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Frick J, Frobert A, Quintela Pousa AM, Balaphas A, Meyer J, Schäfer K, Giraud MN, Egger B, Bühler L, Gonelle-Gispert C. Evidence for platelet-derived transforming growth factor β1 as an early inducer of liver regeneration after hepatectomy in mice. FASEB J 2024; 38:e70039. [PMID: 39258958 DOI: 10.1096/fj.202400345r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 08/08/2024] [Accepted: 08/27/2024] [Indexed: 09/12/2024]
Abstract
Platelets play a crucial role in tissue regeneration, and their involvement in liver regeneration is well-established. However, the specific contribution of platelet-derived Transforming Growth Factor Beta 1 (TGFβ1) to liver regeneration remains unexplored. This study investigated the role of platelet-derived TGFβ1 in initiating liver regeneration following 2/3 liver resection. Using platelet-specific TGFβ1 knockout (Plt.TGFβ1 KO) mice and wild-type littermates (Plt.TGFβ1 WT) as controls, the study assessed circulating levels and hepatic gene expression of TGFβ1, Platelet Factor 4 (PF4), and Thrombopoietin (TPO) at early time points post-hepatectomy (post-PHx). Hepatocyte proliferation was quantified through Ki67 staining and PCNA expression in total liver lysates at various intervals, and phosphohistone-H3 (PHH3) staining was employed to mark mitotic cells. Circulating levels of hepatic mitogens, Hepatocyte Growth Factor (HGF), and Interleukin-6 (IL6) were also assessed. Results revealed that platelet-TGFβ1 deficiency significantly reduced total plasma TGFβ1 levels at 5 h post-PHx in Plt.TGFβ1 KO mice compared to controls. While circulating PF4 levels, liver platelet recruitment and activation appeared normal at early time points, Plt.TGFβ1 KO mice showed more stable circulating platelet numbers with higher numbers at 48 h post-PHx. Notably, hepatocyte proliferation was significantly reduced in Plt.TGFβ1 KO mice. The results show that a lack of TGFβ1 in platelets leads to an unbalanced expression of IL6 in the liver and to strongly increased HGF levels 48 h after liver resection, and yet liver regeneration remains reduced. The study identifies platelet-TGFβ1 as a regulator of hepatocyte proliferation and platelet homeostasis in the early stages of liver regeneration.
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Affiliation(s)
- Johanna Frick
- Surgical Research Unit, Department of MSS, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Aurelien Frobert
- Cardiology, Department of EMC, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Ana Maria Quintela Pousa
- Surgical Research Unit, Department of MSS, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Alexandre Balaphas
- Division of Digestive Surgery, University Hospitals of Geneva, Geneva, Switzerland
| | - Jeremy Meyer
- Division of Digestive Surgery, University Hospitals of Geneva, Geneva, Switzerland
| | - Katrin Schäfer
- Department of Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
| | - Marie-Noelle Giraud
- Cardiology, Department of EMC, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Bernhard Egger
- Surgical Research Unit, Department of MSS, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Leo Bühler
- Surgical Research Unit, Department of MSS, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Carmen Gonelle-Gispert
- Surgical Research Unit, Department of MSS, Section of Medicine, University of Fribourg, Fribourg, Switzerland
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Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: Biological mechanisms and implications. iScience 2024; 27:108683. [PMID: 38155779 PMCID: PMC10753089 DOI: 10.1016/j.isci.2023.108683] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2023] Open
Abstract
The liver possesses a unique regenerative ability to restore its original mass, in this regard, partial hepatectomy (PHx) and partial liver transplantation (PLTx) can be executed smoothly and safely, which has important implications for the treatment of liver disease. Liver regeneration (LR) can be the very complicated procedure that involves multiple cytokines and transcription factors that interact with each other to activate different signaling pathways. Activation of these pathways can drive the LR process, which can be divided into three stages, namely, the initiation, progression, and termination stages. Therefore, it is important to investigate the pathways involved in LR to elucidate the mechanism of LR. This study reviews the latest research on the key signaling pathways in the different stages of LR.
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Affiliation(s)
- Chunyan Zhang
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Caifang Sun
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Yabin Zhao
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Bingyu Ye
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - GuoYing Yu
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
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Niemelä O, Bloigu A, Bloigu R, Nivukoski U, Kultti J, Pohjasniemi H. Patterns of IgA Autoantibody Generation, Inflammatory Responses and Extracellular Matrix Metabolism in Patients with Alcohol Use Disorder. Int J Mol Sci 2023; 24:13124. [PMID: 37685930 PMCID: PMC10487441 DOI: 10.3390/ijms241713124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Recent data have emphasized the role of inflammation and intestinal immunoglobulin A (IgA) responses in the pathogenesis of alcoholic liver disease (ALD). In order to further explore such associations, we compared IgA titers against antigens targeted to ethanol metabolites and tissue transglutaminase with pro- and anti-inflammatory mediators of inflammation, markers of liver status, transferrin protein desialylation and extracellular matrix metabolism in alcohol-dependent patients with or without liver disease and in healthy controls. Serum IgAs against protein adducts with acetaldehyde (HbAch-IgA), the first metabolite of ethanol, and tissue transglutaminase (tTG-IgA), desialylated transferrin (CDT), pro- and anti-inflammatory cytokines, markers of liver status (GT, ALP) and extracellular matrix metabolism (PIIINP, PINP, hyaluronic acid, ICTP and CTx) were measured in alcohol-dependent patients with (n = 83) or without (n = 105) liver disease and 88 healthy controls representing either moderate drinkers or abstainers. In ALD patients, both tTG-IgA and HbAch-IgA titers were significantly higher than those in the alcoholics without liver disease (p < 0.0005 for tTG-IgA, p = 0.006 for Hb-Ach-IgA) or in healthy controls (p < 0.0005 for both comparisons). The HbAch-IgA levels in the alcoholics without liver disease also exceeded those found in healthy controls (p = 0.0008). In ROC analyses, anti-tTG-antibodies showed an excellent discriminative value in differentiating between ALD patients and healthy controls (AUC = 0.95, p < 0.0005). Significant correlations emerged between tTG-IgAs and HbAch-IgAs (rs = 0.462, p < 0.0005), CDT (rs = 0.413, p < 0.0001), GT (rs = 0.487, p < 0.0001), alkaline phosphatase (rs = 0.466, p < 0.0001), serum markers of fibrogenesis: PIIINP (rs = 0.634, p < 0.0001), hyaluronic acid (rs = 0.575, p < 0.0001), ICTP (rs = 0.482, p < 0.0001), pro-inflammatory cytokines IL-6 (rs = 0.581, p < 0.0001), IL-8 (rs = 0.535, p < 0.0001) and TNF-α (rs = 0.591, p < 0.0001), whereas significant inverse correlations were observed with serum TGF-β (rs = -0.366, p < 0.0001) and CTx, a marker of collagen degradation (rs = -0.495, p < 0.0001). The data indicate that the induction of IgA immune responses toward ethanol metabolites and tissue transglutaminaseis a characteristic feature of patients with AUD and coincides with the activation of inflammation, extracellular matrix remodeling and the generation of aberrantly glycosylated proteins. These processes appear to work in concert in the sequence of events leading from heavy drinking to ALD.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland; (U.N.); (J.K.); (H.P.)
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland
| | - Aini Bloigu
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland;
| | - Risto Bloigu
- Infrastructure of Population Studies, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland;
| | - Ulla Nivukoski
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland; (U.N.); (J.K.); (H.P.)
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland
| | - Johanna Kultti
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland; (U.N.); (J.K.); (H.P.)
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland
| | - Heidi Pohjasniemi
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland; (U.N.); (J.K.); (H.P.)
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland
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Ma JT, Xia S, Zhang BK, Luo F, Guo L, Yang Y, Gong H, Yan M. The pharmacology and mechanisms of traditional Chinese medicine in promoting liver regeneration: A new therapeutic option. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154893. [PMID: 37236047 DOI: 10.1016/j.phymed.2023.154893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/04/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023]
Abstract
BACKGROUND The liver is renowned for its remarkable regenerative capacity to restore its structure, size and function after various types of liver injury. However, in patients with end-stage liver disease, the regenerative capacity is inhibited and liver transplantation is the only option. Considering the limitations of liver transplantation, promoting liver regeneration is suggested as a new therapeutic strategy for liver disease. Traditional Chinese medicine (TCM) has a long history of preventing and treating various liver diseases, and some of them have been proven to be effective in promoting liver regeneration, suggesting the therapeutic potential in liver diseases. PURPOSE This review aims to summarize the molecular mechanisms of liver regeneration and the pro-regenerative activity and mechanism of TCM formulas, extracts and active ingredients. METHODS We conducted a systematic search in PubMed, Web of Science and the Cochrane Library databases using "TCM", "liver regeneration" or their synonyms as keywords, and classified and summarized the retrieved literature. The PRISMA guidelines were followed. RESULTS Forty-one research articles met the themes of this review and previous critical studies were also reviewed to provide essential background information. Current evidences indicate that various TCM formulas, extracts and active ingredients have the effect on stimulating liver regeneration through modulating JAK/STAT, Hippo, PI3K/Akt and other signaling pathways. Besides, the mechanisms of liver regeneration, the limitation of existing studies and the application prospect of TCM to promote liver regeneration are also outlined and discussed in this review. CONCLUSION This review supports TCM as new potential therapeutic options for promoting liver regeneration and repair of the failing liver, although extensive pharmacokinetic and toxicological studies, as well as elaborate clinical trials, are still needed to demonstrate safety and efficacy.
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Affiliation(s)
- Jia-Ting Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Bi-Kui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Fen Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Yan Yang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China.
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacy, Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China.
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5
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Ferrer M, Anthony TG, Ayres JS, Biffi G, Brown JC, Caan BJ, Cespedes Feliciano EM, Coll AP, Dunne RF, Goncalves MD, Grethlein J, Heymsfield SB, Hui S, Jamal-Hanjani M, Lam JM, Lewis DY, McCandlish D, Mustian KM, O'Rahilly S, Perrimon N, White EP, Janowitz T. Cachexia: A systemic consequence of progressive, unresolved disease. Cell 2023; 186:1824-1845. [PMID: 37116469 PMCID: PMC11059056 DOI: 10.1016/j.cell.2023.03.028] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/15/2023] [Accepted: 03/23/2023] [Indexed: 04/30/2023]
Abstract
Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.
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Affiliation(s)
- Miriam Ferrer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; MRC Cancer Unit, University of Cambridge, Hutchison Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
| | - Tracy G Anthony
- Department of Nutritional Sciences, Rutgers School of Environmental and Biological Sciences, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Janelle S Ayres
- Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Giulia Biffi
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK
| | - Justin C Brown
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
| | - Bette J Caan
- Kaiser Permanente Northern California Division of Research, Oakland, CA 94612, USA
| | | | - Anthony P Coll
- Wellcome Trust-MRC Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Richard F Dunne
- University of Rochester Medical Center, University of Rochester, Rochester, NY 14642, USA
| | - Marcus D Goncalves
- Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jonas Grethlein
- Ruprecht Karl University of Heidelberg, Heidelberg 69117, Germany
| | - Steven B Heymsfield
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
| | - Sheng Hui
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
| | - Mariam Jamal-Hanjani
- Department of Medical Oncology, University College London Hospitals, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence and Cancer Metastasis Laboratory, University College London Cancer Institute, London WC1E 6DD, UK
| | - Jie Min Lam
- Cancer Research UK Lung Cancer Centre of Excellence and Cancer Metastasis Laboratory, University College London Cancer Institute, London WC1E 6DD, UK
| | - David Y Lewis
- The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow G61 1BD, UK
| | - David McCandlish
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Karen M Mustian
- University of Rochester Medical Center, University of Rochester, Rochester, NY 14642, USA
| | - Stephen O'Rahilly
- Wellcome Trust-MRC Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Norbert Perrimon
- Department of Genetics, Blavatnik Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Eileen P White
- Rutgers Cancer Institute of New Jersey, Department of Molecular Biology and Biochemistry, Rutgers University, The State University of New Jersey, New Brunswick, NJ 08901, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY 11042, USA.
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Uehara S, Higuchi Y, Yoneda N, Ito R, Takahashi T, Murayama N, Yamazaki H, Murai K, Hikita H, Takehara T, Suemizu H. HepaSH cells: Experimental human hepatocytes with lesser inter-individual variation and more sustainable availability than primary human hepatocytes. Biochem Biophys Res Commun 2023; 663:132-141. [PMID: 37121123 DOI: 10.1016/j.bbrc.2023.04.054] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 05/02/2023]
Abstract
Primary human hepatocytes (PHHs) have been commonly used as the gold standard in many drug metabolism studies, regardless of having large inter-individual variation. These inter-individual variations in PHHs arise primarily from genetic polymorphisms, as well as from donor health conditions and storage conditions prior to cell processing. To equalize the effects of the latter two factors, PHHs were transplanted to quality-controlled mice providing human hepatocyte proliferation niches, and engrafted livers were generated. Cells that were harvested from engrafted livers, call this as experimental human hepatocytes (EHH; termed HepaSH cells), were stably and reproducibly produced from 1014 chimeric mice produced by using 17 different PHHs. Expression levels of acute phase reactant (APR) genes as indicators of a systemic reaction to the environmental/inflammatory insults of liver donors varied widely among PHHs. In contrast to PHHs, the expression of APR genes in HepaSH cells was found to converge within a narrower range than in donor PHHs. Further, large individual differences in the expression levels of drug metabolism-related genes (28 genes) observed in PHHs were greatly reduced among HepaSH cells produced in a unified in vivo environment, and none deviated from the range of gene expression levels in the PHHs. The HepaSH cells displayed a similar level of drug-metabolizing enzyme activity and gene expression as the average PHHs but retained their characteristics for drug-metabolizing enzyme gene polymorphisms. Furthermore, long-term 2D culture was possible and HBV infection was confirmed. These results suggest that the stably and reproducibly providable HepaSH cells with lesser inter-individual differences in drug-metabolizing properties, may have a potential to substitution for PHH as practical standardized human hepatocytes in drug discovery research.
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Affiliation(s)
- Shotaro Uehara
- Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Kawasaki, 210-0821, Japan
| | - Yuichiro Higuchi
- Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Kawasaki, 210-0821, Japan
| | - Nao Yoneda
- Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Kawasaki, 210-0821, Japan
| | - Ryoji Ito
- Human Disease Model Laboratory, Department of Applied Research for Laboratory Animals, Kawasaki, 210-0821, Japan
| | - Takeshi Takahashi
- Immunology Laboratory, Department of Basic Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki, 210-0821, Japan
| | - Norie Murayama
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, 194-8543, Japan
| | - Hiroshi Yamazaki
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, 194-8543, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan
| | - Hiroshi Suemizu
- Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Kawasaki, 210-0821, Japan.
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Di-Iacovo N, Pieroni S, Piobbico D, Castelli M, Scopetti D, Ferracchiato S, Della-Fazia MA, Servillo G. Liver Regeneration and Immunity: A Tale to Tell. Int J Mol Sci 2023; 24:1176. [PMID: 36674692 PMCID: PMC9864482 DOI: 10.3390/ijms24021176] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.
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Affiliation(s)
- Nicola Di-Iacovo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Stefania Pieroni
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Danilo Piobbico
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Marilena Castelli
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Damiano Scopetti
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Simona Ferracchiato
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Maria Agnese Della-Fazia
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Giuseppe Servillo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
- Centro Universitario di Ricerca sulla Genomica Funzionale (C.U.R.Ge.F.), University of Perugia, 06123 Perugia, Italy
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8
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Tamaki Y, Shibata Y, Hayakawa M, Kato N, Machii A, Ikeda Y, Nanizawa E, Hayashi Y, Suemizu H, Ito H, Ishikawa T. Treatment with hepatocyte transplantation in a novel mouse model of persistent liver failure. Biochem Biophys Rep 2022; 32:101382. [DOI: 10.1016/j.bbrep.2022.101382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
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9
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Riddiough GE, Jalal Q, Perini MV, Majeed AW. Liver regeneration and liver metastasis. Semin Cancer Biol 2021; 71:86-97. [PMID: 32532594 DOI: 10.1016/j.semcancer.2020.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022]
Abstract
Surgical resection for primary and secondary hepatic neoplasms provides the best chance of cure. Advanced surgical techniques such as portal vein embolisation, two-staged hepatectomy and associated liver partition and portal vein ligation for staged-hepatectomy (ALPPS) have facilitated hepatic resection in patients with previously unresectable, bi-lobar disease. These techniques are frequently employed to ensure favourable clinical outcomes and avoid potentially fatal post-operative complications such as small for size syndrome and post-hepatectomy liver failure. However, they rely on the innate ability of the liver to regenerate. As our knowledge of liver organogenesis, liver regeneration and hepatocarcinogenesis has expanded in recent decades it has come to light that liver regeneration may also drive tumour recurrence. Clinical studies in patients undergoing portal vein embolisation indicate that tumours may progress following the procedure in concordance with liver regeneration and hypertrophy, however overall survival in these patients has not been shown to be worse. In this article, we delve into the mechanisms underlying liver regeneration to better understand the complex ways in which this may affect tumour behaviour and ultimately inform clinical decisions.
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Affiliation(s)
- Georgina E Riddiough
- Department of Surgery at Austin Health, The University of Melbourne, Level 8, Lance Townsend Building, 145 Studley Road, Heidelberg, VIC 3084, Australia.
| | - Qaiser Jalal
- Sheffield Teaching Hospitals, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.
| | - Marcos V Perini
- Department of Surgery at Austin Health, The University of Melbourne, Level 8, Lance Townsend Building, 145 Studley Road, Heidelberg, VIC 3084, Australia.
| | - Ali W Majeed
- Sheffield Teaching Hospitals, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.
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10
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The two facets of gp130 signalling in liver tumorigenesis. Semin Immunopathol 2021; 43:609-624. [PMID: 34047814 PMCID: PMC8443519 DOI: 10.1007/s00281-021-00861-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
The liver is a vital organ with multiple functions and a large regenerative capacity. Tumours of the liver are the second most frequently cause of cancer-related death and develop in chronically inflamed livers. IL-6-type cytokines are mediators of inflammation and almost all members signal via the receptor subunit gp130 and the downstream signalling molecule STAT3. We here summarize current knowledge on how gp130 signalling and STAT3 in tumour cells and cells of the tumour micro-environment drives hepatic tumorigenesis. We furthermore discuss very recent findings describing also anti-tumorigenic roles of gp130/STAT3 and important considerations for therapeutic interventions.
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11
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Functional changes of cocultured hepatocyte sheets subjected to continuous liver regeneration stimulation in cDNA-uPA/SCID mouse: Differences in transplantation sites. Regen Ther 2021; 18:7-11. [PMID: 33816721 PMCID: PMC8010356 DOI: 10.1016/j.reth.2021.02.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 02/05/2021] [Accepted: 02/21/2021] [Indexed: 11/23/2022] Open
Abstract
Aim The formation of a secondary liver is expected in ectopic transplants in liver therapy. It is reported that the transplantation of hepatocyte sheets constitutes one of the techniques used to form a secondary liver. Accordingly, we established a subcutaneous transplant for hepatocyte/fibroblast sheets in previous studies. In this development study with hepatocyte/fibroblast sheets, we evaluated the differences in transplantation sites to promote the maturation of transplanted tissue in a liver injury model. Methods A cocultured hepatocyte sheet of fibroblasts (TIG-118 cells) and human hepatocytes (PXB cells) was prepared on a temperature-responsive culture dish. The prepared cocultured hepatocyte sheet was either transplanted subcutaneously or on the liver surface of a persistent liver injury model (cDNA-uPA/SCID mouse: uPA mouse), and was evaluated by the human albumin concentration in mouse blood. As a control group, hepatocyte cell sheets were used that were transplanted to both areas and compared. Results Although the cocultured hepatocyte sheet led to functional improvements in the early stages of culture in subcutaneous transplantation, these did not last in the long-term after transplantation. Although coculture effects were not observed in the liver surface transplantation case, long-term functional expressions in mono- and cocultured sheets in the case of liver surface transplantation were exhibited compared with subcutaneous administration. Conclusion These results suggest that sustained stimulation of liver regenerationvaries depending on the transplant site and is largely involved in the maturation of hepatocyte tissue.
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Neri AA, Dontas IA, Iliopoulos DC, Karatzas T. Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis. In Vivo 2021; 34:953-964. [PMID: 32354880 DOI: 10.21873/invivo.11863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Ischemia and reperfusion injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The impact of ischemia-reperfusion injury (IRI) on the liver depends on its substrate, the percentage of liver ischemic tissue subjected to IRI and the ischemia time. The consequences of IRI are more evident in pathologic liver substrates, such as steatotic livers. This review is the result of an extended bibliographic PubMed search focused on the last 20 years. It highlights basic differences encountered during IRI in lean and steatotic livers based on studies using rodent experimental models. CONCLUSION The main difference in cell death between lean and steatotic livers is the prevalence of apoptosis in the former and necrosis in the latter. There are also major changes in the effect of intracellular mediators, such as TNFα and IL-1β. Further experimental studies are needed in order to increase current knowledge of IRI effects and relevant mechanisms in both lean and steatotic livers, so that new preventive and therapeutic strategies maybe developed.
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Affiliation(s)
- Anna-Aikaterini Neri
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Ismene A Dontas
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Dimitrios C Iliopoulos
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
| | - Theodore Karatzas
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.,2 Department of Propedeutic Surgery, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
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Osorio EY, Medina-Colorado AA, Travi BL, Melby PC. In-situ proliferation contributes to the accumulation of myeloid cells in the spleen during progressive experimental visceral leishmaniasis. PLoS One 2020; 15:e0242337. [PMID: 33180876 PMCID: PMC7660562 DOI: 10.1371/journal.pone.0242337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 10/30/2020] [Indexed: 12/03/2022] Open
Abstract
Visceral leishmaniasis (VL) is characterized by expansion of myeloid cells in the liver and spleen, which leads to a severe splenomegaly associated with higher risk of mortality. This increased cellularity is thought to be a consequence of recruitment of cells to the viscera. We studied whether the local proliferation of splenic myeloid cells contributes to increased splenic cellularity. We found that a monocyte-like population of adherent splenic cells from Leishmania donovani-infected hamsters had enhanced replicative capacity ex vivo and in vivo (BrdU incorporation, p<0.0001). In vitro assays demonstrated that proliferation was more pronounced in the proinflammatory M1 environment and that intracellular infection prevented proliferation. Secondary analysis of the published splenic transcriptome in the hamster model of progressive VL revealed a gene expression signature that included division of tumoral cells (Z = 2.0), cell cycle progression (Z = 2.3), hematopoiesis (Z = 2.8), proliferation of stem cells (Z = 2.5) and overexpression of proto-oncogenes. Regulators of myeloid cell proliferation were predicted in-silico (CSF2, TLR4, IFNG, IL-6, IL-4, RTK signaling, and STAT3). The in-silico prediction was confirmed with chemical inhibitors of PI3K/AKT, MAPK and STAT3 which decreased splenic myeloid cell division ex vivo. Hamsters infected with L. donovani treated with a STAT3 inhibitor had reduced in situ splenic myeloid proliferation (p = 0.03) and parasite burden. We conclude that monocyte-like myeloid cells have increased STAT3-dependent proliferation in the spleen of hamsters with visceral leishmaniasis and that inhibition of STAT3 reduces myeloid cell proliferation and parasite burden.
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Affiliation(s)
- E. Yaneth Osorio
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Audrie A. Medina-Colorado
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Bruno L. Travi
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America
- Center for Tropical Diseases and Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Peter C. Melby
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Center for Tropical Diseases and Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
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14
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Shi JH, Yan X, Zhang SJ, Line PD. Simulated model of RAPID concept: highlighting innate inflammation and liver regeneration. BJS Open 2020; 4:893-903. [PMID: 32666716 PMCID: PMC7528512 DOI: 10.1002/bjs5.50322] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/05/2020] [Accepted: 06/05/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND The resection and partial liver segment II/III transplantation with delayed total hepatectomy (RAPID) concept is a novel transplantation technique for removal of non-resectable liver tumours. The aim of this study was to establish a simulated RAPID model to explore the mechanism involved in the liver regeneration. METHODS A RAPID model was created in rats involving cold ischaemia and reperfusion of the selected future liver remnant (FLR), portal vein ligation, followed by resection of the deportalized lobes in a second step. Histology, liver regeneration and inflammatory markers in RAPID-treated rats were compared with those in controls that underwent 70 per cent hepatectomy with the same FLR size. The effects of interleukin (IL) 6 and macrophage polarization on hepatocyte viability were evaluated in an in vitro co-culture system of macrophages and BRL hepatocytes. RESULTS The survival rate in RAPID and control hepatectomy groups was 100 per cent. The regeneration rate was higher in the RAPID-treated rats, with higher levels of IL-6 and M1 macrophage polarization (P < 0·050). BRL hepatocytes co-cultured with M1 macrophages showed a higher proliferation rate through activation of the IL-6/signal transducer and activator of transcription 3/extracellular signal-regulated kinase pathway. This enhancement of proliferation was inhibited by tocilizumab or gadolinium trichloride (P < 0·050). CONCLUSION The surgical model provides a simulation of RAPID that can be used to study the liver regeneration profile. Surgical Relevance The mechanisms sustaining liver regeneration are a relevant field of research to reduce the 'small for size' liver syndrome when the future liver remnant is not adequate. Several surgical strategies have been introduced both for liver resection and transplant surgery, mostly related to this issue and to the scarcity of grafts, among these the RAPID concept involving the use of an auxiliary segment II/III donor liver that expands to a sufficient size until a safe second-stage hepatectomy can be performed. Understanding the mechanisms and pitfalls of the liver regeneration profile may help in tailoring surgical strategies and in selecting patients. In this experimental model the authors investigated liver histology, regeneration and inflammatory markers in RAPID-treated rats.
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Affiliation(s)
- J. H. Shi
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ TransplantationFirst Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
- Department of Transplantation MedicineOslo University HospitalRikshospitaletNorway
| | - X. Yan
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ TransplantationFirst Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - S. J. Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ TransplantationFirst Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - P. D. Line
- Department of Transplantation MedicineOslo University HospitalRikshospitaletNorway
- Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloOsloNorway
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Jiao T, Yao X, Zhao Y, Zhou Y, Gao Y, Fan S, Chen P, Li X, Jiang Y, Yang X, Gonzalez FJ, Huang M, Bi H. Dexamethasone-Induced Liver Enlargement Is Related to PXR/YAP Activation and Lipid Accumulation but Not Hepatocyte Proliferation. Drug Metab Dispos 2020; 48:830-839. [PMID: 32561593 PMCID: PMC7497622 DOI: 10.1124/dmd.120.000061] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
Dexamethasone (Dex), a widely prescribed anti-inflammatory drug, was reported to induce liver enlargement (hepatomegaly) in clinical practice and in animal models. However, the underlying mechanisms are not elucidated. Dex is a known activator of pregnane X receptor (PXR). Yes-associated protein (YAP) has been implicated in chemically induced liver enlargement. Here, the roles of PXR and YAP pathways were investigated in Dex-induced hepatomegaly. Upregulation of PXR downstream proteins, including cytochrome P450 (CYP) 3A11, 2B10, and organic anion transporter polypeptide 2 (OATP2), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 μM activated PXR in the dual-luciferase reporter gene assay. Dex also increased the expression of total YAP, nuclear YAP, and YAP downstream proteins, including connective tissue growth factor and cysteine-rich angiogenic inducer 61, indicating activation of the YAP pathway. Furthermore, nuclear translocation of YAP was promoted by activation of PXR. However, hepatocyte proliferation was inhibited with significant decrease in the expression of proliferation-related proteins cyclin D1 and proliferating cell nuclear antigen as well as other regulatory factors, such as forkhead box protein M1, c-MYC, and epidermal growth factor receptor. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. β-catenin staining revealed enlarged hepatocytes, which were mostly attributable to the accumulation of lipids, such as triglycerides. In summary, high-dose Dex increased liver size accompanied by enlarged hepatocytes, and this was due to the activation of PXR/YAP and their effects on lipid accumulation but not hepatocyte proliferation. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly. SIGNIFICANCE STATEMENT: This study identified the roles of pregnane X receptor (PXR) and yes-associated protein (YAP) pathways in dexamethasone (Dex)-induced hepatomegaly. Dex induced PXR/YAP activation, enlarged hepatocytes, and promoted liver enlargement with lipid accumulation, such as triglycerides. However, hepatocyte proliferation was inhibited by the anti-inflammatory effect of Dex. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly.
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Affiliation(s)
- Tingying Jiao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xinpeng Yao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yingyuan Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yanying Zhou
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Panpan Chen
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xuan Li
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yiming Jiang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xiao Yang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Frank J Gonzalez
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
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16
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Peixoto da Silva S, Santos JMO, Costa E Silva MP, Gil da Costa RM, Medeiros R. Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia. J Cachexia Sarcopenia Muscle 2020; 11:619-635. [PMID: 32142217 PMCID: PMC7296264 DOI: 10.1002/jcsm.12528] [Citation(s) in RCA: 203] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/07/2019] [Accepted: 11/21/2019] [Indexed: 12/16/2022] Open
Abstract
Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass, along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities leading to functional impairment. Cancer cachexia has long been recognized as a direct cause of complications in cancer patients, reducing quality of life and worsening disease outcomes. Some related conditions, like sarcopenia (age-related muscle wasting), anorexia (appetite loss) and asthenia (reduced muscular strength and fatigue), share some key features with cancer cachexia, such as weakness and systemic inflammation. Understanding the interplay and the differences between these conditions is critical to advance basic and translational research in this field, improving the accuracy of diagnosis and contributing to finally achieve effective therapies for affected patients.
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Affiliation(s)
- Sara Peixoto da Silva
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Joana M O Santos
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Maria Paula Costa E Silva
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.,Palliative Care Service, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Rui M Gil da Costa
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,Postgraduate Programme in Adult Health (PPGSAD) and Tumour Biobank, Federal University of Maranhão (UFMA), São Luís, Brazil
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.,Virology Service, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Biomedical Research Center (CEBIMED), Faculty of Health Sciences of the Fernando Pessoa University, Porto, Portugal.,Research Department, Portuguese League Against Cancer - Regional Nucleus of the North (Liga Portuguesa Contra o Cancro - Núcleo Regional do Norte), Porto, Portugal
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Role of interleukin 6 in liver cell regeneration after hemi-hepatectomy, correlation with liver enzymes and flow cytometric study. Clin Exp Hepatol 2020; 6:42-48. [PMID: 32166123 PMCID: PMC7062121 DOI: 10.5114/ceh.2020.93055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
Aim of the study Liver regeneration after hemi-hepatectomy may be affected by several growth factors and cytokines. The aim is to evaluate the importance of interleukin 6 (IL-6) in the induction of liver cell regeneration and find correlations with other parameters such as liver enzymes, and DNA analysis by flow cytometric studies. Material and methods 80 adult male Sprague-Dawley rats were obtained and divided into two equal groups (n = 40 rats) to undergo 70% partial hepatectomy: group 1 - untreated (control) group; 40 rats not treated; and group 2 - treated group, 40 rats treated with IL-6 35 μg/100 gm body weight according to a lethality study for a period of 4 days, then hepatic resection was carried out according to the steps of Higgins and Anderson. Assessment of liver enzymes and bilirubin level was done. Flow cytometric study was done using a flow cytometer (FACSCalibur; Becton Dickinson) and DNA content was estimated with CellQuest software (Becton Dickinson). Results The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were significantly higher in the untreated group of rats with liver resection. A higher value of bilirubin was observed in the treated group. Rat weight at sacrification was significantly lower in the group of rats treated with IL-6 than those without treatment, p < 0.001. Liver weight at sacrification was significantly higher in the group of rats treated with IL-6 (p < 0.001). The percentage of apoptotic cells with hypodiploid DNA content was determined from DNA histograms. Untreated rat resected liver showed a peak pattern that represented liver damage with high damage of 73.4%. Conclusions Interleukin 6 is of value in induction of liver cell regeneration after seventy percent hemi-hepatectomy as evident by increased liver cell mass, liver enzymes and flow cytometric analysis.
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18
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Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
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Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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19
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Dijk FJ, van Dijk M, Dorresteijn B, van Norren K. DPA shows comparable chemotherapy sensitizing effects as EPA upon cellular incorporation in tumor cells. Oncotarget 2019; 10:5983-5992. [PMID: 31666929 PMCID: PMC6800265 DOI: 10.18632/oncotarget.27236] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023] Open
Abstract
Dietary supplementation with ω-3 polyunsaturated fatty acids (PUFAs) has been reported to enhance the sensitivity of tumor cells towards chemotherapy. Most enhancing effects are described for ω-3 PUFAs EPA and DHA; less evidence is available with the intermediate DPA. We studied the chemotherapy enhancing effects of EPA, DPA and DHA in murine colon C26 adenocarcinoma cells and showed that DPA displayed similar chemosensitizing effects as EPA. Moreover, EPA supplementation increased cellular DPA content. In a C26 tumor-bearing mouse model, we studied the incorporation of ω-3 PUFA in tumor and skeletal muscle after a diet with different ω-3 PUFA sources. Although little DPA was present in the fatty acid food sources, in those that contained considerable EPA concentrations, DPA levels were higher in tumor and muscle tissue. From these studies, we conclude that EPA and DPA show chemosensitizing effects and that intake of EPA or EPA-containing nutrition leads to increased cellular DPA content by elongation. These findings support the use of ω-3 PUFA containing nutritional supplementations in cancer patients during chemotherapy treatment.
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Affiliation(s)
- Francina J Dijk
- Danone Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, The Netherlands
| | - Miriam van Dijk
- Danone Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, The Netherlands
| | - Bram Dorresteijn
- Danone Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, The Netherlands
| | - Klaske van Norren
- Nutritional Biology, Department of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
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Dong X, Liu J, Xu Y, Cao H. Role of macrophages in experimental liver injury and repair in mice. Exp Ther Med 2019; 17:3835-3847. [PMID: 31007731 PMCID: PMC6468932 DOI: 10.3892/etm.2019.7450] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 12/06/2018] [Indexed: 02/06/2023] Open
Abstract
Liver macrophages make up the largest proportion of tissue macrophages in the host and consist of two dissimilar groups: Kupffer cells (KCs) and monocyte-derived macrophages (MoMø). As the liver is injured, KCs sense the injury and initiate inflammatory cascades mediated by the release of inflammatory cytokines and chemokines. Subsequently, inflammatory monocytes accumulate in the liver via chemokine-chemokine receptor interactions, resulting in massive inflammatory MoMø infiltration. When live r injury ceases, restorative macrophages, derived from recruited inflammatory monocytes (lymphocyte antigen 6 complex, locus Chi monocytes), promote the resolution of hepatic damage and fibrosis. Consequently, a large number of studies have assessed the mechanisms by which liver macrophages exert their opposing functions at different time-points during liver injury. The present review primarily focuses on the diverse functions of macrophages in experimental liver injury, fibrosis and repair in mice and illustrates how macrophages may be targeted to treat liver disease.
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Affiliation(s)
- Xiaotian Dong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jingqi Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Yanping Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Hardee JP, Counts BR, Carson JA. Understanding the Role of Exercise in Cancer Cachexia Therapy. Am J Lifestyle Med 2019; 13:46-60. [PMID: 30627079 PMCID: PMC6311610 DOI: 10.1177/1559827617725283] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/12/2017] [Accepted: 07/19/2017] [Indexed: 12/17/2022] Open
Abstract
Cachexia, the unintentional loss of body weight, is prevalent in many cancer types, and the associated skeletal muscle mass depletion increases patient morbidity and mortality. While anorexia can be present, cachexia is not reversible with nutritional therapies alone. Pharmacological agents have been proposed to treat this condition, but there are currently no approved treatments. Nonetheless, the hallmark characteristics associated with cancer cachexia remain viable foundations for future therapies. Regular physical activity holds a promising future as a nonpharmacological alternative to improve patient survival through cachexia prevention. Evidence suggests exercise training is beneficial during cancer treatment and survival. However, the mechanistic examination of cachectic skeletal muscle's response to exercise is both needed and justified. The primary objective of this review is to discuss the role of exercise for the prevention and treatment of cancer-associated muscle wasting. Initially, we provide an overview of systemic alterations induced by cancer and their role in the regulation of wasting processes during cachexia progression. We then discuss how exercise could alter disrupted regulatory pathways related to growth and metabolism during cancer-induced muscle atrophy. Last, we outline current exercise prescription guidelines and how exercise could be a potential behavioral therapy to curtail cachexia development in cancer patients.
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Affiliation(s)
- Justin P. Hardee
- Department of Exercise Science (JPH, BRC, JAC), University of South Carolina, Columbia, South Carolina
- Center for Colon Cancer Research (JAC), University of South Carolina, Columbia, South Carolina
| | - Brittany R. Counts
- Department of Exercise Science (JPH, BRC, JAC), University of South Carolina, Columbia, South Carolina
- Center for Colon Cancer Research (JAC), University of South Carolina, Columbia, South Carolina
| | - James A. Carson
- James A. Carson, PhD, Department of Exercise Science, University of South Carolina, 921 Assembly Street, Public Health Research Center, Rm 301, Columbia, SC 29208; e-mail:
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Nahar S, Nakashima Y, Miyagi-Shiohira C, Kinjo T, Toyoda Z, Kobayashi N, Saitoh I, Watanabe M, Noguchi H, Fujita J. Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease. World J Stem Cells 2018; 10:146-159. [PMID: 30631390 PMCID: PMC6325075 DOI: 10.4252/wjsc.v10.i11.146] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/07/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs) are a treatment cell source for patients with chronic liver injury. ADSCs are characterized by being harvested from the patient's own subcutaneous adipose tissue, a high cell yield (i.e., reduced immune rejection response), accumulation at a disease nidus, suppression of excessive immune response, production of various growth factors and cytokines, angiogenic effects, anti-apoptotic effects, and control of immune cells via cell-cell interaction. We previously showed that conditioned medium of ADSCs promoted hepatocyte proliferation and improved the liver function in a mouse model of acute liver failure. Furthermore, as found by many other groups, the administration of ADSCs improved liver tissue fibrosis in a mouse model of liver cirrhosis. A comprehensive protein expression analysis by liquid chromatography with tandem mass spectrometry showed that the various cytokines and chemokines produced by ADSCs promote the healing of liver disease. In this review, we examine the ability of expressed protein components of ADSCs to promote healing in cell therapy for liver disease. Previous studies demonstrated that ADSCs are a treatment cell source for patients with chronic liver injury. This review describes the various cytokines and chemokines produced by ADSCs that promote the healing of liver disease.
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Affiliation(s)
- Saifun Nahar
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Yoshiki Nakashima
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Takao Kinjo
- Department of Basic Laboratory Sciences, School of Health Sciences in the Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Zensei Toyoda
- Department of Basic Laboratory Sciences, School of Health Sciences in the Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | | | - Issei Saitoh
- Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata 951-8514, Japan
| | - Masami Watanabe
- Department of Urology, Okayama Univer sity Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
| | - Jiro Fujita
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
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23
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Han R, Zhang F, Wan C, Liu L, Zhong Q, Ding W. Effect of perfluorooctane sulphonate-induced Kupffer cell activation on hepatocyte proliferation through the NF-κB/TNF-α/IL-6-dependent pathway. CHEMOSPHERE 2018; 200:283-294. [PMID: 29494909 DOI: 10.1016/j.chemosphere.2018.02.137] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 02/21/2018] [Accepted: 02/22/2018] [Indexed: 05/18/2023]
Abstract
Perfluorooctane sulfonate (PFOS), one member of polyfluoroalkyl chemicals (PFASs), persist in the environment and are found in relatively high concentrations in animal livers. PFOS has been shown to induce tumour of the liver in rats following chronic dietary administration. However, the molecular mechanisms involved in PFOS-induced hepatocellular hypertrophy are still not well characterized. In this study, male Sprague-Dawley rats were daily gavaged with PFOS (1 or 10 mg/kg body weight) for 28 days. Rat primary cultured Kupffer cells or hepatocytes were exposed to 100 μM PFOS for 0-48 h. Our results showed that PFOS exposure caused serious hepatocellular damage and obvious inflammatory cell infiltration and increased serum tumour necrosis factor-ɑ (TNF-α) and interleukin-6 (IL-6) levels. Particularly, PFOS exposure triggered Kupffer cell activation and significantly upregulated the expression of proliferating cell nuclear antigen (PCNA), c-Jun, c-MYC and Cyclin D1 (CyD1) in liver. In vitro, PFOS significantly induced production of TNF-α and IL-6 in Kupffer cells and increased PCNA, c-Jun, c-MYC and CyD1 expression in the primary hepatocytes co-cultured with Kupffer cells. However, Kupffer cell activation was mostly abolished by anti-TNF-α or anti-IL6 treatment. Furthermore, blockage of TNF-α and IL-6 significantly inhibited hepatocyte proliferation by gadolinium chloride (GdCl3) pre-treatment in PFOS-treated mice and primary cultured Kupffer cells. On the other hand, NF-κB inhibitor (PDTC) and c-Jun amino-terminal kinase (JNK) inhibitor (SP600125) significantly inhibited production of PFOS-induced TNF-α and IL-6. Taken together, these data suggest that PFOS induces Kupffer cell activation, leading to hepatocyte proliferation by through the NF-κB/TNF-ɑ/IL-6-dependent pathway.
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Affiliation(s)
- Rui Han
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Fang Zhang
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Chong Wan
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Limin Liu
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Zhong
- Department of Emergency Medicine, Tongji Hospital Affiliated to Tongji Medical College Huazhong, University of Science & Technology, Wuhan, China.
| | - Wenjun Ding
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
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Pons M, Koniaris LG, Moe SM, Gutierrez JC, Esquela-Kerscher A, Zimmers TA. GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure. Surgery 2018; 164:262-273. [PMID: 29731246 DOI: 10.1016/j.surg.2018.03.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 03/04/2018] [Accepted: 03/05/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases. METHODS In vitro renal cell lines, genetic, and murine in vivo renal injury models were examined. RESULTS Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely after 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, or unilateral ureteric obstruction. Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis, and expression of fibrosis-associated genes both at baseline and after unilateral ureteric obstruction compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted epithelial-to-mesenchymal transition of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner. CONCLUSION Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function.
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Affiliation(s)
- Marianne Pons
- Department of Surgery, Indiana University School of Medicine, Indianapolis
| | | | - Sharon M Moe
- Department of Medicine, Indiana University School of Medicine, Indianapolis; Roudebush Veterans Administration Medical Center, Indianapolis, IN
| | | | - Aurora Esquela-Kerscher
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk
| | - Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis; Departments of Anatomy and Cell Biology, Biochemistry and Molecular Biology and Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis; IU Simon Cancer Center, Indianapolis, IN
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Lei C, Dong Z, Wan J, Xiao X, Lu F, Wang B. Transferring the exudate in the tissue engineering chamber as a trigger to incubate large amount adipose tissue in remote area. J Tissue Eng Regen Med 2017; 12:e1549-e1558. [DOI: 10.1002/term.2580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 08/21/2017] [Accepted: 09/23/2017] [Indexed: 01/26/2023]
Affiliation(s)
- Chen Lei
- Department of Plastic and Cosmetic Surgery, Nanfang HospitalSouthern Medical University Guang Zhou Guang Dong P.R. China
- Department of Plastic and Cosmetic SurgeryThe First Affiliated Hospital of Fujian Medical University Fuzhou Fujian P.R. China
| | - Ziqing Dong
- Department of Plastic and Cosmetic Surgery, Nanfang HospitalSouthern Medical University Guang Zhou Guang Dong P.R. China
| | - Jinlin Wan
- Department of Plastic and Cosmetic Surgery, Nanfang HospitalSouthern Medical University Guang Zhou Guang Dong P.R. China
| | - Xiaolian Xiao
- Department of Plastic and Cosmetic Surgery, Nanfang HospitalSouthern Medical University Guang Zhou Guang Dong P.R. China
| | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang HospitalSouthern Medical University Guang Zhou Guang Dong P.R. China
| | - Biao Wang
- Department of Plastic and Cosmetic SurgeryThe First Affiliated Hospital of Fujian Medical University Fuzhou Fujian P.R. China
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Zimmers TA, Jin X, Zhang Z, Jiang Y, Koniaris LG. Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice. Am J Physiol Endocrinol Metab 2017; 313:E440-E449. [PMID: 28655714 PMCID: PMC5668597 DOI: 10.1152/ajpendo.00032.2017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 05/01/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023]
Abstract
Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation.
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Affiliation(s)
- Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
- Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
| | - Xiaoling Jin
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Zongxiu Zhang
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Yanlin Jiang
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana;
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
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Moran DM, Koniaris LG, Jablonski EM, Cahill PA, Halberstadt CR, McKillop IH. Microencapsulation of Engineered Cells to Deliver Sustained High Circulating Levels of Interleukin-6 to Study Hepatocellular Carcinoma Progression. Cell Transplant 2017; 15:785-98. [PMID: 17269449 DOI: 10.3727/000000006783981477] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Interlukin-6 (IL-6) is a pleitropic cytokine that plays a central role in normal and abnormal hepatic function and response. The aims of the current study were to determine the viability of using cell encapsulation technology to introduce a genetically modified xenogeneic (CHO) cell population to elevate circulating levels of rhIL-6 in a rat model and determine the effects of sustained high rhIL-6 levels on hepatocellular carcinoma (HCC) progression in vivo. An alginate matrix was combined with transfected CHO cells, selected for their ability to synthesize rhIL-6, and used to generate uniform alginate–cell beads. Once encapsulated transfected cells continued to undergo replication, formed colonies within the bead, and synthesized/released large quantities of rhIL-6 into culture medium in vitro. Intraperitoneal implantation of beads into rats resulted in significantly increased circulating and intrahepatic levels of rhIL-6 up to 4 days postimplantation. Prolonged implantation led to the escape of CHO cells from the bead, resulting in a host response and CHO cell death within the bead. Subsequently CHO-IL-6 encapsulated cells were implanted into rats previously inoculated intrahepatically with the H4IIE HCC cell line. These studies demonstrated the maintenance of high circulating/intrahepatic rhIL-6 levels in this model. Despite significantly increased rhIL-6, this technique did not significantly alter the rate of net tumor progression. However, Stat3 activity was significantly increased in both normal liver and HCC tissue resected from animals implanted with CHO-IL-6 cells. Collectively these data demonstrate the short-term viability of using cell encapsulation technology to generate high levels of active circulating and intrahepatic cytokines and raise the possibility of modifying specific signal transduction cascades identified to be important during tumor progression.
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Affiliation(s)
- Diarmuid M Moran
- Department of Biology, University of North Carolina at Charlotte, 9201 University City Boulevard, Charlotte, NC 28223, USA
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Zimmers TA, Jiang Y, Wang M, Liang TW, Rupert JE, Au ED, Marino FE, Couch ME, Koniaris LG. Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic Res Cardiol 2017. [PMID: 28647906 DOI: 10.1007/s00395-017-0639-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.
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Affiliation(s)
- Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA. .,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,IUPUI Center for Cachexia Research, Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,IU Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, R3-C518, Indianapolis, IN, 46202, USA.
| | - Yanling Jiang
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA
| | - Meijing Wang
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA
| | - Tiffany W Liang
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA
| | - Joseph E Rupert
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Ernie D Au
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Francesco E Marino
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA
| | - Marion E Couch
- Otolaryngology, Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,IUPUI Center for Cachexia Research, Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,IU Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, R3-C518, Indianapolis, IN, 46202, USA
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Emerson 511, Indianapolis, IN, 46202, USA. .,IUPUI Center for Cachexia Research, Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,IU Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, R3-C518, Indianapolis, IN, 46202, USA.
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de Jonge J, Olthoff KM. Liver regeneration. BLUMGART'S SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS, 2-VOLUME SET 2017:93-109.e7. [DOI: 10.1016/b978-0-323-34062-5.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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30
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Inoue N, Shimizu M, Tsunoda S, Kawano M, Matsumura M, Yachie A. Cytokine profile in adult-onset Still's disease: Comparison with systemic juvenile idiopathic arthritis. Clin Immunol 2016; 169:8-13. [DOI: 10.1016/j.clim.2016.05.010] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 05/24/2016] [Accepted: 05/24/2016] [Indexed: 11/29/2022]
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Zimmers TA, Fishel ML, Bonetto A. STAT3 in the systemic inflammation of cancer cachexia. Semin Cell Dev Biol 2016; 54:28-41. [PMID: 26860754 PMCID: PMC4867234 DOI: 10.1016/j.semcdb.2016.02.009] [Citation(s) in RCA: 166] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 02/04/2016] [Indexed: 02/07/2023]
Abstract
Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both pathological and protective functions for STAT3 in other organs during cachexia. STAT3 also contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia and the potential and perils for targeting STAT3 to reduce cachexia and prolong survival in cancer patients.
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Affiliation(s)
- Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States; IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
| | - Melissa L Fishel
- IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
| | - Andrea Bonetto
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States; IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States; IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
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Zhang YM, Liu ZR, Cui ZL, Yang C, Yang L, Li Y, Shen ZY. Interleukin-22 contributes to liver regeneration in mice with concanavalin A-induced hepatitis after hepatectomy. World J Gastroenterol 2016; 22:2081-91. [PMID: 26877612 PMCID: PMC4726680 DOI: 10.3748/wjg.v22.i6.2081] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 07/21/2015] [Accepted: 10/23/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the therapeutic effects and mechanisms of interleukin (IL)-22 in liver regeneration in mice with concanavalin A (ConA)-induced liver injury following 70% hepatectomy. METHODS Mice were injected intravenously with ConA at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline. RESULTS IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3 (STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein mRNA expression was significantly elevated after IL-22 treatment. CONCLUSION In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy.
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Xu J, Ji B, Wen G, Yang Y, Jin H, Liu X, Xie R, Song W, Song P, Dong H, Tuo B. Na+/H+ exchanger 1, Na+/Ca2+ exchanger 1 and calmodulin complex regulates interleukin 6-mediated cellular behavior of human hepatocellular carcinoma. Carcinogenesis 2016; 37:290-300. [PMID: 26775040 DOI: 10.1093/carcin/bgw004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 01/03/2016] [Indexed: 02/07/2023] Open
Abstract
Interleukin 6 (IL6) is a key cytokine involved in the development and progression of inflammation-associated hepatocellular carcinoma (HCC). However, the mechanisms of IL6 action on HCC remain largely unknown. Proton and Ca(2+) are two intracellular messenger ions, which are believed to play a central role in tumorigenesis and tumor progression. In this study, we found that IL6 stimulation markedly increased intracellualr pH recovery rates of human HCC cells, Huh7 and HepG2, after NH4Cl acidification, and the NH4Cl acidification induced transient intracellular Ca(2+) increases in the HCC cells. The inhibition of Na(+)/H(+) exchanger 1 (NHE1), Na(+)/Ca(2+) exchanger 1 (NCX1) and calmodulin (CaM) inhibited the IL6 stimulation-induced intracellular pH recovery increases and NH4Cl acidification-induced intracellular Ca(2+) increases. IL6 stimulation also induced the structural interaction of NHE1, NCX1 and CaM proteins. The protein expression levels of NHE1, NCX1 and CaM in native human HCC tissues were markedly higher than those in normal liver tissues. IL6 upregulated the expressions of NHE1, NCX1 and CaM in Huh7 and HepG2 cells. NHE1, NCX1 and CaM mediated the promotion of IL6 on the proliferation, migration and invasion of Huh7 and HepG2 cells and the growth of HCC in nude mice. In conclusion, IL6 activates the functional activity of NHE1 and induces the functional and structural interaction of NHE1, NCX1 and CaM. The interaction of NHE1, NCX1 and CaM mediates the effects of IL6 on human HCC.
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Affiliation(s)
- Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.,Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China
| | - Bei Ji
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China
| | - Guorong Wen
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.,Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China
| | - Yuan Yang
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.,Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China
| | - Xuemei Liu
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China
| | - Wenfeng Song
- Key Laboratory of Combined Multi-organ Transplantation, Zhejiang University, Hangzhou 310003, China and.,Collaborative innovation center for Diagnosis treatment of infectious diseases, Zhejiang Province, Hangzhou 310003, China
| | - Penghong Song
- Key Laboratory of Combined Multi-organ Transplantation, Zhejiang University, Hangzhou 310003, China and.,Collaborative innovation center for Diagnosis treatment of infectious diseases, Zhejiang Province, Hangzhou 310003, China
| | - Hui Dong
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.,Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.,Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China
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34
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Karp SJ. Biology of hepatocyte regeneration in acute liver failure. Liver Transpl 2015; 21 Suppl 1:S34-5. [PMID: 26342203 DOI: 10.1002/lt.24320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 08/26/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Seth J Karp
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
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Nowatari T, Murata S, Nakayama K, Sano N, Maruyama T, Nozaki R, Ikeda N, Fukunaga K, Ohkohchi N. Sphingosine 1-phosphate has anti-apoptotic effect on liver sinusoidal endothelial cells and proliferative effect on hepatocytes in a paracrine manner in human. Hepatol Res 2015; 45:1136-45. [PMID: 25371278 DOI: 10.1111/hepr.12446] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 10/28/2014] [Accepted: 10/30/2014] [Indexed: 01/01/2023]
Abstract
AIM Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite released from erythrocytes and platelets, and is a potent stimulus for endothelial cell proliferation. However, the role of S1P on human liver sinusoidal endothelial cells (LSEC) remains unclear. The proliferation and inhibition of apoptosis in LSEC are involved in the promotion of liver regeneration and the suppression of liver injury after liver resection and transplantation. The aim of this study is to investigate the role of S1P on human LSEC and the interaction between S1P and LSEC in hepatocyte proliferation in vitro. METHODS Immortalized human LSEC were used. LSEC were cultured with S1P, and the cell proliferation, anti-apoptosis, signal transductions and production of cytokines and growth factors were subsequently examined. To investigate the interaction between S1P and LSEC in hepatocyte proliferation, primary human hepatocytes were cultured with the supernatants of LSEC with and without S1P. DNA synthesis and signal transductions in hepatocytes were examined. RESULTS S1P induced LSEC proliferation through activation of Akt and extracellular signal-related kinase pathways and suppressed LSEC apoptosis by affecting the expression levels of Bcl-2, Bax and cleaved caspase-3. S1P promoted interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) production in LSEC. The supernatants of LSEC cultured with S1P enhanced hepatocyte DNA synthesis more strongly than the supernatants of LSEC cultured without S1P through activation of the signal transducer and activator of transcription-3 pathway. CONCLUSION S1P has proliferative and anti-apoptotic effects and promotes the production of IL-6 and VEGF in human LSEC, thereby promoting hepatocyte proliferation.
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Affiliation(s)
- Takeshi Nowatari
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Soichiro Murata
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Ken Nakayama
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Naoki Sano
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Takehito Maruyama
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Reiji Nozaki
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Naoya Ikeda
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kiyoshi Fukunaga
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Nobuhiro Ohkohchi
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, University of Tsukuba, Tsukuba, Ibaraki, Japan
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36
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Mouse CD11b+Kupffer Cells Recruited from Bone Marrow Accelerate Liver Regeneration after Partial Hepatectomy. PLoS One 2015; 10:e0136774. [PMID: 26333171 PMCID: PMC4557907 DOI: 10.1371/journal.pone.0136774] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 08/08/2015] [Indexed: 01/11/2023] Open
Abstract
TNF and Fas/FasL are vital components, not only in hepatocyte injury, but are also required for hepatocyte regeneration. Liver F4/80+Kupffer cells are classified into two subsets; resident radio-resistant CD68+cells with phagocytic and bactericidal activity, and recruited radio-sensitive CD11b+cells with cytokine-producing capacity. The aim of this study was to investigate the role of these Kupffer cells in the liver regeneration after partial hepatectomy (PHx) in mice. The proportion of Kupffer cell subsets in the remnant liver was examined in C57BL/6 mice by flow cytometry after PHx. To examine the role of CD11b+Kupffer cells/Mφ, mice were depleted of these cells before PHx by non-lethal 5 Gy irradiation with or without bone marrow transplantation (BMT) or the injection of a CCR2 (MCP-1 receptor) antagonist, and liver regeneration was evaluated. Although the proportion of CD68+Kupffer cells did not significantly change after PHx, the proportion of CD11b+Kupffer cells/Mφ and their FasL expression was greatly increased at three days after PHx, when the hepatocytes vigorously proliferate. Serum TNF and MCP-1 levels peaked one day after PHx. Irradiation eliminated the CD11b+Kupffer cells/Mφ for approximately two weeks in the liver, while CD68+Kupffer cells, NK cells and NKT cells remained, and hepatocyte regeneration was retarded. However, BMT partially restored CD11b+Kupffer cells/Mφ and recovered the liver regeneration. Furthermore, CCR2 antagonist treatment decreased the CD11b+Kupffer cells/Mφ and significantly inhibited liver regeneration. The CD11b+Kupffer cells/Mφ recruited from bone marrow by the MCP-1 produced by CD68+Kupffer cells play a pivotal role in liver regeneration via the TNF/FasL/Fas pathway after PHx.
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Nádia Backes A, Aoun Tannuri AC, Mendonça Coelho MC, Mendes Gibelli NE, Backes FN, Tannuri U. Liver regeneration model in growing rats with hepatic artery ligation: histologic and molecular studies. Transplant Proc 2015; 47:1033-7. [PMID: 26036512 DOI: 10.1016/j.transproceed.2015.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Liver transplantation is an effective treatment for irreversible liver diseases. The incidence of hepatic artery thrombosis remains high. Our objective was to analyze the effect of ligature of the hepatic artery on liver regeneration in a growing animal model. METHODS Seventy-five male Wistar rats were divided into the following 3 groups: group 1 (sham, G1): incision without intervention; group 2 (G2): 70% hepatectomy; group 3 (G3): 70% hepatectomy and ligation of the hepatic artery. Preceding the 70% hepatectomy, a hepatic artery ligature was performed with resection of a segment of the artery. The liver specimens were stained with hematoxylin-eosin, and immunohistochemical staining for Ki-67 was performed. The expression of the interleukin (IL) 6 gene was studied by means of reverse-transcription polymerase chain reaction. RESULTS G2 and G3 demonstrated similar tendencies toward an increase in the gain weight ratio over time. The mitotic activity was significantly lower at 72 hours in G3 than in G2. There was no difference between Ki-67 staining between G2 and G3. The expression of the IL-6 gene was present in all of the groups, lower in G1, with no difference between G2 and G3. CONCLUSIONS The experimental model was feasible and adequate for these investigations. Hepatectomy stimulated hepatocyte proliferation, and the obstruction of the arterial flow did not affect liver regeneration.
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Affiliation(s)
- A Nádia Backes
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of São Paulo Medical School, São Paulo, Brazil.
| | - A C Aoun Tannuri
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of São Paulo Medical School, São Paulo, Brazil
| | - M C Mendonça Coelho
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of São Paulo Medical School, São Paulo, Brazil
| | - N E Mendes Gibelli
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of São Paulo Medical School, São Paulo, Brazil
| | - F N Backes
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of São Paulo Medical School, São Paulo, Brazil
| | - U Tannuri
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of São Paulo Medical School, São Paulo, Brazil
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38
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Yoshiya S, Shirabe K, Imai D, Toshima T, Yamashita YI, Ikegami T, Okano S, Yoshizumi T, Kawanaka H, Maehara Y. Blockade of the apelin-APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy. J Gastroenterol 2015; 50:573-82. [PMID: 25148722 DOI: 10.1007/s00535-014-0992-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 08/04/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Liver regeneration after massive hepatectomy or living donor liver transplantation is critical. The apelin-APJ system is involved in the regulation of cardiovascular function, inflammation, fluid homeostasis, the adipo-insular axis, and angiogenesis, but its function in liver regeneration remains unclear. METHODS We investigated the impact of pharmacologic blockade of the apelin-APJ system, using the specific APJ antagonist F13A on liver regeneration after hepatectomy in mice. RESULTS F13A-treated mice had significantly higher serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than control mice, due to F13A-promoted activation of Kupffer cells. Compared with untreated mice, F13A enhanced the signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways, stimulated cell-cycle progression, and promoted hepatocyte proliferation and liver regeneration without inducing apoptosis or inflammation in regenerating livers. In vitro, Kupffer cells expressed APJ and were activated directly by F13A treatment, releasing TNF-α and IL-6. Moreover, F13A-treated mice had a higher survival rate than untreated mice in the extended hepatectomy model. CONCLUSIONS F13A treatment promotes early phase liver regeneration after hepatectomy by promoting the activation of Kupffer cells and increasing serum levels of TNF-α and IL-6. F13A treatment may become a therapeutic option to facilitate efficient liver regeneration after liver surgery.
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Affiliation(s)
- Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan,
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Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice. Biochim Biophys Acta Mol Basis Dis 2015; 1852:1001-11. [DOI: 10.1016/j.bbadis.2015.01.017] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 01/16/2015] [Accepted: 01/21/2015] [Indexed: 01/30/2023]
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40
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Narsale AA, Enos RT, Puppa MJ, Chatterjee S, Murphy EA, Fayad R, Pena MO, Durstine JL, Carson JA. Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression. PLoS One 2015; 10:e0119888. [PMID: 25789991 PMCID: PMC4366213 DOI: 10.1371/journal.pone.0119888] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 01/21/2015] [Indexed: 02/04/2023] Open
Abstract
The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-κB (Nuclear factor—κB) signaling.
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Affiliation(s)
- Aditi A. Narsale
- Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
| | - Reilly T. Enos
- Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America
| | - Melissa J. Puppa
- Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, South Carolina, United States of America
| | - E. Angela Murphy
- Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America
| | - Raja Fayad
- Center for Colon Cancer Research, Columbia, South Carolina, United States of America
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
| | - Majorette O’ Pena
- Center for Colon Cancer Research, Columbia, South Carolina, United States of America
| | - J. Larry Durstine
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
| | - James A. Carson
- Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
- Center for Colon Cancer Research, Columbia, South Carolina, United States of America
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America
- * E-mail:
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Meng Q, Chen XL, Wang CY, Liu Q, Sun HJ, Sun PY, Huo XK, Liu ZH, Yao JH, Liu KX. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis. Toxicol Appl Pharmacol 2015; 283:178-86. [PMID: 25655198 DOI: 10.1016/j.taap.2015.01.020] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 01/18/2015] [Accepted: 01/23/2015] [Indexed: 12/18/2022]
Abstract
Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes.
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Affiliation(s)
- Qiang Meng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Xin-Li Chen
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Chang-Yuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Qi Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Hui-Jun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Peng-Yuan Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Xiao-Kui Huo
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Zhi-Hao Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Ji-Hong Yao
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China
| | - Ke-Xin Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
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Tsugawa D, Oya Y, Masuzaki R, Ray K, Engers DW, Dib M, Do N, Kuramitsu K, Ho K, Frist A, Yu PB, Bloch KD, Lindsley CW, Hopkins CR, Hong CC, Karp SJ. Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration. J Pharmacol Exp Ther 2014; 351:549-58. [PMID: 25271257 PMCID: PMC4244585 DOI: 10.1124/jpet.114.216903] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 09/25/2014] [Indexed: 12/21/2022] Open
Abstract
Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.
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Affiliation(s)
- Daisuke Tsugawa
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Yuki Oya
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Ryota Masuzaki
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Kevin Ray
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Darren W Engers
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Martin Dib
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Nhue Do
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Kaori Kuramitsu
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Karen Ho
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Audrey Frist
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Paul B Yu
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Kenneth D Bloch
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Craig W Lindsley
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Corey R Hopkins
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Charles C Hong
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
| | - Seth J Karp
- The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)
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Meng Q, Chen X, Wang C, Liu Q, Sun H, Sun P, Peng J, Liu K. Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor. Biochem Pharmacol 2014; 92:289-298. [PMID: 25278094 DOI: 10.1016/j.bcp.2014.09.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 09/03/2014] [Accepted: 09/08/2014] [Indexed: 02/08/2023]
Abstract
Liver resection has become a common treatment for liver tumors and hepatocellular carcinoma over the past decades. However, after surgery, the remnant livers in some patients fail to regenerate. Therefore, there is an urgent medical need to develop drugs that can promote liver regeneration. The purpose of the current study is to investigate the promotive effect of alisol B 23-acetate (AB23A) on liver regeneration in mice following partial hepatectomy (PH), and further elucidate the involvement of farnesoid X receptor (FXR) in the liver regeneration-promotive effect using in vivo and in vitro experiments. The results showed that AB23A dose-dependently promoted hepatocyte proliferation via upregulating hepatocyte proliferation-related protein forkhead box M1b (FoxM1b), Cyclin D1 and Cyclin B1 expression, and attenuated liver injury via an inhibition in Cyp7a1 and an induction in efflux transporters Bsep expression resulting in reduced hepatic bile acid levels. These changes in the genes, as well as accelerated liver regeneration in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly showed the regulation of these genes by AB23A was abrogated when FXR was silenced. Luciferase reporter assay in HepG2 cells and molecular docking further demonstrated the effect of AB23A on FXR activation in vitro. In conclusions, AB23A produces promotive effect on liver regeneration, due to FXR-mediated regulation of genes involved in hepatocyte proliferation and hepato-protection. AB23A has the potential to be a novel therapeutic option for facilitating efficient liver regeneration in patients subjected to liver resection.
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Affiliation(s)
- Qiang Meng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Xinli Chen
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Changyuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Qi Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Huijun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Pengyuan Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Jinyong Peng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China
| | - Kexin Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044, China.
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Gürgen SG, Yücel AT, Karakuş AÇ, Çeçen D, Özen G, Koçtürk S. Usage of whey protein may cause liver damage via inflammatory and apoptotic responses. Hum Exp Toxicol 2014; 34:769-79. [PMID: 25352651 DOI: 10.1177/0960327114556787] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The purpose of this study was to investigate the long- and short-term inflammatory and apoptotic effects of whey protein on the livers of non-exercising rats. Thirty rats were divided into three groups namely (1) control group, (2) short-term whey (WS) protein diet (252 g/kg for 5 days), and (3) long-term whey (WL) protein diet (252 g/kg for 4 weeks). Interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and cytokeratin 18 (CK-18-M30) were assessed using enzyme-linked immunosorbent assay and immunohistochemical methods. Apoptosis was evaluated using the terminal transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. Hepatotoxicity was evaluated by quantitation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Based on the biochemical levels and immunohistochemical results, the highest level of IL-1β was identified in the WL group (p < 0.01). The IL-6 and TNF-α results were slightly lower in the WS group than in the control group and were highest in the WL group (p < 0.01). The CK-18-M30 and TUNEL results were highest in the WS group and exhibited medium intensity in the WL group (p < 0.01). AST results were statistically significant for all groups, while our ALT groups were particularly significant between the WL and control groups (p < 0.01). The results showed that when whey protein is used in an uninformed manner and without exercising, adverse effects on the liver may occur by increasing the apoptotic signal in the short term and increasing inflammatory markers and hepatotoxicity in the long term.
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Affiliation(s)
- S G Gürgen
- Department of Histology and Embryology, School of Vocational Health Service, Celal Bayar University, Uncubozkoy, Manisa, Turkey
| | - A T Yücel
- Department of Anatomy, School of Vocational Health Service, Celal Bayar University, Uncubozkoy, Manisa, Turkey
| | - A Ç Karakuş
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, İnciraltı, İzmir, Turkey
| | - D Çeçen
- Department of Nursing, Celal Bayar University, Manisa Health Sciences College, Manisa, Turkey
| | - G Özen
- Department of Molecular Medicine, Health Science Institute, Dokuz Eylul University Inciraltı, İzmir, Turkey
| | - S Koçtürk
- Department of Biochemistry, Faculty of Medicine, Dokuz Eylül University, İnciraltı, İzmir, Turkey
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Schmidt F, Kny M, Zhu X, Wollersheim T, Persicke K, Langhans C, Lodka D, Kleber C, Weber-Carstens S, Fielitz J. The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2014; 18:545. [PMID: 25263070 PMCID: PMC4231194 DOI: 10.1186/s13054-014-0545-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 09/11/2014] [Indexed: 12/03/2022]
Abstract
Introduction ICU-acquired weakness (ICUAW) complicates the disease course of critically ill patients. Inflammation and acute-phase response occur directly within myocytes and contribute to ICUAW. We observed that tripartite motif–containing 62 (TRIM62), an E3 ubiquitin ligase and modifier of inflammation, is increased in the skeletal muscle of ICUAW patients. We investigated the regulation and function of muscular TRIM62 in critical illness. Methods Twenty-six critically ill patients with Sequential Organ Failure Assessment scores ≥8 underwent two skeletal muscle biopsies from the vastus lateralis at median days 5 and 15 in the ICU. Four patients undergoing elective orthopedic surgery served as controls. TRIM62 expression and protein content were analyzed in these biopsies. The kinetics of Trim62, Atrogin1 and MuRF1 expression were determined in the gastrocnemius/plantaris and tibialis anterior muscles from mouse models of inflammation-, denervation- and starvation-induced muscle atrophy to differentiate between these contributors to ICUAW. Cultured myocytes were used for mechanistic analyses. Results TRIM62 expression and protein content were increased early and remained elevated in muscles from critically ill patients. In all three animal models, muscular Trim62 expression was early and continuously increased. Trim62 was expressed in myocytes, and its overexpression activated the atrophy-inducing activator protein 1 signal transduction pathway. Knockdown of Trim62 by small interfering RNA inhibited lipopolysaccharide-induced interleukin 6 expression. Conclusions TRIM62 is activated in the muscles of critically ill patients. It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes. Trial registration Current Controlled Trials ID: ISRCTN77569430 (registered 13 February 2008) Electronic supplementary material The online version of this article (doi:10.1186/s13054-014-0545-6) contains supplementary material, which is available to authorized users.
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Maria ATJ, Le Quellec A, Jorgensen C, Touitou I, Rivière S, Guilpain P. Adult onset Still's disease (AOSD) in the era of biologic therapies: dichotomous view for cytokine and clinical expressions. Autoimmun Rev 2014; 13:1149-59. [PMID: 25183244 DOI: 10.1016/j.autrev.2014.08.032] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 06/03/2014] [Indexed: 01/10/2023]
Abstract
Adult onset Still's disease (AOSD) is a rare inflammatory disorder characterized by hectic spiking fever, evanescent rash and joint involvement. Prognosis is highly variable upon disease course and specific involvements, ranging from benign and limited outcome to chronic destructive polyarthritis and/or life-threatening events in case of visceral complications or reactive hemophagocytic lymphohistiocytosis (RHL). AOSD remains a debatable entity at the frontiers of autoimmune diseases and autoinflammatory disorders. The pivotal role of macrophage cell activation leading to a typical Th1 cytokine storm is now well established in AOSD, and confirmed by the benefits using treatments targeting TNF-α, IL-1β or IL-6 in refractory patients. However, it remains difficult to determine predictive factors of outcome and to draw guidelines for patient management. Herein, reviewing literature and relying on our experience in a series of 8 refractory AOSD patients, we question nosology and postulate that different cytokine patterns could underlie contrasting clinical expressions, as well as responses to targeted therapies. We therefore propose to dichotomize AOSD according to its clinical presentation. On the one hand, 'systemic AOSD' patients, exhibiting the highest inflammation process driven by excessive IL-18, IL-1β and IL-6 production, would be at risk of life-threatening complications (such as multivisceral involvements and RHL), and would preferentially respond to IL-1β and IL-6 antagonists. On the other hand, 'rheumatic AOSD' patients, exhibiting pre-eminence of joint involvement driven by IL-8 and IFN-γ production, would be at risk of articular destructions, and would preferentially respond to TNF-α blockers.
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Affiliation(s)
- Alexandre Thibault Jacques Maria
- Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France; Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France
| | - Alain Le Quellec
- Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France
| | - Christian Jorgensen
- Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France; Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie Hospital, 191 Avenue du Doyen Gaston Giraud, F-34295 Montpellier, France
| | - Isabelle Touitou
- Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France; Auto-Inflammatory Diseases Unit, Genetic Laboratory, Arnaud De Villeneuve Hospital, 191 Avenue du Doyen Gaston Giraud, F-34295 Montpellier, France
| | - Sophie Rivière
- Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France
| | - Philippe Guilpain
- Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France; Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France.
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Mendes-Braz M, Elias-Miró M, Kleuser B, Fayyaz S, Jiménez-Castro MB, Massip-Salcedo M, Gracia-Sancho J, Ramalho FS, Rodes J, Peralta C. The effects of glucose and lipids in steatotic and non-steatotic livers in conditions of partial hepatectomy under ischaemia-reperfusion. Liver Int 2014; 34:e271-e289. [PMID: 24107124 DOI: 10.1111/liv.12348] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 09/25/2013] [Indexed: 01/04/2023]
Abstract
BACKGROUND Steatosis is a risk factor in partial hepatectomy (PH) under ischaemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. Nutritional support strategies, as well as the role of peripheral adipose tissue as energy source for liver regeneration, remain poorly investigated. AIMS To investigate whether the administration of either glucose or a lipid emulsion could protect steatotic and non-steatotic livers against damage and regenerative failure in an experimental model of PH under I/R. The relevance of peripheral adipose tissue in liver regeneration following surgery is studied. METHODS Steatotic and non-steatotic rat livers were subjected to surgery and the effects of either glucose or lipid treatment on damage and regeneration, and part of the underlying mechanisms, were investigated. RESULTS In non-steatotic livers, treatment with lipids or glucose provided the same protection against damage, regeneration failure and ATP drop. Adipose tissue was not required to regenerate non-steatotic livers. In the presence of hepatic steatosis, lipid treatment, but not glucose, protected against damage and regenerative failure by induction of cell cycle, maintenance of ATP levels and elevation of sphingosine-1-phosphate/ceramide ratio and phospholipid levels. Peripheral adipose tissue was required for regenerating the steatotic liver but it was not used as an energy source. CONCLUSION Lipid treatment in non-steatotic livers provides the same protection as that afforded by glucose in conditions of PH under I/R, whereas the treatment with lipids is preferable to reduce the injurious effects of liver surgery in the presence of steatosis.
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Affiliation(s)
- Mariana Mendes-Braz
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Departamento de Patologia e Medicina Legal, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
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Shi X, Chang CC, Basson MD, Upham BL, Wei L, Zhang P. Alcohol Disrupts Human Liver Stem/Progenitor Cell Proliferation and Differentiation. JOURNAL OF STEM CELL RESEARCH & THERAPY 2014; 4:205. [PMID: 27547491 PMCID: PMC4988687 DOI: 10.4172/2157-7633.1000205] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Excessive alcohol consumption injures the liver resulting in various liver diseases including liver cirrhosis. Advanced liver disease continues to be a major challenge to human health. Liver stem/progenitor cells (LSPCs) are tissue specific precursors with a distinct capacity of multi-lineage differentiation. These precursor cells may play an important role in the process of tissue injury repair and pathological transition of liver structures. At the present time, knowledge about the effect of alcohol on LSPC function during the development of alcoholic liver disease remains absent. This study was conducted to investigate changes in LSPC activity of proliferation and differentiation following alcohol exposure. The disruption of cell signaling mechanisms underlying alcohol-induced alteration of LSPC activities was also examined. METHODS Primary and immortalized human liver stem cells (HL1-1 cells and HL1-hT1 cells, respectively) were cultured in media optimized for cell proliferation and hepatocyte differentiation in the absence and presence of ethanol. Changes in cell morphology, proliferation and differentiation were determined. Functional disruption of cell signaling components following alcohol exposure was examined. RESULTS Ethanol exposure suppressed HL1-1 cell growth [as measured by cell 5-bromo-2-deoxyuridine (BrdU) incorporation] mediated by epidermal growth factor (EGF) or EGF plus interleukin-6 (IL-6) in an ethanol dose-dependent manner. Similarly, ethanol inhibited BrdU incorporation into HL1-hT1 cells. Cyclin D1 mRNA expression by HL1-hT1 cells was suppressed when cells were cultured with 50 and 100 mM ethanol. Ethanol exposure induced morphological change of HL1-1 cells toward a myofibroblast-like phenotype. Furthermore, ethanol down-regulated E-cadherin expression while increasing collagen I expression by HL1-1 cells. Ethanol also stimulated Snail transcriptional repressor (Snail) and α-smooth muscle actin (α-SMA) gene expression by HL1-1 cells. CONCLUSION These results demonstrate that the direct effect of alcohol on LSPCs is inhibiting their proliferation and promoting mesenchymal transition during their differentiation. Alcohol interrupts LSPC differentiation through interfering Snail signaling.
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Affiliation(s)
- Xin Shi
- Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Chia-Cheng Chang
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Marc D Basson
- Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Brad L Upham
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Ping Zhang
- Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
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Backes AN, Tannuri ACA, Backes FN, Queiroz AJR, Coelho MCM, da Silva EL, de Mello ES, Tannuri U. Effects of tacrolimus and insulin in a liver regeneration model in growing animals with portal vein stenosis: immunohistochemical and molecular studies. Pediatr Surg Int 2014; 30:423-9. [PMID: 24468714 DOI: 10.1007/s00383-014-3464-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The aim of the present investigation was to describe a new model of liver regeneration in growing rats with reduced portal flow. In addition, it was studied whether tacrolimus and insulin could have any pro-regenerative effect under such conditions. Ninety-five rats were divided into five groups: Group 1 (sham), abdominal incision without intervention; Group 2, 70% hepatectomy; Group 3, 70% hepatectomy + PV stenosis; Group 4, 70% hepatectomy + portal vein stenosis + insulin; and Group 5, 70% hepatectomy + portal vein stenosis + tacrolimus. The remnant liver lobes were harvested for analyses. The liver weight decreased in the PV stenosis group and it increased with the use of insulin and tacrolimus. The mitotic activity was higher in the hepatectomy, insulin and tacrolimus groups and this parameter was reduced by portal stenosis. Levels of interleukin 6 (IL-6) were higher in the hepatectomy group compared to the sham and PV stenosis groups. The expression of IL-6 and Ki67 was significantly increased in the insulin and tacrolimus groups compared to the portal stenosis group. A highly reproducible model was standardized to study liver regeneration with portal blood inflow reduction in weaning rats. It was demonstrated that insulin or tacrolimus administration may partially reverse the harmful effects of PV stenosis.
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Affiliation(s)
- Ariane Nadia Backes
- Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
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Asquith M, Pasala S, Engelmann F, Haberthur K, Meyer C, Park B, Grant KA, Messaoudi I. Chronic ethanol consumption modulates growth factor release, mucosal cytokine production, and microRNA expression in nonhuman primates. Alcohol Clin Exp Res 2014; 38:980-93. [PMID: 24329418 PMCID: PMC3984381 DOI: 10.1111/acer.12325] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 10/07/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chronic alcohol consumption has been associated with enhanced susceptibility to both systemic and mucosal infections. However, the exact mechanisms underlying this enhanced susceptibility remain incompletely understood. METHODS Using a nonhuman primate model of ethanol (EtOH) self-administration, we examined the impact of chronic alcohol exposure on immune homeostasis, cytokine, and growth factor production in peripheral blood, lung, and intestinal mucosa following 12 months of chronic EtOH exposure. RESULTS EtOH exposure inhibited activation-induced production of growth factors hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), and vascular-endothelial growth factor (VEGF) by peripheral blood mononuclear cells (PBMC). Moreover, EtOH significantly reduced the frequency of colonic Th1 and Th17 cells in a dose-dependent manner. In contrast, we did not observe differences in lymphocyte frequency or soluble factor production in the lung of EtOH-consuming animals. To uncover mechanisms underlying reduced growth factor and Th1/Th17 cytokine production, we compared expression levels of microRNAs in PBMC and intestinal mucosa. Our analysis revealed EtOH-dependent up-regulation of distinct microRNAs in affected tissues (miR-181a and miR-221 in PBMC; miR-155 in colon). Moreover, we were able to detect reduced expression of the transcription factors STAT3 and ARNT, which regulate expression of VEGF, G-CSF, and HGF and contain targets for these microRNAs. To confirm and extend these observations, PBMC were transfected with either mimics or antagomirs of miR-181 and miR-221, and protein levels of the transcription factors and growth factors were determined. Transfection of microRNA mimics led to a reduction in both STAT3/ARNT as well as VEGF/HGF/G-CSF levels. The opposite outcome was observed when microRNA antagomirs were transfected. CONCLUSIONS Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in microRNA expression.
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Affiliation(s)
- Mark Asquith
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
| | - Sumana Pasala
- Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, CA 92521
| | - Flora Engelmann
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
| | - Kristen Haberthur
- Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA
| | - Christine Meyer
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
| | - Byung Park
- Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Kathleen A. Grant
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Ilhem Messaoudi
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
- Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, CA 92521
- Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA
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