both doses of levosimendan had preventive effects on the alterations that occurred in the intestinal tissues after IR. Levosimendan administration attenuated in reperfusion injury of intestine and consequently protects intestinal mucosa and oxidant-antioxidant balance of ileum.
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Affiliation(s)
- Beyzagul Polat
- 1 Department of Pharmacology, School of Pharmacy, Ataturk University, Erzurum, Turkey
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Liu SQ, Lei P, Cui XH, Lv Y, Li JH, Song YL, Zhao G. Sutureless anastomoses using magnetic rings in canine liver transplantation model. J Surg Res 2013; 185:923-33. [DOI: 10.1016/j.jss.2013.07.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 07/04/2013] [Accepted: 07/11/2013] [Indexed: 01/16/2023]
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Chen YL, Peng HC, Tan SW, Tsai CY, Huang YH, Wu HY, Yang SC. Amelioration of ethanol-induced liver injury in rats by nanogold flakes. Alcohol 2013; 47:467-72. [PMID: 23830375 DOI: 10.1016/j.alcohol.2013.05.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 05/14/2013] [Accepted: 05/14/2013] [Indexed: 12/20/2022]
Abstract
The purpose of this study was to investigate the protective effects of nanogold flakes against alcoholic liver disease. Six-week-old male Wistar rats were divided into 6 groups: C (control liquid diet), CLF (control liquid diet with gold flakes at 1.03 mg/kg body weight [BW]/day), CHF (control liquid diet with gold flakes at 5.15 mg/kg BW/day), E (ethanol liquid diet), ELF (ethanol liquid diet with gold flakes at 1.03 mg/kg BW/day), and EHF (ethanol liquid diet with gold flakes at 5.15 mg/kg BW/day). The liquid diets were prepared daily. Gold flakes were added to the ethanol 1 h before preparing the ethanol liquid diets, as an aging process. After 10 weeks, rats in group E showed significantly higher plasma aspartate transaminase (AST) and alanine transaminase (ALT) activities than those in group C. A significantly increased concentration of hepatic triglyceride (TG) was found in group E. Furthermore, higher hepatic glutathione reductase (GRD), superoxide dismutase (SOD), and catalase (CAT) activities together with higher tumor necrosis factor (TNF)-α concentration and higher hepatic cytochrome (CYP2E1) protein expression were also observed in group E. In contrast, the hepatic TG concentration in group EHF was significantly lower than that of group E. In addition, hepatic glutathione peroxidase (GPX), SOD, and CAT activities together with TNF-α concentration and hepatic CYP2E1 protein expression in group EHF were significantly lower than those in group E. We concluded that nanogold flakes might ameliorate alcohol-induced liver injury by maintaining the hepatic antioxidative status. In addition, nanogold flakes may reduce fat accumulation caused by chronic ethanol feeding via decreasing hepatic TNF-α.
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Propofol Protects against Ischemia/Reperfusion Injury Associated with Reduced Apoptosis in Rat Liver. ACTA ACUST UNITED AC 2013. [DOI: 10.1155/2013/517478] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Propofol is an intravenous anesthetic, reported to have a protective effect against ischemia/reperfusion (I/R) injury in heart and brain, but no definite data are available concerning its effect in hepatic I/R. This work investigated the effect of propofol anesthesia on hepatic I/R injury using in vivo rat model. Four groups of rats were included: sham operated, I/R (30 min ischemia and 2 h reperfusion), I/R treated with propofol (10 mg/kg/h), and I/R treated with propofol (20 mg/kg/h). Liver enzyme leakage, TNF-α and caspase-3 levels, and antiapoptotic Bcl-xL/apoptotic Bax gene expression, together with histopathological changes, were used to evaluate the extent of hepatic I/R injury. Compared with sham-operated group, I/R group showed significant increase in serum levels of liver enzymes (ALT, AST), TNF-α, and caspase-3 and significant decrease in the Bcl-xL/Bax ratio, associated with histopathologic damage in liver. Propofol infusion significantly attenuated these changes with reduced hepatic histopathologic lesions compared with nonpreconditioned I/R group. However, no significant differences were found between two groups treated with different doses of propofol. In conclusion, propofol infusion reduced hepatic I/R injury with decreased markers of cellular apoptosis. Therefore, propofol anesthesia may provide a useful hepatic protection during liver surgery.
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Yang Q, Zheng FP, Zhan YS, Tao J, Tan SW, Liu HL, Wu B. Tumor necrosis factor-α mediates JNK activation response to intestinal ischemia-reperfusion injury. World J Gastroenterol 2013; 19:4925-4934. [PMID: 23946597 PMCID: PMC3740422 DOI: 10.3748/wjg.v19.i30.4925] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 05/02/2013] [Accepted: 06/20/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether tumor necrosis factor-α (TNF-α) mediates ischemia-reperfusion (I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase (JNK) activation.
METHODS: In this study, intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion, and the rats were pretreated with a TNF-α inhibitor, pentoxifylline, or the TNF-α antibody infliximab. After surgery, part of the intestine was collected for histological analysis. The mucosal layer was harvested for RNA and protein extraction, which were used for further real-time polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses. The TNF-α expression, intestinal mucosal injury, cell apoptosis, activation of apoptotic protein and JNK signaling pathway were analyzed.
RESULTS: I/R significantly enhanced expression of mucosal TNF-α at both the mRNA and protein levels, induced severe mucosal injury and cell apoptosis, activated caspase-9/caspase-3, and activated the JNK signaling pathway. Pretreatment with pentoxifylline markedly downregulated TNF-α at both the mRNA and protein levels, whereas infliximab pretreatment did not affect the expression of TNF-α induced by I/R. However, pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling.
CONCLUSION: The results indicate there was a TNF-α-mediated JNK activation response to intestinal I/R injury.
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Lloris Carsi JM, Cejalvo Lapeña D, Toledo AH, Zaragoza Fernandez C, Toledo Pereyra LH. Pentoxifylline Protects the Small Intestine After Severe Ischemia and Reperfusion. EXP CLIN TRANSPLANT 2013; 11:250-8. [DOI: 10.6002/ect.2012.0222] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Datta G, Fuller BJ, Davidson BR. Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models. World J Gastroenterol 2013; 19:1683-98. [PMID: 23555157 PMCID: PMC3607745 DOI: 10.3748/wjg.v19.i11.1683] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 06/29/2012] [Accepted: 07/09/2012] [Indexed: 02/06/2023] Open
Abstract
Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery. Understanding the mechanisms of liver ischemia reperfusion injury (IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation, as well as expanding the potential pool of usable donor grafts. The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes, increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis. Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury. IRI involves a complex interplay between neutrophils, natural killer T-cells cells, CD4+ T cell subtypes, cytokines, nitric oxide synthases, haem oxygenase-1, survival kinases such as the signal transducer and activator of transcription, Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways. Transgenic animals, particularly genetic knockout models, have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies. Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein. This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI.
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Kireev R, Bitoun S, Cuesta S, Tejerina A, Ibarrola C, Moreno E, Vara E, Tresguerres JAF. Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis. Eur J Pharmacol 2012; 701:185-93. [PMID: 23220161 DOI: 10.1016/j.ejphar.2012.11.038] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 11/22/2012] [Accepted: 11/26/2012] [Indexed: 12/16/2022]
Abstract
Fatty livers occur in up to 20% of potential liver donors and increase cellular injury during the ischemia/reperfusion phase, so any intervention that could enable a better outcome of grafts for liver transplantation would be very useful. The effect of melatonin on liver ischemia/reperfusion injury in a rat model of obesity and hepatic steatosis has been investigated. Forty fa/fa Zucker rats were divided in 4 groups. 3 groups were subjected to 35 min of warm hepatic ischemia and 36 h of reperfusion. One experimental group remained untreated and 2 were given 10mg/kg melatonin intraperitoneally or orally. Another group was sham-operated. Plasma ALT, AST and hepatic content of ATP, MDA, hydroxyalkenals, NOx metabolites, antioxidant enzyme activity, caspase-9 and DNA fragmentation were determined in the liver. The expression of iNOS, eNOS, Bcl2, Bax, Bad and AIF were determined by RT-PCR Melatonin was effective at decreasing liver injury by both ways as assessed by liver transaminases, markers of apoptosis, of oxidative stress and improved liver ATP content. Melatonin administration decreased the activities or levels of most of the parameters measured in a beneficial way, and our study identified also some of the mechanisms of protection. We conclude that administration of melatonin improved liver function, as well as markers of pro/antioxidant status and apoptosis following ischemia/reperfusion in obese rats with fatty liver. These data suggest that this substance could improve outcome in patients undergoing liver transplantation who receive a fatty liver implant and suggest the need of clinical trials with it in liver transplantation.
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Affiliation(s)
- Roman Kireev
- Department of Physiology, Medical School, University Complutense of Madrid, Madrid, Spain.
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Lentsch AB. Regulatory mechanisms of injury and repair after hepatic ischemia/reperfusion. SCIENTIFICA 2012; 2012:513192. [PMID: 24278708 PMCID: PMC3820555 DOI: 10.6064/2012/513192] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 09/12/2012] [Indexed: 06/02/2023]
Abstract
Hepatic ischemia/reperfusion injury is an important complication of liver surgery and transplantation. The mechanisms of this injury as well as the subsequent reparative and regenerative processes have been the subject of thorough study. In this paper, we discuss the complex and coordinated responses leading to parenchymal damage after liver ischemia/reperfusion as well as the manner in which the liver clears damaged cells and regenerates functional mass.
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Affiliation(s)
- Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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