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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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Ghanbari M, Ebrahimi H, Bagheri A, Khonakdar-Tarsi A, Mousavi H. Investigating Network and Experimental Effect of Silibinin on Lipin-1 and Lipin-2 Gene Expression during Ischemia-reperfusion of the Liver in Rats. Cell Biochem Biophys 2025:10.1007/s12013-025-01751-0. [PMID: 40246771 DOI: 10.1007/s12013-025-01751-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/19/2025]
Abstract
This study aims to investigate the impact of silibinin (SILI) on the expression of the Lipin-1 and Lipin-2 genes during warm ischemia-reperfusion (I/R) of the liver. Network pharmacology was employed to identify potential targets of SILI in the context of liver inflammation and to elucidate the mechanism underlying the regulation of Lipin gene expression. The rats were allocated into four groups, each comprising eight individuals: vehicle group: These rats underwent a median laparotomy, and were administered normal saline. (2) SILI group: Rats in this group received 50 mg/kg of SILI after laparotomy. (3) I/R group: Rats in this group experienced I/R and were administered normal saline. (4) I/R+SILI group: In this group, rats were treated with SILI in conjunction with the I/R procedure. Western and real-time PCR were used to measure protein levels, and assess Lipin-1 and Lipin-2 gene expression. The analysis identified 18 shared targets between SILI (Severe Acute Liver Injury) and liver inflammation, linking them to 107 KEGG pathways, with the mTOR signaling pathway standing out as a critical connection to Lipin. Docking studies of targets in the mTOR signaling pathway revealed binding energies of -9.7 kcal/mol for PIK3CA and -10.4 kcal/mol for mTOR protein. Furthermore, the protein level and gene expression of Lipin-1 and Lipin-2 genes were significantly elevated during I/R compared to the vehicle group (P < 0.001). However, SILI was observed to reduce their expression during I/R (P < 0.05). The beneficial effects of SILI can be attributed to the modulation of Lipin-1 and Lipin-2 gene expression during I/R, which is likely one of the mechanisms underlying its beneficial effects during I/R.
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Affiliation(s)
- Mahboubeh Ghanbari
- Molecular and Cell biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hossein Ebrahimi
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Science, Sari, Iran
| | - Abouzar Bagheri
- Molecular and Cell biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abbas Khonakdar-Tarsi
- Molecular and Cell biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Hadis Mousavi
- Molecular and Cell biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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Jeddou H, Tzedakis S, Chaouch MA, Sulpice L, Samson M, Boudjema K. Viability Assessment During Normothermic Machine Liver Perfusion: A Literature Review. Liver Int 2025; 45:e16244. [PMID: 39821671 PMCID: PMC11740183 DOI: 10.1111/liv.16244] [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: 06/30/2024] [Revised: 12/25/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
BACKGROUND AND OBJECTIVE The discrepancy between donor organ availability and demand leads to a significant waiting-list dropout rate and mortality. Although quantitative tools such as the Donor Risk Index (DRI) help assess organ suitability, many potentially viable organs are still discarded due to the lack of universally accepted markers to predict post-transplant outcomes. Normothermic machine perfusion (NMP) offers a platform to assess viability before transplantation. Thus, livers considered unsuitable for transplantation based on the DRI can be evaluated and potentially transplanted. During NMP, various viability criteria have been proposed. These criteria are neither homogeneous nor consensual. In this review, we aimed to describe the viability criteria during NMP and evaluate their ability to predict hepatic graft function following transplantation. We conducted a PubMed search using the terms 'liver transplantation', 'normothermic machine perfusion' and 'assessment', including only English publications up to February 2024. Viability assessment during NMP includes multiple hepatocellular and cholangiocellular criteria. Lactate clearance and bile production are commonly used indicators, but their ability to predict post-transplant outcomes varies significantly. The predictive value of cholangiocellular criteria such as bile pH, bicarbonate and glucose levels remains under investigation. Novel markers, such as microRNAs and proteomic profiles, offer the potential to enhance graft evaluation accuracy and provide insights into the molecular mechanisms underlying liver viability. Combining perfusion parameters with biomarkers may improve the prediction of long-term graft survival. Future research should focus on standardising viability assessment protocols and exploring real-time biomarker evaluations, which could enhance transplantation outcomes and expand the donor pool.
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Affiliation(s)
- Heithem Jeddou
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Stylianos Tzedakis
- Department of Hepato‐Biliary, Digestive and Endocrine SurgeryCochin Hospital, APHPParisFrance
- Université Paris CitéParisFrance
| | - Mohamed Ali Chaouch
- Department of Visceral and Digestive SurgeryMonastir University HospitalMonastirTunisia
| | - Laurent Sulpice
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- INSERM OSS U1242, University Hospital, Rennes 1 UniversityRennesFrance
| | - Michel Samson
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Karim Boudjema
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
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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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Hu C, Wang L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2024; 15:474. [PMID: 39696473 DOI: 10.1186/s13287-024-04087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.
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Affiliation(s)
- Changlong Hu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China.
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Xu M, Alwahsh SM, Kim MH, Kollmar O. A Multidrug Donor Preconditioning Improves Steatotic Rat Liver Allograft Function and Recipient Survival After Transplantation. Transpl Int 2024; 37:13557. [PMID: 39726675 PMCID: PMC11671227 DOI: 10.3389/ti.2024.13557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024]
Abstract
The scarcity of donors has prompted the growing utilization of steatotic livers, which are susceptible to injuries following orthotopic liver transplantation (OLT). This study aims to assess the efficacy of multidrug donor preconditioning (MDDP) in alleviating injuries of steatotic grafts following rat OLT. Lean rats were subjected to a Western-style diet with high-fat (HF) and high-fructose (HFr) for 30 days to induce steatosis. Both lean and steatotic livers were implanted into lean recipients fed with a chow diet after OLT. The HF + HFr diet effectively elevated blood triglyceride and cholesterol levels and induced fat accumulation in rat livers. Our results demonstrated a significant decrease in alanine aminotransferase levels (p = 0.003), aspartate aminotransferase levels (p = 0.021), and hepatic Suzuki scores (p = 0.045) in the steatotic rat liver allograft group following MDDP treatment on post-operation day (POD) 7. Furthermore, the survival rates of steatotic rat liver allografts with MDDP (19/21, 90.5%) were significantly higher than those in the steatotic control (12/21, 57.1%, *p = 0.019). These findings indicate that MDDP treatment improves steatotic rat liver allograft function and recipient survival following OLT.
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Affiliation(s)
- Min Xu
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
- Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Salamah M. Alwahsh
- Department of Gastroenterology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany
- Program of Medicine, College of Medicine and Health Sciences, Palestine Polytechnic University, Hebron, Palestine
| | - Myung-Ho Kim
- Department of Internal Korean Medicine, Woosuk University Medical Center, Jeonju, Republic of Korea
| | - Otto Kollmar
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, University Hospital Basel, Basel, Switzerland
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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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Bardallo RG, Chullo G, Alva N, Rosello-Catafau J, Fundora-Suárez Y, Carbonell T, Panisello-Rosello A. Mitigating Cold Ischemic Injury: HTK, UW and IGL-2 Solution's Role in Enhancing Antioxidant Defence and Reducing Inflammation in Steatotic Livers. Int J Mol Sci 2024; 25:9318. [PMID: 39273266 PMCID: PMC11394993 DOI: 10.3390/ijms25179318] [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: 07/22/2024] [Revised: 08/21/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Liver transplantation remains the only definitive treatment for end-stage liver diseases. However, the increasing prevalence of fatty liver disease among potential donors exacerbates the shortage of suitable organs. This study evaluates the efficacy of the preservation solution Institut Georges Lopez-2 (IGL-2) compared to Histidine-Tryptophan-Ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions in mitigating ischemia-reperfusion injury (IRI) in steatotic livers. Using Zucker Obese rat livers, we assessed the impact of 24-h static cold storage (SCS) with each solution on transaminase release, glutathione redox balance, antioxidant enzyme activity, lipoperoxidation, and inflammation markers. IGL-2 and UW solutions demonstrated reduced transaminase and lactate levels compared to HTK, indicating better preservation of liver integrity. IGL-2 maintained a higher reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, suggesting more effective management of oxidative stress. Antioxidant enzyme activities catalase, superoxide dismutase, and glutathione peroxidase (CAT, SOD, GPX) were higher in IGL-2 preserved livers, contributing to decreased oxidative damage. Lipid peroxidation markers and inflammatory markers were lower in IGL-2 than in HTK, indicating reduced oxidative stress and inflammation. Additionally, improved mitochondrial function was observed in the IGL-2 group, correlating with reduced reactive oxygen species (ROS) production and lipid peroxidation. These findings suggest that IGL-2 offers superior preservation of liver viability, reduces oxidative stress, and minimizes inflammation compared to HTK and UW solutions. By maintaining a higher ratio of reduced glutathione and antioxidant enzyme activity, IGL-2 effectively mitigates the harmful effects of ischemia-reperfusion injury. The reduced lipid peroxidation and inflammation in the IGL-2 group further underscore its potential in improving liver transplant outcomes. These results highlight the importance of optimizing preservation solutions to enhance the viability and functionality of donor organs, potentially expanding the donor pool and improving the success rates of liver transplantation. Future research should focus on refining preservation techniques and exploring additional protective agents to further improve organ preservation and transplant outcomes.
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Affiliation(s)
- Raquel G. Bardallo
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain (N.A.); (T.C.)
| | - Gabriela Chullo
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (G.C.); (J.R.-C.); (Y.F.-S.)
| | - Norma Alva
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain (N.A.); (T.C.)
| | - Joan Rosello-Catafau
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (G.C.); (J.R.-C.); (Y.F.-S.)
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona—Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain
| | - Yiliam Fundora-Suárez
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (G.C.); (J.R.-C.); (Y.F.-S.)
| | - Teresa Carbonell
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain (N.A.); (T.C.)
| | - Arnau Panisello-Rosello
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (G.C.); (J.R.-C.); (Y.F.-S.)
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona—Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain
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9
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Deng RM, Zhou J. Targeting NF-κB in Hepatic Ischemia-Reperfusion Alleviation: from Signaling Networks to Therapeutic Targeting. Mol Neurobiol 2024; 61:3409-3426. [PMID: 37991700 DOI: 10.1007/s12035-023-03787-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: 09/15/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver trauma, resection, and transplantation that can lead to liver dysfunction and failure. Scholars have proposed a variety of liver protection methods aimed at reducing ischemia-reperfusion damage, but there is still a lack of effective treatment methods, which urgently needs to find new effective treatment methods for patients. Many studies have reported that signaling pathway plays a key role in HIRI pathological process and liver function recovery mechanism, among which nuclear transfer factor-κB (NF-κB) signaling pathway is one of the signal transduction closely related to disease. NF-κB pathway is closely related to HIRI pathologic process, and inhibition of this pathway can delay oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction. In addition, NF-κB can also interact with PI3K/Akt, MAPK, and Nrf2 signaling pathways to participate in HIRI regulation. Based on the role of NF-κB pathway in HIRI, it may be a potential target pathway for HIRI. This review emphasizes the role of inhibiting the NF-κB signaling pathway in oxidative stress, inflammatory response, cell death, and mitochondrial dysfunction in HIRI, as well as the effects of related drugs or inhibitors targeting NF-κB on HIRI. The objective of this review is to elucidate the role and mechanism of NF-κB pathway in HIRI, emphasize the important role of NF-κB pathway in the prevention and treatment of HIRI, and provide a theoretical basis for the target NF-κB pathway as a therapy for HIRI.
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Affiliation(s)
- Rui-Ming Deng
- Department of Anesthesiology, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China
| | - Juan Zhou
- The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
- Department of Thyroid and Breast Surgery, Ganzhou People's Hospital, 16 Meiguan Avenue, Ganzhou, Jiangxi Province, 341000, People's Republic of China.
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10
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Zeng X, Jin X, Wu Z, Hu J, Zhou W, Shen X, Du J. Enhanced external counterpulsation treatment improves multi-organ hemodynamics for postoperative liver transplantation patient. A case report. J Cardiothorac Surg 2024; 19:284. [PMID: 38730503 PMCID: PMC11088020 DOI: 10.1186/s13019-024-02783-y] [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: 12/28/2023] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
INTRODUCTION Post liver transplantation (LT) patients endure high morbidity rate of multi-organ ischemic symptoms following reperfusion. We hypothesize that enhanced external counterpulsation (EECP) as a typical non-invasive assisted circulation procedure, which can efficiently inhibit the relative ischemic symptoms via the systemic improvement of hemodynamics. CASE PRESENTATION A 51-year-old male patient, 76 kg, 172 cm, received orthotopic LT surgery for viral hepatitis B induced acute-on-chronic liver failure hepatic failure. His medical records revealed ischemic symptoms in multi-organ at the time of hospital discharge, including headache, refractory insomnia, abdominal paralysis, and lower limb pain. The EECP treatment was introduced for assisted rehabilitation and to improve the postoperative quality of life. Doppler Ultrasound examination showed significant augmentation of blood flow volume in the carotid arteries, the hepatic artery, the portal vein and the femoral artery during EECP intervention. A standard 35-hour EECP treatment led to significant improvement in quality of life, e.g. sleep quality and walking ability. CONCLUSION We report a case of multi-organ ischemic symptoms in a post LT patient. EECP treatment can significantly improve the quality of life via the systematic promotion of hemodynamics.
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Affiliation(s)
- Xinchen Zeng
- Department of Liver Surgery, The Third People's Hospital of Shenzhen, Shenzhen, 518112, China
| | - Xin Jin
- Department of Liver Surgery, The Third People's Hospital of Shenzhen, Shenzhen, 518112, China
| | - Zi'an Wu
- Medical Research Center, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, China
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen, 518107, China
| | - Jun Hu
- Medical Research Center, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, China
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen, 518107, China
| | - Wenjuan Zhou
- Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, China
| | - Xuelian Shen
- Department of Ultrasound Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, China
| | - Jianhang Du
- Medical Research Center, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, China.
- National Health Commission (NHC), Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, 510080, China.
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11
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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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12
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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13
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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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14
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Shao JL, Wang LJ, Xiao J, Yang JF. Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury. World J Gastroenterol 2023; 29:4927-4941. [PMID: 37731999 PMCID: PMC10507504 DOI: 10.3748/wjg.v29.i33.4927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/22/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the major complication of liver surgery and liver transplantation, that may increase the postoperative morbidity, mortality, tumor progression, and metastasis. The underlying mechanisms have been extensively investigated in recent years. Among these, oxidative stress, inflammatory responses, immunoreactions, and cell death are the most studied. Non-coding RNAs (ncRNAs) are defined as the RNAs that do not encode proteins, but can regulate gene expressions. In recent years, ncRNAs have emerged as research hotspots for various diseases. During the progression of HIRI, ncRNAs are differentially expressed, while these dysregulations of ncRNAs, in turn, have been verified to be related to the above pathological processes involved in HIRI. ncRNAs mainly contain microRNAs, long ncRNAs, and circular RNAs, some of which have been reported as biomarkers for early diagnosis or assessment of liver damage severity, and as therapeutic targets to attenuate HIRI. Here, we briefly summarize the common pathophysiology of HIRI, describe the current knowledge of ncRNAs involved in HIRI in animal and human studies, and discuss the potential of ncRNA-targeted therapeutic strategies. Given the scarcity of clinical trials, there is still a long way to go from pre-clinical to clinical application, and further studies are needed to uncover their potential as therapeutic targets.
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Affiliation(s)
- Jia-Li Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Li-Juan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Ji Xiao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Feng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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15
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Esteban-Zubero E, López-Pingarrón L, Ramírez JM, Reyes-Gonzales MC, Azúa-Romeo FJ, Soria-Aznar M, Agil A, García JJ. Melatonin Preserves Fluidity in Cell and Mitochondrial Membranes against Hepatic Ischemia-Reperfusion. Biomedicines 2023; 11:1940. [PMID: 37509579 PMCID: PMC10377318 DOI: 10.3390/biomedicines11071940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
We evaluated the in vivo effects of melatonin treatment on oxidative damage in the liver in an experimental model of ischemia-reperfusion. A total of 37 male Sprague-Dawley rats were randomly divided into four groups: control, ischemia, ischemia + reperfusion, and ischemia + reperfusion + melatonin. Hepatic ischemia was maintained for 20 min, and the clamp was removed to initiate vascular reperfusion for 30 min. Melatonin (50 mg/kg body weight) was intraperitoneally administered. Fluidity was measured by polarization changes in 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene-p-toluene sulfonate). After 20 min of ischemia, no significant changes were observed in cell and mitochondrial membrane fluidity levels, lipid peroxidation, and protein carbonylation. However, after 30 min of reperfusion, membrane fluidity decreased compared to controls. Increases in lipid and protein oxidation were also seen in hepatic homogenates of animals exposed to reperfusion. Melatonin injected 30 min before ischemia and reperfusion fully prevented membrane rigidity and both lipid and protein oxidation. Livers from ischemia-reperfusion showed histopathological alterations and positive labeling with antibodies to oxidized lipids and proteins. Melatonin reduced the severity of these morphological changes and protected against in vivo ischemia-reperfusion-induced toxicity in the liver. Therefore, melatonin might be a candidate for co-treatment for patients with hepatic vascular occlusion followed by reperfusion.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Laura López-Pingarrón
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | | | - Marcos César Reyes-Gonzales
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Francisco Javier Azúa-Romeo
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Marisol Soria-Aznar
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Ahmad Agil
- Department of Pharmacology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - José Joaquín García
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
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16
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Kartal B, Alimoğulları E, Elçi P, Demir H. Adipose delivered stem cells protect liver after ischemia-reperfusion injury by controlling autophagy. Injury 2023:110839. [PMID: 37248113 DOI: 10.1016/j.injury.2023.110839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/08/2023] [Accepted: 05/19/2023] [Indexed: 05/31/2023]
Abstract
OBJECTIVE Ischemia-reperfusion(I/R) injury is an unavoidable side effect of liver surgery and transplantation. A potentially useful tool for cellular therapy and tissue engineering is adipose-derived stem cells (ADSCs).The process of autophagy is used by the cell to break down inappropriate molecules.The study's goal was to examine the impact of ADSCs on the autophagic pathway after rat hepatic ischemia-reperfusion injury. MATERIAL AND METHODS Thirty male rats used in our study were divided into control, ADSC, ischemia, I/R, and I/R+ ADSC groups (n = 6). Liver tissues were stained with hematoxylin-eosin and histological changes were evaluated with Suzuki scoring. Immunoexpressions of transforming growth factor (TGF-β) and autophagy markers LC3B, p62 were analyzed using the immunohistochemical method. RESULTS As a result of histological evaluation the ischemia and I/R groups displayed sinusoid congestion, vacuolization, and necrosis in liver tissues. We showed that the immunostaining of LC3B and TGF- β were elevated, and p62 decreased in the rat liver from ischemia and I/R groups when compared to the control group. CONCLUSION ADSCs reduced the excessive level of autophagy and structural damage to hepatocytes and the pathological alterations in the liver after ıschemia-reperfusion injury.
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Affiliation(s)
- Bahar Kartal
- Ankara Yıldırım Beyazıt University, Medical Faculty, Department of Histology and Embryology, Ankara, Turkey.
| | - Ebru Alimoğulları
- Ankara Yıldırım Beyazıt University, Medical Faculty, Department of Histology and Embryology, Ankara, Turkey
| | - Pınar Elçi
- Health Sciences University, Gulhane Health Sciences Institute,Stem Cell Laboratory, Ankara, Turkey
| | - Hazal Demir
- Ankara Yıldırım Beyazıt University, Medical Faculty, Department of Histology and Embryology, Ankara, Turkey
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17
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Ge J, Li H, Yang JQ, Yue Y, Lu SY, Nie HY, Zhang T, Sun PM, Yan HF, Sun HW, Yang JW, Zhou JL, Cui Y. Autophagy in hepatic macrophages can be regulator and potential therapeutic target of liver diseases: A review. Medicine (Baltimore) 2023; 102:e33698. [PMID: 37171337 PMCID: PMC10174421 DOI: 10.1097/md.0000000000033698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 05/13/2023] Open
Abstract
Hepatic macrophages are a complex population of cells that play an important role in the normal functioning of the liver and in liver diseases. Autophagy, as a maintainer of cellular homeostasis, is closely connected to many liver diseases. And its roles are not always beneficial, but manifesting as a double-edged sword. The polarization of macrophages and the activation of inflammasomes are mediated by intracellular and extracellular signals, respectively, and are important ways for macrophages to take part in a variety of liver diseases. More attention should be paid to autophagy of hepatic macrophages in liver diseases. In this review, we focus on the regulatory role of hepatic macrophages' autophagy in a variety of liver diseases; especially on the upstream regulator of polarization and inflammasomes activation of the hepatic macrophages. We believe that the autophagy of hepatic macrophages can become a potential therapeutic target for management of liver diseases.
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Affiliation(s)
- Jun Ge
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Hao Li
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Jia-Qi Yang
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Yuan Yue
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Sheng-Yu Lu
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Hong-Yun Nie
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Tao Zhang
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Pei-Ming Sun
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Hong-Feng Yan
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Hong-Wei Sun
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Jian-Wu Yang
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
| | - Jin-Lian Zhou
- Department of Pathology, Strategic Support Force Medical Center, Beijing 100101, China
| | - Yan Cui
- Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing 100101, China
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18
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Li J, Lu H, Zhang J, Li Y, Zhao Q. Comprehensive Approach to Assessment of Liver Viability During Normothermic Machine Perfusion. J Clin Transl Hepatol 2023; 11:466-479. [PMID: 36643041 PMCID: PMC9817053 DOI: 10.14218/jcth.2022.00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/14/2022] [Accepted: 08/10/2022] [Indexed: 01/18/2023] Open
Abstract
Liver transplantation is the most effective treatment of advanced liver disease, and the use of extended criteria donor organs has broadened the source of available livers. Although normothermic machine perfusion (NMP) has become a useful tool in liver transplantation, there are no consistent criteria that can be used to evaluate the viability of livers during NMP. This review summarizes the criteria, indicators, and methods used to evaluate liver viability during NMP. The shape, appearance, and hemodynamics of the liver can be analyzed at a macroscopic level, while markers of liver injury, indicators of liver and bile duct function, and other relevant indicators can be evaluated by biochemical analysis. The liver can also be assessed by tissue biopsy at the microscopic level. Novel methods for assessment of liver viability are introduced. The limitations of evaluating liver viability during NMP are discussed and suggestions for future clinical practice are provided.
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Affiliation(s)
| | | | | | | | - Qiang Zhao
- Correspondence to: Qiang Zhao, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. ORCID: https://orcid.org/0000-0002-6369-1393. Tel: +86-15989196835, E-mail:
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19
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Banker A, Bhatt N, Rao PS, Agrawal P, Shah M, Nayak M, Mohanka R. A Review of Machine Perfusion Strategies in Liver Transplantation. J Clin Exp Hepatol 2023; 13:335-349. [PMID: 36950485 PMCID: PMC10025749 DOI: 10.1016/j.jceh.2022.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 02/17/2023] Open
Abstract
The acceptance of liver transplantation as the standard of care for end-stage liver diseases has led to a critical shortage of donor allografts. To expand the donor organ pool, many countries have liberalized the donor criteria including extended criteria donors and donation after circulatory death. These marginal livers are at a higher risk of injury when they are preserved using the standard static cold storage (SCS) preservation techniques. In recent years, research has focused on optimizing organ preservation techniques to protect these marginal livers. Machine perfusion (MP) of the expanded donor liver has witnessed considerable advancements in the last decade. Research has showed MP strategies to confer significant advantages over the SCS techniques, such as longer preservation times, viability assessment and the potential to recondition high risk allografts prior to implantation. In this review article, we address the topic of MP in liver allograft preservation, with emphasis on current trends in clinical application. We discuss the relevant clinical trials related to the techniques of hypothermic MP, normothermic MP, hypothermic oxygenated MP, and controlled oxygenated rewarming. We also discuss the potential applications of ex vivo therapeutics which may be relevant in the future to further optimize the allograft prior to transplantation.
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Key Words
- ALP, Alkaline phosphatase
- ALT, Alanine transaminase
- ASO, Antisense oligonucleotides
- AST, Aspartate transaminase
- CIT, Cold ischemia times
- COPE, Consortium for Organ Preservation in Europe
- COR, Controlled oxygenated rewarming
- DBD, Donation after brain death
- DCD, Donation after circulatory death
- DHOPE, dual hypothermic oxygenated machine perfusion
- EAD, Early allograft dysfunction
- ECD, Extended criteria donors
- ETC, Electron transport chain
- GGT, Gamma glutamyl transferase
- HCV, Hepatitis C virus
- HMP, Hypothermic machine perfusion
- HOPE, Hypothermic oxygenated machine perfusion
- ICU, Intensive care unit
- IGL, Institute George Lopez-1
- INR, International normalized ratio
- IRI, ischemia reperfusion injury
- LDH, Lactate dehydrogenase
- MELD, Model for end-stage liver disease
- MP, Machine perfusion
- NAS, Non-anastomotic biliary strictures
- NMP, Normothermic machine perfusion
- NO, Nitric oxide
- PNF, Primary nonfunction
- ROS, Reactive oxygen species
- RT-PCR, Reverse transcription polymerase chain reaction
- SNMP, Sub-normothermic machine perfusion
- UW, University of Wisconsin
- WIT, Warm ischemia times
- hypothermic machine perfusion
- hypothermic oxygenated machine perfusion
- machine perfusion
- normothermic machine perfusion
- static cold storage
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Affiliation(s)
- Amay Banker
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Neha Bhatt
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Prashantha S. Rao
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Pravin Agrawal
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Mitul Shah
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Madhavi Nayak
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Ravi Mohanka
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
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20
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Liu L, Zhang C, Lu T, Li X, Jiang Z, Tian H, Hao X, Yang K, Guo T. The efficacy and safety of glucocorticoid for perioperative patients with hepatectomy: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2023; 17:59-71. [PMID: 36576056 DOI: 10.1080/17474124.2023.2162878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Glucocorticoids have been used in patients undergoing perioperative hepatectomy, however their safety and efficacy remain controversial. This meta-analysis was conducted to investigate this issue and further provide reference for clinical practice. METHODS PubMed/MEDLINE, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) from database inception to December 2022. Literature screening and data extraction were performed independently by two reviewers. The methodological quality of the RCTs was assessed using the Jadad scale. RevMan 5.4 was used for the meta-analysis. RESULTS A total of 11 RCTs involving 905 patients were included. Compared with the control group, we found perioperative glucocorticoid administration significantly lowered overall complication rate [RR = 0.67; 95% CI (0.55, 0.83); P = 0.0003], infectious complication rate [RR = 0.41; 95% CI (0.21, 0.82); P = 0.01] and postoperative liver failure [RR = 0.63; 95% CI (0.41, 0.97); P = 0.03]. In addition, glucocorticoids appear to improve liver function (TBil) [MD = -0.36, 95% CI (-0.59, -0.14), P = 0.001] and reduce the release of certain inflammatory cytokines (IL-6) [MD = -48.52, 95% CI (-56.88, -40.16), P < 0.00001]. CONCLUSION Based on the available evidence, glucocorticoids appear to be safe and effective in patients undergoing hepatectomy, but further research is needed.
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Affiliation(s)
- Lili Liu
- The First Clinical Medicine College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China.,Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
| | - Chengren Zhang
- Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China.,General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Tingting Lu
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.,Institution of Clinical Research and Evidence Based Medicine, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
| | - Xiong Li
- Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China.,General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Zhiliang Jiang
- The First Clinical Medicine College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China.,Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
| | - Hongwei Tian
- Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
| | - Kehu Yang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou University, Lanzhou, Gansu, China
| | - Tiankang Guo
- The First Clinical Medicine College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China.,Department of General Surgery, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
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21
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Sparrelid E, Olthof PB, Dasari BVM, Erdmann JI, Santol J, Starlinger P, Gilg S. Current evidence on posthepatectomy liver failure: comprehensive review. BJS Open 2022; 6:6840812. [PMID: 36415029 PMCID: PMC9681670 DOI: 10.1093/bjsopen/zrac142] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/21/2022] [Accepted: 10/03/2022] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Despite important advances in many areas of hepatobiliary surgical practice during the past decades, posthepatectomy liver failure (PHLF) still represents an important clinical challenge for the hepatobiliary surgeon. The aim of this review is to present the current body of evidence regarding different aspects of PHLF. METHODS A literature review was conducted to identify relevant articles for each topic of PHLF covered in this review. The literature search was performed using Medical Subject Heading terms on PubMed for articles on PHLF in English until May 2022. RESULTS Uniform reporting on PHLF is lacking due to the use of various definitions in the literature. There is no consensus on optimal preoperative assessment before major hepatectomy to avoid PHLF, although many try to estimate future liver remnant function. Once PHLF occurs, there is still no effective treatment, except liver transplantation, where the reported experience is limited. DISCUSSION Strict adherence to one definition is advised when reporting data on PHLF. The use of the International Study Group of Liver Surgery criteria of PHLF is recommended. There is still no widespread established method for future liver remnant function assessment. Liver transplantation is currently the only effective way to treat severe, intractable PHLF, but for many indications, this treatment is not available in most countries.
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Affiliation(s)
- Ernesto Sparrelid
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Pim B Olthof
- Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.,Department of Surgery, Amsterdam UMC, Amsterdam, The Netherlands
| | - Bobby V M Dasari
- Department of HPB Surgery and Liver Transplantation, Queen Elizabeth Hospital, Birmingham, UK.,University of Birmingham, Birmingham, UK
| | - Joris I Erdmann
- Department of Surgery, Amsterdam UMC, Amsterdam, The Netherlands
| | - Jonas Santol
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria.,Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Division of General Surgery, Department of Surgery, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.,Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, New York, USA
| | - Stefan Gilg
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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22
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Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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23
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SIRT5 alleviates hepatic ischemia and reperfusion injury by diminishing oxidative stress and inflammation via elevating SOD1 and IDH2 expression. Exp Cell Res 2022; 419:113319. [PMID: 35995176 DOI: 10.1016/j.yexcr.2022.113319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 11/21/2022]
Abstract
Hepatic ischemia/reperfusion (I/R) injury, a common and unavoidable pathophysiological process during liver transplantation or resection operation, may impede postoperative liver function recovery, and its mechanism and targeted therapy remain largely unknown. SIRT5 is a well-known deacetylase and participates in the regulation of many physiological and pathological processes, including I/R. The role of SIRT5 in I/R is controversial or tissue-specific, restricting I/R progression in the heart while deteriorating injury in the kidney and brain, while its effect on hepatic I/R remains unclear. In this study, we investigated the function of SIRT5 in hepatic I/R using AAV8 and lentivirus to overexpress SIRT5 in vivo and in vitro. The data showed that SIRT5 overexpression alleviated liver I/R injury in mice and hypoxia/reoxygenation treated AML-12 cells. Moreover, gain- and loss-of-function of SIRT5, SOD1 and IDH2 experiments in AML-12 were performed. Our results demonstrated that SOD1 and IDH2 knockdown abolished the effect of SIRT5 on restraining oxidative stress and inflammation. Therefore, our work revealed that SIRT5 may alleviates hepatic I/R injury by diminishing oxidative stress and inflammation via up-regulating the SOD1 and IDH2 expression, which enriches the theory and therapeutic strategies of hepatic I/R injury.
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24
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Li Y, Palmer A, Lupu L, Huber-Lang M. Inflammatory response to the ischaemia-reperfusion insult in the liver after major tissue trauma. Eur J Trauma Emerg Surg 2022; 48:4431-4444. [PMID: 35831749 DOI: 10.1007/s00068-022-02026-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Polytrauma is often accompanied by ischaemia-reperfusion injury to tissues and organs, and the resulting series of immune inflammatory reactions are a major cause of death in patients. The liver is one of the largest organs in the body, a characteristic that makes it the most vulnerable organ after multiple injuries. In addition, the liver is an important digestive organ that secretes a variety of inflammatory mediators involved in local as well as systemic immune inflammatory responses. Therefore, this review considers the main features of post-traumatic liver injury, focusing on the immuno-pathophysiological changes, the interactions between liver organs, and the principles of treatment deduced. METHODS We focus on the local as well as systemic immune response involving the liver after multiple injuries, with emphasis on the pathophysiological mechanisms. RESULTS An overview of the mechanisms underlying the pathophysiology of local as well as systemic immune responses involving the liver after multiple injuries, the latest research findings, and the current mainstream therapeutic approaches. CONCLUSION Cross-reactivity between various organs and cascade amplification effects are among the main causes of systemic immune inflammatory responses after multiple injuries. For the time being, the pathophysiological mechanisms underlying this interaction remain unclear. Future work will continue to focus on identifying potential signalling pathways as well as target genes and intervening at the right time points to prevent more severe immune inflammatory responses and promote better and faster recovery of the patient.
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Affiliation(s)
- Yang Li
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Annette Palmer
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Ludmila Lupu
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany.
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25
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Soler-Botija C, Monguió-Tortajada M, Munizaga-Larroudé M, Gálvez-Montón C, Bayes-Genis A, Roura S. Mechanisms governing the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles: A scoping review of preclinical evidence. Biomed Pharmacother 2022; 147:112683. [PMID: 35144050 DOI: 10.1016/j.biopha.2022.112683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/26/2022] [Accepted: 01/31/2022] [Indexed: 12/14/2022] Open
Abstract
Compelling evidence supports the therapeutic benefit of extracellular vesicles (EVs). EVs are nanostructures with a lipid bilayer membrane that are secreted by multiple cells, including mesenchymal stromal cells (MSCs), as means of cellular communication. MSC-EVs, resembling their MSC origin, carry protected immunomodulatory and pro-regenerative cargoes to targeted neighboring or distant cells and tissues. Though treatments focused on MSC-EVs have emerged as greatly versatile approaches to modulate multiple inflammatory-related conditions, crucial concerns, including the possibility of increasing therapeutic outcomes by pre-conditioning parental MSCs or engineering derived EVs and clarification of the most relevant mechanisms of action, remain. Here, we summarize the large amount of preclinical research surrounding the modulation of beneficial effects by MSC-EVs.
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Affiliation(s)
- Carolina Soler-Botija
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Monguió-Tortajada
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; REMAR-IVECAT Group, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Micaela Munizaga-Larroudé
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
| | - Carolina Gálvez-Montón
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
| | - Antoni Bayes-Genis
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain; Department of Medicine, UAB, Barcelona, Spain
| | - Santiago Roura
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain; CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Barcelona 08500, Spain.
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26
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AMALIAH R, YANI A. Effects of intestinal strangulation release on liver following intestinal ischemia-reperfusion injury on Sprague Dawley rat. Chirurgia (Bucur) 2022. [DOI: 10.23736/s0394-9508.20.05208-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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27
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Chen K, Obara H, Matsubara Y, Fukuda K, Yagi H, Ono-Uruga Y, Matsubara K, Kitagawa Y. Adipose-Derived Mesenchymal Stromal/Stem Cell Line Prevents Hepatic Ischemia/Reperfusion Injury in Rats by Inhibiting Inflammasome Activation. Cell Transplant 2022; 31:9636897221089629. [PMID: 35438583 PMCID: PMC9021522 DOI: 10.1177/09636897221089629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown potential in the treatment of degenerative diseases, including ischemia/reperfusion injury (IRI), which occurs during organ transplantation and represents the main cause of post-transplant graft dysfunction. However, MSCs have heterogeneous characteristics, and studies of MSCs therapy have shown a variety of outcomes. To establish a new effective MSCs therapy, we developed an adipose-derived mesenchymal stromal/stem cell line (ASCL) and compared its therapeutic effects on primary adipose-derived MSCs (ASCs) using a hepatocyte co-culture model of hypoxia/reoxygenation in vitro and a rat model of hepatic IRI in vivo. The results showed that both ASCL and ASCs protect against hypoxia by improving hepatocyte viability, inhibiting reactive oxygen species release, and upregulating transforming growth factor-β in vitro. In vivo, ASCL or ASCs were infused into the spleen 24 h before the induction of rat hepatic IRI. The results showed that ASCL significantly improved the survival outcomes compared with the control (normal saline infusion) with the significantly decreased serum levels of liver enzymes and less damage to liver tissues compared with ASCs. Both ASCL and ASCs suppressed NOD-like receptor family pyrin domain-containing 3 inflammasome activation and subsequently reduced the release of activated IL-1β and IL-18, which is considered an important mechanism underlying ASCL and ASCs infusion in hepatic IRI. In addition, ASCL can promote the release of interleukin-1 receptor antagonist, which was previously reported as a key factor in hampering the inflammatory cascade during hepatic IRI. Our results suggest ASCL as a new candidate for hepatic IRI treatment due to its relatively homogeneous characteristics.
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Affiliation(s)
- Kaili Chen
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideaki Obara
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yumiko Matsubara
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan
| | - Kazumasa Fukuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Yagi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yukako Ono-Uruga
- Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan
| | - Kentaro Matsubara
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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28
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Aliyeva D, Amanvermez R, Karabulut K, Gün S. The effects of silymarin plus glutathione on the prevention of liver ischemia-reperfusion injury. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Affiliation(s)
| | | | | | - Seda Gün
- Ondokuz Mayıs University, Turkey
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29
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Kollaras V, Valsami G, Lambropoulou M, Konstandi O, Kostomistsopoulos N, Pikoulis E, Simopoulos C, Tsaroucha A. Effect of silibinin on the expression of MMP2, MMP3, MMP9 and TIMP2 in kidney and lung after hepatic ischemia/reperfusion injury in an experimental rat model. Acta Cir Bras 2021; 36:e360904. [PMID: 34755764 PMCID: PMC8580512 DOI: 10.1590/acb360904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/12/2021] [Indexed: 11/22/2022] Open
Abstract
PURPOSE The protective effect of silibinin on kidney and lung parenchyma during hepatic ischemia/reperfusion injury (IRI) is explored. METHODS Sixty-three Wistar rats were separated into three groups: sham; control (45 min IRI); and silibinin (200 μL silibinin administration after 45 min of ischemia and before reperfusion). Immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to evaluate the expression levels of MMP2, MMP3, MMP9, and TIMP2 on kidney and lung. RESULTS Comparing sham vs. control groups, confirmed that hepatic IRI increased both renal and lung MMP2, MMP3, MMP9 and TIMP2 expressions starting at 180 min (p<0.001). Comparison of the control vs. silibinin groups showed a statistically significant decrease in the expression levels of MMP2, MMP3, and MMP9 and increase of TIMP2 in kidney and lung parenchyma. The starting point of this decrease was at 120 min after reperfusion, both for kidney and lung parameters, and it was statistically significant at 240 min (p<0.001) for kidney, while silibinin showed a peak of lung protection at 180 min after hepatic reperfusion (p<0.001). CONCLUSIONS Hepatic IRI causes distant kidney and lung damage, while a statistically significant protective action, both on kidney and lung parenchyma, is conveyed by the intravenous administration of silibinin.
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30
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Protective Effect of Adipose-Derived Mesenchymal Stem Cell Secretome against Hepatocyte Apoptosis Induced by Liver Ischemia-Reperfusion with Partial Hepatectomy Injury. Stem Cells Int 2021; 2021:9969372. [PMID: 34457008 PMCID: PMC8390152 DOI: 10.1155/2021/9969372] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/07/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is an inevitable complication of liver surgery and liver transplantation. Hepatocyte apoptosis plays a significant role in the pathological process of hepatic IRI. Adipose-derived stem cells (ADSCs) are known to repair and regenerate damaged tissues by producing bioactive factors, including cytokines, exosomes, and extracellular matrix components, which collectively form the secretome of these cells. The aim of this study was to assess the protective effects of the ADSCs secretome after liver ischemia-reperfusion combined with partial hepatectomy in miniature pigs. We successfully established laparoscopic liver ischemia-reperfusion with partial hepatectomy in miniature pigs and injected saline, DMEM, ADSC-secretome, and ADSCs directly into the liver parenchyma immediately afterwards. Both ADSCs and the ADSC-secretome improved the IR-induced ultrastructural changes in hepatocytes and significantly decreased the proportion of TUNEL-positive apoptotic cells along with caspase activity. Consistent with this, P53, Bax, Fas, and Fasl mRNA and protein levels were markedly decreased, while Bcl-2 was significantly increased in the animals treated with ADSCs and ADSC-secretome. Our findings indicate that ADSCs exert therapeutic effects in a paracrine manner through their secretome, which can be a viable alternative to cell-based regenerative therapies.
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Liu H, Man K. New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation. Int J Mol Sci 2021; 22:ijms22158210. [PMID: 34360975 PMCID: PMC8348697 DOI: 10.3390/ijms22158210] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.
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The Role of Dexmedetomidine in Hepatic Ischemia-Reperfusion Injury Via a Nitric Oxide-Dependent Mechanism in Rats. Transplant Proc 2021; 53:2060-2069. [PMID: 34238590 DOI: 10.1016/j.transproceed.2021.05.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/20/2021] [Accepted: 05/04/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Dexmedetomidine is known to protect against ischemia-reperfusion (IR) in various organs; however, the mechanisms of dexmedetomidine in the liver remain unclear. We investigated whether dexmedetomidine preconditioning leads to hepatic protection and whether nitric oxide was associated with this protective mechanism by employing N-nitro-l-arginine methyl ester (l-NAME), a nitrous oxide synthase inhibitor. METHODS Experiment 1 included 24 rats in 4 groups: sham, IR, 30 μg/kg of dexmedetomidine, and 50 μg/kg of dexmedetomidine. Experiment 2 included 36 rats in 6 groups: IR, 50 μg/kg of dexmedetomidine, 10 mg/kg of l-NAME, 10 mg/kg of l-NAME + 50 μg/kg of dexmedetomidine, 30 of mg/kg l-NAME, and 30 mg/kg of l-NAME + 50 μg/kg of dexmedetomidine. All drugs were administered intraperitoneally. The levels of serum transaminases, malondialdehyde, superoxide dismutase, tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinase were measured 6 hours after hepatic surgery. RESULTS Dexmedetomidine demonstrated a dose-dependent decrease in serum transaminase levels. The 50-μg/kg dexmedetomidine group showed a significant decrease in malondialdehyde levels (P = .002), increase in superoxide dismutase levels (P = .002), and a significantly lower level of phosphorylated tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinase (P = .002, respectively) compared with the IR injury group. These protective effects of dexmedetomidine were partially reversed by pretreatment with l-NAME (P < .01 for 20 and 30 mg/kg of l-NAME). CONCLUSION In hepatic IR injury, dexmedetomidine might protect the liver via antioxidative and anti-inflammatory responses, and nitric oxide production could play a role in these protective mechanisms.
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Abstract
Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.
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Yaron JR, Zhang L, Guo Q, Haydel SE, Lucas AR. Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms. Front Cardiovasc Med 2021; 8:648947. [PMID: 33869309 PMCID: PMC8044766 DOI: 10.3389/fcvm.2021.648947] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, "off-the-shelf" system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are the serine protease inhibitors, termed serpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a "respiratory" coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.
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Affiliation(s)
- Jordan R. Yaron
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
- School for Engineering of Matter, Transport and Energy, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, United States
| | - Liqiang Zhang
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Qiuyun Guo
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Shelley E. Haydel
- Center for Bioelectronics and Biosensors, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
| | - Alexandra R. Lucas
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
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Jia F, Deng F, Xu P, Li S, Wang X, Hu P, Ren H, Tong S, Yin W. NOD1 Agonist Protects Against Lipopolysaccharide and D-Galactosamine-Induced Fatal Hepatitis Through the Upregulation of A20 Expression in Hepatocytes. Front Immunol 2021; 12:603192. [PMID: 33746949 PMCID: PMC7969647 DOI: 10.3389/fimmu.2021.603192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 02/17/2021] [Indexed: 01/13/2023] Open
Abstract
Increasing evidence suggests that NODs are involved in liver diseases; however, the underlying mechanisms remain obscure. In the present study, we analyzed the effect of NOD1 agonist pretreatment on acute liver failure induced by lipopolysaccharide (LPS) in D-galactosamine (D-GalN)-sensitized mice. We found that pretreatment with the NOD1 agonist markedly reduced LPS/D-GalN-induced mortality, elevation of serum ALT levels, and hepatocyte apoptosis. The protective effect of NOD1 agonist was independent of tumor necrosis factor (TNF)-α inhibition. NOD1 agonist pretreatment also attenuated TNF-α/D-GalN-induced apoptotic liver damage. The anti-apoptotic protein A20 expression was more pronounced in NOD1 agonist pretreated mice than in controls, and knockdown of A20 abrogated the protective effect of NOD1 agonist on LPS/D-GalN-induced liver injury and hepatocyte apoptosis. Further experiments showed that NOD1 agonist-induced A20 upregulation required the presence of kupffer cells and TNF-α. Taken together, our data strongly indicate that NOD1 is involved in the regulation of liver injury and could be a potential therapeutic target for liver diseases.
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Affiliation(s)
- Fang Jia
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an Jiaotong University, Xi'an, China
| | - Fuxue Deng
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an Jiaotong University, Xi'an, China
| | - Pan Xu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiying Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuefu Wang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiwen Tong
- Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenwei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Ferreira-Silva M, Faria-Silva C, Baptista PV, Fernandes E, Fernandes AR, Corvo ML. Drug delivery nanosystems targeted to hepatic ischemia and reperfusion injury. Drug Deliv Transl Res 2021; 11:397-410. [PMID: 33660214 DOI: 10.1007/s13346-021-00915-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
Hepatic ischemia and reperfusion injury (IRI) is an acute inflammatory process that results from surgical interventions, such as liver resection surgery or transplantation, or hemorrhagic shock. This pathology has become a severe clinical issue, due to the increasing incidence of hepatic cancer and the high number of liver transplants. So far, an effective treatment has not been implemented in the clinic. Despite its importance, hepatic IRI has not attracted much interest as an inflammatory disease, and only a few reviews addressed it from a therapeutic perspective with drug delivery nanosystems. In the last decades, drug delivery nanosystems have proved to be a major asset in therapy because of their ability to optimize drug delivery, either by passive or active targeting. Passive targeting is achieved through the enhanced permeability and retention (EPR) effect, a main feature in inflammation that allows the accumulation of the nanocarriers in inflammation sites, enabling a higher efficacy of treatment than conventional therapies. These systems also can be actively targeted to specific compounds, such as inflammatory markers and overexpressed receptors in immune system intermediaries, allowing an even more specialized therapy that have already showed encouraging results. In this manuscript, we review drug delivery nanosystems designed for hepatic IRI treatment, addressing their current state in clinical trials, discussing the main hurdles that hinder their successful translation to the market and providing some suggestions that could potentially advance their clinical translation.
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Affiliation(s)
- Margarida Ferreira-Silva
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal
| | - Catarina Faria-Silva
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal
| | - Pedro Viana Baptista
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516, Caparica, Portugal
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Alexandra Ramos Fernandes
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516, Caparica, Portugal
| | - Maria Luísa Corvo
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal.
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Steatotic Livers Are More Susceptible to Ischemia Reperfusion Damage after Transplantation and Show Increased γδ T Cell Infiltration. Int J Mol Sci 2021; 22:ijms22042036. [PMID: 33670793 PMCID: PMC7922678 DOI: 10.3390/ijms22042036] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/04/2021] [Accepted: 02/06/2021] [Indexed: 12/27/2022] Open
Abstract
Liver transplantation (LTx) is often the only possible therapy for many end-stage liver diseases, but successful long-term transplant outcomes are limited by multiple factors, including ischemia reperfusion injury (IRI). This situation is aggravated by a shortage of transplantable organs, thus encouraging the use of inferior quality organs. Here, we have investigated early hepatic IRI in a retrospective, exploratory, monocentric case-control study considering organ marginality. We analyzed standard LTx biopsies from 46 patients taken at the end of cold organ preparation and two hours after reperfusion, and we showed that early IRI was present after two hours in 63% of cases. Looking at our data in general, in accordance with Eurotransplant criteria, a marginal transplant was allocated at our institution in about 54% of cases. We found that patients with a marginal-organ LTx showing evidence of IRI had a significantly worse one-year survival rate (51% vs. 75%). As we saw in our study cohort, the marginality of these livers was almost entirely due to steatosis. In contrast, survival rates in patients receiving a non-marginal transplant were not influenced by the presence or absence of IRI. Poorer outcomes in marginal organs prompted us to examine pre- and post-reperfusion biopsies, and it was revealed that transplants with IRI demonstrated significantly greater T cell infiltration. Molecular analyses showed that higher mRNA expression levels of CXCL-1, CD3 and TCRγ locus genes were found in IRI livers. We therefore conclude that the marginality of an organ, namely steatosis, exacerbates early IRI by enhancing effector immune cell infiltration. Preemptive strategies targeting immune pathways could increase the safety of using marginal organs for LTx.
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Neri AA, Dontas IA, Iliopoulos DC, Karatzas T. Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis. In Vivo 2021; 34:953-964. [PMID: 32354880 DOI: 10.21873/invivo.11863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Ischemia and reperfusion injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The impact of ischemia-reperfusion injury (IRI) on the liver depends on its substrate, the percentage of liver ischemic tissue subjected to IRI and the ischemia time. The consequences of IRI are more evident in pathologic liver substrates, such as steatotic livers. This review is the result of an extended bibliographic PubMed search focused on the last 20 years. It highlights basic differences encountered during IRI in lean and steatotic livers based on studies using rodent experimental models. CONCLUSION The main difference in cell death between lean and steatotic livers is the prevalence of apoptosis in the former and necrosis in the latter. There are also major changes in the effect of intracellular mediators, such as TNFα and IL-1β. Further experimental studies are needed in order to increase current knowledge of IRI effects and relevant mechanisms in both lean and steatotic livers, so that new preventive and therapeutic strategies maybe developed.
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Affiliation(s)
- Anna-Aikaterini Neri
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Ismene A Dontas
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Dimitrios C Iliopoulos
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
| | - Theodore Karatzas
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.,2 Department of Propedeutic Surgery, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
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Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury. Toxicol Appl Pharmacol 2020; 410:115340. [PMID: 33264646 DOI: 10.1016/j.taap.2020.115340] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/07/2020] [Accepted: 11/13/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75μg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner. METHODS Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. RESULTS OCT pretreatment at doses (50 or 75 μg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. CONCLUSION OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.
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Xu Y, Tang Y, Lu J, Zhang W, Zhu Y, Zhang S, Ma G, Jiang P, Zhang W. PINK1-mediated mitophagy protects against hepatic ischemia/reperfusion injury by restraining NLRP3 inflammasome activation. Free Radic Biol Med 2020; 160:871-886. [PMID: 32947010 DOI: 10.1016/j.freeradbiomed.2020.09.015] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 08/28/2020] [Accepted: 09/11/2020] [Indexed: 12/21/2022]
Abstract
Activation of nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) inflammasome in Kupffer cells (KCs) contributes significantly to hepatic ischemia/reperfusion (I/R) injury, while the mechanism of how NLRP3 inflammasome is regulated remains less well defined. Recent evidence has showed that mitophagy acts as a central player for maintaining mitochondrial homeostatis through elimination of damaged mitochondria, leading to the prevention of hyperinflammation triggered by NLRP3 activation. In this study, we aimed at investigating the potential role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in hepatic I/R injury. C57BL/6 mice subjected to partial warm hepatic I/R or primary KCs exposed to anoxia/reoxygenation (A/R) was used as in vivo or in vitro model, respectively. Mitophagy was measured by protein levels of PINK1, Parkin, LC3B-II, TOMM20 and p62. NLRP3, caspase-1 and IL-1β at mRNA and/or protein levels were used as indicators of inflammasome activation. Our results demonstrated remarkable hepatic inflammation and NLRP3 inflammasome activation during hepatic I/R, along with increased PINK1-mediated mitophagy. Notably, overexpression of PINK1 in vivo attenuated hepatic I/R injury, ROS production, NLRP3 activation and hepatic inflammation. In parallel, A/R challenge in vitro also triggered NLRP3 activation in KCs accompanied by increase in mitophagy. Enhanced mitophagy mediated by PINK1 overexpression further inhibited NLRP3 activation and reversed the KC-mediated inflammatory injury to hepatocytes. Kinase-dead mutation of PINK1 completely abolished the above protective effects by PINK1. Blocking of mitophagy/autophagy by silencing of PINK1/Parkin, ATG5, NDP52 or OPTN showed the totally opposite effects, respectively. Treatment with different autophagic inhibitors also consistently reversed the PINK1-mediated effects, suggesting that an intact PINK1-mediated mitophagy signaling was crucial for ablation of NLRP3 signaling in the presence of A/R. Together, these results support a critical role of PINK1-mediated mitophagy in mitochondrial quality control for KC activation and function in hepatic I/R.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Yinbing Tang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jiawei Lu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Weiya Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Yan Zhu
- Department of Respiration, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shouliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
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Sabet Sarvestani F, Azarpira N, Al-Abdullah IH, Tamaddon AM. microRNAs in liver and kidney ischemia reperfusion injury: insight to improve transplantation outcome. Biomed Pharmacother 2020; 133:110944. [PMID: 33227704 DOI: 10.1016/j.biopha.2020.110944] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/03/2020] [Accepted: 10/25/2020] [Indexed: 12/26/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is a condition that occurs wherever blood flow and oxygen is reduced or absent, such as trauma, vascular disease, stroke, and solid organ transplantation. This condition can lead to tissue damage, especially during organ transplantation. Under such circumstances, some signaling pathways are activated, leading to up- or down- regulation of several genes such as microRNAs (miRNAs) that might attenuate or ameliorate this status. Therefore, by manipulating miRNAs level, they can be used as a biomarker for early diagnosis of IRI or suggestive to be therapeutic agents in clinical situation in future.
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Affiliation(s)
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Ismail H Al-Abdullah
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, USA.
| | - Ali-Mohammad Tamaddon
- Department of Pharmaceutics and Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Czigany Z, Craigie EC, Lurje G, Song S, Yonezawa K, Yamamoto Y, Minor T, Tolba RH. Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation. Int J Mol Sci 2020; 21:E6747. [PMID: 32938013 PMCID: PMC7555737 DOI: 10.3390/ijms21186747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 12/14/2022] Open
Abstract
Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20-25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany;
- Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany;
| | - Eve Christiana Craigie
- Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany;
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum–Charité-Universitätsmedizin, 13353 Berlin, Germany;
| | - Shaowei Song
- Department of Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110122, China;
| | - Kei Yonezawa
- Department of Surgery, Shizuoka City Hospital, Shizuoka 420-8527, Japan;
| | - Yuzo Yamamoto
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita 010-0825, Japan;
| | - Thomas Minor
- Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, 45147 Essen, Germany;
| | - René Hany Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany;
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Tang Y, Kong W, Zhao J, Chen Y, Liu L, Zhang G. Can Viscoelasticity Measurements Obtained Through Shear-Wave US Elastography be used to Monitor Hepatic Ischemia-Reperfusion Injury and Treatment Response? An Animal Study. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:2464-2471. [PMID: 32553529 DOI: 10.1016/j.ultrasmedbio.2020.04.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 06/11/2023]
Abstract
This study aimed to investigate whether viscoelasticity measurements can be used to quantitatively analyze and monitor therapy response in hepatic ischemia-reperfusion injury (HIRI). All animals were divided into three groups: a sham operation group (n = 12), an ischemia-reperfusion injury (IRI) group (n = 12) and an andrographolide pre-treatment group (n = 6). To assess the feasibility of using shear-wave velocity (SWV) and shear-wave dispersion (SWD), shear-wave ultrasound elastography was applied onto IRI rats after 4 and 24 h of reperfusion or sham operation (each time point subgroup n = 6). For the verification experiments, six additional rats received andrographolide injection 2 h before IRI and were examined 24 h after reperfusion. The rats were sacrificed for biochemical and histopathological analyses after ultrasound scanning was performed. Compared with the sham group, the IRI group exhibited significantly higher SWD after both 4 and 24 h of reperfusion（10.69 ± 0.69 vs. 15.20 ± 3.23 and 9.01 ± 0.46 vs. 19.35 ± 0.86; p < 0.05). A positive correlation was found between SWD values and Suzuki's score (r = 0.621; p < 0.05). No correlation was found between SWV and Suzuki's score (r = 0.283; p > 0.05), although significant differences were found between the two groups after 24 h of reperfusion. Andrographolide treatment resulted in a significantly decreased SWD (15.24 ± 0.45 vs. 19.35 ± 0.86; p < 0.05), whereas SWV showed no statistically significant difference. This study demonstrated the potential of using viscoelasticity measurements for the diagnosis and therapeutic monitoring of HIRI, and that the use of SWD was significantly more advantageous than SWV.
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Affiliation(s)
- Ying Tang
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin 300192, China.
| | - Weina Kong
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin 300192, China
| | - Jingwen Zhao
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin 300192, China
| | - Yun Chen
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin 300192, China
| | - Lei Liu
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin 300192, China
| | - Guoying Zhang
- Department of Ultrasound, Tianjin First Center Hospital, Tianjin 300192, China
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Choi EK, Jung H, Jeon S, Lim JA, Lee J, Kim H, Hong SW, Jang MH, Lim DG, Kwak KH. Role of Remote Ischemic Preconditioning in Hepatic Ischemic Reperfusion Injury. Dose Response 2020; 18:1559325820946923. [PMID: 32848526 PMCID: PMC7427033 DOI: 10.1177/1559325820946923] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/25/2020] [Accepted: 07/07/2020] [Indexed: 12/19/2022] Open
Abstract
The effect of remote ischemic preconditioning (RIPC) has been proposed that mediates the protective response in ischemia reperfusion injury (IRI) of various organs. In this study, we investigated the effect of RIPC in hepatic IRI, by assessing biomarker of oxidative stress and inflammatory cytokines. Moreover, we intended to demonstrate any such protective effect through nitric oxide (NO). Twenty-five rats were divided into the 5 groups: (1) Sham; (2) RIPC; (3) hepatic IRI; (4) RIPC + hepatic IRI; (5) C-PTIO, 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide, + RIPC + hepatic IRI. RIPC downregulated the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), histologic damage, and activity of Malondialdehyde (MDA). However, there was no significant reduction in the level of tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). AST and ALT levels, and hepatic tissue morphology in the C-PTIO group showed a significant improvement compared to those of the RIPC + hepatic IRI group. The application of RIPC before hepatic ischemia downregulated the oxidative stress, not the inflammatory cytokines. Moreover, these protective effect of RIPC would be mediated through the activation of NO as well as anti-oxidant effect.
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Affiliation(s)
- Eun Kyung Choi
- Department of Anesthesiology and Pain Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Hoon Jung
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sungmin Jeon
- Department of Anesthesiology and Pain Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jung A Lim
- Department of Anesthesiology and Pain Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jungwon Lee
- Department of Anesthesiology and Pain Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Hyunjee Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Seong Wook Hong
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Min Hye Jang
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Dong Gun Lim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Kyung Hwa Kwak
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
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Inhaled Argon Impedes Hepatic Regeneration after Ischemia/Reperfusion Injury in Rats. Int J Mol Sci 2020; 21:ijms21155457. [PMID: 32751707 PMCID: PMC7432339 DOI: 10.3390/ijms21155457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 11/16/2022] Open
Abstract
Organoprotective effects of noble gases are subject of current research. One important field of interest is the effect of noble gases on hepatic regenerative capacity. For the noble gas argon, promising studies demonstrated remarkable experimental effects in neuronal and renal cells. The aim of this study was to investigate the effects of argon on the regenerative capacity of the liver after ischemia/reperfusion injury (IRI). Male, Sprague-Dawley rats underwent hepatic IRI by clamping of the hepatic artery. Expression of hepatoproliferative genes (HGF, IL-1β, IL-6, TNF), cell cycle markers (BrdU, TUNEL, Ki-67), and liver enzymes (ALT, AST, Bilirubin, LDH) were assessed 3, 36, and 96 h after IRI. Expression of IL-1β and IL-6 was significantly higher after argon inhalation after 36 h (IL-1β 5.0 vs. 8.7 fold, p = 0.001; IL-6 9.6 vs. 19.1 fold, p = 0.05). Ki-67 was higher in the control group compared to the argon group after 36 h (214.0 vs. 38.7 positive cells/1000 hepatocytes, p = 0.045). Serum levels of AST and ALT did not differ significantly between groups. Our data indicate that argon inhalation has detrimental effects on liver regeneration after IRI as measured by elevated levels of the proinflammatory cytokines IL-1β and IL-6 after 36 h. In line with these results, Ki-67 is decreased in the argon group, indicating a negative effect on liver regeneration in argon inhalation.
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The effect of fullerenol C60 on skeletal muscle after lower limb ischemia reperfusion injury in streptozotocin-induced diabetic rats. JOURNAL OF SURGERY AND MEDICINE 2020. [DOI: 10.28982/josam.756665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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Jadhav PV, Kothakota SR, Sasidharan M, Kareem H, Nair AK. Effect of Donor Hepatic Steatosis on Ischemia Reperfusion Injury in Liver Transplant Recipient. J Clin Exp Hepatol 2020; 10:236-244. [PMID: 32405180 PMCID: PMC7212288 DOI: 10.1016/j.jceh.2019.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 07/05/2019] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION Ischemia reperfusion injury (IRI) is an important complication of liver transplant (LT). The donor risk index, which does not incorporate steatosis, includes several variables known to impact on allograft survival. The purpose of this study was to report on donor liver allograft steatosis and its association with severity of IRI. AIM The aim of this study was to determine the effect of type and grade of donor liver steatosis on the occurrence and severity of IRI in LT recipients. METHODS This was an observational study conducted at a single center over a period of 37 months from July 2013 to August 2016. Liver biopsy was performed twice, initially at the time of procurement before graft perfusion for steatosis assessment. Steatosis was classified as microsteatosis (MiS) or macrosteatosis (MaS) with mild, moderate, or severe grade. Second biopsy for IRI assessment was taken before skin closure in death donor LT (DDLT) and at the time of transaminitis in postoperative period (<72 hrs) in living donor LT (LDLT). IRI was graded as per neutrophil infiltrate, apoptosis, and hepatocyte cell dropout. Prevalence of IRI and association steatosis was studied along with other factors. RESULTS Among 53 subjects, 35 were DDLTs and 18 were LDLTs. All live donor grafts were restricted to <15% MaS and the deceased liver grafts had different type and degree of steatosis. In DDLTs, the association between occurrence of IRI and MaS was not statistically significant (P = 0.201). In DDLTs, the mild steatosis was not significantly associated with IRI. Death donor and ischemic time were significantly associated with IRI. Child's stage and MELD scores, gender, and age were not associated with risk of IRI. Severity of IRI is significantly associated with 3-month mortality (P = 0.001). CONCLUSION In patients with mild steatosis, IRI does not correlate with steatosis. However, more patients with moderate and severe steatosis are needed to define the relationship of the two in this group of patients.
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Key Words
- ALT, alanine transferase
- AST, aspartate transferase
- CIT, cold ischemia time
- DDLT, death donor liver transplant
- DRI, donor risk index
- ECD, extended criteria donor
- EHBA, extrahepatic biliary atresia
- H&E, haematoxilin & eosin
- HBV, hepatitis B virus
- HCV, hepatitis C virus
- HPE, histopathological examination
- IRI, ischemia reperfusion injury
- LAI, liver attenuation index
- LDLT, living donor liver transplant
- LT, liver transplant
- MELD, model for end-stage liver disease
- MaS, macrosteatosis
- MiS, microsteatosis
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- PNF, primary nonfunction (graft)
- WIT, warm ischemia time
- cold ischemic time
- ischemia reperfusion injury
- macrosteatosis
- microsteatosis
- warm ischemic time
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Affiliation(s)
- Prafulla V. Jadhav
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
| | | | - Madhu Sasidharan
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
| | - Harish Kareem
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
| | - Ajith K. Nair
- Department of Gastroenterology, KIMS Hospital, Trivandrum, Kerala, India
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Kim HG, Kim YH, Lee SB, Lee JS, Chae SW, Kim DG, Son CG. An Herbal Formula CG plus Ameliorates Stress-Induced Hepatic Injury in a BALB/c Mouse Model. Front Pharmacol 2020; 11:447. [PMID: 32346367 PMCID: PMC7171450 DOI: 10.3389/fphar.2020.00447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 03/23/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Stress is a well-known factor for inflammation in diverse organs/tissues. Stress also leads to liver injury, which was supported by clinical observations and animal studies. We herein investigated the hepatoprotective property of an herbal formula (called as CGplus) consisting of Artemisia gmelinii Weber ex Stechm. (syn, Artemisia iwayomogi Kitamura), Wurfbainia villosa var. xanthioides (Wall. ex Baker) Skornick. & A.D.Poulsen (syn, Amomum xanthioides Wallich), and Salvia miltiorrhiza Bunge against stress-induced hepatic damage. METHODS Male BALB/c mice were orally administered water extract of CGplus (0, 50, 100, or 200 mg/kg) daily for 5 days, and then subjected to immobilization stress for 6 h on the 5th day. RESULTS Acute immobilization stress elevated remarkably serum concentrations of stress hormones (corticosterone and adrenaline) and two hepatic injury parameters (ALT and AST), while these alterations were significantly attenuated by the administration of CGplus. The increases of oxidative parameters (ROS, NO, lipid peroxidation, and protein carbonyl) and deviation of IL-1β and IL-10 in opposite directions in hepatic tissues were significantly normalized by CGplus. Pre-treatment with CGplus also notably ameliorated the abnormal activation of toll-like receptor 4 (TLR4), CD14, and lipopolysaccharide-binding protein (LPB) as well as infiltration of neutrophils in hepatic tissues. CONCLUSION These results suggest that an herbal formula (CGplus) derived from traditional pharmaceutical theory has a potent protective effect against stress-induced hepatic injury via regulation of pro- (IL-1β) and anti-inflammatory (IL-10) cytokines.
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Affiliation(s)
- Hyeong-Geug Kim
- Liver and Immunology Research Center, Dunsan Oriental Hospital of Daejeon University, Daejeon, South Korea
| | - Yun-Hee Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea
| | - Sung-Bae Lee
- Liver and Immunology Research Center, Dunsan Oriental Hospital of Daejeon University, Daejeon, South Korea
| | - Jin-Seok Lee
- Liver and Immunology Research Center, Dunsan Oriental Hospital of Daejeon University, Daejeon, South Korea
| | - Sung-Wook Chae
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea
| | - Dong-Gu Kim
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, South Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Dunsan Oriental Hospital of Daejeon University, Daejeon, South Korea
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Hu X, Zhou C, He G, Cheng Y, Pan M, Gao Y. Frizzled-2 small interfering RNA protects hepatic BRL-3A cells against Hypoxia / Reoxygenation via modulation of autophagy. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:167-179. [PMID: 32141827 DOI: 10.5152/tjg.2020.18507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS Autophagy plays a positive role in the prevention of liver damage after hepatic ischemia-reperfusion injury (HIRI); however, the molecular mechanism is still a mystery. Understanding the molecular events behind this injury may have important implications for devising proper strategies for managing liver injury. This study investigated the effects of Frizzled-2 expression on autophagy as well as Ca2+ concentration and apoptosis in BRL-3A cells. MATERIALS AND METHODS BRL-3A cells exposed to the hypoxia/reoxygenation (H/R) condition were used as an in vitro HIRI hepatic cell model. The transfection of Frizzled-2 small interfering RNA (siRNA) or expression vector was performed to silence or overexpress Frizzled-2 in BRL-3A cells. The intracellular Ca2+ concentration was monitored by the fluorescence of Ca+. Western blot was used to detect autophagy-related proteins and apoptotic marker Caspase-3. The cellular autophagosome was observed by a transmission electron microscope. RESULTS Beclin-1 and Atg7 expressions were considerably induced by H/R treatment, and this induction was attenuated by Frizzled-2 siRNA in BRL-3A cells. The LC3B-II/I ratio was inhibited by H/R treatment, although it was considerably induced by Frizzled-2 siRNA. The overexpression of Frizzled-2 induced intracellular Ca2+ concentration and expressed autophagy-related proteins and Caspase-3 except for the suppression of LC3B-II/I ratio in BRL-3A cells in the normoxia condition. CONCLUSION The overexpression of Frizzled-2 mimicked H/R treatment and suppressed autophagy activity, whereas Frizzled-2 siRNA induced cellular autophagy and attenuated the H/R-induced hepatic injury in BRL-3A cells. These developments suggest that Frizzled-2 siRNA protects hepatic BRL-3A cells from the injury of H/R via autophagy modulation.
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Affiliation(s)
- Xiang Hu
- Department of Hepatobiliary Surgery II, State Key Laboratory of Organ Failure Research, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China;Department of General Surgery, The Second Hospital of Shenzhen Baoan People's Hospital Group, Shenzhen, China
| | - Chenjie Zhou
- Department of Hepatobiliary Surgery II, State Key Laboratory of Organ Failure Research, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Guolin He
- Department of Hepatobiliary Surgery II, State Key Laboratory of Organ Failure Research, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Cheng
- Department of Hepatobiliary Surgery II, State Key Laboratory of Organ Failure Research, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - MingXin Pan
- Department of Hepatobiliary Surgery II, State Key Laboratory of Organ Failure Research, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, State Key Laboratory of Organ Failure Research, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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