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Mouratidou C, Pavlidis ET, Katsanos G, Kotoulas SC, Tsoulfas G, Mouloudi E, Taitzoglou IA, Galanis IN, Pavlidis TE. Off-label use of treprostinil in adult patients in clinical cases. World J Clin Cases 2025; 13:107279. [DOI: 10.12998/wjcc.v13.i23.107279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/03/2025] [Accepted: 05/07/2025] [Indexed: 06/04/2025] Open
Abstract
Treprostinil is a relatively new tricyclic prostacyclin analog with a stable structure, extended half-life and improved potency. Currently, treprostinil is indicated by the Food and Drug Administration in the United States for the treatment of pulmonary arterial hypertension (group 1 in the pulmonary hypertension classification of the World Health Organization). It has a potent vasodilating effect along with the inhibition of platelet aggregation and the attenuation of the inflammatory response in pulmonary and systemic circulation. It is available in the following formulations: Subcutaneous, intravenous, inhaled and oral. Although unknown to many clinicians, several encouraging reports of off-label treprostinil use in the adult population suggest its potential effectiveness in other clinical conditions. Currently under investigation are digital ischemia secondary to systemic sclerosis, chronic limb ischemia, hepatic ischemia-reperfusion injury and group 3 and 4 pulmonary hypertension. Based on review and analysis of the available literature, this article provides a thorough update on the off-label use of treprostinil in adult patients.
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Affiliation(s)
| | - Efstathios T Pavlidis
- The 2nd Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | | | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Eleni Mouloudi
- Intensive Care Unit, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Ioannis A Taitzoglou
- Laboratory of Physiology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Ioannis N Galanis
- The 2nd Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Theodoros E Pavlidis
- The 2nd Department of Propaedeutic Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Archie WH, Baimas-George M, Haynes N, Kundu S, Peterson K, Wehrle CJ, Huckleberry D, Eskind L, Levi D, Soto JR, Denny R, Casingal V, Cochran A, Rein EH, Vrochides D. Upper limit of normothermic machine preservation of liver grafts from donation after circulatory death yet to be defined. World J Transplant 2025; 15:99170. [DOI: 10.5500/wjt.v15.i2.99170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/07/2024] [Accepted: 12/11/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The normothermic machine perfusion pump (NMPP) could shape the future of transplantation. Providing ex-vivo optimization, NMPP attenuates ischemic insult while replenishing energy. An understanding of machine perfusion time (MPT) impact and potential clinical benefits is paramount and necessitates exploration.
AIM To investigate the relationship between MPT and post-transplant graft function.
METHODS Retrospective review of the first 50 donation after circulatory death (DCD) grafts preserved using NMPP in a tertiary institution was performed. Essential preservation time points, graft parameters, recipient information, and postoperative outcomes were prospectively recorded. Early allograft dysfunction (EAD), L-Graft7 score and 90-day outcomes were collected for all grafts. The first 20 recipients were allocated into the early group, considered the learning curve population for the center. The subsequent 30 were allocated into the late group. Recipients were also stratified into cohorts depending on MPT, i.e., short (< 8 hours), medium (8-16 hours) and long (> 16 hours).
RESULTS NMPP operational parameters were not predictive of EAD, L-GrAFT7 or 90-day outcomes. The early group had significantly less MPT and cold ischemia time than the late group (553 minutes vs 850 minutes, P < 0.001) and (127.5 minutes vs 154 minutes, P = 0.025), respectively. MPT had no impact in either group.
CONCLUSION Increased MPT of DCD liver grafts had no adverse recipient results for the times utilized in this population, indicating its upper limits, likely beyond 24 hours, are not demonstrated within this study. Future studies are necessary to determine whether longer MPT is beneficial or detrimental to graft function and, if the latter, what is the maximum safe duration. Further studies of the effect of normothermic machine perfusion pump duration on long-term outcomes are also needed.
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Affiliation(s)
- William H Archie
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Maria Baimas-George
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Nathanael Haynes
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Souma Kundu
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Katheryn Peterson
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Chase J Wehrle
- Department of Hepato-Pancreato-Biliary/Liver Transplant Surgery, Cleveland Clinic Transplant Research Center, Cleveland, OH 44195, United States
| | - Damien Huckleberry
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Lon Eskind
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - David Levi
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Jose R Soto
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Roger Denny
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Vincent Casingal
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Allyson Cochran
- Department of Surgery, Carolinas Center for Surgical Outcomes Science, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Erin H Rein
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Dionisios Vrochides
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
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Puchany AJ, Hilmi I. Post-reperfusion syndrome in liver transplant recipients: What is new in prevention and management? World J Crit Care Med 2025; 14:101777. [PMID: 40491878 PMCID: PMC11891853 DOI: 10.5492/wjccm.v14.i2.101777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/22/2024] [Accepted: 12/19/2024] [Indexed: 02/27/2025] Open
Abstract
Post-reperfusion syndrome (PRS) in liver transplant recipients remains one of the most dreaded complications in liver transplant surgery. PRS can impact the short-term and long-term patient and graft outcomes. The definition of PRS has evolved over the years, from changes in arterial blood pressures and heart and/or decreases in the systemic vascular resistance and cardiac output to including the fibrinolysis and grading the severity of PRS. However, all that did not reflect on the management of PRS or its impact on the outcomes. In recent years, new scientific techniques and new technology have been in the pipeline to better understand, manage and maybe prevent PRS. These new methods and techniques are still in the infancy, and they have to be proven not in prevention and management of PRS but their effects in the patient and graft outcomes. In this article, we will review the long history of PRS, its definition, etiology, management and most importantly the new advances in science and technology to prevent and properly manage PRS.
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Affiliation(s)
- Austin James Puchany
- Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Ibtesam Hilmi
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Department of Anesthesiology and Perioperative Medicine, Clinical and Translational Science Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, United States
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Mariorakis C, Lambropoulou M, Oikonomou P, Tsalikidis C, Pitiakoudis M, Anestiadou E, Ioannidis O, Tsaroucha AK. Apigenin Attenuates Hepatic Ischemia-Reperfusion-Induced Lung Injury via Downregulation of MMP-3 and MCP-1: An Experimental Study in Rats. J Clin Med 2025; 14:3530. [PMID: 40429525 PMCID: PMC12112546 DOI: 10.3390/jcm14103530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Revised: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: In liver transplant surgery, ischemia-reperfusion (I-R) maneuvers are frequently employed to control bleeding; however, such interventions can result in injury not only to the liver but also to remote organs. The lungs, in particular, are highly susceptible due to their extensive vascularization and inflammatory response. While pulmonary injury secondary to hepatic I-R is recognized, and despite the fact that various antioxidant compounds have been investigated for their potential to mitigate I-R-induced damage to hepatic tissue, few studies have focused on evaluating therapeutic agents aimed at mitigating lung damage in this setting. This study aimed to evaluate the protective effect of apigenin on pulmonary tissue following liver I-R injury using an experimental rat model. Methods: Sixty-three male albino Wistar rats (approximately 15 weeks old, weighing 220-350 g) were randomly allocated into three groups: a sham group (open-close surgery; n = 7), a control (C) group subjected to liver I-R injury only (n = 28), and an apigenin (Ap) group receiving intraperitoneal apigenin administration immediately after liver ischemia and prior to reperfusion (n = 28). Both the C and Ap groups were subdivided into four equal subgroups corresponding to euthanasia at 60-, 120-, 180-, and 240 min post-reperfusion. Lung tissues were harvested for immunohistochemical analysis targeting the expression of matrix metalloproteinase-3 (MMP-3) and monocyte chemoattractant protein-1 (MCP-1). Results: The apigenin-treated groups exhibited significantly reduced expression levels of MMP-3 and MCP-1 across all time points when compared to the control groups. In contrast, no expression of MMP-3 or MCP-1 was observed in the sham group. Conclusions: The findings support the protective role of the antioxidant apigenin in reducing pulmonary injury following liver I-R. The diminished expression of MMP-3 and MCP-1 in the apigenin-treated rats provides compelling evidence for its protective effects on remote organs.
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Affiliation(s)
- Chrysovalantis Mariorakis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.M.); (M.L.); (P.O.); (M.P.); (A.K.T.)
| | - Maria Lambropoulou
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.M.); (M.L.); (P.O.); (M.P.); (A.K.T.)
- Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Panagoula Oikonomou
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.M.); (M.L.); (P.O.); (M.P.); (A.K.T.)
- Laboratory of Experimental Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Christos Tsalikidis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.M.); (M.L.); (P.O.); (M.P.); (A.K.T.)
- Second Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Michail Pitiakoudis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.M.); (M.L.); (P.O.); (M.P.); (A.K.T.)
- Second Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Elissavet Anestiadou
- Fourth Department of Surgery, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, General Hospital “George Papanikolaou”, 57010 Thessaloniki, Greece;
| | - Orestis Ioannidis
- Fourth Department of Surgery, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, General Hospital “George Papanikolaou”, 57010 Thessaloniki, Greece;
| | - Alexandra K. Tsaroucha
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.M.); (M.L.); (P.O.); (M.P.); (A.K.T.)
- Laboratory of Bioethics, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
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Jaber F, Abuelazm M, Soliman Y, Madi M, Abusuilik H, Mazen Amin A, Saeed A, Gowaily I, Abdelazeem B, Rana A, Qureshi K, Lee TH, Cholankeril G. Machine perfusion strategies in liver transplantation: A systematic review, pairwise, and network meta-analysis of randomized controlled trials. Liver Transpl 2025; 31:596-615. [PMID: 39868927 DOI: 10.1097/lvt.0000000000000567] [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: 01/26/2024] [Accepted: 12/04/2024] [Indexed: 01/28/2025]
Abstract
Machine perfusion (MP), including hypothermic oxygenated machine perfusion (HOPE), dual HOPE, normothermic machine perfusion (NMP), NMP ischemia-free liver transplantation (NMP-ILT), and controlled oxygenated rewarming (COR), is increasingly being investigated to improve liver graft quality from extended criteria donors and donors after circulatory death and expand the donor pool. This network meta-analysis investigates the comparative efficacy and safety of various liver MP strategies versus traditional static cold storage (SCS). We searched PubMed, Scopus, Web of Science, and Cochrane Controlled Register of Trials for randomized controlled trials comparing liver transplantation outcomes between SCS and MP techniques. The primary outcome was the incidence of early allograft dysfunction. Secondary endpoints included 1-year graft survival, the incidence of graft failure/loss, post-reperfusion syndrome, biliary complications, the need for renal replacement therapy, graft-related patient mortality, and the length of intensive care unit and hospital stay. R-software was used to conduct a network meta-analysis using a frequentist framework (PROSPERO ID: CRD42024549254). We included 12 randomized controlled trials involving 1628 patients undergoing liver transplantation (801 in the liver MP groups and 832 in the SCS group). Compared to SCS, HOPE/dHOPE, but not other MP strategies, was associated with a significantly lower risk of early allograft dysfunction (RR: 0.53, 95% CI [0.37, 0.74], p =0.0002), improved 1-year graft survival rate (RR: 1.07, 95% CI [1.01, 1.14], p =0.02), decreased graft failure/loss (RR: 0.38, 95% CI [0.16, 0.90], p =0.03), and reduced the risk of biliary complications (RR: 0.52, 95% CI [0.43, 0.75], p < 0.0001). Compared to SCS, NMP (RR: 0.49, 95% CI [0.24, 0.96]) and NMP-ILT (RR: 0.15, 95% CI [0.04, 0.57]), both significantly reduced the risk of postperfusion syndrome. There is no difference between SCS and MP groups in the risk of renal replacement therapy, graft-related patient mortality, and intensive care unit and hospital stay length. Our meta-analysis showed that HOPE/dual-HOPE is a promising alternative to SCS for donor liver preservation. These new techniques can help expand the donor pool with similar or even better post-liver transplantation outcomes.
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Affiliation(s)
- Fouad Jaber
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Mohamed Abuelazm
- Department of Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Youssef Soliman
- Department of Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud Madi
- Division of Gastroenterology and Hepatology, Department of Medicine, University School of Medicine, Saint Louis, Missouri, USA
| | - Husam Abusuilik
- Department of Medicine, The Hashemite University, Zarqa, Jordan
| | | | - Abdallah Saeed
- Department of Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ibrahim Gowaily
- Department of Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Basel Abdelazeem
- Department of Cardiology, West Virginia University, Morgantown, West Virginia, USA
| | - Abbas Rana
- Hepatology Program, Department of General Surgery, Division of Abdominal Transplantation, Michael E DeBakey Baylor College of Medicine, Houston, Texas, USA
| | - Kamran Qureshi
- Division of Gastroenterology and Hepatology, Department of Medicine, University School of Medicine, Saint Louis, Missouri, USA
| | - Tzu-Hao Lee
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Hepatology Program, Department of General Surgery, Division of Abdominal Transplantation, Michael E DeBakey Baylor College of Medicine, Houston, Texas, USA
| | - George Cholankeril
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Hepatology Program, Department of General Surgery, Division of Abdominal Transplantation, Michael E DeBakey Baylor College of Medicine, Houston, Texas, USA
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6
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Wang D, Zhai Y, Wang Y, Fu X, Ji Y, Li R. Dual-color reversible fluorescent carbon dots designed for dynamic monitoring of cellular superoxide anion radicals. J Mater Chem B 2025; 13:5163-5170. [PMID: 40205991 DOI: 10.1039/d5tb00099h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
The superoxide anion radical (O2˙-) represents the primary reactive oxygen species generated in biological systems. Real-time monitoring of its dynamic fluctuations provides valuable insights into disease progression and enables early diagnosis of hepatic ischemia-reperfusion injury (HIRI). In this work, we developed a novel dual-color fluorescent carbon dot (CD) probe through a one-step hydrothermal synthesis for reversible O2˙- detection. The CDs demonstrated excellent sensitivity, dynamically detecting O2˙- concentrations ranging from 0 to 60 μM with a detection limit of 0.56 μM. The probe exhibited remarkable reversibility, maintaining stable performance through at least three complete oxidation-reduction cycles following glutathione (GSH) treatment. In practical applications, the CDs achieved 95.2-104% recovery rates when detecting O2˙- in serum samples. Cellular imaging experiments confirmed the probe's effectiveness in normal hepatocytes (LO2), showing clear reversible responses to O2˙- fluctuations. Application in a HIRI cell model revealed significant elevation of O2˙- levels and provided new evidence for its role in HIRI-related signaling pathways. This study not only presents an effective dual-color fluorescent probe for dynamic O2˙- monitoring but also establishes a versatile synthetic strategy that could be adapted for imaging other biologically relevant molecules in living cells.
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Affiliation(s)
- Dan Wang
- Department of Analytical Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Yanke Zhai
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Nanjing 210009, China.
| | - Yun Wang
- Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Gansu, Lanzhou, 730000, China.
| | - Xu Fu
- Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Gansu, Lanzhou, 730000, China.
| | - Yibing Ji
- Department of Analytical Chemistry, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Nanjing 210009, China.
| | - Ruijun Li
- Department of Analytical Chemistry, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Nanjing 210009, China.
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Abolfazli S, Karav S, Johnston TP, Sahebkar A. Regulatory effects of resveratrol on nitric oxide signaling in cardiovascular diseases. Pharmacol Rep 2025; 77:355-374. [PMID: 39832074 DOI: 10.1007/s43440-025-00694-w] [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: 10/22/2024] [Revised: 01/04/2025] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
Cardiovascular illnesses are multifactorial disorders and represent the primary reasons for death worldwide, according to the World Health Organization. As a signaling molecule, nitric oxide (NO) is extremely permeable across cellular membranes owing to its unique molecular features, like its small molecular size, lipophilicity, and free radical properties. Some of the biological effects of NO are vasodilation, inhibition in the growth of vascular smooth muscle cells, and functional regulation of cardiac cells. Several therapeutic approaches have been tested to increase the production of NO or some downstream NO signaling pathways. The health benefits of red wine are typically attributed to the polyphenolic phytoalexin, resveratrol (3,5,4'-trihydroxy-trans-stilbene), which is found in several plant species. Resveratrol has beneficial cardiovascular properties, some of which are mediated through endothelial nitric oxide synthase production (eNOS). Resveratrol promotes NO generation from eNOS through various methods, including upregulation of eNOS expression, activation in the enzymatic activity of eNOS, and reversal of eNOS uncoupling. Additionally, by reducing of oxidative stress, resveratrol inhibits the formation of superoxide and inactivation NO, increasing NO bioavailability. This review discusses the scientific literature on resveratrol's beneficial impact on NO signaling and how this effect improves the function of vascular endothelium.
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Affiliation(s)
- Sajad Abolfazli
- Student Research Committee, School of Pharmacy, Mazandaran University of Medical Science, Sari, Iran
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, 17100, Turkey
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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8
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Wang F, Lu J, Yang T, Ren Y, Ratti F, Marques HP, Silva S, Soubrane O, Lam V, Poultsides GA, Popescu I, Grigorie R, Alexandrescu S, Martel G, Workneh A, Guglielmi A, Hugh T, Aldrighetti L, Endo I, Lv Y, Zhang XF, Pawlik TM. Perioperative Changes in Serum Transaminase Levels: Impact on Postoperative Morbidity After Liver Resection of Hepatocellular Carcinoma. Ann Surg 2025; 281:624-631. [PMID: 38348655 DOI: 10.1097/sla.0000000000006235] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
OBJECTIVES To define how dynamic changes in pre versus postoperative serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels may impact postoperative morbidity after curative-intent resection of hepatocellular carcinoma (HCC). BACKGROUND Hepatic ischemia/reperfusion can occur at the time of liver resection and may be associated with adverse outcomes after liver resection. METHODS Patients who underwent curative resection for HCC between 2010 and 2020 were identified from an international multi-institutional database. Changes in AST and ALT (CAA) on postoperative day 3 versus preoperative values ( ) were calculated using the formula: based on a fusion index through the Euclidean norm, which was examined relative to the Comprehensive Complication Index (CCI). The impact of CAA on CCI was assessed by the restricted cubic spline regression and Random Forest analyses. RESULTS A total of 759 patients were included in the analytic cohort. Median CAA was 1.7 (range: 0.9-3.25); 431 (56.8%) patients had a CAA <2 215 (28.3%) patients with CAA 2 to 5, and 113 (14.9%) patients had CAA ≥5. The incidence of postoperative complications was 65.0% (n = 493) with a median CCI of 20.9 (interquartile range: 20.9-33.5). Spline regression analysis demonstrated a nonlinear incremental association between CAA and CCI. The optimal cutoff value of CAA was 5, identified by the recursive partitioning technique. After adjusting for other competing risk factors, CAA ≥5 remained strongly associated with the risk of postoperative complications (reference CAA <5, odds ratio: 1.63, 95% CI: 1.05-2.55, P = 0.03). In fact, the use of CAA to predict postoperative complications was very good in both the derivative (area under the curve: 0.88) and external (area under curve: 0.86) cohorts (n = 1137). CONCLUSIONS CAA was an independent predictor of CCI after liver resection for HCC. The use of routine laboratories, such as AST and ALT, can help identify patients at the highest risk of postoperative complications after HCC resection.
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Affiliation(s)
- Fumin Wang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Jingming Lu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Yaoxing Ren
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Silvia Silva
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | | | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Grigorie
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Aklile Workneh
- Department of Surgery, University of Ottawa, Ottawa, Canada
| | | | - Tom Hugh
- Department of Surgery, The University of Sydney, School of Medicine, Sydney, Australia
| | | | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Yi Lv
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, PR China
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
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Zhang Y, Lv J, Bai J, Zhang X, Wu G, Lei X, Li W, Zhang Z. TXNIP knockdown ameliorates hepatic ischemia/reperfusion injury by inhibiting apoptosis and improving mitochondrial dysfunction via HIF-1α. Mol Cell Biochem 2025; 480:2291-2300. [PMID: 38872070 DOI: 10.1007/s11010-024-05037-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 05/14/2024] [Indexed: 06/15/2024]
Abstract
This study aims to investigate whether thioredoxin-interacting protein (TXNIP) regulates cell viability, cell apoptosis and mitochondrial damage in OGD/R-induced hepatocytes and to explore its underlying mechanism. AML12 cells were cultured under oxygen-glucose deprivation/reperfusion (OGD/R) conditions. TXNIP mRNA was detected using qRT-PCR, and the TXNIP protein was analyzed using western blotting. TXNIP-targeted short hairpin RNA (sh-TXNIP) lentivirus was used to infect the AML12 cells. CCK8 and TUNEL assays were applied to detect cell viability and apoptosis, respectively. DCFH-DA probe was used to determine reactive oxygen species (ROS) release level, and JC-1 probe was used to evaluate mitochondrial membrane potential (MMP). The localization of TXNIP and HIF-1α was observed using immunofluorescence. Our results showed that TXNIP markedly increased in AML12 cells treated with OGD/R. TXNIP knockdown increased cell viability and reduced cell apoptosis under OGD/R treatment. Moreover, MMP significantly increased and ROS release decreased in cells after TXNIP knockdown under OGD/R treatment. Additionally, TXNIP knockdown markedly increased the expression of HIF-1α. HIF-1α exhibited nuclear translocation following OGD/R induction, and TXNIP knockdown further promoted it. Compared with the OGD/R + sh-TXNIP group, HIF-1α agonist ML228 inhibited cell apoptosis and ROS release, and increased MMP. However, HIF-1α inhibitor PX478 had the opposite effect. In summary, TXNIP deletion ameliorated AML12 cell injury caused by OGD/R via promoting HIF-1α expression and nuclear translocation, manifested by inhibiting cell apoptosis and alleviating mitochondrial dysfunction.
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Affiliation(s)
- Yong Zhang
- Department of Anesthesia, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Jianrui Lv
- Department of Anesthesia, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Jian Bai
- Department of General Surgery, Xuanwu Hospital Capital Medical University, Beijing, 100032, China
| | - Xue Zhang
- Department of General Practice, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Gang Wu
- Department of Anesthesia, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Xiaoming Lei
- Department of Anesthesia, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Wei Li
- Department of Anesthesia, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Zhenni Zhang
- Department of Anesthesia, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, 710004, Shaanxi, China.
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10
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Li J, Bao J, Liu Y, Chen M, Chen Y, Tuolihong L, Jiang F, Xie S, Lyu F, Sun Y, Cao Y, Chen H, Chen Z, Zeng Z. Lentinan enhances microbiota-derived isoursodeoxycholic acid levels to alleviate hepatic ischemia-reperfusion injury in mice. Int J Biol Macromol 2025; 304:140717. [PMID: 39920949 DOI: 10.1016/j.ijbiomac.2025.140717] [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: 12/16/2024] [Revised: 01/28/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is an essential clinical concern caused by liver transplantation, resection, trauma, and shock that must be addressed immediately. Although the mechanisms underlying HIRI are well-documented, effective prevention and treatment strategies are still lacking. Inflammation is a central mechanism of HIRI, with macrophages playing a crucial role in initiating and amplifying the inflammatory response. Numerous plant polysaccharides exhibit substantial anti-inflammatory and hepatoprotective properties. However, the function of Lentinan (LNT) in HIRI has not been fully explored. Thus, this study aims to investigate the preventive potential of LNT in HIRI. Here, we reveal that oral administration of LNT considerably reduces hepatic inflammation and improves liver pathology in mice with HIRI by modulating gut microbiota. Specifically, LNT considerably increased microbiota-derived isoursodeoxycholic acid (IsoUDCA). Further experiments showed that IsoUDCA alleviates hepatic injury by suppressing macrophage inflammation. Mechanistically, IsoUDCA directly binds to and activates the neuron-derived clone 77 (Nur77) transcription factor, inhibiting the NF-κB signaling pathway in macrophages. Our findings shed light on the significant role of the LNT-microbiota-IsoUDCA-Nur77 axis in attenuating macrophage inflammation during HIRI, offering novel insights into potential therapeutic targets and avenues for preventing HIRI.
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Affiliation(s)
- Jiaxin Li
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jingna Bao
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yihong Liu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Meiling Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yuqi Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Lina Tuolihong
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Fuhui Jiang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shihao Xie
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Fengyuan Lyu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ye Sun
- Department of Critical Care Medicine, Yuebei People's Hospital, Shaoguan 512000, Guangdong, China
| | - Yan Cao
- Department of Critical Care Medicine, Yuebei People's Hospital, Shaoguan 512000, Guangdong, China
| | - Huarong Chen
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Zhongqing Chen
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Zhenhua Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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11
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Zhang P, Qin Y, Wang H, Wang J. Vagus nerve stimulation alleviates myocardial injury following hepatic ischemia-reperfusion in rats by inhibiting ferroptosis via the activation of the SLC7A11/GPX4 axis. Eur J Med Res 2025; 30:162. [PMID: 40075496 PMCID: PMC11900121 DOI: 10.1186/s40001-025-02416-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Vagus nerve stimulation (VNS) exhibits protective effects against remote organ injury following ischemia-reperfusion (I/R). However, its effects on acute myocardial injury induced by hepatic I/R in rats, and the underlying mechanisms, remain unclear. METHODS Thirty male rats were randomly assigned to five groups: Sham, I/R, VNS, VNS + Erastin, and VNS + DMSO. A hepatic I/R injury model was established by occluding the arterial and portal veins of the left and middle lobes of the liver for 1 h followed by 6 h of reperfusion. VNS was performed throughout the hepatic I/R process. Erastin was administered intraperitoneally 60 min before hepatic ischemia. Blood samples were collected from the left common carotid artery post-reperfusion to measure liver injury markers (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and the myocardial injury marker (cardiac troponin I [cTnI]). Left ventricular myocardial tissue was also collected for ultrastructural analysis via transmission electron microscopy, reactive oxygen species (ROS) detection using dihydroethidium staining, and measurements of Fe2⁺ levels, malondialdehyde (MDA) concentration, glutathione (GSH) levels, and superoxide dismutase (SOD) activity. Western blotting assessed the expression of ferroptosis-related proteins SLC7A11 and GPX4 in the myocardial tissue. RESULTS VNS significantly reduced serum levels of ALT, AST, and cTnI, while also mitigating mitochondrial damage in cardiomyocytes. Additionally, VNS decreased ROS levels, alleviated iron overload, and reduced lipid peroxidation in myocardial tissue. These protective effects were associated with the activation of the SLC7A11/GPX4 axis, as evidenced by increased expression of these proteins in the VNS group. However, the cardioprotective effects of VNS were negated by the ferroptosis activator erastin, indicating that ferroptosis is involved in VNS-mediated cardioprotection. CONCLUSION VNS protects against myocardial injury from hepatic ischemia-reperfusion, likely by inhibiting oxidative stress and ferroptosis through activation of the SLC7A11/GPX4 axis.
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Affiliation(s)
- Po Zhang
- College of Anesthesiology, Shanxi Medical University, 86 Xinjiannan Road, Taiyuan, 030001, Shanxi, China
| | - Yuanjing Qin
- College of Anesthesiology, Shanxi Medical University, 86 Xinjiannan Road, Taiyuan, 030001, Shanxi, China
| | - Haiyan Wang
- College of Anesthesiology, Shanxi Medical University, 86 Xinjiannan Road, Taiyuan, 030001, Shanxi, China
| | - Jinping Wang
- Department of Anesthesiology, Jincheng People's Hospital, 1666 Baishui East Street, Jincheng, 048026, Shanxi, China.
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12
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Singh P, Chaudhary M, Kazmi JS, Kuschner CE, Volpe BT, Chaudhuri TD, Becker LB. Vagus nerve stimulation: A targeted approach for reducing tissue-specific ischemic reperfusion injury. Biomed Pharmacother 2025; 184:117898. [PMID: 39923406 DOI: 10.1016/j.biopha.2025.117898] [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: 09/16/2024] [Revised: 01/31/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025] Open
Abstract
Vagus Nerve Stimulation (VNS), a neuromodulation technique of applying controlled electrical impulses to the vagus nerve, has now emerged as a potential therapeutic approach for ischemia-reperfusion insults. It provides a pivotal link in improving functional outcomes for the central nervous system and multiple target organs affected by ischemia-reperfusion injury (I/RI). Reduced blood flow during ischemia and subsequent resumption of blood supply during reperfusion to the tissue compromises cellular health because of the combination of mitochondrial dysfunction, oxidative stress, cytokine release, inflammation, apoptosis, intracellular calcium overload, and endoplasmic reticulum stress, which ultimately leads to cell death and irreversible tissue damage. Furthermore, inflammation and apoptosis also play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that VNS in I/RI may act in an anti-inflammatory capacity, reducing oxidative stress and apoptosis, while also improving endothelial and mitochondrial function leading to reduced infarct sizes and cytoprotection in skeletal muscle, gastrointestinal tract, liver, kidney, lung, heart, and brain tissue. In this review, we attempt to shed light on the mechanistic links between tissue-specific damage following I/RI and the therapeutic approach of VNS in attenuating damage, considering both direct and remote I/RI scenarios. Thus, we want to advance the understanding of VNS that could further warrant its clinical implementation, especially as a treatment for I/RI.
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Affiliation(s)
- Parmeshar Singh
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Department of Emergency Medicine, Northwell Health, NY, USA
| | - Manju Chaudhary
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jacob S Kazmi
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Cyrus E Kuschner
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Department of Emergency Medicine, Northwell Health, NY, USA
| | - Bruce T Volpe
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Timir D Chaudhuri
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Lance B Becker
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Department of Emergency Medicine, Northwell Health, NY, USA; Department of Emergency Medicine, Kindai University Faculty of Medicine, Osaka, Japan.
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13
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Qian B, Yin B, Yu H, Wang C, Lu S, Ke S, Li Z, Li X, Hua Y, Li Z, Zhou Y, Meng Z, Fu Y, Tang W, Ma Y. Axin formation inhibitor 1 aggravates hepatic ischemia‒reperfusion injury by promoting the ubiquitination and degradation of PPARβ. Nat Commun 2025; 16:1776. [PMID: 39971912 PMCID: PMC11840116 DOI: 10.1038/s41467-025-56967-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/28/2025] [Indexed: 02/21/2025] Open
Abstract
Hepatic ischemia‒reperfusion injury (HIRI) is a common pathological phenomenon after hepatectomy and liver transplantation. Here, we aim to explore the role of Axin formation inhibitor 1 (Axin1) in HIRI. In this work, we find that the expression of Axin1 is upregulated after HIRI. Cellular experiments confirme that Axin1 knockdown alleviated hypoxia/reoxygenation (H/R)-induced inflammation and apoptosis. Subsequently, we construct a HIRI model based on transgenic hepatocellular-specific Axin1 knockout and overexpression male mice and find that Axin1 deletion alleviated inflammation and apoptosis. Transcriptome sequencing reveal that the genes whose expression differed after Axin1 overexpression are significantly enriched in the PPAR signaling pathway. Furthermore, we demonstrate that Axin1 negatively regulates the expression of PPARβ, thereby activating the NF-κB pathway. Mechanistically, Axin1 binds to PPARβ to enhance the ubiquitination-mediated degradation of PPARβ by the E3 ubiquitin ligase RBBP6. Notably, adenovirus-mediated Axin1 knockdown block I/R damage in mice. Our study results demonstrate that Axin1 exacerbates HIRI by promoting the ubiquitination and degradation of PPARβ, which in turn activates the NF-κB signaling pathway. These results suggest that Axin1 may be a potential therapeutic target for HIRI.
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Affiliation(s)
- Baolin Qian
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Yin
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongjun Yu
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoqun Wang
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Shounan Lu
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shanjia Ke
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zihao Li
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Li
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongliang Hua
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongyu Li
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongzhi Zhou
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhanzhi Meng
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yao Fu
- Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Tang
- International Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Yong Ma
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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14
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Alotaibi K, Arulkumaran N, Dyson A, Singer M. Therapeutic strategies to ameliorate mitochondrial oxidative stress in ischaemia-reperfusion injury: A narrative review. Clin Sci (Lond) 2025; 139:CS20242074. [PMID: 39899361 DOI: 10.1042/cs20242074] [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: 09/12/2024] [Revised: 12/26/2024] [Accepted: 01/08/2025] [Indexed: 02/04/2025]
Abstract
Mitochondrial reactive oxygen species (mROS) play a crucial physiological role in intracellular signalling. However, high levels of ROS can overwhelm antioxidant defences and lead to detrimental modifications in protein, lipid and DNA structure and function. Ischaemia-reperfusion injury is a multifaceted pathological state characterised by excessive production of mROS. There is a significant clinical need for therapies mitigating mitochondrial oxidative stress. To date, a variety of strategies have been investigated, ranging from enhancing antioxidant reserve capacity to metabolism reduction. While success has been achieved in non-clinical models, no intervention has yet successfully transitioned into routine clinical practice. In this article, we explore the different strategies investigated and discuss the possible reasons for the lack of translation.
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Affiliation(s)
- Khalid Alotaibi
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Nishkantha Arulkumaran
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
| | - Alex Dyson
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London, U.K
| | - Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K
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15
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Jahagirdar V, Ahmed M, Fatima I, Ali H, Alba L, Helzberg JH, Cummings LS, Wilkinson M, Forster J, Likhitsup A. Prostaglandin E1 administration post liver transplantation and renal outcomes: A retrospective single center experience. World J Transplant 2024; 14:98797. [PMID: 39697460 PMCID: PMC11438947 DOI: 10.5500/wjt.v14.i4.98797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/21/2024] [Accepted: 09/02/2024] [Indexed: 09/20/2024] Open
Abstract
BACKGROUND Prostaglandin E1 (PGE1), or alprostadil, is a potent vasodilator that improves hepatic blood flow and reduces ischemia-reperfusion injury post-liver transplantation (LT). However, the benefits of PGE1 on renal function after LT have not yet been well described. AIM To assess the impact of PGE1 administration on renal function in patients who underwent liver or liver-kidney transplant. METHODS This retrospective study included all patients who underwent liver or liver-kidney transplant at our institution from January, 2011 to December, 2021. Patients were classified based on whether they received PGE1. PGE1 was administered post-LT to those with transaminases > 1000 U/L in the immediate postoperative period. Demographics, post-LT treatments and/or complications, renal function, and survival were analyzed. Multivariable logistic regression analysis was performed, and a two-tailed P value < 0.05 was considered statistically significant. RESULTS A total of 145 patients underwent LT, with 44 (30%) receiving PGE1. Baseline patient characteristics were comparable, except the PGE1 group had significantly higher aspartate aminotransferase (AST) (1961.9 U/L ± 1862.3 U/L vs 878 U/L ± 741.4 U/L, P = 0.000), alanine aminotransferase (1070.6 U/L ± 895 U/L vs 547.7 U/L ± 410 U/L, P = 0.000), international normalized ratio on post-LT day 1 (2 ± 0.74 vs 1.8 ± 0.4, P = 0.03), a longer intensive care unit stay (8.1 days ± 11.8 days vs 3.8 days ± 4.6 days, P = 0.003), more vasopressor use (55.53 hours ± 111 hours vs 16.33 hours ± 26.3 hours, P = 0.002), and higher immediate postoperative complications (18.6% vs 4.9%, P = 0.04). The PGE1 group also had a significantly higher 90-day readmission rate (29.6% vs 13.1%, P = 0.02) and lower 1-year liver graft survival (87.5% vs 98.9%, P = 0.005). However, 30-day readmission (31.6% vs 27.4%, P = 0.64), LT complications (hepatic artery thrombosis, biliary complications, rejection of liver graft, cardiomyopathy), 1-year patient survival (96.9% vs 97.8%, P = 0.77), overall liver graft survival, and overall patient survival were similar between the two groups (95.4% vs 93.9%, P = 0.74 and 88.4% vs 86.9%, P = 0.81 respectively). Although the PGE1 group had a significantly lower glomerular filtration rate (eGFR) on post-LT day 7 (46.3 mL/minute ± 26.7 mL/minute vs 62.5 mL/minute ± 34 mL/minute, P = 0.009), the eventual need for renal replacement therapy (13.6% vs 5.9%, P = 0.09), the number of dialysis sessions (0.91 vs 0.27, P = 0.13), and eGFR at 1-month (37.2 mL/minute ± 35.9 mL/minute vs 42 mL/minute ± 36.9 mL/minute, P = 0.49), 6-months (54.8 mL/minute ± 21.6 mL/minute vs 62 mL/minute ± 21.4 mL/minute, P = 0.09), and 12-months (63.7 mL/minute ± 20.7 mL/minute vs 62.8 mL/minute ± 20.3 mL/minute, P = 0.85) post-LT were similar to those in the non-PGE1 group. CONCLUSION In patients who received PGE1 for ischemia-reperfusion injury, despite immediate acute renal injury post-LT, the renal function at 1-month, 6-months, and 12-months post-LT was similar compared to those without ischemia-reperfusion injury. Prospective clinical trials are needed to further elucidate the benefits of PGE1 use in renal function.
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Affiliation(s)
- Vinay Jahagirdar
- Department of Internal Medicine, Saint Luke’s Health System of Kansas City and the University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Mohamed Ahmed
- Department of Internal Medicine, Saint Luke’s Health System of Kansas City and the University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Ifrah Fatima
- Department of Internal Medicine, Saint Luke’s Health System of Kansas City and the University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Hassam Ali
- Department of Gastroenterology and Hepatology, East Carolina University Brody School of Medicine, Greenville, NC 27834, United States
| | - Laura Alba
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Saint Luke’s Health System of Kansas City and University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - John H Helzberg
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Saint Luke’s Health System of Kansas City and University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Lee S Cummings
- Department of Surgery, University of Missouri-Kansas City and Transplant Surgery, Saint Luke’s Hospital of Kansas City, Kansas City, MO 64111, United States
| | - Matthew Wilkinson
- Department of Surgery, University of Missouri-Kansas City and Transplant Surgery, Saint Luke’s Hospital of Kansas City, Kansas City, MO 64111, United States
| | - Jameson Forster
- Department of Surgery, University of Missouri-Kansas City and Transplant Surgery, Saint Luke’s Hospital of Kansas City, Kansas City, MO 64111, United States
| | - Alisa Likhitsup
- Department of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, United States
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16
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Lian YQ, Li PF, Guo Y, Tao YL, Liu YN, Liang ZY, Zhu SF. Interaction between ischemia-reperfusion injury and intestinal microecology in organ transplantation and its therapeutic prospects. Front Immunol 2024; 15:1495394. [PMID: 39712022 PMCID: PMC11659223 DOI: 10.3389/fimmu.2024.1495394] [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: 09/12/2024] [Accepted: 11/15/2024] [Indexed: 12/24/2024] Open
Abstract
Organ transplantation is a vital intervention for end-stage organ failure; however, ischemia-reperfusion injury is a complication of transplantation, affecting the prognosis and survival of transplant recipients. As a complex ecosystem, recent research has highlighted the role of the intestinal microecology in transplantation, revealing its significant interplay with ischemia-reperfusion injury. This review explores the interaction between ischemia-reperfusion injury and intestinal microecology, with a special focus on how ischemia-reperfusion injury affects intestinal microecology and how these microecological changes contribute to complications after organ transplantation, such as infection and rejection. Based on a comprehensive analysis of current research advances, this study proposes potential strategies to improve transplant outcomes, offering guidance for future research and clinical practice.
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Affiliation(s)
- Yong-qi Lian
- Department of Critical Care Medicine, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Peng-fei Li
- Department of Orthopaedics, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yan Guo
- Pathology Department, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yan-lin Tao
- Department of Surgery ICU, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Ya-nan Liu
- Department of Surgery ICU, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Zhao-yu Liang
- Department of Critical Care Medicine, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Shu-fen Zhu
- Physical Examination Center, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
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17
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Liu J, Yin D, Zhang W, Wang X, James TD, Li P, Tang B. A multifunctional "three-in-one" fluorescent theranostic system for hepatic ischemia-reperfusion injury. Chem Sci 2024; 15:19820-19833. [PMID: 39568886 PMCID: PMC11575585 DOI: 10.1039/d4sc04962d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/01/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the main cause of postoperative liver dysfunction and liver failure. Traditional separation of HIRI diagnosis and therapy confers several disadvantages, including the inability to visualize the therapeutic and asynchronous action. However, developing a versatile material with integrated diagnosis and treatment for HIRI remains a great challenge. Given that hypochlorous acid (HOCl) plays a crucial oxidative role in HIRI, we developed a single-component multifunctional fluorescent theranostic platform (MB-Gly) with a "three-in-one" molecular design incorporating a near-infrared fluorophore methylene blue, glycine and a HOCl-response unit, which could not only provide real-time visualization of HIRI but also boost targeted drug delivery. Using MB-Gly, we were able to achieve real-time and dynamic monitoring of HOCl during HIRI in hepatocytes and mouse livers and reduce the liver damage in hepatocytes and mice. RNA sequencing illustrated the therapeutic role of MB-Gly associated with changes in gene expression related to apoptosis, oxidative stress, metabolism and inflammation. To the best of our knowledge, this is the first multifunctional fluorescent theranostic system for HIRI reported to date. Our smart "three-in-one" approach shines light on the etiology and pathogenesis of HIRI, providing profound insights into the development of potential therapeutic targets.
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Affiliation(s)
- Jihong Liu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- Key Laboratory for Advanced Materials, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Shanghai Key Laboratory of Functional Materials Chemistry, Institute of Fine Chemicals, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology Shanghai 200237 People's Republic of China
| | - Dongni Yin
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
| | - Wen Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
| | - Xin Wang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
| | - Tony D James
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- Department of Chemistry, University of Bath Bath BA2 7AY UK
- School of Chemistry and Chemical Engineering, Henan Normal University Xinxiang 453007 People's Republic of China
| | - Ping Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- College of Chemistry and Chemical Engineering, Northwest Normal University Lanzhou 730070 People's Republic of China
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- Laoshan Laboratory Qingdao 266237 People's Republic of China
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18
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Owen MC, Kopecky BJ. Targeting Macrophages in Organ Transplantation: A Step Toward Personalized Medicine. Transplantation 2024; 108:2045-2056. [PMID: 38467591 PMCID: PMC11390981 DOI: 10.1097/tp.0000000000004978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Organ transplantation remains the most optimal strategy for patients with end-stage organ failure. However, prevailing methods of immunosuppression are marred by adverse side effects, and allograft rejection remains common. It is imperative to identify and comprehensively characterize the cell types involved in allograft rejection, and develop therapies with greater specificity. There is increasing recognition that processes mediating allograft rejection are the result of interactions between innate and adaptive immune cells. Macrophages are heterogeneous innate immune cells with diverse functions that contribute to ischemia-reperfusion injury, acute rejection, and chronic rejection. Macrophages are inflammatory cells capable of innate allorecognition that strengthen their responses to secondary exposures over time via "trained immunity." However, macrophages also adopt immunoregulatory phenotypes and may promote allograft tolerance. In this review, we discuss the roles of macrophages in rejection and tolerance, and detail how macrophage plasticity and polarization influence transplantation outcomes. A comprehensive understanding of macrophages in transplant will guide future personalized approaches to therapies aimed at facilitating tolerance or mitigating the rejection process.
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Affiliation(s)
- Macee C Owen
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MI
| | - Benjamin J Kopecky
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MI
- Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO
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Whalen C, Verma A, Kurashima K, Carter J, Nazzal H, Jain A. Novel Models for Assessing and Pathophysiology of Hepatic Ischemia-Reperfusion Injury Mechanisms. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1507. [PMID: 39336548 PMCID: PMC11434406 DOI: 10.3390/medicina60091507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/09/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024]
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a major cause of postoperative hepatic dysfunction and liver failure involving cellular damage to previously ischemic tissues to which blood flow is restored. The reestablishment of blood flow is essential for salvaging ischemic tissues. The reperfusion itself, however, can paradoxically lead to further cellular damage, which involves a multi-factorial process resulting in extensive tissue damage, which can threaten the function and viability of the liver and other organ systems. The following review outlines multiple models for in-lab analysis of the various hepatic IRI mechanisms, including murine, porcine, cell lines, and machine perfusion models.
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Affiliation(s)
- Connor Whalen
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Arun Verma
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Kento Kurashima
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Jasmine Carter
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Hala Nazzal
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Ajay Jain
- Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA
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20
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Elsayed Abouzed DE, Ezelarab HAA, Selim HMRM, Elsayed MMA, El Hamd MA, Aboelez MO. Multimodal modulation of hepatic ischemia/reperfusion-induced injury by phytochemical agents: A mechanistic evaluation of hepatoprotective potential and safety profiles. Int Immunopharmacol 2024; 138:112445. [PMID: 38944946 DOI: 10.1016/j.intimp.2024.112445] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND Hepatic ischemia-reperfusion (I/R) injury is a clinically fundamental phenomenon that occurs through liver resection surgery, trauma, shock, and transplantation. AIMS OF THE REVIEW This review article affords an expanded and comprehensive overview of various natural herbal ingredients that have demonstrated hepatoprotective effects against I/R injury through preclinical studies in animal models. MATERIALS AND METHODS For the objective of this investigation, an extensive examination was carried out utilizing diverse scientific databases involving PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate. The investigation was conducted based on specific identifiable terms, such as hepatic ischemia/reperfusion injury, liver resection and transplantation, cytokines, inflammation, NF-kB, interleukins, herbs, plants, natural ingredients, phenolic extract, and aqueous extract. RESULTS Bioactive ingredients derived from ginseng, curcumin, resveratrol, epigallocatechin gallate, quercetin, lycopene, punicalagin, crocin, celastrol, andrographolide, silymarin, and others and their effects on hepatic IRI were discussed. The specific mechanisms of action, signaling pathways, and clinical relevance for attenuation of liver enzymes, cytokine production, immune cell infiltration, oxidative damage, and cell death signaling in rodent studies are analyzed in depth. Their complex molecular actions involve modulation of pathways like TLR4, NF-κB, Nrf2, Bcl-2 family proteins, and others. CONCLUSION The natural ingredients have promising values in the protection and treatment of various chronic aggressive clinical conditions, and that need to be evaluated on humans by clinical studies.
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Affiliation(s)
- Deiaa E Elsayed Abouzed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
| | - Hend A A Ezelarab
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
| | - Heba Mohammed Refat M Selim
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, AlMaarefa University, Diriyah 13713, Riyadh, Saudi Arabia; Department of Microbiology and Immunology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 35527, Egypt.
| | - Mahmoud M A Elsayed
- Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
| | - Mohamed A El Hamd
- Department of Pharmaceutical Chemistry, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt.
| | - Moustafa O Aboelez
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt
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21
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Dong MQ, Xie Y, Tang ZL, Zhao XW, Lin FZ, Zhang GY, Huang ZH, Liu ZM, Lin Y, Liu FY, Zhou WJ. Leukocyte cell-derived chemotaxin 2 (LECT2) regulates liver ischemia-reperfusion injury. LIVER RESEARCH 2024; 8:165-171. [PMID: 39957753 PMCID: PMC11771270 DOI: 10.1016/j.livres.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/26/2024] [Accepted: 09/10/2024] [Indexed: 02/18/2025]
Abstract
Background and aim Hepatic ischemia-reperfusion injury (IRI) is a significant challenge in liver transplantation, trauma, hypovolemic shock, and hepatectomy, with limited effective interventions available. This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2 (LECT2) in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA (shRNA) delivered through adeno-associated virus (AAV) vectors. Materials and methods This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver. Lect2-knockout and C57BL/6J mice were used. Hepatic IRI was induced by clamping the hepatic pedicle. Treatments included recombinant human LECT2 (rLECT2) and AAV-Lect2-shRNA. LECT2 expression levels and serum biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) were measured. Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed. Results Serum and liver LECT2 levels were elevated during hepatic IRI. Serum LECT2 protein and mRNA levels increased post reperfusion. Lect2-knockout mice had reduced weight loss; hepatic necrosis; and serum ALT, AST, creatinine, and BUN levels. rLECT2 treatment exacerbated weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN). AAV-Lect2-shRNA treatment significantly reduced weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN), indicating therapeutic potential. Conclusions Elevated LECT2 levels during hepatic IRI increased liver damage. Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage, indicating its therapeutic potential. AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI, offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.
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Affiliation(s)
- Meng-Qi Dong
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuan Xie
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Zhi-Liang Tang
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Xue-Wen Zhao
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Fu-Zhen Lin
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Guang-Yu Zhang
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Zhi-Hao Huang
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi-Min Liu
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuan Lin
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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22
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Aboelez MO, Ezelarab HAA, Alotaibi G, Abouzed DEE. Inflammatory setting, therapeutic strategies targeting some pro-inflammatory cytokines and pathways in mitigating ischemia/reperfusion-induced hepatic injury: a comprehensive review. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6299-6315. [PMID: 38643452 DOI: 10.1007/s00210-024-03074-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 03/28/2024] [Indexed: 04/22/2024]
Abstract
Ischemia/reperfusion injury (IRI) is a key determining agent in the pathophysiology of clinical organ dysfunction. It is characterized by an aseptic local inflammatory reaction due to a decrease in blood supply, hence deprivation of dependent oxygen and nutrients. In instances of liver transplantation, this injury may have irreversible implications, resulting in eventual organ rejection. The deterioration associated with IRI is affected by the hepatic health status and various factors such as alterations in metabolism, oxidative stress, and pro-inflammatory cytokines. The primary cause of inflammation is the initial immune response of pro-inflammatory cytokines, while Kupffer cells (KFCs) and neutrophil-produced chemokines also play a significant role. Upon reperfusion, the activation of inflammatory responses can elicit further cellular damage and organ dysfunction. This review discusses the interplay between chemokines, pro-inflammatory cytokines, and other inflammatory mediators that contribute to the damage to hepatocytes and liver failure in rats following IR. Furthermore, it delves into the impact of anti-inflammatory therapies in safeguarding against liver failure and hepatocellular damage in rats following IR. This review investigates the correlation between cytokine factors and liver dysfunction via examining databases, such as PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate.
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Affiliation(s)
- Moustafa O Aboelez
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt.
| | - Hend A A Ezelarab
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minya, 61519, Egypt.
| | - Ghallab Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Al-Dawadmi Campus, 11961, Al-Dawadmi, Saudi Arabia
| | - Deiaa E Elsayed Abouzed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt
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23
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Zhang Y, Jia K, Li Y, Ma Z, Fan G, Luo R, Li Y, Yang Y, Li F, Liu R, Liu J, Li X. Rehmanniae Radix Praeparata aqueous extract improves hepatic ischemia/reperfusion injury by restoring intracellular iron homeostasis. Chin J Nat Med 2024; 22:769-784. [PMID: 39326972 DOI: 10.1016/s1875-5364(24)60719-3] [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: 11/12/2023] [Indexed: 09/28/2024]
Abstract
Hepatic ischemia/reperfusion injury (HIRI) is a common pathophysiological condition occurring during or after liver resection and transplantation, leading to hepatic viability impairment and functional deterioration. Recently, ferroptosis, a newly recognized form of programmed cell death, has been implicated in IRI. Rehmanniae Radix Praeparata (RRP), extensively used in Chinese herbal medicine for its hepatoprotective, anti-inflammatory, and antioxidant properties, presents a potential therapeutic approach. However, the mechanisms by which RRP mitigates HIRI, particularly through the regulation of ferroptosis, remain unclear. In this study, we developed a HIRI mouse model and monocrotaline (MCT)- and erastin-induced in vitro hepatocyte injury models. We conducted whole-genome transcriptome analysis to elucidate the protective effects and mechanisms of RRP on HIRI. The RRP aqueous extract was characterized by the presence of acteoside, rehmannioside D, and 5-hydroxymethylfurfural. Our results demonstrate that the RRP aqueous extract ameliorated oxidative stress, reduced intracellular iron accumulation, and attenuated HIRI-induced liver damage. Additionally, RRP significantly inhibited hepatocyte death by restoring intracellular iron homeostasis both in vivo and in vitro. Mechanistically, the RRP aqueous extract reduced intrahepatocellular iron accumulation by inhibiting ZIP14-mediated iron uptake, promoting hepcidin- and ferroportin-mediated iron efflux, and ameliorating mitochondrial iron aggregation through upregulation of Cisd1 expression. Moreover, siRNA-mediated inhibition of hamp synergistically enhanced the RRP aqueous extract's inhibitory effect on ferroptosis. In conclusion, our study elucidates the mechanisms by which RRP aqueous extracts alleviate HIRI, highlighting the restoration of iron metabolic balance. These findings position RRP as a promising candidate for clinical intervention in HIRI treatment.
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Affiliation(s)
- Yinhao Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Kexin Jia
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yufei Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhi Ma
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Guifang Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ranyi Luo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yajing Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yang Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Fanghong Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jia Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China.
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24
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Xiong Y, Chen J, Liang W, Li K, Huang Y, Song J, Zhang B, Qiu X, Qiu D, Zhang Q, Qin Y. Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway. J Transl Med 2024; 22:796. [PMID: 39198913 PMCID: PMC11351313 DOI: 10.1186/s12967-024-05588-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated. METHODS Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models. RESULTS Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization. CONCLUSIONS The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
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Affiliation(s)
- Yi Xiong
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Jiawen Chen
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Wei Liang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Kun Li
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Yingqi Huang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Jingwen Song
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Baoyu Zhang
- Neurosurgery Department, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China
| | - Xiusheng Qiu
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China
| | - Dongbo Qiu
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
| | - Qi Zhang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
| | - Yunfei Qin
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
- Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
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25
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Fernández J, Blasi A, Hidalgo E, Karvellas CJ. Bridging the critically ill patient with acute to chronic liver failure to liver transplantation. Am J Transplant 2024; 24:1348-1361. [PMID: 38548058 DOI: 10.1016/j.ajt.2024.03.026] [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: 12/21/2023] [Revised: 03/16/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024]
Abstract
Liver transplantation (LT) has emerged as an effective therapy for severe forms of acute-on-chronic liver failure (ACLF), an entity characterized by the development of multiorgan failure and high short-term mortality. The aim of critical care management of ACLF patients is to rapidly treat precipitating events and aggressively support failing organs to ensure that patients may successfully undergo LT or, less frequently, recover. Malnutrition and sarcopenia are frequently present, adversely impacting the prognosis of these patients. Management of critical care patients with ACLF is complex and requires the participation of different specialties. Once the patient is stabilized, a rapid evaluation for salvage LT should be performed because the time window for LT is often narrow. The development of sepsis and prolonged organ support may preclude LT or diminish its chances of success. The current review describes strategies to bridge severe ACLF patients to LT, highlights the minimal evaluation required for listing and the currently suggested contraindications to proceed with LT, and addresses different aspects of management during the perioperative and early posttransplant period.
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Affiliation(s)
- Javier Fernández
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain; EF Clif, EASL-CLIF Consortium, Barcelona, Spain.
| | - Annabel Blasi
- Anesthesiology Department, Hospital Clínic, and University of Barcelona, Spain
| | - Ernest Hidalgo
- Hepatolobiliary Surgery Department, Hospital Vall d'Hebron, Barcelona, Spain
| | - Constantine J Karvellas
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada; Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
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26
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Kim H, Kim Y. Correlation Between Serum Transaminase Levels and Estimated Glomerular Filtration Rate After Living-Donor Kidney Transplantation. Transplant Proc 2024; 56:1241-1246. [PMID: 39003207 DOI: 10.1016/j.transproceed.2024.02.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 02/05/2024] [Accepted: 02/22/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND There is a risk of hypoperfusion during kidney transplantation surgery owing to patients' underlying disease and ischemia-reperfusion injury; further, hypoperfusion may cause injury to major organs. We hypothesized that the decrease in blood pressure after ischemia-reperfusion injury during kidney transplantation may be associated with indicators of liver injury and kidney graft function. METHODS Data regarding living-donor kidney transplantations performed at our institution between 2018 and 2022 were retrospectively evaluated. Exclusion criteria included pediatric recipients or donors aged <18 years, multiple organ transplantation, and elevated postoperative serum transaminase levels. Correlations among blood pressure, serum transaminase levels on postoperative days 3 to 5, and estimated glomerular filtration rate (eGFR) on postoperative days 7 and 14 were analyzed. Further, a subgroup analysis was performed based on eGFR. RESULTS A total of 276 patients were included in the final analysis. Serum transaminase levels were significantly negatively correlated with eGFR (partial correlation coefficient-0.26, P < .001). The postreperfusion decrease in blood pressure was not correlated with serum transaminase levels. However, the postreperfusion decrease in blood pressure and baseline blood pressure correlated with the eGFR (partial correlation coefficient = -0.18, P = .004). CONCLUSION These findings indicate a correlation between intraoperative liver injury and kidney graft function, suggesting the importance of intraoperative management of organ perfusion. Since postreperfusion blood pressure changes did not significantly correlate with liver injury indicators, it is important to consider other causative factors for hypoperfusion in major organs during living-donor kidney transplantation, including microcirculatory failure and organ congestion-related ischemia/reperfusion.
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Affiliation(s)
- Hyunjee Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
| | - Yeongun Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
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Yu Q, Mei C, Cui M, He Q, Liu X, Du X. Nepetoidin B Alleviates Liver Ischemia/Reperfusion Injury via Regulating MKP5 and JNK/P38 Pathway. Drug Des Devel Ther 2024; 18:2301-2315. [PMID: 38911032 PMCID: PMC11192200 DOI: 10.2147/dddt.s457130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 06/01/2024] [Indexed: 06/25/2024] Open
Abstract
Background Nepetoidin B (NB) has been reported to possess anti-inflammatory, antibacterial, and antioxidant properties. However, its effects on liver ischemia/reperfusion (I/R) injury remain unclear. Methods In this study, a mouse liver I/R injury model and a mouse AML12 cell hypoxia reoxygenation (H/R) injury model were used to investigate the potential role of NB. Serum transaminase levels, liver necrotic area, cell viability, oxidative stress, inflammatory response, and apoptosis were evaluated to assess the effects of NB on liver I/R and cell H/R injury. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to measure mRNA and protein expression levels, respectively. Molecular docking was used to predict the binding capacity of NB and mitogen-activated protein kinase phosphatase 5 (MKP5). Results The results showed that NB significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrosis, oxidative stress, reactive oxygen species (ROS) content, inflammatory cytokine content and expression, inflammatory cell infiltration, and apoptosis after liver I/R and AML12 cells H/R injury. Additionally, NB inhibited the JUN protein amino-terminal kinase (JNK)/P38 pathway. Molecular docking results showed good binding between NB and MKP5 proteins, and Western blotting results showed that NB increased the protein expression of MKP5. MKP5 knockout (KO) significantly diminished the protective effects of NB against liver injury and its inhibitory effects on the JNK/P38 pathway. Conclusion NB exerts hepatoprotective effects against liver I/R injury by regulating the MKP5-mediated P38/JNK signaling pathway.
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Affiliation(s)
- Qiwen Yu
- Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Chaopeng Mei
- Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Mengwei Cui
- Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Qianqian He
- Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Xudong Liu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
| | - Xiaoxiao Du
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China
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Wang Y, Piao C, Liu T, Lu X, Ma Y, Zhang J, Ma H, Wang H. Exosomes Derived from Adipose Mesenchymal Stem Cells Promote Regeneration of Injured Liver in Minipigs. Int J Mol Sci 2024; 25:6604. [PMID: 38928308 PMCID: PMC11203699 DOI: 10.3390/ijms25126604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/04/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is an important factor affecting liver regeneration and functional recovery postoperatively. Many studies have suggested that mesenchymal stem cells (MSCs) contribute to hepatic tissue repair and functional recovery through paracrine mechanisms mediated by exosomes. Minipigs exhibit much more similar characteristics of the liver to those of humans than rodents. This study aimed to explore whether exosomes from adipose-derived MSCs (ADSCs-exo) could actively promote liver regeneration after hepatectomy combined with HIRI in minipigs and the role they play in the cell proliferation process. This study also compared the effects and differences in the role of ADSCs and ADSCs-exo in the inflammatory response and liver regeneration. The results showed that ADSCs-exo suppressed histopathological changes and reduced inflammatory infiltration in the liver; significantly decreased levels of ALT, TBIL, HA, and the pro-inflammatory cytokines TNF-α, IL-6, and CRP; increased levels of the anti-inflammatory cytokine IL-10 and the pro-regeneration factors Ki67, PCNA, CyclinD1, HGF, STAT3, VEGF, ANG1, ANG2; and decreased levels of the anti-regeneration factors SOCS3 and TGF-β. These indicators above showed similar changes with the ADSCs intervention group. Indicating that ADSCs-exo can exert the same role as ADSCs in regulating inflammatory responses and promoting liver regeneration. Our findings provide experimental evidence for the possibility that ADSCs-exo could be considered a safe and effective cell-free therapy to promote regeneration of injured livers.
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Affiliation(s)
| | | | | | | | | | | | | | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (Y.W.); (C.P.); (T.L.); (X.L.); (Y.M.); (J.Z.); (H.M.)
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Zhang T, Wang X. Modafinil lightens apoptosis and inflammatory response in hepatic ischemia-reperfusion injury through inactivation of TLR9/Myd88/p38 signaling. Drug Dev Res 2024; 85:e22210. [PMID: 38812444 DOI: 10.1002/ddr.22210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/08/2024] [Accepted: 05/07/2024] [Indexed: 05/31/2024]
Abstract
Hepatic ischemia/reperfusion injury (IRI) remains a severe threat during liver surgery and transplantation, accounting for unfavorable clinical outcomes. Modafinil (MOD), a wakefulness-inducing compound, is increasingly disclosed to protect against IRI. However, the specific literatures covering the association between MOD and hepatic IRI are few. Here, this paper is committed to unraveling the role and response mechanism of MOD in hepatic IRI. After the establishment of hepatic IRI mice model and cell model, relevant assay kits measured the concentrations of biochemical indicators of hepatotoxicity and hematoxylin and eosin staining estimated liver morphology. Enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and western blot evaluated inflammatory levels. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling assay and western blot appraised apoptosis. Western blot also analyzed the expression of Toll-like receptor 9 (TLR9)/myeloid differentiation primary response gene 88 (MyD88)/p38 signaling-associated proteins. Cell counting kit-8 method judged cell viability. MOD was discovered to mitigate liver dysfunction and morphological damage, inflammatory response, apoptosis in vivo and improve cell viability, suppress inflammatory response and apoptosis in vitro. In addition, MOD inactivated TLR9/Myd88/p38 signaling both in vitro and in vivo. Further, TLR9 elevation reversed the inhibitory role of MOD in inflammatory response and cell apoptosis in vitro. Anyway, MOD blocked TLR9/Myd88/p38 signaling to exhibit anti-inflammatory and anti-apoptotic properties in hepatic IRI.
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Affiliation(s)
- Tairan Zhang
- Immunology Department, College of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Xidong Wang
- Department of Hepatobiliary, Pancreatic and Spleen Surgery, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia, China
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Rokop ZP, Zhang W, Ghosh N, Biswas N, Das A, Lin J, Sen CK, Kubal C. Exacerbated ischemia-reperfusion injury in fatty livers is mediated by lipid peroxidation stress and ferroptosis. Surgery 2024; 175:1539-1546. [PMID: 38508920 DOI: 10.1016/j.surg.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/28/2024] [Accepted: 02/02/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND Ischemia-reperfusion injury is a common problem in liver surgery and transplantation. Although ischemia-reperfusion injury is known to be more pronounced in fatty livers, the underlying mechanisms for this difference remain poorly understood. We hypothesized that ferroptosis plays a significant role in fatty liver ischemia-reperfusion injury due to increased lipid peroxidation in the presence of stored iron in the fatty liver. To test this hypothesis, the ferroptosis pathway was evaluated in a murine fatty liver ischemia-reperfusion injury model. METHODS C57BL6 mice were fed with a normal diet or a high fat, high sucrose diet for 12 weeks. At 22 weeks of age, liver ischemia-reperfusion injury was induced through partial (70%) hepatic pedicle clamping for 60 minutes, followed by 24 hours of reperfusion before tissue harvest. Acyl-coenzyme A synthetase long-chain family member 4 and 4-hydroxynonenal were quantified in the liver tissues. In separate experiments, liproxstatin-1 or vehicle control was administered for 7 consecutive days before liver ischemia-reperfusion injury. RESULTS Exacerbated ischemia-reperfusion injury was observed in the livers of high fat, high sucrose diet fed mice. High fat, high sucrose diet + ischemia-reperfusion injury (HDF+IRI) livers had a significantly greater abundance of acyl-coenzyme A synthetase long-chain family member 4 and 4-hydroxynonenal compared with normal diet + ischemia-reperfusion injury (ND+IRI) livers or sham fatty livers, which indicated an increase of ferroptosis. HFD fed animals receiving liproxstatin-1 injections had a significant reduction in serum aspartate transaminase and alanine transaminase after ischemia-reperfusion injury, consistent with attenuation of ischemia-reperfusion injury in the liver. CONCLUSION Ferroptosis plays a significant role in ischemia-reperfusion injury in fatty livers. Inhibiting ferroptotic pathways in the liver may serve as a novel therapeutic strategy to protect the fatty liver in the setting of ischemia-reperfusion injury.
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Affiliation(s)
- Zachary P Rokop
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Wenjun Zhang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Nandini Ghosh
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; IU Health Comprehensive Wound Center, Indiana University School of Medicine, Indianapolis, IN; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN
| | - Nirupam Biswas
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; IU Health Comprehensive Wound Center, Indiana University School of Medicine, Indianapolis, IN; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN
| | - Amitava Das
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; IU Health Comprehensive Wound Center, Indiana University School of Medicine, Indianapolis, IN; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN
| | - Jingmei Lin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Chandan K Sen
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; IU Health Comprehensive Wound Center, Indiana University School of Medicine, Indianapolis, IN; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN. https://twitter.com/ChandanKSen
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Akhigbe R, Odetayo A, Akhigbe T, Hamed M, Ashonibare P. Pathophysiology and management of testicular ischemia/reperfusion injury: Lessons from animal models. Heliyon 2024; 10:e27760. [PMID: 38694115 PMCID: PMC11058307 DOI: 10.1016/j.heliyon.2024.e27760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 02/24/2024] [Accepted: 03/06/2024] [Indexed: 05/03/2024] Open
Abstract
Testicular torsion is a urological emergency that involves the twisting of the spermatic cord along its course. Compelling pieces of evidence have implicated oxidative stress-sensitive signaling in pathogenesis of testicular I/R injury. Although, surgical detorsion is the mainstay management; blockade of the pathways involved in the pathogenesis may improve the surgical outcome. Experimental studies using various testicular I/R models have been reported in a bid to explore the mechanisms associated with testicular I/R and evaluate the benefits of potential therapeutic measures; however, most are limited by their shortcomings. Thus, this review was intended to describe the details of the available testicular I/R models as well as their merits and drawbacks, the pathophysiological basis and consequences of testicular I/R, and the pharmacological agents that have being proposed to confer testicular benefits against testicular I/R. This provides an understanding of the pathophysiological events and available models used in studying testicular I/R. In addition, this research provides evidence-based molecules with therapeutic potentials as well as their mechanisms of action in testicular I/R.
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Affiliation(s)
- R.E. Akhigbe
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
| | - A.F. Odetayo
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Physiology, University of Ilorin, Ilorin, Kwara State, Nigeria
| | - T.M. Akhigbe
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Breeding and Plant Genetics Unit, Department of Agronomy, Osun State University, Osun State, Nigeria
| | - M.A. Hamed
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Medical Laboratory Science, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
- The Brainwill Laboratory, Osogbo, Osun State, Nigeria
| | - P.J. Ashonibare
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
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Lyu J, Sheng M, Cao Y, Jia L, Zhang C, Weng Y, Yu W. Ischemia and reperfusion-injured liver-derived exosomes elicit acute lung injury through miR-122-5p regulated alveolar macrophage polarization. Int Immunopharmacol 2024; 131:111853. [PMID: 38503014 DOI: 10.1016/j.intimp.2024.111853] [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: 11/02/2023] [Revised: 02/16/2024] [Accepted: 03/10/2024] [Indexed: 03/21/2024]
Abstract
Acute lung injury (ALI) is a common postoperative complication, particularly in pediatric patients after liver transplantation. Hepatic ischemia-reperfusion (HIR) increases the release of exosomes (IR-Exos) in peripheral circulation. However, the role of IR-Exos in the pathogenesis of ALI induced by HIR remains unclear. Here, we explored the role of exosomes derived from the HIR-injured liver in ALI development. Intravenous injection of IR-Exos caused lung inflammation in naive rats, whereas pretreatment with an inhibitor of exosomal secretion (GW4869) attenuated HIR-related lung injury. In vivo and in vitro results show that IR-Exos promoted proinflammatory responses and M1 macrophage polarization. Furthermore, miRNA profiling of serum identified miR-122-5p as the exosomal miRNA with the highest increase in young rats with HIR compared with controls. Additionally, IR-Exos transferred miR-122-5p to macrophages and promoted proinflammatory responses and M1 phenotype polarization by targeting suppressor of cytokine signaling protein 1(SOCS-1)/nuclear factor (NF)-κB. Importantly, the pathological role of exosomal miR-122-5p in initiating lung inflammation was reversed by inhibition of miR-122-5p. Clinically, high levels of miR-122-5p were found in serum and correlated to the severity of lung injury in pediatric living-donor liver transplant recipients with ALI. Taken together, our findings reveal that IR-Exos transfer liver-specific miR-122-5p to alveolar macrophages and elicit ALI by inducing M1 macrophage polarization via the SOCS-1/NF-κB signaling pathway.
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Affiliation(s)
- Jingshu Lyu
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China; Department of Anesthesiology and Perioperative Medicine, Zhengzhou University People's Hospital, Henan University People's Hospital, Henan Provincial People's Hospital, 450000 Zhengzhou, China
| | - Mingwei Sheng
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China
| | - Yingli Cao
- School of Medicine, Nankai University, 300071 Tianjin, China
| | - Lili Jia
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China
| | - Chen Zhang
- Department of Anesthesiology, The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Yiqi Weng
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China
| | - Wenli Yu
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China; School of Medicine, Nankai University, 300071 Tianjin, China.
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Pan B, Ma X, Zhou S, Cheng X, Fang J, Yi Q, Li Y, Li S, Yang J. Predicting mitophagy-related genes and unveiling liver endothelial cell heterogeneity in hepatic ischemia-reperfusion injury. Front Immunol 2024; 15:1370647. [PMID: 38694511 PMCID: PMC11061384 DOI: 10.3389/fimmu.2024.1370647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/02/2024] [Indexed: 05/04/2024] Open
Abstract
Background Hepatic Ischemia-Reperfusion Injury (HIRI) is a major complication in liver transplants and surgeries, significantly affecting postoperative outcomes. The role of mitophagy, essential for removing dysfunctional mitochondria and maintaining cellular balance, remains unclear in HIRI. Methods To unravel the role of mitophagy-related genes (MRGs) in HIRI, we assembled a comprehensive dataset comprising 44 HIRI samples alongside 44 normal control samples from the Gene Expression Omnibus (GEO) database for this analysis. Using Random Forests and Support Vector Machines - Recursive Feature Elimination (SVM-RFE), we pinpointed eight pivotal genes and developed a logistic regression model based on these findings. Further, we employed consensus cluster analysis for classifying HIRI patients according to their MRG expression profiles and conducted weighted gene co-expression network analysis (WGCNA) to identify clusters of genes that exhibit high correlation within different modules. Additionally, we conducted single-cell RNA sequencing data analysis to explore insights into the behavior of MRGs within the HIRI. Results We identified eight key genes (FUNDC1, VDAC1, MFN2, PINK1, CSNK2A2, ULK1, UBC, MAP1LC3B) with distinct expressions between HIRI and controls, confirmed by PCR validation. Our diagnostic model, based on these genes, accurately predicted HIRI outcomes. Analysis revealed a strong positive correlation of these genes with monocytic lineage and a negative correlation with B and T cells. HIRI patients were divided into three subclusters based on MRG profiles, with WGCNA uncovering highly correlated gene modules. Single-cell analysis identified two types of endothelial cells with different MRG scores, indicating their varied roles in HIRI. Conclusions Our study highlights the critical role of MRGs in HIRI and the heterogeneity of endothelial cells. We identified the macrophage migration inhibitory factor (MIF) and cGAS-STING (GAS) pathways as regulators of mitophagy's impact on HIRI. These findings advance our understanding of mitophagy in HIRI and set the stage for future research and therapeutic developments.
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Affiliation(s)
- Bochen Pan
- Department of Biochemistry, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xuan Ma
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Shihuan Zhou
- Department of Biochemistry, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xiaoling Cheng
- Department of Cell Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jianwei Fang
- Department of Biochemistry, Zunyi Medical University, Zunyi, Guizhou, China
| | - Qiuyun Yi
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yuke Li
- Department of Biochemistry, Zunyi Medical University, Zunyi, Guizhou, China
| | - Song Li
- Department of Biochemistry, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jiawei Yang
- Department of Biochemistry, Zunyi Medical University, Zunyi, Guizhou, China
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Zhu C, Shi S, Jiang P, Huang X, Zhao J, Jin Y, Shen Y, Zhou X, Liu H, Cai J. Curcumin Alleviates Hepatic Ischemia-Reperfusion Injury by Inhibiting Neutrophil Extracellular Traps Formation. J INVEST SURG 2023; 36:2164813. [PMID: 36603844 DOI: 10.1080/08941939.2022.2164813] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (IRI) is a common innate immune-mediated sterile inflammatory response in liver transplantation and liver tumor resection. Neutrophil extracellular traps (NETs) can aggravate liver injury and activates innate immune response in the process of liver IRI. However, Curcumin (Cur) can reverse this damage and reduce NETs formation. Nevertheless, the specific regulatory mechanism is still unclear in liver IRI. This study aimed to explore the potential mechanisms that how does Cur alleviate hepatic IRI by inhibits NETs production and develop novel treatment regimens. METHODS We established a hepatic IRI model by subjecting C57BL/6J mice to 60 min of ischemia, followed by reperfusion for 2 h, 6 h, 12 h, and 24 h respectively. Subsequently, we were separated into 5 groups, namely the I/R group, Cur group, DNase-1 group, Cur + DNase1 group and sham operation group. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST), Hematoxylin-eosin staining, immunofluorescence, and TUNEL analysis were applied to assess liver injury degree and NETs levels. Western blot assay was used to detect the protein levels of apoptosis-related proteins and MEK pathway proteins. RESULTS Cur could alleviate hepatic IRI by inhibiting the generation of NETs via suppressing the MEK/ERK pathway. In addition, this study also revealed that DNase-1 is vital for alleviating hepatic IRI by reducing the generation of NETs. CONCLUSIONS Cur combined with DNase-1 was more effective than the two drugs administered alone in alleviating hepatic IRI by inhibiting the generation of NETs. These results also suggested that curcumin combined with DNase-1 was a potential therapeutic strategy to mitigate hepatic IRI.
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Affiliation(s)
- Cunle Zhu
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China.,Organ Transplantation Center, The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Shangheng Shi
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Peng Jiang
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Xijian Huang
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Jinxin Zhao
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Yan Jin
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Yuntai Shen
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Xin Zhou
- The Institute of Transplantation Science, Qingdao University, Qingdao, Shandong Province, China
| | - Huan Liu
- Organ Transplantation Center, The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Jinzhen Cai
- Organ Transplantation Center, The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
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Wang Y, Jia L, Wei M, Lyu J, Sheng M, Sun Y, Dong Z, Han W, Ren Y, Weng Y, Yu W. Circulating Exosomes Mediate Neurodegeneration Following Hepatic Ischemia-reperfusion Through Inducing Microglial Pyroptosis in the Developing Hippocampus. Transplantation 2023; 107:2364-2376. [PMID: 37291725 PMCID: PMC10593148 DOI: 10.1097/tp.0000000000004664] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 06/10/2023]
Abstract
BACKGROUND Poor neurodevelopmental outcomes after pediatric liver transplantation seriously affect the long-term quality of life of recipients, in whom hepatic ischemia reperfusion (HIR) is considered to play a pivotal role. However, the link between HIR and brain injury remains unclear. Because circulating exosomes are considered as the key mediators of information transmission over long distances, we aimed to assess the role of circulating exosomes in HIR-induced hippocampal injury in young rats. METHODS We administered exosomes extracted from the sera of HIR model rats to normal young rats via the tail vein. Western blotting, enzyme-linked immunosorbent assay, histological examination, and real-time quantitative polymerase chain reaction were used to evaluate the role of exosomes in neuronal injury and activation of microglial pyroptosis in the developing hippocampus. Primary microglial cells were cocultured with exosomes to further assess the effect of exosomes on microglia. To further explore the potential mechanism, GW4869 or MCC950 was used to block exosome biogenesis or nod-like receptor family protein 3, respectively. RESULTS Serum-derived exosomes played a crucial role in linking HIR with neuronal degeneration in the developing hippocampus. Microglia were found to be the target cells of ischemia-reperfusion derived exosomes (I/R-exosomes). I/R-exosomes were taken up by microglia and promoted the occurrence of microglial pyroptosis in vivo and in vitro. Moreover, the exosome-induced neuronal injury was alleviated by suppressing the occurrence of pyroptosis in the developing hippocampus. CONCLUSIONS Microglial pyroptosis induced by circulating exosomes plays a vital role in developing hippocampal neuron injury during HIR in young rats.
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Affiliation(s)
- Yidan Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Lili Jia
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
| | - Min Wei
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Jingshu Lyu
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Mingwei Sheng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
| | - Ying Sun
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
| | - Zhonglan Dong
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Wenhui Han
- School of Medicine, Nankai University, Tianjin, China
| | - Yinghui Ren
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
| | - Yiqi Weng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
| | - Wenli Yu
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
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Lv J, Zhu X, Xing C, Chen Y, Bian H, Yin H, Gu X, Su L. Stimulator of interferon genes (STING): Key therapeutic targets in ischemia/reperfusion injury. Biomed Pharmacother 2023; 167:115458. [PMID: 37699319 DOI: 10.1016/j.biopha.2023.115458] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/25/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023] Open
Abstract
The Stimulator of Interferon Genes (STING) is predominantly expressed in immune cells, including macrophages, natural killer cells, dendritic cells, and T cells, functioning as a pattern recognition receptor. STING activation upon detecting cytosolic DNA released from damaged cells initiates downstream pathways, leading to the production of inflammatory cytokines such as IFNs, IL-6, and TNF-α. Dysregulated STING activation has been implicated in inflammatory and metabolic diseases. Ischemia/reperfusion injury (I/RI) is common in stroke, acute myocardial infarction, organ transplantation, and surgeries for certain end-stage diseases. Recent studies suggest that STING could be a novel therapeutic target for I/RI treatment. In this review, we provide a concise overview of the cGAS-STING signaling pathway's general functions and summarize STING's role in I/RI across various organs, including the heart, liver, kidney, and lung. Moreover, we explore potential therapeutic approaches for I/RI by targeting STING.
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Affiliation(s)
- Juan Lv
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, China; Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
| | - Xuanxuan Zhu
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, China
| | - Chunlei Xing
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
| | - Yuhong Chen
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
| | - Huihui Bian
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
| | - Heng Yin
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, China.
| | - Xiaofeng Gu
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, China.
| | - Li Su
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, China; Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
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Mouratidou C, Pavlidis ET, Katsanos G, Kotoulas SC, Mouloudi E, Tsoulfas G, Galanis IN, Pavlidis TE. Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog. World J Gastrointest Surg 2023; 15:1858-1870. [PMID: 37901735 PMCID: PMC10600776 DOI: 10.4240/wjgs.v15.i9.1858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatic ischemia-reperfusion syndrome has been the subject of intensive study and experimentation in recent decades since it is responsible for the outcome of several clinical entities, such as major hepatic resections and liver transplantation. In addition to the organ's post reperfusion injury, this syndrome appears to play a central role in the dysfunction of distant tissues and systems. Thus, continuous research should be directed toward finding effective therapeutic options to improve the outcome and reduce the postoperative morbidity and mortality rates. Treprostinil is a synthetic analog of prostaglandin I2, and its experimental administration has shown encouraging results. It has already been approved by the Food and Drug Administration in the United States for pulmonary arterial hypertension and has been used in liver transplantation, where preliminary encouraging results showed its safety and feasibility by using continuous intravenous administration at a dose of 5 ng/kg/min. Treprostinil improves renal and hepatic function, diminishes hepatic oxidative stress and lipid peroxidation, reduces hepatictoll-like receptor 9 and inflammation, inhibits hepatic apoptosis and restores hepatic adenosine triphosphate (ATP) levels and ATP synthases, which is necessary for functional maintenance of mitochondria. Treprostinil exhibits vasodilatory properties and antiplatelet activity and regulates proinflammatory cytokines; therefore, it can potentially minimize ischemia-reperfusion injury. Additionally, it may have beneficial effects on cardiovascular parameters, and much current research interest is concentrated on this compound.
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Affiliation(s)
| | - Efstathios T Pavlidis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Georgios Katsanos
- Department of Transplantation, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | | | - Eleni Mouloudi
- Intensive Care Unit, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis N Galanis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Theodoros E Pavlidis
- 2nd Propedeutic Department of Surgery, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Liu J, Zhang W, Wang X, Ding Q, Wu C, Zhang W, Wu L, James TD, Li P, Tang B. Unveiling the Crucial Roles of O 2•- and ATP in Hepatic Ischemia-Reperfusion Injury Using Dual-Color/Reversible Fluorescence Imaging. J Am Chem Soc 2023; 145:19662-19675. [PMID: 37655757 PMCID: PMC10510312 DOI: 10.1021/jacs.3c04303] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Indexed: 09/02/2023]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is mainly responsible for morbidity or death due to graft rejection after liver transplantation. During HIRI, superoxide anion (O2•-) and adenosine-5'-triphosphate (ATP) have been identified as pivotal biomarkers associated with oxidative stress and energy metabolism, respectively. However, how the temporal and spatial fluctuations of O2•- and ATP coordinate changes in HIRI and particularly how they synergistically regulate each other in the pathological mechanism of HIRI remains unclear. Herein, we rationally designed and successfully synthesized a dual-color and dual-reversible molecular fluorescent probe (UDP) for dynamic and simultaneous visualization of O2•- and ATP in real-time, and uncovered their interrelationship and synergy in HIRI. UDP featured excellent sensitivity, selectivity, and reversibility in response to O2•- and ATP, which rendered UDP suitable for detecting O2•- and ATP and generating independent responses in the blue and red fluorescence channels without spectral crosstalk. Notably, in situ imaging with UDP revealed for the first time synchronous O2•- bursts and ATP depletion in hepatocytes and mouse livers during the process of HIRI. Surprisingly, a slight increase in ATP was observed during reperfusion. More importantly, intracellular O2•-─succinate dehydrogenase (SDH)─mitochondrial (Mito) reduced nicotinamide adenine dinucleotide (NADH)─Mito ATP─intracellular ATP cascade signaling pathway in the HIRI process was unveiled which illustrated the correlation between O2•- and ATP for the first time. This research confirms the potential of UDP for the dynamic monitoring of HIRI and provides a clear illustration of HIRI pathogenesis.
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Affiliation(s)
- Jihong Liu
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Wen Zhang
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Xin Wang
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Qi Ding
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Chuanchen Wu
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Wei Zhang
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Luling Wu
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
- Department
of Chemistry, University of Bath, Bath BA2 7AY, U.K.
| | - Tony D. James
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
- Department
of Chemistry, University of Bath, Bath BA2 7AY, U.K.
- School
of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang 453007, People’s
Republic of China
| | - Ping Li
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
| | - Bo Tang
- College
of Chemistry, Chemical Engineering and Materials Science, Key Laboratory
of Molecular and Nano Probes, Ministry of Education, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People’s Republic of China
- Laoshan
Laboratory, Qingdao 266237, People’s Republic
of China
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Suryono S, Rohman MS, Widjajanto E, Prayitnaningsih S, Wihastuti TA, Oktaviono YH. Effect of Colchicine in reducing MMP-9, NOX2, and TGF- β1 after myocardial infarction. BMC Cardiovasc Disord 2023; 23:449. [PMID: 37697278 PMCID: PMC10496361 DOI: 10.1186/s12872-023-03464-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 08/22/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND According to WHO 2020, CAD is the second leading cause of death in Indonesia with death cases reaching 259,297 or 15.33% of total deaths. Unfortunately, most of the patients of CAD in Indonesia did not match the golden period or decline to be treated with Percutaneous Coronary Intervention (PCI). Based on the recent study, there were increases in MMP-9, NOX2, and TGF-β1 in STEMI patients which contribute to cardiac remodeling. Moreover, there is controversy regarding the benefit of late PCI (12-48 hours after onset of STEMI) in stable patients. Lately, colchicine is widely used in cardiovascular disease. This study was conducted to explore the effect of colchicine to reduce MMP- 9, NOX2, and TGF-β1 levels after myocardial infarction in stable patients. METHOD In this clinical trial study, we assessed 129 STEMI patients, about 102 patients who met inclusion criteria were randomized into four groups. Around 25 patients received late PCI (12-48 h after the onset of chest pain), optimal medical treatment (OMT) for STEMI, and colchicine; 24 patients received late PCI and OMT; 22 patients didn't get the revascularization (No Revas), OMT, and colchicine; and 31 patients received No Revas and OMT only. The laboratory test for MMP-9, NOX2, and TGF-β1 were tested in Day-1 and Day-5. The data were analyzed using Mann-Whitney. RESULTS A total of 102 patients with mean age of 56 ± 9.9, were assigned into four groups. The data analysis showed significant results within No Revas + OMT + Colchicine group versus No Revas + OMT + Placebo in MMP-9 (Day-1: p = 0.001; Day-5: p = 0.022), NOX2 (Day-1: p = 0.02; Day-5: p = 0.026), and TGF-β1 (Day-1: p = 0.00; Day-5: p = 0.00) with the less three markers in OMT + Colchicine group than OMT + Placebo group. There were no significant differences within the late PCI + OMT + colchicine group and PCI + OMT + Placebo group. CONCLUSIONS Colchicine could significantly reduce MMP-9, NOX2, and TGF-β1 levels in stable STEMI patients. So that, colchicine could be a potential agent in STEMI patients and prevent cardiac remodeling events.
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Affiliation(s)
- Suryono Suryono
- Doctoral Program of Medical Science, Brawijaya University, Malang, East Java, Indonesia.
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Jember University, Jember, East Java, Indonesia.
| | - Mohammad Saifur Rohman
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia
- Brawijaya Cardiovascular Research Centre, Brawijaya University, Malang, East Java, Indonesia
| | - Edi Widjajanto
- Department of Clinical Pathology, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia
| | - Seskoati Prayitnaningsih
- Department of Ophthalmology, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia
| | - Titin Andri Wihastuti
- Department of Biomedical, Nursing Science, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia
| | - Yudi Her Oktaviono
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University, Surabaya, Indonesia
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Schnider TW, Nieuwenhuijs-Moeke GJ, Beck-Schimmer B, Hemmerling TM. Pro-Con Debate: Should All General Anesthesia Be Done Using Target-Controlled Propofol Infusion Guided by Objective Monitoring of Depth of Anesthesia? Anesth Analg 2023; 137:565-575. [PMID: 37590801 DOI: 10.1213/ane.0000000000006293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Abstract
In this Pro-Con commentary article, we discuss whether all general anesthesia should be done using target-controlled propofol anesthesia guided by monitoring of depth of anesthesia. This is an ongoing debate since more than 25 years, representing a scientific, cultural as well as geographical divide in the anesthesia community. The Pro side argues that total intravenous anesthesia causes less postoperative nausea and higher patient satisfaction than anesthesia using volatile anesthetics. Target-controlled infusion (TCI) of anesthetic agents allows for better titration of intravenous anesthesia using pharmacokinetic models. Processed EEG monitors, such as bispectral index monitoring, allows for better assessing the effect of TCI anesthesia than solely assessment of clinical parameters, such as ECG or blood pressure. The combination of TCI propofol and objective depth of anesthesia monitoring allows creating a pharmacokinetic-pharmacodynamic profile for each patient. Finally, anesthesia using volatile anesthetics poses health risks for healthcare professionals and contributes to greenhouse effect. The Con side argues that for procedures accompanied with ischemia and reperfusion injury of an organ or tissue and for patients suffering from a severe inflammation' the use of volatile anesthetics might well have its advantages above propofol. In times of sudden shortage of drugs, volatile anesthetics can overcome the restriction in the operating theater or even on the intensive care unit, which is another advantage. Volatile anesthetics can be used for induction of anesthesia when IV access is impossible, end-tidal measurements of volatile anesthetic concentration allows confirmation that patients receive anesthetics. Taking environmental considerations into account, both propofol and volatile anesthetics bear certain harm to the environment, be it as waste product or as greenhouse gases. The authors therefore suggest to carefully considering advantages and disadvantages for each patient in its according environment. A well-balanced choice based on the available literature is recommended. The authors recommend careful consideration of advantages and disadvantages of each technique when tailoring an anesthetic to meet patient needs. Where appropriate, anesthesia providers are encouraged to account for unique features of anesthetic drug behavior, patient-reported and observed postoperative outcomes, and economic and environmental considerations when choosing any of the 2 described techniques.
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Affiliation(s)
- Thomas W Schnider
- From the Department for Anesthesiology, Intensive, Rescue and Pain medicine, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Gertrude J Nieuwenhuijs-Moeke
- Department of Anesthesiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
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Guo Z, Zhao Q, Jia Z, Huang C, Wang D, Ju W, Zhang J, Yang L, Huang S, Chen M, Zhu X, Hu A, Ma Y, Wu L, Chen Y, Han M, Tang Y, Wang G, Wang L, Li L, Xiong W, Zhang Z, Shen Y, Tang Z, Zhu C, Chen X, Hu X, Guo Y, Chen H, Ma Y, Zhang T, Huang S, Zeng P, Lai S, Wang T, Chen Z, Gong J, Yu J, Sun C, Li C, Tan H, Liu Y, Dong Y, Sun C, Liao B, Ren J, Zhou Z, Andrea S, Björn N, Cai C, Gong F, Rong J, Huang W, Guan X, Clavien PA, Stefan TG, Huang J, He X. A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease. J Hepatol 2023; 79:394-402. [PMID: 37086919 DOI: 10.1016/j.jhep.2023.04.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/13/2023] [Accepted: 04/03/2023] [Indexed: 04/24/2023]
Abstract
BACKGROUND & AIMS Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.
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Affiliation(s)
- Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China; NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, China.
| | - Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Zehua Jia
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Changjun Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Jian Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510080, China
| | - Lu Yang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shanzhou Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Anbin Hu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Yi Ma
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Linwei Wu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Yinghua Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Ming Han
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Guodong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Linhe Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Lifen Li
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Wei Xiong
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhiheng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Yuekun Shen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhaoxia Tang
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Caihui Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Xiaoxiang Chen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiaoguang Hu
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Yiwen Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Honghui Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Yihao Ma
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Tao Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Shunwei Huang
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Ping Zeng
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Simei Lai
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Tielong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Zhitao Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Jinlong Gong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Jia Yu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Canhui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Chang Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Haiyi Tan
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yao Liu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Yuqi Dong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Chengjun Sun
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China
| | - Bing Liao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jun Ren
- Department of Blood Transfusion, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhenhai Zhou
- Department of Blood Transfusion, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Schlegel Andrea
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20100, Italy
| | - Nashan Björn
- Organ Transplantation Center, The First Affiliated Hospital of the University of Science and Technology of China, Hefei, 230001, China
| | - Changjie Cai
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Fengqiu Gong
- Operating Room and Anesthesia Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jian Rong
- Department of Cardiopulmonary Bypass, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Wenqi Huang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiangdong Guan
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Pierre-Alain Clavien
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Zurich 8044, Switzerland
| | - Tullius G Stefan
- Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA
| | - Jiefu Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, 510080, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, 510080, China.
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Yu Q, Chen S, Li J, Tang H, Shi J, Guo W, Zhang S. Mitogen activated protein kinase phosphatase 5 alleviates liver ischemia-reperfusion injury by inhibiting TAK1/JNK/p38 pathway. Sci Rep 2023; 13:11110. [PMID: 37429895 PMCID: PMC10333288 DOI: 10.1038/s41598-023-37768-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/27/2023] [Indexed: 07/12/2023] Open
Abstract
Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of the MKP family and has been implicated in diverse biological and pathological conditions. However, it is unknown what role MKP5 plays in liver ischemia/reperfusion (I/R) injury. In the present study, we used MKP5 global knockout (KO) and MKP5 overexpressing mice to establish a liver I/R injury model in vivo, and MKP5 knockdown or MKP5 overexpressing HepG2 cells to establish a hypoxia-reoxygenation (H/R) model in vitro. In this study we demonstrated that protein expression of MKP5 was significantly downregulated in liver tissue of mice after I/R injury, and HepG2 cells subjected to H/R injury. MKP5 KO or knockdown significantly increased liver injury, as demonstrated by elevated serum transaminases, hepatocyte necrosis, infiltrating inflammatory cells, secretion of pro-inflammatory cytokines, apoptosis, oxidative stress. Conversely, MKP5 overexpression significantly attenuated liver and cell injury. Furthermore, we showed that MKP5 exerted its protective effect by inhibiting c-Jun N-terminal kinase (JNK)/p38 activity, and its action was dependent on Transforming growth factor-β-activated kinase 1 (TAK1) activity. According to our results, MKP5 inhibited the TAK1/JNK/p38 pathway to protect liver from I/R injury. Our study identifies a novel target for the diagnosis and treatment of liver I/R injury.
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Affiliation(s)
- Qiwen Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Sanyang Chen
- Department of Emergency Surgery, the First Affiliated Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Jiye Li
- Department of Emergency Surgery, the First Affiliated Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Hongwei Tang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Jihua Shi
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, China.
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China.
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Hou Y, He Z, Han Y, Zhang T, Wang S, Wang X, Mao J. Mechanism of new optimized Sheng-Mai-San Formula to regulate cardiomyocyte apoptosis through NMDAR pathway. Heliyon 2023; 9:e16631. [PMID: 37416647 PMCID: PMC10320033 DOI: 10.1016/j.heliyon.2023.e16631] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 07/08/2023] Open
Abstract
Background and objectives Ischemic heart failure (HF) has become a disease that seriously endangers people's life and health. As a herbal formula widely used in clinical practice, new optimized Sheng-Mai-San (NO-SMS) has been shown to be significantly effective in improving cardiac function, increasing exercise tolerance, and slowing the progression of myocardial fibrosis in heart failure patients in multi-center clinical studies in various regions of China. In our previous pharmacodynamic and toxicological studies, we found that a medium-dose formulation (8.1 g of raw drug/kg) was the most effective in the treatment of heart failure, but its mechanism of action is still being investigated. The present study is exploring its relationship with cardiomyocyte apoptosis. Materials and methods We investigated and verified this through two parts of experiments, in vivo and in vitro. Firstly, we prepared male SD rats with heart failure models by ligating the left anterior descending branch of the coronary artery (EF ≤ 50%), which were treated with NO-SMS Formula (8.1 g of raw drug/kg/d), Ifenprodil (5.4 mg/kg/d) or Enalapril (0.9 mg/kg/d) prepared suspensions by gavage for 4 weeks. The cardiac and structural changes were evaluated by echocardiography, H&E, and MASSON staining. The apoptosis of cardiomyocytes in each group was detected by Western blot, qRT-PCR, and ELISA. In vitro cell experiments include H9c2 cardiomyocyte injury induced by H2O2 and NMDA respectively, and the groups were incubated with NO-SMS and Ifenprodil-containing serum for 24 h. Apoptosis was detected by Annexin V-FITC/PI double-staining method, and the rest of the assays were consistent with the in vivo experiments. Results Compared with the model group, the NO-SMS formula group and the Ifenprodil group could significantly improve cardiac function, delay myocardial fibrosis, reduce the expression of pro-apoptotic proteins, mRNA, and the concentration levels of Ca2+ and ROS in heart failure rats and H9c2 cardiomyocytes with H2O2 and NMDA-induced injury, which could significantly reduce the apoptosis rate of damaged cardiomyocytes and effectively inhibit the apoptosis of cardiomyocytes. Conclusion NO-SMS Formula improved cardiac function, inhibited ventricular remodeling and cardiomyocyte apoptosis in HF rats, and its mechanism may be related to the regulation of the NMDAR signaling pathway, inhibition of large intracellular Ca2+ inward flow, and ROS production in cardiomyocytes.
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Affiliation(s)
- Yazhu Hou
- Department of Cardiovascular Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Zixun He
- Department of Cardiovascular Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yixiao Han
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Tongyan Zhang
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China
| | - Shuai Wang
- Department of Cardiovascular Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Xianliang Wang
- Department of Cardiovascular Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Jingyuan Mao
- Department of Cardiovascular Diseases, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
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Zhong C, Yang J, Zhang Y, Fan X, Fan Y, Hua N, Li D, Jin S, Li Y, Chen P, Chen Y, Cai X, Zhang Y, Jiang L, Yang W, Yu P, Lin H. TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca 2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression. RESEARCH (WASHINGTON, D.C.) 2023; 6:0159. [PMID: 37275121 PMCID: PMC10232356 DOI: 10.34133/research.0159] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 05/03/2023] [Indexed: 06/07/2023]
Abstract
Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.
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Affiliation(s)
- Cheng Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Jing Yang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yiyin Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yang Fan
- Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Ning Hua
- Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province,
Xinxiang Medical University, 453003 Xinxiang, Henan, P.R. China
| | - Duguang Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Peng Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Yongle Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
| | - Xiaobo Cai
- Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
| | - Yi Zhang
- Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
| | - Linhua Jiang
- Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province,
Xinxiang Medical University, 453003 Xinxiang, Henan, P.R. China
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, UK
| | - Wei Yang
- Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
| | - Peilin Yu
- Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, P.R. China
- Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital,
School of Medicine, Zhejiang University, Hangzhou 310020, P.R. China
- College of Biomedical Engineering and Instrument Science,
Zhejiang University, Hangzhou 310058, P.R. China
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Gao H, Bai M, Chu A, Pan C, Zhao J, Zhang Z, Shang X. Safety and efficacy of perioperative continuous renal replacement therapy for percutaneous coronary intervention in severe acute myocardial infarction patients. J Med Life 2023; 16:719-724. [PMID: 37520492 PMCID: PMC10375348 DOI: 10.25122/jml-2022-0270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 03/27/2023] [Indexed: 08/01/2023] Open
Abstract
This retrospective study aimed to evaluate the safety and efficacy of continuous renal replacement therapy (CRRT) during percutaneous coronary intervention (PCI) in patients with severe acute myocardial infarction (AMI). The study analyzed data from 945 AMI patients hospitalized between January 2016 and December 2017, out of which 21 patients underwent perioperative CRRT for PCI. We assessed the baseline characteristics of severe AMI patients before and after CRRT and examined the effect of CRRT on cardiac, renal, and liver function, as well as other indicators. The heart rate of patients undergoing CRRT was significantly lower at 24 h and 48 h after CRRT than before CRRT (p=0.038). There was a moderate but not significant decrease in the mean systolic blood pressure or diastolic blood pressure (p>0.05). Importantly, we found that significantly more patients showed Killip class I-II and significantly improved cardiac function after CRRT (23.8% vs. 57.1%, p=0.001). The levels of urea nitrogen, creatinine, aspartate aminotransferase, glutamic pyruvic transaminase, and total bilirubin were significantly lowered after CRRT treatment (p<0.05). Perioperative management of CRRT was safe and effective for severe AMI patients.
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Affiliation(s)
- Hanxiang Gao
- Department of Cardiology, First Hospital of Lanzhou University, Lanzhou, China
| | - Ming Bai
- Department of Cardiology, First Hospital of Lanzhou University, Lanzhou, China
| | - Aiai Chu
- Department of Cardiology, Gansu Provincial Hospital, Lanzhou, China
| | - Chenliang Pan
- Department of Cardiology, First Hospital of Lanzhou University, Lanzhou, China
| | - Jing Zhao
- Department of Cardiology, First Hospital of Lanzhou University, Lanzhou, China
| | - Zheng Zhang
- Department of Cardiology, First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaofeng Shang
- Department of Cardiology, Zhangye People's Hospital Affiliated Hexi College, Zhangye, Gansu, China
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Kükner A, Toros P, Söyler G, Isik S, Ögütçü G, Edebal O, Meriçli F. Effects of Coriandrum sativum on distant organ inflammation and apoptosis due to liver ischemia/reperfusion injury. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2023; 64:207-213. [PMID: 37518878 PMCID: PMC10520375 DOI: 10.47162/rjme.64.2.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/16/2023] [Indexed: 08/01/2023]
Abstract
Liver ischemia/reperfusion (IR) often affects distant organs, such as small intestine, kidney, and lung. Coriandrum sativum (CS) has an antioxidant and anti-inflammatory effect on liver damage. The aim of this study was to investigate the anti-inflammatory and antiapoptotic effects of CS extract on small intestine, lung, and kidney after the liver IR injury. Small intestine, lung, and kidney tissues were evaluated and scored in terms of cell degeneration, inflammation, and congestion, as well as caspase-3 (Cas-3) and cluster of differentiation 31 (CD31) immunostainings were carried out. Renal enzymes, creatinine and urea levels were measured biochemically in serum. After IR, a decrease in villi size, diffuse degeneration, epithelial cell shedding and extensive congestion in the capillaries were observed. Meanwhile, the number of degenerated villi and congestion decreased in the IR+CS group. Due to IR, increased congestion was detected in the interalveolar septum of the lungs and in the capillaries between the kidney tubules. It was also observed that the positively stained cells with Cas-3 and CD31 were increased in the lung, kidney, and small intestine tissues of the IR group, and decreased in the IR+CS group. Kidney enzymes, urea and creatinine levels were significantly increased in the IR group and decreased in the IR+CS group. In conclusion, it was observed that liver IR caused changes in distant organs, especially in the small intestine, lung, and kidneys. Damaging effects of IR as well as apoptosis and inflammation were found to be decreased in the groups treated with CS.
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Affiliation(s)
- Aysel Kükner
- Department of Histology and Embryology, Faculty of Medicine, Near East University, Nicosia, Cyprus;
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Rowe CJ, Walsh SA, Dragon AH, Rhodes AM, Pak OL, Ronzier E, Levi B, Potter BK, Spreadborough PJ, Davis TA. Tourniquet-induced ischemia creates increased risk of organ dysfunction and mortality following delayed limb amputation. Injury 2023:S0020-1383(23)00179-1. [PMID: 36906480 DOI: 10.1016/j.injury.2023.02.047] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/06/2023] [Accepted: 02/23/2023] [Indexed: 03/13/2023]
Abstract
Tourniquets are critical for the control of traumatic extremity hemorrhage. In this study, we sought to determine, in a rodent blast-related extremity amputation model, the impact of prolonged tourniquet application and delayed limb amputation on survival, systemic inflammation, and remote end organ injury. Adult male Sprague Dawley rats were subjected to blast overpressure (120±7 kPa) and orthopedic extremity injury consisting femur fracture, one-minute soft tissue crush injury (20 psi), ± 180 min of tourniquet-induced hindlimb ischemia followed by delayed (60 min of reperfusion) hindlimb amputation (dHLA). All animals in the non-tourniquet group survived whereas 7/21 (33%) of the animals in the tourniquet group died within the first 72 h with no deaths observed between 72 and 168 h post-injury. Tourniquet induced ischemia-reperfusion injury (tIRI) likewise resulted in a more robust systemic inflammation (cytokines and chemokines) and concomitant remote pulmonary, renal, and hepatic dysfunction (BUN, CR, ALT. AST, IRI/inflammation-mediated genes). These results indicate prolonged tourniquet application and dHLA increases risk of complications from tIRI, leading to greater risk of local and systemic complications including organ dysfunction or death. We thus need enhanced strategies to mitigate the systemic effects of tIRI, particularly in the military prolonged field care (PFC) setting. Furthermore, future work is needed to extend the window within which tourniquet deflation to assess limb viability remains feasible, as well as new, limb-specific or systemic point of care tests to better assess the risks of tourniquet deflation with limb preservation in order to optimize patient care and save both limb and life.
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Affiliation(s)
- Cassie J Rowe
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, United States
| | - Sarah A Walsh
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States
| | - Andrea H Dragon
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, United States
| | - Alisha M Rhodes
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, United States
| | - Olivia L Pak
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, United States
| | - Elsa Ronzier
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, United States
| | - Benjamin Levi
- Center for Organogenesis Research and Trauma, University of Texas Southwestern, Dallas, TX, United States
| | - Benjamin K Potter
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States
| | - Philip J Spreadborough
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States; Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, United Kingdom
| | - Thomas A Davis
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, United States.
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48
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Liu Y, Sheng M, Jia L, Zhu M, Yu W. Protective effects of cordycepin pretreatment against liver ischemia/reperfusion injury in mice. Immun Inflamm Dis 2023; 11:e792. [PMID: 36988254 PMCID: PMC10013135 DOI: 10.1002/iid3.792] [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: 11/09/2022] [Revised: 01/20/2023] [Accepted: 02/09/2023] [Indexed: 03/16/2023] Open
Abstract
INTRODUCTION Cordycepin has been reported to exhibit hepatic protective and anti-inflammatory properties. Here, we investigated the role of cordycepin in ischemia/reperfusion (IR)-induced liver injury in a mouse model. METHODS Mice were pretreated with cordycepin by gavage for 3 weeks, followed by the establishment of the IR modeling. Liver injury, Suzuki's histological grading, hepatic apoptosis, and inflammatory responses were evaluated by biochemical and pathological analysis. RESULTS It was found that Cordycepin pretreatment at 50 mg/kg for 3 weeks attenuated IR-induced liver injury, as reflected by the significant decrease of the levels of aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and low-density lipoprotein. Cordycepin pretreatment also reduced histopathological changes, attenuated hepatocyte apoptosis, inflammatory responses in the livers of IR mice. Mechanically, toll-like receptor 4/nuclear factor kappa-B signaling in liver tissues was inhibited by Cordycepin pretreatment. CONCLUSIONS In conclusion, Cordycepin pretreatment protects IR-induced liver injury, which demonstrates its potential for the treatment of IR in the liver.
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Affiliation(s)
- Yunxia Liu
- Department of AnesthesiologyTianjin First Central HospitalTianjinChina
| | - Mingwei Sheng
- Department of AnesthesiologyTianjin First Central HospitalTianjinChina
| | - Lili Jia
- Department of AnesthesiologyTianjin First Central HospitalTianjinChina
| | - Min Zhu
- Department of AnesthesiologyTianjin First Central HospitalTianjinChina
| | - Wenli Yu
- Department of AnesthesiologyTianjin First Central HospitalTianjinChina
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Berezin AA, Obradovic Z, Berezina TA, Boxhammer E, Lichtenauer M, Berezin AE. Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines. Antioxidants (Basel) 2023; 12:516. [PMID: 36830074 PMCID: PMC9951884 DOI: 10.3390/antiox12020516] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Cardiac hepatopathy refers to acute or chronic liver damage caused by cardiac dysfunction in the absence of any other possible causative reasons of liver injury. There is a large number of evidence of the fact that cardiac hepatopathy is associated with poor clinical outcomes in patients with acute or actually decompensated heart failure (HF). However, the currently dominated pathophysiological background does not explain a role of metabolic regulative proteins secreted by hepatocytes in progression of HF, including adverse cardiac remodeling, kidney injury, skeletal muscle dysfunction, osteopenia, sarcopenia and cardiac cachexia. The aim of this narrative review was to accumulate knowledge of hepatokines (adropin; fetuin-A, selenoprotein P, fibroblast growth factor-21, and alpha-1-microglobulin) as adaptive regulators of metabolic homeostasis in patients with HF. It is suggested that hepatokines play a crucial, causative role in inter-organ interactions and mediate tissue protective effects counteracting oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and necrosis. The discriminative potencies of hepatokines for HF and damage of target organs in patients with known HF is under on-going scientific discussion and requires more investigations in the future.
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Affiliation(s)
- Alexander A. Berezin
- Internal Medicine Department, Zaporozhye Medical Academy of Postgraduate Education, 69000 Zaporozhye, Ukraine
- Klinik Barmelweid, Department of Psychosomatic Medicine and Psychotherapy, 5017 Barmelweid, Switzerland
| | - Zeljko Obradovic
- Klinik Barmelweid, Department of Psychosomatic Medicine and Psychotherapy, 5017 Barmelweid, Switzerland
| | - Tetiana A. Berezina
- Department of Internal Medicine & Nephrology, VitaCenter, 69000 Zaporozhye, Ukraine
| | - Elke Boxhammer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
| | - Alexander E. Berezin
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
- Internal Medicine Department, Zaporozhye State Medical University, 69035 Zaporozhye, Ukraine
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Gobut H, Kucuk A, Şengel N, Arslan M, Ozdemir C, Mortas T, Kasapbası E, Kurtipek O, Kavutcu M. Effects of cerium oxide (CeO 2) on liver tissue in liver ischemia-reperfusion injury in rats undergoing desflurane anesthesia. BMC Anesthesiol 2023; 23:40. [PMID: 36737682 PMCID: PMC9896676 DOI: 10.1186/s12871-023-01999-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION During liver surgery and transplantation, periods of partial or total vascular occlusion are inevitable and result in ischemia-reperfusion injury (IRI). Nanomedicine uses the latest technology, which has emerged with interdisciplinary effects, such as biomedical sciences, physics, and engineering, to protect and improve human health. Interdisciplinary research has brought along the introduction of antioxidant nanoparticles as potential therapeutics. The goal of this study was to investigate the effects of cerium oxide (CeO2) administration and desflurane anesthesia on liver tissue in liver IR injury. MATERIAL AND METHODS Thirty rats were randomly divided into five groups: control (C), ischemia-reperfusion (IR), IR-desflurane (IRD), cerium oxide-ischemia reperfusion (CeO2-IR), and cerium oxide-ischemia reperfusion-desflurane (CeO2-IRD). In the IR, IRD, and CeO2-IRD groups, hepatic ischemia was induced after the porta hepatis was clamped for 120 min, followed by 120 min of reperfusion. Intraperitoneal 0.5 mg/kg CeO2 was administered to the CeO2 groups 30 min before ischemia. Desflurane (6%) was administered to the IRD and CeO2-IRD groups during IR. All groups were sacrificed under anesthesia. Liver tissue samples were examined under a light microscope by staining with hematoxylin-eosin (H&E). Malondialdehyde (MDA) levels, catalase (CAT), glutathione-s-transferase (GST), and arylesterase (ARE) enzyme activities were measured in the tissue samples. RESULTS The IR group had considerably more hydropic degeneration, sinusoidal dilatation, and parenchymal mononuclear cell infiltration than the IRD, CeO2-IR, and CeO2-IRD groups. Catalase and GST enzyme activity were significantly higher in the CeO2-IR group than in the IR group. The MDA levels were found to be significantly lower in the IRD, CeO2-IR, and CeO2-IRD groups than in the IR group. CONCLUSION Intraperitoneal CeO2 with desflurane reduced oxidative stress and corrected liver damage.
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Affiliation(s)
- Huseyin Gobut
- Department of General Surgery, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Aysegul Kucuk
- Department of Physiology, Kutahya Health Sciences University Faculty of Medicine, Kutahya, Turkey
| | - Necmiye Şengel
- Department of Oral and Maxillofacial Surgery (as a specialist in Anesthesiology and Reanimation), Gazi University Faculty of Dentistry, Ankara, Turkey
| | - Mustafa Arslan
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, 06510, Ankara, Turkey.
- Gazi University, Life Sciences and Application Research Centre, Ankara, Turkey.
| | - Cagrı Ozdemir
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, 06510, Ankara, Turkey
| | - Tulay Mortas
- Department of Histology and Embryology, Kırıkkale University Faculty of Medicine, Kırıkkale, Turkey
| | - Esat Kasapbası
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, 06510, Ankara, Turkey
| | - Omer Kurtipek
- Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, 06510, Ankara, Turkey
| | - Mustafa Kavutcu
- Department of Medical Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey
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