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Wang Y, Lan T, Wu SH, Ma J, Zou X. A betaine-contained solution reduced cold ischemia damage through inhibiting vacuolar degeneration in livers. Transpl Immunol 2024; 87:102144. [PMID: 39491596 DOI: 10.1016/j.trim.2024.102144] [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: 08/04/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/05/2024]
Abstract
A new osmoprotectant-containing multiple saccharide (MS) solution was formulated for this study. The primary objectives were to compare the effects of the MS solution with those of the University of Wisconsin (UW) solution and hypertonic citrate adenine (HCA) solution on liver cold preservation, as well as to investigate the mechanisms underlying osmolarity-induced injury. Rat livers were cold-stored for 18 h at 4 °C using the different solutions and subsequently subjected to 2 h of normothermic machine perfusion (NMP) for functional assessment. The livers were categorized into four groups: HCA, UW, MS, and a control group. Liver function and histological changes were evaluated using biochemical markers such as lactate dehydrogenase (LDH), alongside histopathological analysis. Additionally, the expression of aquaporin 9 (AQP9) and hydrogen peroxide (H2O2) in hepatocytes was examined. Liver damage was significantly reduced in the UW and MS groups (p < 0.05). Histopathological analysis revealed a decrease in hepatic apoptosis and injury scores in the MS group compared to the HCA group (p < 0.05). No significant differences in liver function changes were observed between the MS and UW groups. Furthermore, examination of liver tissue showed increased H2O2 fluorescence intensity and decreased AQP9 protein levels in livers exhibiting vacuolar degeneration. In conclusion, the MS solution demonstrated superior effectiveness in preserving the liver during cold storage by inhibiting vacuolar degeneration caused by intracellular H2O2 accumulation.
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Affiliation(s)
- Yu Wang
- Department of Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Tingting Lan
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Shao-Hua Wu
- Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China
| | - Jiangong Ma
- Department of Chemistry and Key Laboratory of Advanced Energy Materials Chemistry (MOE), College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xunfeng Zou
- Department of General Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China.
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2
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Kuang B, Wang M, Yan H, Jiang Q, Wang Z, Ni H, Hou S, Peng X, Gu S, Zhao Y, Ou T, Gong N. Genetic and pharmacological targeting of XBP1 alleviates hepatic ischemia reperfusion injury by enhancing FoxO1-dependent mitophagy. Transl Res 2024; 272:162-176. [PMID: 38494125 DOI: 10.1016/j.trsl.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/10/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Hepatic ischemia reperfusion (I/R) injury is a common clinical complication. X-box binding protein 1 (XBP1), as a critical regulator of the endoplasmic reticulum stress, has been implicated in a variety of diseases. In this study, we aimed to investigate the effects and the underlying mechanism of XBP1 in the progression of hepatic I/R injury. Hepatocyte-specific XBP1 knockout mice, multiple viral delivery systems and specific pharmacological inhibitors were applied in vivo in a partial hepatic I/R injury mouse model and in vitro in a cell model of hypoxia-reoxygenation (H/R) injury. Mitophagy and autophagic flux were evaluated and fluorescence resonance energy transfer (FRET) as well as immunoprecipitation were performed. The results demonstrated that reperfusion for 6 h represented a critical timepoint in hepatic I/R injury and resulted in significant intracellular mitochondrial dysfunction; led to the breakdown of hepatocytes accompanied by the highest expression levels of XBP1. Hepatocyte-specific XBP1 knockout alleviated hepatic I/R injury via enhanced mitophagy, as demonstrated by the reduction in hepatocellular damage/necrosis and increased expression of mitophagy markers. Mechanistically, XBP1 interacted with FoxO1 directly and catalyzed the ubiquitination of FoxO1 for proteasomal degradation. Targeting XBP1 by genetic or pharmacological techniques potentiated the protein levels of FoxO1, further promoting the activity of the PINK1/Parkin signaling pathway, thus augmenting mitophagy and exerting hepatoprotective effects upon I/R injury. In conclusion, the inhibition of XBP1 potentiated FoxO1-mediated mitophagy in hepatic I/R injury. Specific genetic and pharmacological treatment targeting XBP1 in the perioperative 6 h prior to reperfusion exerted beneficial effects, thus providing a novel therapeutic approach.
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Affiliation(s)
- Baicheng Kuang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Mengqin Wang
- Department of Cardiothoracic surgery, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Hao Yan
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Qin Jiang
- Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei China
| | - Zhiheng Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Haiqiang Ni
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Shuaiheng Hou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Xuan Peng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Shiqi Gu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Tongwen Ou
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China.
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China.
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3
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Zhu MX, Ma XF, Niu X, Fan GB, Li Y. Mitochondrial unfolded protein response in ischemia-reperfusion injury. Brain Res 2022; 1797:148116. [PMID: 36209898 DOI: 10.1016/j.brainres.2022.148116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/27/2022] [Accepted: 10/02/2022] [Indexed: 11/21/2022]
Abstract
Mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that activates the transcriptional program of mitochondrial chaperone proteins and proteases to keep protein homeostasis in mitochondria. Ischemia-reperfusion injury results in multiple severe clinical issues linked to high morbidity and mortality in various disorders. The pathophysiology and pathogenesis of ischemia-reperfusion injury are complex and multifactorial. Emerging evidence showed the roles of UPRmt signaling in ischemia-reperfusion injury. Herein, we discuss the regulatory mechanisms underlying UPRmt signaling in C. elegans and mammals. Furthermore, we review the recent studies into the roles and mechanisms of UPRmt signaling in ischemia-reperfusion injury of the heart, brain, kidney, and liver. Further research of UPRmt signaling will potentially develop novel therapeutic strategies against ischemia-reperfusion injury.
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Affiliation(s)
- Ming-Xi Zhu
- Department of Anatomy, School of Basic Medicine and Life Science, Hainan Medical University, Hainan, China
| | - Xiao-Fei Ma
- Department of ICU, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xing Niu
- Department of Second Clinical College, Shengjing Hospital of China Medical University, Shenyang, China
| | - Gui-Bo Fan
- Department of Anesthesiology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Yan Li
- Department of Anesthesiology, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China.
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4
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Micó-Carnero M, Zaouali MA, Rojano-Alfonso C, Maroto-Serrat C, Ben Abdennebi H, Peralta C. A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation. Cells 2022; 11:2763. [PMID: 36078175 PMCID: PMC9455584 DOI: 10.3390/cells11172763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs.
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Affiliation(s)
- Marc Micó-Carnero
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mohamed Amine Zaouali
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Carlos Rojano-Alfonso
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | | | - Hassen Ben Abdennebi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Carmen Peralta
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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5
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Zhang S, Rao S, Yang M, Ma C, Hong F, Yang S. Role of Mitochondrial Pathways in Cell Apoptosis during He-Patic Ischemia/Reperfusion Injury. Int J Mol Sci 2022; 23:ijms23042357. [PMID: 35216473 PMCID: PMC8877300 DOI: 10.3390/ijms23042357] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/13/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatic ischemia-reperfusion injury is a major cause of post-operative hepatic dysfunction and liver failure after transplantation. Mitochondrial pathways can be either beneficial or detrimental to hepatic cell apoptosis during hepatic ischemia/reperfusion injury, depending on multiple factors. Hepatic ischemia/reperfusion injury may be induced by opened mitochondrial permeability transition pore, released apoptosis-related proteins, up-regulated B-cell lymphoma-2 gene family proteins, unbalanced mitochondrial dynamics, and endoplasmic reticulum stress, which are integral parts of mitochondrial pathways. In this review, we discuss the role of mitochondrial pathways in apoptosis that account for the most deleterious effect of hepatic ischemia/reperfusion injury.
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Affiliation(s)
- Sen Zhang
- Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, China; (S.Z.); (S.R.); (C.M.)
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Sijing Rao
- Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, China; (S.Z.); (S.R.); (C.M.)
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Meiwen Yang
- Department of Surgery, Fuzhou Medical College, Nanchang University, Fuzhou 344099, China;
| | - Chen Ma
- Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, China; (S.Z.); (S.R.); (C.M.)
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Fengfang Hong
- Experimental Center of Pathogen Biology, College of Medicine, Nanchang University, Nanchang 330006, China; (S.Z.); (S.R.); (C.M.)
- Correspondence: (F.H.); or (S.Y.)
| | - Shulong Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
- Department of Physiology, Fuzhou Medical College, Nanchang University, Fuzhou 344099, China
- Correspondence: (F.H.); or (S.Y.)
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6
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Wang PP, Huang X, Yang MW, Fang SY, Hong FF, Yang SL. Effects of non-drug treatment on liver cells apoptosis during hepatic ischemia-reperfusion injury. Life Sci 2021; 275:119321. [PMID: 33711387 DOI: 10.1016/j.lfs.2021.119321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 02/27/2021] [Accepted: 03/01/2021] [Indexed: 01/20/2023]
Abstract
Hepatic ischemia reperfusion injury (HIRI) is an important cause of liver dysfunction after liver transplantation for the patients suffered from fatty liver, non-alcoholic cirrhosis, or liver cancer. It is closely related to liver cells apoptosis. Therefore, how to maintain the stable state of cell apoptosis is important to protect the liver from HIRI. Drug treatment basically applies some active substances directly or indirectly, reducing HIRI. But their toxic side effects limit the clinical applications. Differently, non-drug treatment means making use of other kinds of measures to reduce the damage, such as non-pharmaceutical preparations, surgical methods, inhalation or perfusion gas, and so on. Non-drug treatments have been shown to balance cell apoptosis and reduce liver damage during HIRI. This review summarized the progresses in the roles of non-drug treatments on liver cells apoptosis during HIRI in recent years, focusing on apoptosis inducing factors, its signal transduction pathway, and downstream molecules, etc., expecting to elucidate non-drug treatments of anti-HIRI more systematically.
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Affiliation(s)
- Pei-Pei Wang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China; Department of Stomatology, Affiliated Third Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, China
| | - Xia Huang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Mei-Wen Yang
- Department of Nurse, Nanchang University Hospital, Nanchang 330006, Jiangxi Province, China
| | - Shi-Yao Fang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Fen-Fang Hong
- Department of Experimental Teaching Center, Nanchang University, Nanchang 330031, China.
| | - Shu-Long Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China.
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7
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Di Pasqua LG, Berardo C, Cagna M, Verta R, Collotta D, Nicoletti F, Ferrigno A, Collino M, Vairetti M. Metabotropic Glutamate Receptor Blockade Reduces Preservation Damage in Livers from Donors after Cardiac Death. Int J Mol Sci 2021; 22:ijms22052234. [PMID: 33668105 PMCID: PMC7956702 DOI: 10.3390/ijms22052234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/18/2021] [Accepted: 02/20/2021] [Indexed: 12/13/2022] Open
Abstract
We previously demonstrated that the blockade of mGluR5 by 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces both cold and warm ischemia/reperfusion injury. Here we evaluated whether MPEP reduces the hepatic preservation injury in rat livers from cardiac-death-donors (DCDs). Livers from DCD rats were isolated after an in situ warm ischemia (30 min) and preserved for 22 h at 4 °C with UW solution. Next, 10 mg/Kg MPEP or vehicle were administered 30 min before the portal clamping and added to the UW solution (3 µM). LDH released during washout was quantified. Liver samples were collected for iNOS, eNOS, NO, TNF-α, ICAM-1, caspase-3 and caspase-9 protein expression and nuclear factor-erythroid-2-related factor-2 (Nrf2) gene analysis. Lower LDH levels were detected in control grafts versus DCD groups. An increase in eNOS and NO content occurred after MPEP treatment; iNOS and TNF-α content was unchanged. ICAM-1 expression was reduced in the MPEP-treated livers as well as the levels of caspase-3 and caspase-9. Nrf2, oxidative stress-sensitive gene, was recovered to control value by MPEP. These results suggest that MPEP can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage. MPEP protects against apoptosis and increased eNOS, whose overexpression has been previously demonstrated to be protective in hepatic ischemia/reperfusion damage.
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Affiliation(s)
- Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (L.G.D.P.); (M.C.); (M.V.)
| | - Clarissa Berardo
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (L.G.D.P.); (M.C.); (M.V.)
- Correspondence: (C.B.); (A.F.); Tel.: +39-0382-986-874 (C.B.); +39-0382-986-451 (A.F.)
| | - Marta Cagna
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (L.G.D.P.); (M.C.); (M.V.)
| | - Roberta Verta
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (R.V.); (D.C.); (M.C.)
| | - Debora Collotta
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (R.V.); (D.C.); (M.C.)
| | - Ferdinando Nicoletti
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy;
- IRCCS Neuromed, 86077 Pozzilli, Italy
| | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (L.G.D.P.); (M.C.); (M.V.)
- Correspondence: (C.B.); (A.F.); Tel.: +39-0382-986-874 (C.B.); +39-0382-986-451 (A.F.)
| | - Massimo Collino
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (R.V.); (D.C.); (M.C.)
| | - Mariapia Vairetti
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (L.G.D.P.); (M.C.); (M.V.)
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8
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Slim C, Zaouali MA, Nassrallah H, Ammar HH, Majdoub H, Bouraoui A, Abdennebi HB. Protective potential effects of fucoidan in hepatic cold ischemia-rerfusion injury in rats. Int J Biol Macromol 2020; 155:498-507. [PMID: 32243932 DOI: 10.1016/j.ijbiomac.2020.03.245] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/27/2020] [Accepted: 03/28/2020] [Indexed: 01/14/2023]
Abstract
The necessity to increase the efficiency of organ preservation has pushed physicians to consider the use of pharmacological additives in preservation solutions to minimize ischemia reperfusion injury. Here, we evaluated the effect of fucoidan, sulfated polysaccharide from brown seaweed, as an additive to IGL-1 (Institut Georges Lopez) preservation solution. Livers from Wistar rats were preserved for 24 h at 4 °C in IGL-1 solution, enriched or not with fucoidan (100 mg/L). Thereafter, they were subjected to reperfusion (2 h, at 37 °C) using an isolated perfused rat liver model. The addition of fucoidan to IGL-1 solution reduced hepatic injury (AST, ALT) and improved liver function compared to IGL-1 solution without fucoidan. In addition, we noted a significant increase in the phosphorylation of AMPK, AKT protein kinase and GSK3-β, leading to a reduction in VDAC phosphorylation, as well as a reduction in apoptosis (caspase 3), mitochondrial damage, oxidative stress and endoplasmic reticulum (ER) stress markers. Furthermore, ERK1/2 and P38 MAPKs phosphorylation significantly decreased after supplementation of IGL-1 solution with fucoidan. In conclusion, the supplementation of IGL-1 solution with fucoidan maintained liver graft integrity and function through the prevention of the ER stress, oxidative stress and mitochondrial dysfunction. Fucoidan could be considered as potential natural therapeutic agent to alleviate graft injury.
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Affiliation(s)
- Chérifa Slim
- Laboratoire du Génome Humain et Maladies multifactorielles (LR12ES07), Faculté de Pharmacie de Monastir, Université de Monastir, Tunisia
| | - Mohamed Amine Zaouali
- Laboratoire du Génome Humain et Maladies multifactorielles (LR12ES07), Faculté de Pharmacie de Monastir, Université de Monastir, Tunisia; Département des Sciences du Vivant et Biotechnologie, Institut Supérieur de Biotechnologie de Monastir, Université de Monastir, Tunisia
| | - Hana Nassrallah
- Laboratoire du Génome Humain et Maladies multifactorielles (LR12ES07), Faculté de Pharmacie de Monastir, Université de Monastir, Tunisia
| | - Hiba Hadj Ammar
- Laboratoire des Interfaces et des Matériaux Avancés (LIMA), Faculté des Sciences de Monastir, Université de Monastir, Tunisia
| | - Hatem Majdoub
- Laboratoire des Interfaces et des Matériaux Avancés (LIMA), Faculté des Sciences de Monastir, Université de Monastir, Tunisia
| | - Abderrahman Bouraoui
- Laboratoire du Développement Chimique, Galénique et Pharmacologique des Médicaments (LR12ES09), Faculté de Pharmacie de Monastir, Université de Monastir, Tunisia
| | - Hassen Ben Abdennebi
- Laboratoire du Génome Humain et Maladies multifactorielles (LR12ES07), Faculté de Pharmacie de Monastir, Université de Monastir, Tunisia.
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9
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Melis N, Thuillier R, Steichen C, Giraud S, Sauvageon Y, Kaminski J, Pelé T, Badet L, Richer JP, Barrera-Chimal J, Jaisser F, Tauc M, Hauet T. Emerging therapeutic strategies for transplantation-induced acute kidney injury: protecting the organelles and the vascular bed. Expert Opin Ther Targets 2019; 23:495-509. [PMID: 31022355 DOI: 10.1080/14728222.2019.1609451] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Renal ischemia-reperfusion injury (IRI) is a significant clinical challenge faced by clinicians in a broad variety of clinical settings such as perioperative and intensive care. Renal IRI induced acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and health-care costs. Areas covered: This paper focuses on the pathophysiology of transplantation-related AKI and recent findings on cellular stress responses at the intersection of 1. The Unfolded protein response; 2. Mitochondrial dysfunction; 3. The benefits of mineralocorticoid receptor antagonists. Lastly, perspectives are offered to the readers. Expert opinion: Renal IRI is caused by a sudden and temporary impairment of blood flow to the organ. Defining the underlying cellular cascades involved in IRI will assist us in the identification of novel interventional targets to attenuate IRI with the potential to improve transplantation outcomes. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer several advantages compared to targeting downstream inflammatory and fibrosis processes. An improved understanding of the cellular pathophysiological mechanisms leading to kidney injury will hopefully offer improved targeted therapies to prevent and treat the injury in the future.
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Affiliation(s)
- Nicolas Melis
- a Laboratory of Cellular and Molecular Biology , Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA
| | - Raphael Thuillier
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France.,d CHU Poitiers , Service de Biochimie , Poitiers , France.,e Fédération Hospitalo-Universitaire SUPORT , Poitiers , France
| | - Clara Steichen
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France
| | - Sebastien Giraud
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France.,d CHU Poitiers , Service de Biochimie , Poitiers , France
| | - Yse Sauvageon
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France
| | - Jacques Kaminski
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France
| | - Thomas Pelé
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France
| | - Lionel Badet
- f Faculté de Médecine , Université Claude Bernard Lyon 1 , Villeurbanne , France.,g Hospices Civiles de Lyon , Service d'urologie et de chirurgie de la transplantation , Lyon , France
| | - Jean Pierre Richer
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France.,h CHU de Poitiers , Service de chirurgie générale et endocrinienne , Poitiers , France.,i Faculté de Médecine et de Pharmacie , ABS Lab (Laboratoire d'Anatomie, Biomécanique et Simulation), Université de Poitiers , Poitiers , France
| | - Jonatan Barrera-Chimal
- j Laboratorio de Fisiología Cardiovascular y Trasplante Renal, Unidad de Medicina Traslacional , Instituto de Investigaciones Biomédicas, UNAM and Instituto Nacional de Cardiología Ignacio Chávez , Mexico City , Mexico
| | - Frédéric Jaisser
- k INSERM, UMRS 1138, Team 1 , Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris, Descartes University , Paris , France
| | - Michel Tauc
- l LP2M CNRS-UMR7370, LabEx ICST , Medical Faculty, Université Côte d'Azur , Nice , France
| | - Thierry Hauet
- b IRTOMIT , Inserm U1082 , Poitiers , France.,c Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France.,d CHU Poitiers , Service de Biochimie , Poitiers , France.,e Fédération Hospitalo-Universitaire SUPORT , Poitiers , France.,i Faculté de Médecine et de Pharmacie , ABS Lab (Laboratoire d'Anatomie, Biomécanique et Simulation), Université de Poitiers , Poitiers , France.,m IBiSA Plateforme 'plate-forme MOdélisation Préclinique - Innovation Chirurgicale et Technologique (MOPICT)', Domaine Expérimental du Magneraud , Surgères , France
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10
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Tchilikidi KY. Liver graft preservation methods during cold ischemia phase and normothermic machine perfusion. World J Gastrointest Surg 2019; 11:126-142. [PMID: 31057698 PMCID: PMC6478595 DOI: 10.4240/wjgs.v11.i3.126] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/21/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023] Open
Abstract
The growing demand for donor organs requires measures to expand donor pool. Those include extended criteria donors, such as elderly people, steatotic livers, donation after cardiac death, etc. Static cold storage to reduce metabolic requirements developed by Collins in late 1960s is the mainstay and the golden standard for donated organ protection. Hypothermic machine perfusion provides dynamic organ preservation at 4°C with protracted infusion of metabolic substrates to the graft during the ex vivo period. It has been used instead of static cold storage or after it as short perfusion in transplant center. Normothermic machine perfusion (NMP) delivers oxygen, and nutrition at physiological temperature mimicking regular environment in order to support cellular function. This would minimize effects of ischemia/reperfusion injury. Potentially, NMP may help to estimate graft functionality before implantation into a recipient. Clinical studies demonstrated at least its non-inferiority or better outcomes vs static cold storage. Regular grafts donated after brain death could be safely preserved with convenient static cold storage. Except for prolonged ischemia time where hypothermic machine perfusion started in transplant center could be estimated to provide possible positive reconditioning effect. Use of hypothermic machine perfusion in regular donation instead of static cold storage or in extended criteria donors requires further investigation. Multicenter randomized clinical trial supposed to be completed in December 2021. Extended criteria donors need additional measures for graft storage and assessment until its implantation. NMP is actively evaluating promising method for this purpose. Future studies are necessary for precise estimation and confirmation to issue clinical practice recommendations.
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11
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Zaouali MA, Panisello-Roselló A, Lopez A, Castro Benítez C, Folch-Puy E, García-Gil A, Carbonell T, Adam R, Roselló-Catafau J. Relevance of proteolysis and proteasome activation in fatty liver graft preservation: An Institut Georges Lopez-1 vs University of Wisconsin appraisal. World J Gastroenterol 2017; 23:4211-4221. [PMID: 28694661 PMCID: PMC5483495 DOI: 10.3748/wjg.v23.i23.4211] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 04/08/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To compare liver proteolysis and proteasome activation in steatotic liver grafts conserved in University of Wisconsin (UW) and Institut Georges Lopez-1 (IGL-1) solutions. METHODS Fatty liver grafts from male obese Zücker rats were conserved in UW and IGL-1 solutions for 24 h at 4 °Cand subjected to "ex vivo" normo-thermic perfusion (2 h; 37 °C). Liver proteolysis in tissue specimens and perfusate was measured by reverse-phase high performance liquid chromatography. Total free amino acid release was correlated with the activation of the ubiquitin proteasome system (UPS: measured as chymotryptic-like activity and 20S and 19S proteasome), the prevention of liver injury (transaminases), mitochondrial injury (confocal microscopy) and inflammation markers (TNF 1 alpha, high mobility group box-1 (HGMB-1) and PPAR gamma), and liver apoptosis (TUNEL assay, cytochrome c and caspase 3). RESULTS Profiles of free AA (alanine, proline, leucine, isoleucine, methionine, lysine, ornithine, and threonine, among others) were similar for tissue and reperfusion effluent. In all cases, the IGL-1 solution showed a significantly higher prevention of proteolysis than UW (P < 0.05) after cold ischemia reperfusion. Livers conserved in IGL-1 presented more effective prevention of ATP-breakdown and more inhibition of UPS activity (measured as chymotryptic-like activity). In addition, the prevention of liver proteolysis and UPS activation correlated with the prevention of liver injury (AST/ALT) and mitochondrial damage (revealed by confocal microscopy findings) as well as with the prevention of inflammatory markers (TNF1alpha and HMGB) after reperfusion. In addition, the liver grafts preserved in IGL-1 showed a significant decrease in liver apoptosis, as shown by TUNEL assay and the reduction of cytochrome c, caspase 3 and P62 levels. CONCLUSION Our comparison of these two preservation solutions suggests that IGL-1 helps to prevent ATP breakdown more effectively than UW and subsequently achieves a higher UPS inhibition and reduced liver proteolysis.
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12
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Zaouali MA, Panisello A, Lopez A, Castro C, Folch E, Carbonell T, Rolo A, Palmeira CM, Garcia-Gil A, Adam R, Roselló-Catafau J. GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation. Int J Mol Sci 2017; 18:591. [PMID: 28282906 PMCID: PMC5372607 DOI: 10.3390/ijms18030591] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/20/2017] [Accepted: 02/23/2017] [Indexed: 01/07/2023] Open
Abstract
We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia-reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention.
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Affiliation(s)
- Mohamed Amine Zaouali
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
- Research Unit of Biology and Molecular Anthropology Applied to Development and Health (UR12ES11), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia.
- High Institute of Biotechnology of Monastir, University of Monastir, Monastir 5000, Tunisia.
| | - Arnau Panisello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
| | - Alexandre Lopez
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France.
| | - Carlos Castro
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France.
| | - Emma Folch
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
| | - Teresa Carbonell
- Department of Physiology, Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain.
| | - Anabela Rolo
- Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
| | - Carlos Marques Palmeira
- Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
| | | | - René Adam
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France.
| | - Joan Roselló-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
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13
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Land WG, Agostinis P, Gasser S, Garg AD, Linkermann A. DAMP-Induced Allograft and Tumor Rejection: The Circle Is Closing. Am J Transplant 2016; 16:3322-3337. [PMID: 27529775 DOI: 10.1111/ajt.14012] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/28/2016] [Accepted: 07/31/2016] [Indexed: 01/25/2023]
Abstract
The pathophysiological importance of the immunogenicity of damage-associated molecular patterns (DAMPs) has been pinpointed by their identification as triggers of allograft rejection following release from dying cells, such as after ischemia-reperfusion injury. In cancers, however, this strong trigger of a specific immune response gives rise to the success of cancer immunotherapy. Here, we review the recently literature on the pathophysiological importance of DAMP release and discuss the implications of these processes for allograft rejection and cancer immunotherapy, revealing a striking mechanistic overlap. We conclude that these two fields share a common mechanistic basis of regulated necrosis and inflammation, the molecular characterization of which may be helpful for both oncologists and the transplant community.
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Affiliation(s)
- W G Land
- German Academy of Transplantation Medicine, Munich, Germany.,Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,LabexTRANSPLANTEX, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - P Agostinis
- Cell Death Research and Therapy (CDRT) Lab, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, Leuven, Belgium
| | - S Gasser
- Immunology Programme and Department of Microbiology and Immunology, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - A D Garg
- Cell Death Research and Therapy (CDRT) Lab, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, Leuven, Belgium
| | - A Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.,Cluster of Excellence EXC306, Inflammation at Interfaces, Schleswig-Holstein, Germany.,Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany
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14
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Adiponectin protects the rats liver against chronic intermittent hypoxia induced injury through AMP-activated protein kinase pathway. Sci Rep 2016; 6:34151. [PMID: 27678302 PMCID: PMC5039704 DOI: 10.1038/srep34151] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 09/05/2016] [Indexed: 12/25/2022] Open
Abstract
This study was performed to assess the effect of chronic intermittent hypoxia (CIH) on the liver, the associated mechanisms and the potential therapeutic roles of adiponectin (Ad). Sixty rats were randomly assigned to four groups: the normal control (NC), NC and Ad supplement (NC + Ad), CIH, and CIH and Ad supplement (CIH + Ad) groups. The rats in the CIH and CIH + Ad groups were exposed to a hypoxic environment for 4 months. Rats in the NC + Ad and CIH + Ad groups were also treated with an intravenous injection of Ad (10 ug), twice a week. The plasma levels of hepatic enzymes, serum triglyceride, liver triglyceride, fasting blood glucose and hepatic cell apoptosis in hepatic tissue, were higher in the CIH group than in the NC and NC + Ad groups. However, the Ad supplementation in the CIH + Ad group rescued the hepatic tissue insult by activating the AMP-activated protein kinase (AMPK) pathway. In conclusion, Ad could protect against CIH-induced hepatic injury partly through the AMPK pathway.
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15
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Esteban-Zubero E, García-Gil FA, López-Pingarrón L, Alatorre-Jiménez MA, Ramírez JM, Tan DX, García JJ, Reiter RJ. Melatonin role preventing steatohepatitis and improving liver transplantation results. Cell Mol Life Sci 2016; 73:2911-2927. [PMID: 27022943 PMCID: PMC11108472 DOI: 10.1007/s00018-016-2185-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 03/18/2016] [Indexed: 12/18/2022]
Abstract
Liver steatosis is a prevalent process that is induced due to alcoholic or non-alcoholic intake. During the course of these diseases, the generation of reactive oxygen species, followed by molecular damage to lipids, protein and DMA occurs generating organ cell death. Transplantation is the last-resort treatment for the end stage of both acute and chronic hepatic diseases, but its success depends on ability to control ischemia-reperfusion injury, preservation fluids used, and graft quality. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other because of its efficacy in organs; melatonin has been investigated to improve the outcome of organ transplantation by reducing ischemia-reperfusion injury and due to its synergic effect with organ preservation fluids. Moreover, this indolamine also prevent liver steatosis. That is important because this disease may evolve leading to an organ transplantation. This review summarizes the observations related to melatonin beneficial actions in organ transplantation and ischemic-reperfusion models.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain.
| | - Francisco Agustín García-Gil
- Department of Surgery, Gynaecology and Obstetrics, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Laura López-Pingarrón
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Moisés Alejandro Alatorre-Jiménez
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA
| | - José Manuel Ramírez
- Department of Surgery, Gynaecology and Obstetrics, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA
| | - José Joaquín García
- Department of Pharmacology and Physiology, University of Zaragoza, Calle Domingo Miral s/n, 50009, Saragossa, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
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16
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Folch-Puy E, Panisello A, Oliva J, Lopez A, Castro Benítez C, Adam R, Roselló-Catafau J. Relevance of Endoplasmic Reticulum Stress Cell Signaling in Liver Cold Ischemia Reperfusion Injury. Int J Mol Sci 2016; 17:807. [PMID: 27231901 PMCID: PMC4926341 DOI: 10.3390/ijms17060807] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 05/15/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023] Open
Abstract
The endoplasmic reticulum (ER) is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS). This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR), which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI) of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes.
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Affiliation(s)
- Emma Folch-Puy
- Experimental Pathology Department, Instituto de Investigaciones Biomédicas de Barcelona, Spanish Research Council (IIBB-CSIC), Rosselló 161, 08036-Barcelona, Catalonia, Spain.
| | - Arnau Panisello
- Experimental Pathology Department, Instituto de Investigaciones Biomédicas de Barcelona, Spanish Research Council (IIBB-CSIC), Rosselló 161, 08036-Barcelona, Catalonia, Spain.
| | - Joan Oliva
- Department of Medicine, LaBioMed at Harbor UCLA Medical Center, Torrance, 90502 CA, USA.
| | - Alexandre Lopez
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U935, Université Paris-Sud, Villejuif, 75008 Paris, France.
| | - Carlos Castro Benítez
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U935, Université Paris-Sud, Villejuif, 75008 Paris, France.
| | - René Adam
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U935, Université Paris-Sud, Villejuif, 75008 Paris, France.
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Instituto de Investigaciones Biomédicas de Barcelona, Spanish Research Council (IIBB-CSIC), Rosselló 161, 08036-Barcelona, Catalonia, Spain.
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17
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Su S, Liu J, He K, Zhang M, Feng C, Peng F, Li B, Xia X. Overexpression of the long noncoding RNA TUG1 protects against cold-induced injury of mouse livers by inhibiting apoptosis and inflammation. FEBS J 2016; 283:1261-74. [PMID: 26785829 DOI: 10.1111/febs.13660] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/08/2015] [Accepted: 01/14/2016] [Indexed: 12/16/2022]
Abstract
UNLABELLED Hepatic injury provoked by cold storage is a major problem affecting liver transplantation, as exposure to cold induces apoptosis in hepatic tissues. Long noncoding RNAs (lncRNAs) are increasingly understood to regulate apoptosis, but the contribution of lncRNAs to cold-induced liver injury remains unknown. Using RNA-seq, we determined the differential lncRNA expression profile in mouse livers after cold storage and found that expression of the lncRNA TUG1 was significantly down-regulated. Overexpression of TUG1 attenuated cold-induced apoptosis in mouse hepatocytes and liver sinusoidal endothelial cells LSECs, in part by blocking mitochondrial apoptosis and endoplasmic reticulum (ER) stress pathways. Moreover, TUG1 attenuated apoptosis, inflammation, and oxidative stress in vivo in livers subjected to cold storage. Overexpression of TUG1 also improved hepatocyte function and prolonged hepatic graft survival rates in mice. These results suggest that the lncRNA TUG1 exerts a protective effect against cold-induced liver damage by inhibiting apoptosis in mice, and suggests a potential role for TUG1 as a target for the prevention of cold-induced liver damage in liver transplantation. DATABASES RNA-seq data are available from GEO using accession number GSE76609.
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Affiliation(s)
- Song Su
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Jiang Liu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Kai He
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Mengyu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Chunhong Feng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Fangyi Peng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Bo Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
| | - Xianming Xia
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical College, Sichuan Province, China
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18
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Bejaoui M, Pantazi E, Calvo M, Folch-Puy E, Serafín A, Pasut G, Panisello A, Adam R, Roselló-Catafau J. Polyethylene Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia Reperfusion Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:9096549. [PMID: 26981166 PMCID: PMC4770158 DOI: 10.1155/2016/9096549] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 10/29/2015] [Accepted: 11/02/2015] [Indexed: 02/06/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proven their effectiveness in various in vivo and in vitro models of tissue injury. The present study aims to investigate whether the intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) could be an effective strategy for rat liver preconditioning against IRI. PEG 35 was intravenously administered at 2 and 10 mg/kg to male Sprague Dawley rats. Then, rats were subjected to one hour of partial ischemia (70%) followed by two hours of reperfusion. The results demonstrated that PEG 35 injected intravenously at 10 mg/kg protected efficiently rat liver against the deleterious effects of IRI. This was evidenced by the significant decrease in transaminases levels and the better preservation of mitochondrial membrane polarization. Also, PEG 35 preserved hepatocyte morphology as reflected by an increased F-actin/G-actin ratio and confocal microscopy findings. In addition, PEG 35 protective mechanisms were correlated with the activation of the prosurvival kinase Akt and the cytoprotective factor AMPK and the inhibition of apoptosis. Thus, PEG may become a suitable agent to attempt pharmacological preconditioning against hepatic IRI.
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Affiliation(s)
- Mohamed Bejaoui
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Rossello 161, Barcelona, 08036 Catalonia, Spain
| | - Eirini Pantazi
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Rossello 161, Barcelona, 08036 Catalonia, Spain
| | - Maria Calvo
- Advanced Optical Microscopy Unit CCiTUB, Science and Technology Center, Faculty of Medicine, University of Barcelona, C/Casanova 143, Barcelona, 08036 Catalonia, Spain
| | - Emma Folch-Puy
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Rossello 161, Barcelona, 08036 Catalonia, Spain
| | - Anna Serafín
- Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, 08028 Catalonia, Spain
| | - Gianfranco Pasut
- Pharmaceutical and Pharmacological Sciences Department, University of Padova, 35131 Padova, Italy
- Veneto Institute of Oncology (IOV), IRCCS, 35128 Padova, Italy
| | - Arnau Panisello
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Rossello 161, Barcelona, 08036 Catalonia, Spain
| | - René Adam
- Hepato-Biliary Centre, Paul Brousse Hospital, Inserm U776, Paris-Sud University, Villejuif, 75008 Paris, France
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Rossello 161, Barcelona, 08036 Catalonia, Spain
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19
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Yuan DD, Chi XJ, Jin Y, Li X, Ge M, Gao WL, Guan JQ, Zhang AL, Hei ZQ. Intestinal injury following liver transplantation was mediated by TLR4/NF-κB activation-induced cell apoptosis. Mol Med Rep 2015; 13:1525-32. [PMID: 26707779 PMCID: PMC4732843 DOI: 10.3892/mmr.2015.4719] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell aapoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.
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Affiliation(s)
- Dong-Dong Yuan
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xin-Jin Chi
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yi Jin
- Department of Pathology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xi Li
- Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Mian Ge
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Wan-Ling Gao
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jian-Qiang Guan
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ai-Lan Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zi-Qing Hei
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
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20
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Bejaoui M, Pantazi E, De Luca V, Panisello A, Folch-Puy E, Hotter G, Capasso C, T. Supuran C, Rosselló-Catafau J. Carbonic Anhydrase Protects Fatty Liver Grafts against Ischemic Reperfusion Damage. PLoS One 2015; 10:e0134499. [PMID: 26225852 PMCID: PMC4520486 DOI: 10.1371/journal.pone.0134499] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 07/09/2015] [Indexed: 01/11/2023] Open
Abstract
Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. CAs are involved in numerous physiological and pathological processes, including acid-base homeostasis, electrolyte balance, oxygen delivery to tissues and nitric oxide generation. Given that these processes are found to be dysregulated during ischemia reperfusion injury (IRI), and taking into account the high vulnerability of steatotic livers to preservation injury, we hypothesized a new role for CA as a pharmacological agent able to protect against ischemic damage. Two different aspects of the role of CA II in fatty liver grafts preservation were evaluated: 1) the effect of its addition to Institut Georges Lopez (IGL-1) storage solution after cold ischemia; 2) and after 24h of cold storage followed by two hours of normothermic ex-vivo perfusion. In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined. In case of the ex-vivo perfusion, we further assessed liver function (bile production, bromosulfophthalein clearance) and Western blot analysis of phosphorylated adenosine monophosphate activated protein kinase (AMPK), mitogen activated protein kinases family (MAPKs) and endoplasmic reticulum stress (ERS) parameters (GRP78, PERK, IRE, eIF2α and ATF6). We found that CA II was downregulated after cold ischemia. The addition of bovine CA II to IGL-1 preservation solution efficiently protected steatotic liver against cold IRI. In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation. Interestingly, CA II supplementation was not associated with enhanced CO2 hydration. The results suggest that CA II modulation may be a promising target for fatty liver graft preservation.
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Affiliation(s)
- Mohamed Bejaoui
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Eirini Pantazi
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Viviana De Luca
- Institute of Bioscience and Bioresources (IBBR), National Research Council, Napoli, Italy
| | - Arnau Panisello
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Emma Folch-Puy
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Georgina Hotter
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
| | - Clemente Capasso
- Institute of Bioscience and Bioresources (IBBR), National Research Council, Napoli, Italy
| | | | - Joan Rosselló-Catafau
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona-Spanish National Research Council (IIBB-CSIC), IDIBAPS, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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Tabka D, Bejaoui M, Javellaud J, Roselló-Catafau J, Achard JM, Abdennebi HB. Effects of Institut Georges Lopez-1 and Celsior preservation solutions on liver graft injury. World J Gastroenterol 2015; 21:4159-4168. [PMID: 25892865 PMCID: PMC4394076 DOI: 10.3748/wjg.v21.i14.4159] [Citation(s) in RCA: 16] [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: 11/06/2014] [Revised: 12/30/2014] [Accepted: 01/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To compare Institut Georges Lopez (IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury (IRI). METHODS Two experimental models were used. In the first one, acetylcholine-induced endothelium-dependent relaxation (EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions (24 h at 4 °C). To determine nitric oxide (NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester (L-NAME), an inhibitor of endothelium nitric oxide synthase (eNOS), or with L-NAME plus indomethacin, an inhibitor of cyclooxygenase. In the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 °C and then perfused "ex vivo" for 2 h at 37 °C. Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pAkt, pAMPK, eNOS and MAPKs proteins level. RESULTS After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly altered. In freshly isolated arteries, EDR was exclusively mediated by NO. However, cold-stored arteries showed NO- and COX-dependent relaxation. The decrease in NO-dependent relaxation after cold storage was significantly more marked with Celsior. The second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than Celsior. Liver injury was reduced, function was improved and there was less oxidative stress. IGL-1 solution activated Akt and AMPK, which was concomitant with increased eNOS expression and nitrite/nitrate levels. Furthermore, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were observed. CONCLUSION IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solution and enhanced liver graft preservation.
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Pantazi E, Zaouali MA, Bejaoui M, Folch-Puy E, Ben Abdennebi H, Varela AT, Rolo AP, Palmeira CM, Roselló-Catafau J. Sirtuin 1 in rat orthotopic liver transplantation: an IGL-1 preservation solution approach. World J Gastroenterol 2015; 21:1765-1774. [PMID: 25684941 PMCID: PMC4323452 DOI: 10.3748/wjg.v21.i6.1765] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 10/25/2014] [Accepted: 11/07/2014] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the possible involvement of Sirtuin 1 (SIRT1) in rat orthotopic liver transplantation (OLT), when Institute Georges Lopez 1 (IGL-1) preservation solution is enriched with trimetazidine (TMZ). METHODS Male Sprague-Dawley rats were used as donors and recipients. Livers were stored in IGL-1 preservation solution for 8h at 4 °C, and then underwent OLT according to Kamada's cuff technique without arterialization. In another group, livers were stored in IGL-1 preservation solution supplemented with TMZ, at 10(-6) mol/L, for 8 h at 4 °C and then underwent OLT. Rats were sacrificed 24 h after reperfusion, and liver and plasma samples were collected. Liver injury (transaminase levels), mitochondrial damage (glutamate dehydrogenase activity) oxidative stress (malondialdehyde levels), and nicotinamide adenine dinucleotide (NAD(+)), the co-factor necessary for SIRT1 activity, were determined by biochemical methods. SIRT1 and its substrates (ac-FoxO1, ac-p53), the precursor of NAD(+), nicotinamide phosphoribosyltransferase (NAMPT), as well as the phosphorylation of adenosine monophosphate activated protein kinase (AMPK), p-mTOR, p-p70S6K (direct substrate of mTOR), autophagy parameters (beclin-1, LC3B) and MAP kinases (p-p38 and p-ERK) were determined by Western blot. RESULTS Liver grafts preserved in IGL-1 solution enriched with TMZ presented reduced liver injury and mitochondrial damage compared with those preserved in IGL-1 solution alone. In addition, livers preserved in IGL-1 + TMZ presented reduced levels of oxidative stress. This was consistent with enhanced SIRT1 protein expression and elevated SIRT1 activity, as indicated by decreased acetylation of p53 and FoxO1. The elevated SIRT1 activity in presence of TMZ can be attributed to the enhanced NAMPT protein and NAD(+)/NADH levels. Up-regulation of SIRT1 was consistent with activation of AMPK and inhibition of phosphorylation of mTOR and its direct substrate (p-p70S6K). As a consequence, autophagy mediators (beclin-1 and LC3B) were over-expressed. Furthermore, MAP kinases were regulated in livers preserved with IGL-1 + TMZ, as they were characterized by enhanced p-ERK and decreased p-p38 protein expression. CONCLUSION Our study shows that IGL-1 preservation solution enriched with TMZ protects liver grafts from the IRI associated with OLT, through SIRT1 up-regulation.
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Bejaoui M, Pantazi E, Folch-Puy E, Baptista PM, García-Gil A, Adam R, Roselló-Catafau J. Emerging concepts in liver graft preservation. World J Gastroenterol 2015; 21:396-407. [PMID: 25593455 PMCID: PMC4292271 DOI: 10.3748/wjg.v21.i2.396] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/24/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
The urgent need to expand the donor pool in order to attend to the growing demand for liver transplantation has obliged physicians to consider the use of suboptimal liver grafts and also to redefine the preservation strategies. This review examines the different methods of liver graft preservation, focusing on the latest advances in both static cold storage and machine perfusion (MP). The new strategies for static cold storage are mainly designed to increase the fatty liver graft preservation via the supplementation of commercial organ preservation solutions with additives. In this paper we stress the importance of carrying out effective graft washout after static cold preservation, and present a detailed discussion of the future perspectives for dynamic graft preservation using MP at different temperatures (hypothermia at 4 °C, normothermia at 37 °C and subnormothermia at 20 °C-25 °C). Finally, we highlight some emerging applications of regenerative medicine in liver graft preservation. In conclusion, this review discusses the "state of the art" and future perspectives in static and dynamic liver graft preservation in order to improve graft viability.
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Le Pape S, Dimitrova E, Hannaert P, Konovalov A, Volmer R, Ron D, Thuillier R, Hauet T. Polynomial algebra reveals diverging roles of the unfolded protein response in endothelial cells during ischemia-reperfusion injury. FEBS Lett 2014; 588:3062-7. [PMID: 24945730 DOI: 10.1016/j.febslet.2014.05.065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 05/23/2014] [Accepted: 05/30/2014] [Indexed: 11/16/2022]
Abstract
The unfolded protein response (UPR)--the endoplasmic reticulum stress response--is found in various pathologies including ischemia-reperfusion injury (IRI). However, its role during IRI is still unclear. Here, by combining two different bioinformatical methods--a method based on ordinary differential equations (Time Series Network Inference) and an algebraic method (probabilistic polynomial dynamical systems)--we identified the IRE1α-XBP1 and the ATF6 pathways as the main UPR effectors involved in cell's adaptation to IRI. We validated these findings experimentally by assessing the impact of their knock-out and knock-down on cell survival during IRI.
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Affiliation(s)
- Sylvain Le Pape
- IRTOMIT, INSERM UMR 1082, Université de Médecine et de Pharmacie de Poitiers, Rue de la Milétrie, 86021 Poitiers, France.
| | - Elena Dimitrova
- Mathematical Sciences, Clemson University, Martin O-303, Clemson, SC 29634-0975, United States
| | - Patrick Hannaert
- IRTOMIT, INSERM UMR 1082, Université de Médecine et de Pharmacie de Poitiers, Rue de la Milétrie, 86021 Poitiers, France
| | - Alexander Konovalov
- Centre for Interdisciplinary Research in Computational Algebra, School of Computer Science, University of St Andrews, St Andrews, Fife KY16 9SX, Scotland, United Kingdom
| | - Romain Volmer
- University of Cambridge Metabolic Research Laboratories and National Institute for Health Research, Cambridge Biomedical Research Centre, CB2 0QQ Cambridge, United Kingdom
| | - David Ron
- University of Cambridge Metabolic Research Laboratories and National Institute for Health Research, Cambridge Biomedical Research Centre, CB2 0QQ Cambridge, United Kingdom
| | - Raphaël Thuillier
- IRTOMIT, INSERM UMR 1082, Université de Médecine et de Pharmacie de Poitiers, Rue de la Milétrie, 86021 Poitiers, France
| | - Thierry Hauet
- IRTOMIT, INSERM UMR 1082, Université de Médecine et de Pharmacie de Poitiers, Rue de la Milétrie, 86021 Poitiers, France
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García-Gil FA, Fuentes-Broto L, Albendea CD, Serrano MT, Roselló-Catafau J, Lampreave F, López-Pingarrón L, Escartín J, Soria J, Garcia JJ, Fernández-Cruz L. Evaluation of Institut Georges Lopez-1 preservation solution in pig pancreas transplantation: a pilot study. Transplantation 2014; 97:901-907. [PMID: 24646772 DOI: 10.1097/tp.0000000000000050] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Institut Georges Lopez-1 preservation solution (IGL-1) is an emerging extracellular-type electrolyte solution, low in viscosity, containing polyethylene glycol 35 as a colloid. Although IGL-1 has shown beneficial outcomes in kidney and liver preservation, this pilot study is the first to evaluate the efficacy of IGL-1 in pancreas transplantation (PT) compared with the University of Wisconsin solution (UW). METHODS Sixteen Landrace pigs underwent allogeneic PT with 16 hr of cold ischemia. Grafts were preserved with IGL-1 (n=8) or UW (n=8). No immunosuppression was administered. We analyzed graft function, the acute-phase response, and oxidative stress in the pancreatic graft monitoring membrane fluidity and lipid peroxidation. RESULTS All eight grafts with IGL-1, but only six with UW, were functioning. Graft failures with UW resulted from graft thrombosis. There were no differences between the two solutions in the number of normoglycemic days (IGL-1: 11.5 ± 6.2 versus UW: 8.5 ± 4.4 days, P=0.1357), nor in lipid peroxidation during 16-hr cold ischemia (P=0.672), or reperfusion (P=0.185), but IGL-1 prevented changes in membrane fluidity after reperfusion when compared with UW (P=0.026). CONCLUSION IGL-1 offered the same degree of safety and effectiveness as UW in our model of pig PT with 16 hr of cold ischemia.
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Affiliation(s)
- Francisco A García-Gil
- 1 Department of Surgery, University of Zaragoza, Zaragoza, Spain. 2 Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain. 3 Gastroenterology and Hepatology Department, HCU Lozano Blesa, Zaragoza, Spain. 4 Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research, Spanish National Research Council, Barcelona, Spain. 5 Department of Biochemistry and Molecular Cell Biology, University of Zaragoza, Zaragoza, Spain. 6 Department of Human Anatomy and Histology, University of Zaragoza, Zaragoza, Spain. 7 Department of Pathology, HCU Lozano Blesa, Zaragoza, Spain. 8 Department of Surgery, ICMDM, Hospital Clinic, University of Barcelona, Barcelona, Spain. 9 Address correspondence to: Prof. Francisco A. García-Gil, M.D., Ph.D., Department of Surgery, University of Zaragoza, Domingo Miral, s/n, 50009, Zaragoza, Spain
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Tang WX, Wang LK, Wang YQ, Zong ZJ, Gao ZX, Liu XS, Shen YJ, Shen YX, Li YH. Peroxisome proliferator-activated receptor-α activation protects against endoplasmic reticulum stress-induced HepG2 cell apoptosis. Mol Cell Biochem 2013; 385:179-90. [DOI: 10.1007/s11010-013-1826-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Accepted: 09/13/2013] [Indexed: 12/24/2022]
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Ren LP, Song GY, Hu ZJ, Zhang M, Peng L, Chen SC, Wei L, Li F, Sun W. The chemical chaperon 4-phenylbutyric acid ameliorates hepatic steatosis through inhibition of de novo lipogenesis in high-fructose-fed rats. Int J Mol Med 2013; 32:1029-36. [PMID: 24042997 DOI: 10.3892/ijmm.2013.1493] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 08/19/2013] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease caused by dietary factors such as a high fructose intake is a growing global concern. The aim of this study was to investigate the intervention effects of an endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (PBA) on liver steatosis induced by high-fructose feeding in rats and the possible underlying mechanisms. Wistar rats were divided into the control, high-fructose group (HFru) and PBA intervention (HFru-PBA) groups. PBA intervention was initiated following 4 weeks of high-fructose feeding. After 8 weeks of feeding, the ERS markers p-PERK, p-eIF2α, p-IRE-1, spliced XBP-1, ATF-6 were measured by western blotting. Liver triglyceride contents and morphological changes were examined. The protein expression of lipogenic key enzymes (ACC, FAS and SCD-1) and upstream transcriptional factors (SREBP-1c and ChREBP) were measured. The ERS-related cell events, oxidative stress and apoptosis, were evaluated by standard methods. Results demonstrated that PBA intervention significantly resolved hepatic ERS and improved liver steatosis induced by high-fructose feeding in rats. The protein expression of ACC, FAS, SCD-1 and SREBP-1c was upregulated in high-fructose-fed rats, whereas it decreased following PBA intervention. Oxidative stress and apoptosis were observed in livers of high-fructose-fed rats, but were alleviated by PBA intervention. ERS is involved in the development of fatty liver induced by a high fructose intake. ERS inhibition by PBA can therefore ameliorate liver steatosis through inhibition of hepatic lipogenesis.
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Affiliation(s)
- Lu-Ping Ren
- Department of Endocrinology, General Hospital of Hebei, Shijiazhuang, Hebei 050051, P.R. China
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Zaouali MA, Boncompagni E, Reiter RJ, Bejaoui M, Freitas I, Pantazi E, Folch-Puy E, Abdennebi HB, Garcia-Gil FA, Roselló-Catafau J. AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail. J Pineal Res 2013; 55:65-78. [PMID: 23551302 DOI: 10.1111/jpi.12051] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Accepted: 02/22/2013] [Indexed: 12/11/2022]
Abstract
Ischemia/reperfusion injury (IRI) associated with liver transplantation plays an important role in the induction of graft injury. Prolonged cold storage remains a risk factor for liver graft outcome, especially when steatosis is present. Steatotic livers exhibit exacerbated endoplasmic reticulum (ER) stress that occurs in response to cold IRI. In addition, a defective liver autophagy correlates well with liver damage. Here, we evaluated the combined effect of melatonin and trimetazidine as additives to IGL-1 solution in the modulation of ER stress and autophagy in steatotic liver grafts through activation of AMPK. Steatotic livers were preserved for 24 hr (4°C) in UW or IGL-1 solutions with or without MEL + TMZ and subjected to 2-hr reperfusion (37°C). We assessed hepatic injury (ALT and AST) and function (bile production). We evaluated ER stress (GRP78, PERK, and CHOP) and autophagy (beclin-1, ATG7, LC3B, and P62). Steatotic livers preserved in IGL-1 + MEL + TMZ showed lower injury and better function as compared to those preserved in IGL-1 alone. IGL-1 + MEL + TMZ induced a significant decrease in GRP78, pPERK, and CHOP activation after reperfusion. This was consistent with a major activation of autophagic parameters (beclin-1, ATG7, and LC3B) and AMPK phosphorylation. The inhibition of AMPK induced an increase in ER stress and a significant reduction in autophagy. These data confirm the close relationship between AMPK activation and ER stress and autophagy after cold IRI. The addition of melatonin and TMZ to IGL-1 solution improved steatotic liver graft preservation through AMPK activation, which reduces ER stress and increases autophagy.
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Affiliation(s)
- Mohamed Amine Zaouali
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, IDIBAPS-Ciberehd, Barcelona, Spain
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