|
1
|
Wang M, Zhao J, Chen J, Long T, Xu M, Luo T, Che Q, He Y, Xu D. The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target. PeerJ 2024; 12:e17094. [PMID: 38563003 PMCID: PMC10984179 DOI: 10.7717/peerj.17094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Liver disease is a common and serious threat to human health. The progression of liver diseases is influenced by many physiologic processes, including oxidative stress, inflammation, bile acid metabolism, and autophagy. Various factors lead to the dysfunction of these processes and basing on the different pathogeny, pathology, clinical manifestation, and pathogenesis, liver diseases are grouped into different categories. Specifically, Sirtuin1 (SIRT1), a member of the sirtuin protein family, has been extensively studied in the context of liver injury in recent years and are confirmed the significant role in liver disease. SIRT1 has been found to play a critical role in regulating key processes in liver injury. Further, SIRT1 seems to cause divers outcomes in different types of liver diseases. Recent studies have showed some therapeutic strategies involving modulating SIRT1, which may bring a novel therapeutic target. To elucidate the mechanisms underlying the role of sirtuin1 in liver injury and its potentiality as a therapeutic target, this review outlines the key signaling pathways associated with sirtuin1 and liver injury, and discusses recent advances in therapeutic strategies targeting sirtuin1 in liver diseases.
Collapse
Affiliation(s)
- Mufei Wang
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Juanjuan Zhao
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jiuxia Chen
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
| | - Teng Long
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
| | - Mengwei Xu
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
| | - Tingting Luo
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
| | - Qingya Che
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yihuai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Delin Xu
- Department of Medical Instrumental Analysis, Zunyi Medical University, Zunyi, Guizhou, China
| |
Collapse
|
|
2
|
Patrono D, De Stefano N, Vissio E, Apostu AL, Petronio N, Vitelli G, Catalano G, Rizza G, Catalano S, Colli F, Chiusa L, Romagnoli R. How to Preserve Steatotic Liver Grafts for Transplantation. J Clin Med 2023; 12:3982. [PMID: 37373676 DOI: 10.3390/jcm12123982] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Liver allograft steatosis is a significant risk factor for postoperative graft dysfunction and has been associated with inferior patient and graft survival, particularly in the case of moderate or severe macrovesicular steatosis. In recent years, the increasing incidence of obesity and fatty liver disease in the population has led to a higher proportion of steatotic liver grafts being used for transplantation, making the optimization of their preservation an urgent necessity. This review discusses the mechanisms behind the increased susceptibility of fatty livers to ischemia-reperfusion injury and provides an overview of the available strategies to improve their utilization for transplantation, with a focus on preclinical and clinical evidence supporting donor interventions, novel preservation solutions, and machine perfusion techniques.
Collapse
Affiliation(s)
- Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Nicola De Stefano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Elena Vissio
- Department of Pathology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Ana Lavinia Apostu
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Nicoletta Petronio
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Giovanni Vitelli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Giorgia Catalano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Giorgia Rizza
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Silvia Catalano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Fabio Colli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Luigi Chiusa
- Department of Pathology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Università di Torino, Corso Bramante 88-90, 10126 Turin, Italy
| |
Collapse
|
|
3
|
Machado IF, Palmeira CM, Rolo AP. Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury. Biomedicines 2023; 11:948. [PMID: 36979927 PMCID: PMC10046671 DOI: 10.3390/biomedicines11030948] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity and mortality after surgery. Although the mechanisms leading to the injury of parenchymal and non-parenchymal liver cells are not yet fully understood, mitochondrial dysfunction is recognized as a hallmark of LIRI that exacerbates cellular injury. Mitochondria play a major role in glucose metabolism, energy production, reactive oxygen species (ROS) signaling, calcium homeostasis and cell death. The diverse roles of mitochondria make it essential to preserve mitochondrial health in order to maintain cellular activity and liver integrity during liver ischemia/reperfusion (I/R). A growing body of studies suggest that protecting mitochondria by regulating mitochondrial biogenesis, fission/fusion and mitophagy during liver I/R ameliorates LIRI. Targeting mitochondria in conditions that exacerbate mitochondrial dysfunction, such as steatosis and aging, has been successful in decreasing their susceptibility to LIRI. Studying mitochondrial dysfunction will help understand the underlying mechanisms of cellular damage during LIRI which is important for the development of new therapeutic strategies aimed at improving patient outcomes. In this review, we highlight the progress made in recent years regarding the role of mitochondria in liver I/R and discuss the impact of liver conditions on LIRI.
Collapse
Affiliation(s)
- Ivo F. Machado
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- IIIUC—Institute of Interdisciplinary Research, University of Coimbra, 3000 Coimbra, Portugal
| | - Carlos M. Palmeira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
| | - Anabela P. Rolo
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
| |
Collapse
|
|
4
|
Du G, Yang R, Qiu J, Xia J. Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma. J Clin Transl Hepatol 2023; 11:231-243. [PMID: 36406320 PMCID: PMC9647118 DOI: 10.14218/jcth.2022.00079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/09/2022] [Accepted: 07/20/2022] [Indexed: 12/04/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide, but its pathogenesis remains largely unknown. Nevertheless, genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity. Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects, which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression. Histone deacetylases (HDACs) have been shown to impair a variety of cellular processes of genome stability, including the regulation of DNA damage and repair, reactive oxygen species generation and elimination, and progression to mitosis. In this review, we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.
Collapse
Affiliation(s)
- Gan Du
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
- The First Clinical College, Chongqing Medical University, Chongqing, China
| | - Ruizhe Yang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
- The First Clinical College, Chongqing Medical University, Chongqing, China
| | - Jianguo Qiu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Correspondence to: Jie Xia, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, No. 1 Yi Xue Yuan Road, Yuzhong District, Chongqing 400016, China. ORCID: https://orcid.org/0000-0003-4574-9376. Tel/Fax: +86-23-68486780, E-mail: ; Jianguo Qiu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 You Yi Road, Yuzhong District, Chongqing 400016, China. ORCID: https://orcid.org/0000-0003-4574-9376. Tel: +86-23-68486780, Fax: +86-23-89011016, E-mail:
| | - Jie Xia
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
- Correspondence to: Jie Xia, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, No. 1 Yi Xue Yuan Road, Yuzhong District, Chongqing 400016, China. ORCID: https://orcid.org/0000-0003-4574-9376. Tel/Fax: +86-23-68486780, E-mail: ; Jianguo Qiu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 You Yi Road, Yuzhong District, Chongqing 400016, China. ORCID: https://orcid.org/0000-0003-4574-9376. Tel: +86-23-68486780, Fax: +86-23-89011016, E-mail:
| |
Collapse
|
|
5
|
Lipidomic Analysis of the Protective Effects of Shenling Baizhu San on Non-Alcoholic Fatty Liver Disease in Rats. Molecules 2019; 24:molecules24213943. [PMID: 31683679 PMCID: PMC6864612 DOI: 10.3390/molecules24213943] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
Shenling Baizhu San (SLBZS), a famous traditional Chinese medicine, has been demonstrated to exert protective effects against non-alcoholic fatty liver disease (NAFLD), but its exact mechanisms have not been well understood. The aim of this study was to investigate the mechanisms underlying the protective effects of SLBZS in a rat model of NAFLD using lipidomics and to evaluate the role of Sirtuin 1 (SIRT1) in the mechanism of SLBZS against NAFLD. The rat model of NAFLD was induced by high-fat feeding. An ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based untargeted lipidomics approach was applied to analyze hepatic lipid alterations, and the SIRT1-selective inhibitor EX 527 was used to inhibit SIRT expression in the liver. The results of body and biochemical parameters, as well as histological changes, indicated that SLBZS administration exerted protective effects against NAFLD. Lipidomic analysis showed that 30 lipid species were effectively regulated by SLBZS administration in rats fed a high-fat diet. Pathway analysis indicated that glycerophospholipid metabolism and glycerolipid metabolism were potential target pathways closely involved in the mechanism of SLBZS against NAFLD. Moreover, the beneficial effects of SLBZS on hepatic steatosis, some biochemical parameters and hepatic lipid species were partly diminished by SIRT1 inhibition. In conclusion, our results suggested that SLBZS administration could effectively alter some hepatic lipid species in rats fed a high-fat diet, which was mainly associated with the regulation of glycerophospholipid and glycerolipid metabolism. Furthermore, the beneficial effects of SLBZS on hepatic lipid metabolism may be at least partly attributed to SIRT1 activation in the liver.
Collapse
|
|
6
|
Jiménez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J, Casillas-Ramírez A, Peralta C. Mitogen Activated Protein Kinases in Steatotic and Non-Steatotic Livers Submitted to Ischemia-Reperfusion. Int J Mol Sci 2019; 20:ijms20071785. [PMID: 30974915 PMCID: PMC6479363 DOI: 10.3390/ijms20071785] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/03/2019] [Accepted: 04/09/2019] [Indexed: 12/12/2022] Open
Abstract
We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery.
Collapse
Affiliation(s)
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory IDIBAPS, 08036 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain.
| | - Araní Casillas-Ramírez
- Hospital Regional de Alta Especialidad de Ciudad Vitoria, Ciudad Victoria 87087, Mexico.
- Facultad de Medicina e ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, México.
| | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona 08036, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain.
| |
Collapse
|
|
7
|
Lin J, Huang H, Yang S, Duan J, Xu W, Zeng Z. Protective Effects of Ischemic Preconditioning Protocols on Ischemia-Reperfusion Injury in Rat Liver. J INVEST SURG 2019; 33:876-883. [PMID: 30821527 DOI: 10.1080/08941939.2018.1556753] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Jie Lin
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hanfei Huang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shikun Yang
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jian Duan
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wanggang Xu
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhong Zeng
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| |
Collapse
|
|
8
|
Tang J, Zhuang S. Histone acetylation and DNA methylation in ischemia/reperfusion injury. Clin Sci (Lond) 2019; 133:597-609. [PMID: 30804072 PMCID: PMC7470454 DOI: 10.1042/cs20180465] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 01/25/2019] [Accepted: 02/11/2019] [Indexed: 12/17/2022]
Abstract
Ischemic/reperfusion (I/R) injury causes a series of serious clinical problems associated with high morbidity and mortality in various disorders, such as acute kidney injury (AKI), myocardial infarction, ischemic stroke, circulatory arrest, and peripheral vascular disease. The pathophysiology and pathogenesis of I/R injury is complex and multifactorial. Recent studies have revealed that epigenetic regulation is critically involved in the pathogenesis of I/R-induced tissue injury. In this review, we will sum up recent advances on the modification, regulation, and implication of histone modifications and DNA methylation in I/R injury-induced organ dysfunction. Understandings of I/R-induced epigenetic alterations and regulations will aid in the development of potential therapeutics.
Collapse
Affiliation(s)
- Jinhua Tang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, U.S.A
| |
Collapse
|
|
9
|
Nikseresht S, Khodagholi F, Ahmadiani A. Protective effects of ex-527 on cerebral ischemia-reperfusion injury through necroptosis signaling pathway attenuation. J Cell Physiol 2019; 234:1816-1826. [PMID: 30067864 DOI: 10.1002/jcp.27055] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 06/25/2018] [Indexed: 12/16/2022]
Abstract
Necroptosis, a novel type of programmed cell death, is involved in ischemia-reperfusion-induced brain injury. Sirtuin 1 (Sirt1), as a well-known member of histone deacetylase class III, plays pivotal roles in inflammation, metabolism, and neuron loss in cerebral ischemia. We explored the relationship between Sirt1 and the necroptosis signaling pathway and its downstream events by administration of ex-527, as a selective and potent inhibitor of Sirt1, and necrostatin-1 (nec-1), as a necroptosis inhibitor, in an animal model of focal cerebral ischemia. Our data showed different patterns of sirt1 and necroptosis critical regulators, including receptor-interacting protein kinase 3 and mixed lineage kinase domain-like protein gene expressions in the prefrontal cortex and the hippocampus after ischemia-reperfusion. We found that ex-527 microinjection reduces the infarction volume of ischemic brains and improves the survival rate, but not stroke-associated neurological deficits. Additionally, treatment with ex-527 effectively abolished the elevation of the critical regulators of necroptosis, whereas necroptosis inhibition through nec-1 microinjection did not influence Sirt1 expression levels. Our data also demonstrated that the ex-527 relieves ischemia-induced perturbation of necroptosis-associated metabolic enzymes activity in downstream. This study provides a new approach to the possible neuroprotective potential of ex-527 orchestrated by necroptosis pathway inhibition to alleviate ischemia-reperfusion brain injury.
Collapse
Affiliation(s)
- Sara Nikseresht
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
10
|
Bejaoui M, Zaouali MA, Sakly R, Ben Abdennebi H. Olprinone protects the liver from ischemia–reperfusion injury through oxidative stress prevention and protein kinase Akt activation. Can J Physiol Pharmacol 2018; 96:227-231. [DOI: 10.1139/cjpp-2017-0153] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Liver ischemia–reperfusion (IR) injury is inevitable in surgical procedures such as hepatic resection and liver transplantation. It represents a leading cause of liver graft dysfunction and primary nonfunction after transplantation. Phosphodiesterase (PDE) inhibitors are emerging as effective drugs able to reduce IR damage. The aim of this study was to investigate the effect of selective PDE-3 inhibitor olprinone (Olp) against liver IR injury. Male Wistar rats were subjected to 1 h of partial warm ischemia (70%) followed by 6 h of reperfusion. Before ischemia, rats were treated with saline (IR group), Olp (Olp group), or Olp with Akt inhibitor LY294002 (Olp plus LY group). After reperfusion, hepatic injury (transaminase activities), mitochondrial damage (glutamate dehydrogenase activity), oxidative stress (malondialdehyde and glutathione concentrations and catalase and superoxide dismutase activities), and protein kinase Akt activation were evaluated. Rat treatment with Olp reduced liver injury, prevented mitochondrial damage, decreased lipid peroxidation, and enhanced antioxidant enzymes. Also, Olp induced a significant activation in protein kinase Akt. Inhibition of Akt with LY294002 abolished all of the protective effects of Olp. In conclusion, Olp treatment may be an effective strategy in reducing liver IR injury through oxidative stress prevention and Akt activation.
Collapse
Affiliation(s)
- Mohamed Bejaoui
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| | - Mohamed Amine Zaouali
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| | - Rim Sakly
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| | - Hassen Ben Abdennebi
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
- Research Unit (UR12ES11) “Molecular Biology and Anthropology Applied to Development and Health”, Department of Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| |
Collapse
|
|
11
|
Zeng C, Hu X, He W, Wang Y, Li L, Xiong Y, Ye Q. Hypothermic machine perfusion ameliorates inflammation during ischemia‑reperfusion injury via sirtuin‑1‑mediated deacetylation of nuclear factor‑κB p65 in rat livers donated after circulatory death. Mol Med Rep 2017; 16:8649-8656. [PMID: 29039506 PMCID: PMC5779933 DOI: 10.3892/mmr.2017.7738] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 07/13/2017] [Indexed: 12/11/2022] Open
Abstract
Hypothermic machine perfusion (HMP) effectively reduces ischemia-reperfusion injury (IRI) in livers donated after circulatory death (DCD) when compared with cold storage (CS). However, the underlying mechanisms remain unclear. The current study aimed to investigate the cellular mechanisms by which HMP ameliorates the inflammatory response during IRI. Adult male Sprague-Dawley rat livers were exposed to 30 min of warm ischemia following cardiac arrest and preserved by CS or HMP for 3 h (n=3 per group). The severity of IRI was assessed in vitro on normothermic reperfusion for 2 h, and intrahepatic resistance (IHR) and bile production were subsequently recorded. The perfusate was analyzed for transaminase leakage and oxygen consumption. Livers were subsequently subjected to histological examination, and measurement of adenosine triphosphate (ATP) levels, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide (NAD)+ levels and the ratio of NAD+/NADH. In addition, the protein expression of sirtuin-1 (SIRT-1), acetylated-nuclear factor-κB (NF-κB) p65 and NF-κB p65 was detected by western blotting, and the mRNA expression of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α was determined by reverse transcription-quantitative polymerase chain reaction. Compared with CS, HMP resulted in significantly lower IHR, transaminase leakage and MDA levels, and higher oxygen consumption, ATP levels and SOD activity. In addition, improved preservation of hepatic histology was observed in HMP compared with CS. The mRNA expression of NF-κB p65, IL-6 and TNF-α was significantly decreased in the HMP group compared with CS samples. Under HMP preservation, SIRT-1 activity and protein expression were increased, while the protein expression of acetylated-NF-κB p65 was decreased, compared with CS. These results indicate that HMP may reduce the inflammatory response during IRI via SIRT-1-mediated deacetylation of NF-κB p65. These findings may provide a theoretical basis for the clinical application of HMP as an effective strategy to preserve DCD livers.
Collapse
Affiliation(s)
- Cheng Zeng
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xiaoyan Hu
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Weiyang He
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Ling Li
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yan Xiong
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|
|
12
|
2-Methoxyestradiol protects against ischemia/reperfusion injury in alcoholic fatty liver by enhancing sirtuin 1-mediated autophagy. Biochem Pharmacol 2017; 131:40-51. [DOI: 10.1016/j.bcp.2017.02.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 02/07/2017] [Indexed: 12/31/2022]
|
|
13
|
Wang J, Koh H, Zhou L, Bae U, Lee H, Bang IH, Ka S, Oh S, Bae EJ, Park B. Sirtuin 2 aggravates postischemic liver injury by deacetylating mitogen-activated protein kinase phosphatase-1. Hepatology 2017; 65:225-236. [PMID: 27532371 PMCID: PMC5215544 DOI: 10.1002/hep.28777] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 07/27/2016] [Indexed: 12/20/2022]
Abstract
UNLABELLED Sirtuin 2 (Sirt2) is known to negatively regulate anoxia-reoxygenation injury in myoblasts. Because protein levels of Sirt2 are increased in ischemia-reperfusion (I/R)-injured liver tissues, we examined whether Sirt2 is protective or detrimental against hepatic I/R injury. We overexpressed Sirt2 in the liver of C57BL/6 mice using a Sirt2 adenovirus. Wild-type and Sirt2 knockout mice were subjected to a partial (70%) hepatic ischemia for 45 minutes, followed by various periods of reperfusion. In another set of experiments, wild-type mice were pretreated intraperitoneally with AGK2, a Sirt2 inhibitor. Isolated hepatocytes and Kupffer cells from wild-type and Sirt2 knockout mice were subjected to hypoxia-reoxygenation injury to determine the in vitro effects of Sirt2. Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Prior injection with Sirt2 adenovirus aggravated liver injury, as demonstrated by increases in serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration relative to control virus-injected mice. Pretreatment with AGK2 resulted in significant improvements in serum aminotransferase levels and histopathologic findings. Similarly, experiments with Sirt2 knockout mice also revealed reduced hepatocellular injury. The molecular mechanism of Sirt2's involvement in this aggravation of hepatic I/R injury includes the deacetylation and inhibition of mitogen-activated protein kinase phosphatase-1 and consequent activation of mitogen-activated protein kinases. CONCLUSION Sirt2 is an aggravating factor during hepatic I/R injury. (Hepatology 2017;65:225-236).
Collapse
Affiliation(s)
- Jie Wang
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Hyoung‐Won Koh
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Lu Zhou
- Department of Sports MedicineTaishan Medical UniversityTaianShandongChina
| | - Ui‐Jin Bae
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Hwa‐Suk Lee
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - In Hyuk Bang
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Sun‐O Ka
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| | - Seon‐Hee Oh
- Department of Premedics, School of MedicineChosun UniversityGwangjuRepublic of Korea
| | - Eun Ju Bae
- College of PharmacyWoosuk UniversityWanjuJeonbukRepublic of Korea
| | - Byung‐Hyun Park
- Department of BiochemistryChonbuk National University Medical SchoolJeonjuJeonbukRepublic of Korea
| |
Collapse
|
|
14
|
Meng X, Tan J, Li M, Song S, Miao Y, Zhang Q. Sirt1: Role Under the Condition of Ischemia/Hypoxia. Cell Mol Neurobiol 2017; 37:17-28. [PMID: 26971525 PMCID: PMC11482061 DOI: 10.1007/s10571-016-0355-2] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/24/2016] [Indexed: 12/13/2022]
Abstract
Silent information regulator factor 2-related enzyme 1 (sirtuin 1, Sirt1) is a nicotinamide adenine dinucleotide-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, and is involved in the regulation of many physiological functions, including cell senescence, gene transcription, energy balance, and oxidative stress. Ischemia/hypoxia injury remains an unresolved and complicated situation in the diseases of ischemia stroke, heart failure, and coronary heart disease, especially among the old folks. Studies have demonstrated that aging could enhance the vulnerability of brain, heart, lung, liver, and kidney to ischemia/hypoxia injury and the susceptibility in old folks to ischemia/hypoxia injury might be associated with Sirt1. In this review, we mainly summarize the role of Sirt1 in modulating pathways against energy depletion and its involvement in oxidative stress, apoptosis, and inflammation under the condition of ischemia/hypoxia.
Collapse
Affiliation(s)
- Xiaofei Meng
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | - Jin Tan
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | - Mengmeng Li
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | - Shuling Song
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | | | - Qiang Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China.
| |
Collapse
|
|
15
|
Activation of sirtuin 1/3 improves vascular hyporeactivity in severe hemorrhagic shock by alleviation of mitochondrial damage. Oncotarget 2016; 6:36998-7011. [PMID: 26473372 PMCID: PMC4741911 DOI: 10.18632/oncotarget.6076] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 09/24/2015] [Indexed: 12/11/2022] Open
Abstract
Vascular hyporeactivity is one of the major causes responsible for refractory hypotension and associated mortality in severe hemorrhagic shock. Mitochondrial permeability transition (mPT) pore opening in arteriolar smooth muscle cells (ASMCs) is involved in the pathogenesis of vascular hyporeactivity. However, the molecular mechanism underlying mitochondrial injury in ASMCs during hemorrhagic shock is not well understood. Here we produced an in vivo model of severe hemorrhagic shock in adult Wistar rats. We found that sirtuin (SIRT)1/3 protein levels and deacetylase activities were decreased in ASMCs following severe shock. Immunofluorescence staining confirmed reduced levels of SIRT1 in the nucleus and SIRT3 in the mitochondria, respectively. Acetylation of cyclophilin D (CyPD), a component of mPT pore, was increased. SIRT1 activators suppressed mPT pore opening and ameliorated mitochondrial injury in ASMCs after severe shock. Furthermore, administration of SIRT1 activators improved vasoreactivity in rats under severe shock. Our data suggest that epigenetic mechanisms, namely histone post-translational modifications, are involved in regulation of mPT by SIRT1/SIRT3- mediated deacetylation of CyPD. SIRT1/3 is a promising therapeutic target for the treatment of severe hemorrhagic shock.
Collapse
|
|
16
|
Bejaoui M, Pantazi E, De Luca V, Panisello A, Folch-Puy E, Serafin A, Capasso C, C T S, Rosselló-Catafau J. Acetazolamide protects steatotic liver grafts against cold ischemia reperfusion injury. J Pharmacol Exp Ther 2015; 355:191-198. [PMID: 26330538 DOI: 10.1124/jpet.115.225177] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 08/26/2015] [Indexed: 08/29/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.
Collapse
Affiliation(s)
- Mohamed Bejaoui
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Eirini Pantazi
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Viviana De Luca
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Arnau Panisello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Emma Folch-Puy
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Anna Serafin
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Clemente Capasso
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Supuran C T
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| | - Joan Rosselló-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
| |
Collapse
|
|
17
|
Pantazi E, Folch-Puy E, Bejaoui M, Panisello A, Varela AT, Rolo AP, Palmeira CM, Roselló-Catafau J. PPARα Agonist WY-14643 Induces SIRT1 Activity in Rat Fatty Liver Ischemia-Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2015; 2015:894679. [PMID: 26539534 PMCID: PMC4619850 DOI: 10.1155/2015/894679] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 08/11/2015] [Indexed: 01/16/2023]
Abstract
Ischemia-reperfusion injury (IRI) remains a frequent complication in surgery, especially in case of steatotic livers that present decreased tolerance towards IRI. Apart from its major role in metabolism, activation of peroxisome proliferator-activated receptor α (PPARα) has been related with positive effects on IRI. In addition, the deacetylase enzyme sirtuin 1 (SIRT1) has recently emerged as a promising target for preventing IRI, through its interaction with stress-related mechanisms, such as endoplasmic reticulum stress (ERS). Taking this into account, this study aims to explore whether PPARα agonist WY-14643 could protect steatotic livers against IRI through sirtuins and ERS signaling pathway. Obese Zucker rats were pretreated or not pretreated with WY-14643 (10 mg/kg intravenously) and then submitted to partial (70%) hepatic ischemia (1 hour) followed by 24 hours of reperfusion. Liver injury (ALT levels), lipid peroxidation (MDA), SIRT1 activity, and the protein expression of SIRT1 and SIRT3 and ERS parameters (IRE1α, peIF2, caspase 12, and CHOP) were evaluated. Treatment with WY-14643 reduced liver injury in fatty livers, enhanced SIRT1 activity, and prevented ERS. Together, our results indicated that PPARα agonist WY-14643 may exert its protective effect in fatty livers, at least in part, via SIRT1 induction and ERS prevention.
Collapse
Affiliation(s)
- Eirini Pantazi
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Emma Folch-Puy
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Mohamed Bejaoui
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Arnau Panisello
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Ana Teresa Varela
- Department of Life Sciences and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
| | | | - Carlos Marques Palmeira
- Department of Life Sciences and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
| | - Joan Roselló-Catafau
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, 08036 Catalonia, Spain
| |
Collapse
|
|
18
|
Molecular pathways in protecting the liver from ischaemia/reperfusion injury: a 2015 update. Clin Sci (Lond) 2015; 129:345-62. [PMID: 26014222 DOI: 10.1042/cs20150223] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Ischaemia/reperfusion injury is an important cause of liver damage during surgical procedures such as hepatic resection and liver transplantation, and represents the main cause of graft dysfunction post-transplantation. Molecular processes occurring during hepatic ischaemia/reperfusion are diverse, and continuously include new and complex mechanisms. The present review aims to summarize the newest concepts and hypotheses regarding the pathophysiology of liver ischaemia/reperfusion, making clear distinction between situations of cold and warm ischaemia. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field are described.
Collapse
|
|
19
|
Pantazi E, Bejaoui M, Zaouali MA, Folch-Puy E, Pinto Rolo A, Panisello A, Palmeira CM, Roselló-Catafau J. Losartan activates sirtuin 1 in rat reduced-size orthotopic liver transplantation. World J Gastroenterol 2015; 21:8021-8031. [PMID: 26185373 PMCID: PMC4499344 DOI: 10.3748/wjg.v21.i26.8021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 02/25/2015] [Accepted: 04/03/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate a possible association between losartan and sirtuin 1 (SIRT1) in reduced-size orthotopic liver transplantation (ROLT) in rats. METHODS Livers of male Sprague-Dawley rats (200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 °C prior to ROLT. In an additional group, an antagonist of angiotensin II type 1 receptor (AT1R), losartan, was orally administered (5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the recipients. Transaminase (as an indicator of liver injury), SIRT1 activity, and nicotinamide adenine dinucleotide (NAD(+), a co-factor necessary for SIRT1 activity) levels were determined by biochemical methods. Protein expression of SIRT1, acetylated FoxO1 (ac-FoxO1), NAMPT (the precursor of NAD+), heat shock proteins (HSP70, HO-1) expression, endoplasmic reticulum stress (GRP78, IRE1α, p-eIF2) and apoptosis (caspase 12 and caspase 3) parameters were determined by Western blot. Possible alterations in protein expression of mitogen activated protein kinases (MAPK), such as p-p38 and p-ERK, were also evaluated. Furthermore, the SIRT3 protein expression and mRNA levels were examined. RESULTS The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group, as evidenced by the significant decreases in alanine aminotransferase (358.3 ± 133.44 vs 206 ± 33.61, P < 0.05) and aspartate aminotransferase levels (893.57 ± 397.69 vs 500.85 ± 118.07, P < 0.05). The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity (5.27 ± 0.32 vs 6.08 ± 0.30, P < 0.05). This was concomitant with increased levels of NAD(+) (0.87 ± 0.22 vs 1.195 ± 0.144, P < 0.05) the co-factor necessary for SIRT1 activity, as well as with decreases in ac-FoxO1 expression. Losartan treatment also provoked significant attenuation of endoplasmic reticulum stress parameters (GRP78, IRE1α, p-eIF2) which was consistent with reduced levels of both caspase 12 and caspase 3. Furthermore, losartan administration stimulated HSP70 protein expression and attenuated HO-1 expression. However, no changes were observed in protein or mRNA expression of SIRT3. Finally, the protein expression pattern of p-ERK and p-p38 were not altered upon losartan administration. CONCLUSION The present study reports that losartan induces SIRT1 expression and activity, and that it reduces hepatic injury in a ROLT model.
Collapse
|
|
20
|
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.
Collapse
|
|
21
|
Castillo RL, Zepeda AB, Short SE, Figueroa E, Bustos-Obregon E, Farías JG. Protective effects of polyunsatutared fatty acids supplementation against testicular damage induced by intermittent hypobaric hypoxia in rats. J Biomed Sci 2015; 22:8. [PMID: 25613908 PMCID: PMC4307138 DOI: 10.1186/s12929-015-0112-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 01/07/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Intermittent hypobaric hypoxia (IHH) induces changes in the redox status and structure in rat testis. These effects may be present in people at high altitudes, such as athletes and miners. Polyunsaturated fatty acids (PUFA) can be effective in counteracting these oxidative modifications due to their antioxidants properties. The aim of the work was to test whether PUFA supplementation attenuates oxidative damage in testis by reinforcing the antioxidant defense system. The animals were divided into four groups (7 rats per group): normobaric normoxia (~750 tor; pO2 156 mmHg; Nx); Nx + PUFA, supplemented with PUFA (DHA: EPA = 3:1; 0.3 g kg(-1) of body weight per day); hypoxic hypoxia (~428 tor; pO2 90 mmHg; Hx) and, Hx + PUFA. The hypoxic groups were exposed in 4 cycles to 96 h of HH followed by 96 h of normobaric normoxia for 32 days. Total antioxidant capacity (FRAP) and lipid peroxidation (malondialdehyde, MDA) in plasma and reduced (GSH)/oxidized glutathione (GSSG) ratio, tissue lipid peroxidation (TBARS) and antioxidant enzymes activity were assessed at the end of the study in testis. Also, SIRTUIN 1 and HIF-1 protein expression in testis were determined. RESULTS IHH increased lipid peroxidation in plasma and HIF-1 protein levels in testis. In addition, IHH reduced FRAP levels in plasma, antioxidant enzymes activities and SIRTUIN 1 protein levels in testis. PUFA supplementation attenuated these effects, inducing the increases in FRAP, in the antioxidant enzymes activity and HIF-1 levels. CONCLUSIONS These results suggest that the IHH model induces a prooxidant status in plasma and testis. The molecular protective effect of PUFA may involve the induction of an antioxidant mechanism.
Collapse
Affiliation(s)
- Rodrigo L Castillo
- Pathophysiology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
| | - Andrea B Zepeda
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Casilla 54-D, Temuco, Chile. .,Department of Biochemical and Pharmaceutical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580 - Bloco 16, São Paulo, SP, 05508-900, Brazil.
| | - Stefania E Short
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Casilla 54-D, Temuco, Chile.
| | - Elías Figueroa
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Casilla 54-D, Temuco, Chile. .,School of Aquaculture, Catholic University of Temuco, Faculty of Natural Resources, Temuco, Chile.
| | - Eduardo Bustos-Obregon
- Anatomy and Developmental Biology Program, Faculty of Medicine, University of Chile, Santiago, Chile.
| | - Jorge G Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Casilla 54-D, Temuco, Chile.
| |
Collapse
|
|
22
|
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.
Collapse
|