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1
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Wang ZY, Gao ST, Gou XJ, Qiu FR, Feng Q. IL-1 receptor-associated kinase family proteins: An overview of their role in liver disease. Eur J Pharmacol 2024; 978:176773. [PMID: 38936453 DOI: 10.1016/j.ejphar.2024.176773] [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: 03/19/2024] [Revised: 06/16/2024] [Accepted: 06/23/2024] [Indexed: 06/29/2024]
Abstract
The interleukin-1 receptor-associated kinase (IRAK) family is a group of serine-threonine kinases that regulates various cellular processes via toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-mediated signaling. The IRAK family comprises four members, including IRAK1, IRAK2, IRAK3, and IRAK4, which play an important role in the expression of various inflammatory genes, thereby contributing to the inflammatory response. IRAKs are key proteins in chronic and acute liver diseases, and recent evidence has implicated IRAK family proteins (IRAK1, IRAK3, and IRAK4) in the progression of liver-related disorders, including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis virus infection, acute liver failure, liver ischemia-reperfusion injury, and hepatocellular carcinoma. In this article, we provide a comprehensive review of the role of IRAK family proteins and their associated inflammatory signaling pathways in the pathogenesis of liver diseases. The purpose of this study is to explore whether IRAK family proteins can serve as the main target for the treatment of liver related diseases.
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Affiliation(s)
- Zhuo-Yuan Wang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Si-Ting Gao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao-Jun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China
| | - Fu-Rong Qiu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qin Feng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, 201203, China.
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2
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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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3
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Hargett S, Lahiri S, Kowalski GM, Corley S, Nelson ME, Lackner C, Olzomer EM, Aleksovska I, Hearn BA, Shrestha R, Janitz M, Gorrell MD, Bruce CR, Wilkins M, Hoehn KL, Byrne FL. Bile acids mediate fructose-associated liver tumour growth in mice. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167029. [PMID: 38325224 DOI: 10.1016/j.bbadis.2024.167029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/17/2023] [Accepted: 01/15/2024] [Indexed: 02/09/2024]
Abstract
High fructose diets are associated with an increased risk of liver cancer. Previous studies in mice suggest increased lipogenesis is a key mechanism linking high fructose diets to liver tumour growth. However, these studies administered fructose to mice at supraphysiological levels. The aim of this study was to determine whether liver tumour growth and lipogenesis were altered in mice fed fructose at physiological levels. To test this, we injected male C57BL/6 mice with the liver carcinogen diethylnitrosamine and then fed them diets without fructose or fructose ranging from 10 to 20 % total calories. Results showed mice fed diets with ≥15 % fructose had significantly increased liver tumour numbers (2-4-fold) and total tumour burden (∼7-fold) vs mice fed no-fructose diets. However, fructose-associated tumour burden was not associated with lipogenesis. Conversely, unbiased metabolomic analyses revealed bile acids were elevated in the sera of mice fed a 15 % fructose diet vs mice fed a no-fructose diet. Using a syngeneic ectopic liver tumour model, we show that ursodeoxycholic acid, which decreases systemic bile acids, significantly reduced liver tumour growth in mice fed the 15 % fructose diet but not mice fed a no-fructose diet. These results point to a novel role for systemic bile acids in mediating liver tumour growth associated with a high fructose diet. Overall, our study shows fructose intake at or above normal human consumption (≥15 %) is associated with increased liver tumour numbers and growth and that modulating systemic bile acids inhibits fructose-associated liver tumour growth in mice.
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Affiliation(s)
- Stefan Hargett
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908-0735, USA
| | - Sujoy Lahiri
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908-0735, USA
| | - Greg M Kowalski
- School of Exercise & Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Waurn Ponds, Victoria 3216, Australia
| | - Susan Corley
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Marin E Nelson
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908-0735, USA
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Ellen M Olzomer
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Isabella Aleksovska
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Brandon A Hearn
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Riya Shrestha
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Michael Janitz
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Mark D Gorrell
- Liver Enzymes in Metabolism and Inflammation Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia
| | - Clinton R Bruce
- School of Exercise & Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Waurn Ponds, Victoria 3216, Australia
| | - Marc Wilkins
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Kyle L Hoehn
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908-0735, USA; School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Frances L Byrne
- School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia.
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Albertini MC, Vanzolini T, Perrone S, Weiss MD, Buonocore G, Dell'Orto V, Balduini W, Carloni S. MiR-126 and miR-146a as Melatonin-Responsive Biomarkers for Neonatal Brain Ischemia. J Mol Neurosci 2023; 73:763-772. [PMID: 37725287 PMCID: PMC10694110 DOI: 10.1007/s12031-023-02155-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/07/2023] [Indexed: 09/21/2023]
Abstract
Despite advances in obstetric and neonatal care, challenges remain in early identification of neonates with encephalopathy due to hypoxia-ischemia who are undergoing therapeutic hypothermia. Therefore, there is a deep search for biomarkers that can identify brain injury. The aims of this study were to investigate the serum and brain expressions of two potential biomarkers, miR-126/miR-146a, in a preclinical model of hypoxia-ischemia (HI)-induced brain injury, and to explore their modulation during melatonin treatment. Seven-day-old rats were subjected to permanent ligation of the right carotid artery followed by 2.5 h hypoxia (HI). Melatonin (15 mg/kg) was administered 5 min after HI. Serum and brain samples were collected 1, 6 and 24 h after HI. Results show that HI caused a significant increase in the circulating levels of both miR-126 and miR-146a during the early phase of ischemic brain damage development (i.e. 1 h), with a parallel and opposite pattern in the ischemic cerebral cortex. These effects are not observed 24 h later. Treatment with melatonin restored the HI-induced effects on miR-126/miR-146a expressions, both in the cerebral cortex and in serum. We conclude that miR-126/miR-146a are promising biomarkers of HI injury and demonstrate an associated change in concentration following melatonin treatment.
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Affiliation(s)
- Maria Cristina Albertini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 PU, Urbino, Italy.
| | - Tania Vanzolini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 PU, Urbino, Italy
| | - Serafina Perrone
- Neonatology Unit, University Medical Center of Parma (AOUP) and University of Parma, Parma, Italy
| | - Michael D Weiss
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Giuseppe Buonocore
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Valentina Dell'Orto
- Neonatology Unit, University Medical Center of Parma (AOUP) and University of Parma, Parma, Italy
| | - Walter Balduini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 PU, Urbino, Italy
| | - Silvia Carloni
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 PU, Urbino, Italy.
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Xu Y, Chen Y, Yao M, You Y, Nie B, Zeng M, Jiang H. MicroRNA-146a Improved Acute Lung Injury Induced by hepatic Ischemia-reperfusion Injury by Inhibiting PRDX1. Dose Response 2023; 21:15593258231169805. [PMID: 37063344 PMCID: PMC10103257 DOI: 10.1177/15593258231169805] [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: 10/26/2022] [Accepted: 03/27/2023] [Indexed: 04/18/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI)-induced acute lung injury (ALI) is characterized by high incidence and poor prognosis. The regulatory role of microRNA-146a (miR-146a) in HIRI has been reported, but if miR-146a could affect the progression of HIRI-induced ALI has not been reported. The mice HIRI model was established by ligating left hepatic portal vein and hepatic artery for 60 minutes and then treating with reperfusion for 4 hours. Hypoxia-reoxygenation (HR) was performed to establish cell model. The binding site between miR-146a and Peroxidase 1 (PRDX1) was predicted and validated. The levels of inflammation factors and redox markers were detected with commercial kits. Significant lower expression of miR-146a and higher expression of PRDX1 in HIRI animal model were observed. miR-146a inhibited the liver injury after HIRI induction through targeting PRDX1. miR-146a inhibited the lung injury caused by HIRI via regulating PRDX1. The inhibition of cell apoptosis and inflammation factors by miR-146a were reversed by pcDNA-PRDX1. This research demonstrated that miR-146a improved ALI caused by HIRI by inhibiting apoptosis, inflammation, oxidative condition through targeting PRDX1. This study might provide a novel thought for the prevention and treatment of ALI caused by HIRI by regulating miR-146a/PRDX1 axis.
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Affiliation(s)
- Yiping Xu
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Yili Chen
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Mengxia Yao
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Yisheng You
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Bin Nie
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Meina Zeng
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Hui Jiang
- Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
- Hui Jiang, Department of Anesthesiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No 420 Fuma Road, 350014, Fuzhou, Fujian Province, China.
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Zhu SF, Yuan W, Du YL, Wang BL. Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 2023; 22:45-53. [PMID: 35934611 DOI: 10.1016/j.hbpd.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a common complication of liver surgeries, such as hepatectomy and liver transplantation. In recent years, several non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as factors involved in the pathological progression of HIRI. In this review, we summarized the latest research on lncRNAs, miRNAs and the lncRNA-miRNA regulatory networks in HIRI. DATA SOURCES The PubMed and Web of Science databases were searched for articles published up to December 2021 using the following keywords: "hepatic ischemia-reperfusion injury", "lncRNA", "long non-coding RNA", "miRNA" and "microRNA". The bibliography of the selected articles was manually screened to identify additional studies. RESULTS The mechanism of HIRI is complex, and involves multiple lncRNAs and miRNAs. The roles of lncRNAs such as AK139328, CCAT1, MALAT1, TUG1 and NEAT1 have been established in HIRI. In addition, numerous miRNAs are associated with apoptosis, autophagy, oxidative stress and cellular inflammation that accompany HIRI pathogenesis. Based on the literature, we conclude that four lncRNA-miRNA regulatory networks mediate the pathological progression of HIRI. Furthermore, the expression levels of some lncRNAs and miRNAs undergo significant changes during the progression of HIRI, and thus are potential prognostic markers and therapeutic targets. CONCLUSIONS Complex lncRNA-miRNA-mRNA networks regulate HIRI progression through mutual activation and antagonism. It is necessary to screen for more HIRI-associated lncRNAs and miRNAs in order to identify novel therapeutic targets.
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Affiliation(s)
- Shan-Fei Zhu
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Wei Yuan
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Yong-Liang Du
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Bai-Lin Wang
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China.
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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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MicroRNAs: Novel Targets in Hepatic Ischemia–Reperfusion Injury. Biomedicines 2022; 10:biomedicines10040791. [PMID: 35453542 PMCID: PMC9028838 DOI: 10.3390/biomedicines10040791] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs). miRNAs are ~21 nucleotides in length and well-characterized for their role in gene regulations; they have recently been used for therapeutic approaches in addition to their role as biomarkers for many diseases. miRNAs that are associated with hepatic IRI in in vitro and in vivo animal models are comprehensively summarized in this review. In those studies, the manipulation of miRNAs has been shown for the inhibition of aggravated immune response, reduction of apoptosis, stimulation of tissue repair, and enhancement of cell recovery to attenuate liver damage. Therefore, the utilization of liver-specific miRNA holds great potential as a therapeutic agent to improve early allograft dysfunction, hepatic injury, and patient outcome.
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Profiling circulating microRNAs in patients with cirrhosis and acute-on-chronic liver failure. JHEP Rep 2021; 3:100233. [PMID: 33665588 PMCID: PMC7902550 DOI: 10.1016/j.jhepr.2021.100233] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 12/02/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
Background & Aims MicroRNAs (miRNAs) circulate in several body fluids and can be useful biomarkers. The aim of this study was to identify blood-circulating miRNAs associated with cirrhosis progression and acute-on-chronic liver failure (ACLF). Methods Using high-throughput screening of 754 miRNAs, serum samples from 45 patients with compensated cirrhosis, decompensated cirrhosis, or ACLF were compared with those from healthy individuals (n = 15). miRNA levels were correlated with clinical parameters, organ failure, and disease progression and outcome. Dysregulated miRNAs were evaluated in portal and hepatic vein samples (n = 33), liver tissues (n = 17), and peripheral blood mononuclear cells (PBMCs) (n = 16). Results miRNA screening analysis revealed that circulating miRNAs are dysregulated in cirrhosis progression, with 51 miRNAs being differentially expressed among all groups of patients. Unsupervised clustering and principal component analysis indicated that the main differences in miRNA expression occurred at decompensation, showing similar levels in patients with decompensated cirrhosis and those with ACLF. Of 43 selected miRNAs examined for differences among groups, 10 were differentially expressed according to disease progression. Moreover, 20 circulating miRNAs were correlated with model for end-stage liver disease and Child-Pugh scores. Notably, 11 dysregulated miRNAs were associated with kidney or liver failure, encephalopathy, bacterial infection, and poor outcomes. The most severely dysregulated miRNAs (i.e. miR-146a-5p, miR-26a-5p, and miR-191-5p) were further evaluated in portal and hepatic vein blood and liver tissue, but showed no differences. However, PBMCs from patients with cirrhosis showed significant downregulation of miR-26 and miR-146a, suggesting a extrahepatic origin of some circulating miRNAs. Conclusions This study is a repository of circulating miRNA data following cirrhosis progression and ACLF. Circulating miRNAs were profoundly dysregulated during the progression of chronic liver disease, were associated with failure of several organs and could have prognostic utility. Lay summary Circulating miRNAs are small molecules in the blood that can be used to identify or predict a clinical condition. Our study aimed to identify miRNAs for use as biomarkers in patients with cirrhosis or acute-on-chronic liver failure. Several miRNAs were found to be dysregulated during the progression of disease, and some were also related to organ failure and disease-related outcomes.
Circulating miRNAs are dysregulated with cirrhosis progression and in patients with ACLF. Patient decompensation is associated with important changes in the levels of circulating miRNAs. A total of 11 circulating miRNAs were identified as associated with organ failure and 7 with poor outcome. The miRNAs most dysregulated during cirrhosis progression were miR-146a, miR-26a, and miR-191. miR-146a was dysregulated in PBMCs of patients with decompensated cirrhosis vs. compensated cirrhosis.
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Key Words
- ACLF, acute-on-chronic liver failure
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Biomarkers
- CXCL10, C-X-C motif chemokine ligand 10
- Chronic liver disease
- EF CLIF, European Foundation for the Study of Chronic Liver Failure
- FoxO, forkhead box O
- INR, International Normalised Ratio
- LDH, lactate dehydrogenase
- Liver decompensation
- MAPK, mitogen-activated protein kinase
- MELD, model for end-stage liver disease
- NASH, non-alcoholic steatohepatitis
- Non-coding RNAs
- PBMCs, peripheral blood mononuclear cells
- PCA, principal component analysis
- TGF, transforming growth factor
- TIPS, transjugular intrahepatic portosystemic shunt
- qPCR, quantitative PCR
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10
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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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11
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Zhou W, Lin D, Zhong Z, Ye Q. Roles of TRAFs in Ischemia-Reperfusion Injury. Front Cell Dev Biol 2020; 8:586487. [PMID: 33224951 PMCID: PMC7674171 DOI: 10.3389/fcell.2020.586487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor necrosis factor receptor-associated factor (TRAF) proteins are a family of signaling molecules that function downstream of multiple receptor signaling pathways, and they play a pivotal role in the regulation of intracellular biological progresses. These TRAF-dependent signaling pathways and physiological functions have been involved in the occurrence and progression of ischemia-reperfusion injury (IRI), which is a common pathophysiological process that occurs in a wide variety of clinical events, including ischemic shock, organ transplantation, and thrombolytic therapy, resulting in a poor prognosis and high mortality. IRI occurs in multiple organs, including liver, kidney, heart, lung, brain, intestine, and retina. In recent years, mounting compelling evidence has confirmed that the genetic alterations of TRAFs can cause subversive phenotype changes during IRI of those organs. In this review, based on current knowledge, we summarized and analyzed the regulatory effect of TRAFs on the IRI of various organs, providing clear direction and a firm theoretical basis for the development of treatment strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in IRI-related diseases.
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Affiliation(s)
- Wei Zhou
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan, China
| | - Danni Lin
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan, China.,The First Affiliated Hospital, Zhejiang University School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Innovation Center for the Study of Pancreatic Diseases, Hangzhou, China
| | - Zibiao Zhong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Engineering Research Center of Natural Polymer-based Medical Materials in Hubei Province, Wuhan, China.,The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
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12
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Li Y, Gao M, Xu LN, Yin LH, Qi Y, Peng JY. MicroRNA-142-3p attenuates hepatic ischemia/reperfusion injury via targeting of myristoylated alanine-rich C-kinase substrate. Pharmacol Res 2020; 156:104783. [PMID: 32224251 DOI: 10.1016/j.phrs.2020.104783] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 01/09/2023]
Abstract
MiR-142-3p as one key molecule in oncogenesis and inflammation plays crucial roles in hepatic fibrosis, hepatocellular carcinoma and other liver disease. However, there have no literatures to report its effects on hepatic ischemia-reperfusion (HI/R) injury. In the present work, hypoxia reoxygenation (H/R) models on AML12 and HepG2 cells, and ischemia/reperfusion model in mice were established. The methods of real-time PCR, dual luciferase reporter, mimic, inhibitor, agomir, antagomir and siRNA transfection assays were used. The expression levels of miR-142-3p were decreased in model groups in vitro and in vivo compared with control group or Sham group, which directly targeted MARCKS to regulate its expression. Then, MARCKS activated p38/JNK signal, up-regulated NF-κB expression to accelerate inflammation, and inhibited PI3K/AKT signal to promote apoptosis. Moreover, miR-142-3p mimic in vitro and agomir in vivo lowered the expression levels of MARCKS, thereby alleviating apoptosis and inflammation to relieve HI/R injury. Furthermore, miR-142- 3p inhibitor in vitro and antagomir in vivo up-regulated the expression levels of MARCKS to aggravate HI/R damage via promoting inflammation and apoptosis. Consistently, MARCKS siRNA markedly inhibited HI/R injury by restraining apoptosis and inflamm- ation in mice. MiR-142-3p played a considerable part in adjusting HI/R injury by targeting MARCKS, and miR-142-3p/MARCKS should be a new therapeutic target for HI/R injury.
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Affiliation(s)
- Y Li
- Department of Pharmaceutical Analysis, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - M Gao
- Department of Pharmaceutical Analysis, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - L-N Xu
- Department of Pharmaceutical Analysis, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - L-H Yin
- Department of Pharmaceutical Analysis, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - Y Qi
- Department of Pharmaceutical Analysis, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China
| | - J-Y Peng
- Department of Pharmaceutical Analysis, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China; Key Laboratory for Basic and Applied Research on Pharmacodynamic Substances of Traditional Chinese Medicine of Liaoning Province, Dalian Medical University, Dalian, China; National-Local Joint Engineering Research Center for Drug Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China.
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Hu ZQ, Lu Y, Cui D, Ma CY, Shao S, Chen P, Tao R, Wang JJ. MicroRNAs and long non-coding RNAs in liver surgery: Diagnostic and therapeutic merits. Hepatobiliary Pancreat Dis Int 2020; 19:218-228. [PMID: 32414577 DOI: 10.1016/j.hbpd.2020.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatectomy and liver transplantation (LT) are the two most commonly performed surgical procedures for various hepatic lesions. microRNA (miRNA) and long non-coding RNA (lncRNA) have been gradually unveiled their roles as either biomarkers for early diagnosis or potentially therapeutic tools to manipulate gene expression in many disease entities. This review aimed to discuss the effects of miRNA or lncRNA in the hepatectomy and LT fields. DATA SOURCES We did a literature search from 1990 through January 2018 to summarize the currently available evidence with respect to the effects of miRNA and lncRNA in liver regeneration after partial hepatectomy, as well as their involvement in several key issues related to LT, including ischemia-reperfusion injury, allograft rejection, tolerance, recurrence of original hepatic malignancies, etc. RESULTS: Certain miRNAs and lncRNAs are actively involved in the regulation of various aspects of liver resection and transplantation. During the process of liver regeneration after hepatectomy, the expression of miRNAs and lncRNAs shows dynamic changes. CONCLUSIONS It is now clear that miRNAs and lncRNAs orchestrate in various aspects of the pathophysiological process of LT and hepatectomy. Better understanding of the underlying mechanism and future clinical trials may strengthen their positions as either biomarkers or potential therapeutic targets in the management of complications after liver surgery.
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Affiliation(s)
- Zhi-Qiu Hu
- Department of Surgery, Minhang Hospital, Fudan University, Shanghai 201199, China; Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Yi Lu
- Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China; Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Di Cui
- Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Chen-Yang Ma
- Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Su Shao
- Department of General Surgery, Chun'an 1st People's Hospital, Hangzhou 311700, China
| | - Ping Chen
- Department of Obstetrics and Gynecology, Shaoxing 2nd Hospital, Shaoxing 312000, China
| | - Ran Tao
- Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China; Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Jian-Jun Wang
- Department of General Surgery, Chun'an 1st People's Hospital, Hangzhou 311700, China.
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Chungen Y, Dongfang Z, Guoyuan X. MicroRNA-146a Protects Against Ischemia/Reperfusion Liver Injury Through Inhibition of Toll-like Receptor 4 Signaling Pathway in Rats. Transplant Proc 2020; 52:1007-1013. [PMID: 32143869 DOI: 10.1016/j.transproceed.2020.01.046] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/25/2020] [Indexed: 12/17/2022]
Abstract
Hepatic ischemia/reperfusion injury (IRI) is a severe and common clinical challenge involved in liver surgery and transplantation. MicroRNA-146a (miR-146a) has recently been reported to be abnormally expressed in hepatic IRI, but the underlying mechanism is not fully elucidated. Accumulating evidences showed miR-146a targets Toll-like receptor 4 (TLR4) signaling pathway. Here, we found that miR-146a inhibited TLR4 signaling pathway accompanied by attenuated liver dysfunction, histologic injury and inflammation. Conversely, miR-146a inhibition increased TLR4 and interleukin-1 receptor-associated kinase, accompanied by exacerbated hepatic IRI and inflammation. Taken together, these data indicated that miR-146a protect against hepatic IRI via inhibiting TLR4 signaling pathway. In addition, we verified ultrasound microbubble-mediated gene transfection improved miR-146a transfection efficacy.
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Affiliation(s)
- Yan Chungen
- Department of Gastroenterology, Affiliated Hospital of Shaoxing University, Zhejiang, China.
| | - Zhu Dongfang
- Department of Lab Medicine, Affiliated Hospital of Shaoxing University, Zhejiang, China
| | - Xia Guoyuan
- Department of Ultrasound Diagnosis, Affiliated Hospital of Shaoxing University, Zhejiang, China
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Zheng L, Ling W, Zhu D, Li Z, Kong L. Roquin-1 Regulates Macrophage Immune Response and Participates in Hepatic Ischemia-Reperfusion Injury. THE JOURNAL OF IMMUNOLOGY 2020; 204:1322-1333. [PMID: 31996460 DOI: 10.4049/jimmunol.1900053] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 12/23/2019] [Indexed: 12/19/2022]
Abstract
With the development of liver surgery, ischemia-reperfusion (IR) injury has received increasing attention. Roquin-1 has been shown to play an important role in innate immune and immune balance. We demonstrate that Roquin-1 expression increased at 1 h after IR and then decreased in C57B/L mice. The immunofluorescence double-label showed that Roquin-1 was mainly expressed in macrophages (mø). Furthermore, we used clodronate liposomes to remove mø, and injected the bone marrow-derived mø (BMDM) through the tail vein in 1 h before IR. We found that liver IR injury was aggravated by Roquin-1 interference. The results of PCR and ELISA suggested that after interference with Roquin-1, mø increased toward M1 and decreased toward M2. Then, interference with Roquin-1 promoted the polarization of mø to M1 and inhibited the polarization of M2. By Western blot technology and AMPKα and mTOR inhibitors, we found that Roquin-1 promotes the phosphorylation of mTOR and STAT3 by inhibiting the phosphorylation of AMPKα. We used AICAR to activate AMPKα in mø and found that the level of ubiquitination of AMPKα was decreased after activation of AMPKα. Furthermore, by bioinformatics methods, we identified potential ubiquitination sites on AMPKα. By the point mutation experiments in vitro, we confirmed that the ubiquitination of these sites is regulated by Roquin-1. Meanwhile, Roquin-1 interference inhibited the activation and function of AMPKα. This topic describes the protection of liver IR injury by Roquin-1 and discusses its main mechanism for regulating AMPKα activity through ubiquitination and affecting the polarization of mø.
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Affiliation(s)
- Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 200011 Shanghai, People's Republic of China; and
| | - Wei Ling
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, People's Republic of China
| | - Deming Zhu
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, People's Republic of China
| | - Zhi Li
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, People's Republic of China
| | - Lianbao Kong
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, People's Republic of China
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Zhang L, Song Y, Chen L, Li D, Feng H, Lu Z, Fan T, Chen Z, Livingston MJ, Geng Q. MiR-20a-containing exosomes from umbilical cord mesenchymal stem cells alleviates liver ischemia/reperfusion injury. J Cell Physiol 2019; 235:3698-3710. [PMID: 31566731 DOI: 10.1002/jcp.29264] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 09/03/2019] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSCs) have been proved to exert considerable therapeutic effects on ischemia-reperfusion (I/R)-induced injury, but the underlying mechanism remains unknown. In this study, we aimed to explore the potential molecular mechanism underlying the therapeutic effect of MSCs-derived exosome reinforced with miR-20a in reversing liver I/R injury. Quantitative real-time polymerase chain reaction, Western blot, and IHC were carried out to compare the differential expressions of miR-20a, Beclin-I, FAS, Caspase-3, mTOR and P62 in IR rats and normal rats. TUNEL was performed to assess IR-induced apoptosis in IR rats, and luciferase assay was used to confirm the inhibitory effect of miR-20a on Beclin-I and FAS expression. Among the 12 candidate microRNAs (miRNAs), miR-486, miR-25, miR-24, miR-20a,miR-466 and miR-433-3p were significantly downregulated in I/R. In particular, miR-20a, a miRNA highly expressed in umbilical cord-derived mesenchymal stem cells, was proved to bind to the 3' UTR of Beclin-I and FAS to exert an inhibitory effect on their expressions. Since Beclin-I and FAS were aberrantly upregulated in IR, exosomes separated from UC-MSCs showed therapeutic efficacy in reversing I/R induced apoptosis. In addition, exosomes reinforced with miR-20a and separated from UC-MSCs almost fully alleviated I/R injury. Furthermore, our results showed that miR-20a could alleviate the abnormal expression of genes related to apoptosis and autophagy, such as active Caspase-3, mTOR, P62, and LC3II. This study presented detailed evidence to clarify the mechanism underlying the therapeutic efficacy of UC-MSCs in the treatment of I/R injury.
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Affiliation(s)
- Lin Zhang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yaolin Song
- Department of Thoracic Surgery, Ezhou Central Hospital, Ezhou, Hubei, China
| | - Lei Chen
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Donghang Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Haohao Feng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zilong Lu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tao Fan
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zubin Chen
- Department of Hepatological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Man J Livingston
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Xiao Y, Zhang S, Li Q, Liu Z, Mai W, Chen W, Lei J, Hu H. miR-219a-5p Ameliorates Hepatic Ischemia/Reperfusion Injury via Impairing TP53BP2. Dig Dis Sci 2019; 64:2177-2186. [PMID: 30796685 DOI: 10.1007/s10620-019-05535-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 02/14/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatic ischemia/reperfusion (I/R) injury is a serious complication that occurs upon hypovolemic shock, liver resection, and transplantation. A significant age-dependent difference in the injury response to hepatic I/R in both human and animal models has been reported. Nevertheless, the molecular mechanism is currently unclear. AIMS To clarify the reason why aged animals or people were more vulnerable to hepatic I/R injury. METHODS In the present study, we found decreased miR-219a-5p expression in the old mice more vulnerable to hepatic I/R injury. Administrated with agomir-miR-219a-5p diminished the severity of hepatic I/R injury in old mice, as indicated by lower serum ALT and AST, oxidative parameters including MDA, TOA, and OSI, and decreased apoptotic cell number. The effect of miR-219a-5p was also confirmed in the H2O2-induced apoptosis model in AML-12 and NCTC1469 cells. After miR-219a-5p overexpression, two key apoptosis-related proteins Bax and P21, target genes of TP53, were decreased. Furthermore, TP53BP2 interacts with p53 family members and promotes their transcriptional activities toward pro-apoptosis genes. RESULTS RNA sequencing, western blot, and luciferase reporter assay proved that TP53BP2, a crucial TP53 transcriptional activity enhancer in vivo, was directly regulated by miR-219a-5p. CONCLUSIONS In summary, our study demonstrated that age-related miR-219a-5p can attenuate hepatic I/R injury through inhibiting TP53BP2 and downstream TP53-dependent apoptosis of hepatic cells in mice.
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Affiliation(s)
- Yu Xiao
- Department of Anesthesiology, Jiangxi Provincial Children's Hospital, 122 Yangming Road, Nanchang, 330006, Jiangxi Province, China
| | - Shouhua Zhang
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, Jiangxi Province, China
| | - Qiang Li
- Department of Anesthesiology, Jiangxi Provincial Children's Hospital, 122 Yangming Road, Nanchang, 330006, Jiangxi Province, China
| | - Zhiwen Liu
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, Jiangxi Province, China
| | - Wenli Mai
- Department of Oncology, Jiangxi Provincial Cancer Hospital, Nanchang, 330029, China
| | - Wen Chen
- Department of Oncology, Jiangxi Provincial Cancer Hospital, Nanchang, 330029, China
| | - Jun Lei
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, Jiangxi Province, China
| | - Huakun Hu
- Department of Anesthesiology, Jiangxi Provincial Children's Hospital, 122 Yangming Road, Nanchang, 330006, Jiangxi Province, China.
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Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver. Int J Mol Sci 2018; 19:ijms19051302. [PMID: 29701719 PMCID: PMC5983804 DOI: 10.3390/ijms19051302] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/20/2018] [Accepted: 04/24/2018] [Indexed: 12/22/2022] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ) protects the liver against IRI, but with unidentified direct target gene(s) and unclear mechanism(s). Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.
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Zhang W, Shao M, He X, Wang B, Li Y, Guo X. Overexpression of microRNA-146 protects against oxygen-glucose deprivation/recovery-induced cardiomyocyte apoptosis by inhibiting the NF-κB/TNF-α signaling pathway. Mol Med Rep 2017; 17:1913-1918. [PMID: 29257202 DOI: 10.3892/mmr.2017.8073] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 08/04/2017] [Indexed: 11/06/2022] Open
Abstract
MicroRNA (miR) has been reported to be associated with ischemia and reperfusion (I/R) and cell apoptosis. Suppression of cell apoptosis may reduce the irreversible damage induced by reperfusion. The aims of the current study were to explore the cytoprotective effects of miR-146 against oxygen-glucose deprivation/recovery (OGD/R)-induced injury in H9c2 rat myocardial cells, as well as the underlying mechanisms. Following stimulation with OGD/R, the cells were transfected with miR-146 mimics or negative controls. The levels of miR-146 were analyzed by reverse transcription-quantitative polymerase chain reaction. Thereafter, cell viability and cell apoptosis were analyzed by MTT assay and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assay, respectively. In addition, the levels of tumor necrosis factor (TNF)-α were determined by ELISA and the levels of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2 and phosphorylated (p)-nuclear factor (NF)-κB were measured by western blotting. The results demonstrated that overexpression of miR-146 significantly increased cell viability and decreased apoptosis (P<0.05). It was observed that overexpression of miR-146 statistically reduced the levels of Bax, TNF-α and p-NF-κB but markedly upregulated the levels of Bcl-2 (P<0.05). These results indicate that overexpression of miR-146 may protect against OGD/R-induced cardiomyocyte apoptosis. Overexpression of miR-146 may alleviate the irreversible injury associated with reperfusion and the effects may be achieved by inhibiting the NF-κB/TNF-α signaling pathway.
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Affiliation(s)
- Wenwu Zhang
- Department of Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Mengmeng Shao
- Department of Rehabilitation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaojie He
- Department of Ophthalmology, The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Benji Wang
- Department of Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yuechun Li
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xianyang Guo
- Department of Critical Care Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model. Biosci Rep 2017; 37:BSR20170798. [PMID: 28842516 PMCID: PMC5603753 DOI: 10.1042/bsr20170798] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/20/2017] [Accepted: 08/22/2017] [Indexed: 01/11/2023] Open
Abstract
A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir-miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir-miR-494, and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H2O2-induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H2O2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir-miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats (P<0.05 or 0.01). After H2O2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group (P<0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor (P<0.01). Moreover, HIRI + agomir-miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway.
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Global MicroRNA Expression Profiling of Mouse Livers following Ischemia-Reperfusion Injury at Different Stages. PLoS One 2016; 11:e0148677. [PMID: 26859886 PMCID: PMC4747576 DOI: 10.1371/journal.pone.0148677] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 01/20/2016] [Indexed: 11/21/2022] Open
Abstract
Hepatic ischemia-reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia-reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia-reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondrial function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia-reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic IR injury.
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Jiang W, Ni Q, Tan L, Kong L, Lu Y, Xu X, Kong L. The microRNA-146a/b attenuates acute small-for-size liver graft injury in rats. Liver Int 2015; 35:914-24. [PMID: 25156638 DOI: 10.1111/liv.12674] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 08/17/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS A critical role of the Toll-like receptor (TLR)-4 and its downstream mediators in the pathogenesis of small-for-size liver graft injury has been documented. Recently, the microRNA-146 (miR-146) was identified as a potent negative regulator of the TLR4 signalling pathway. In this study, the role of miR-146a and miR-146b in the attenuation of TLR-4 signalling and small-for-size liver graft injury was investigated. METHODS The expression levels of miR-146a and miR-146b during small-for-size liver graft injury were studied in vivo. In addition, the effects of miR-146a and miR-146b on the expression of IRAK1 and TRAF6 in the rat macrophage cell line NR8383 and rat liver kupffer cells were studied in vitro. The in vivo effect of miR-146a and miR-146b on small-for-size liver graft injury was studied by the tail vein injection of miR-146a mimics and miR-146b mimics. RESULTS The levels of miR-146a and miR-146b decreased with a small-for-size liver graft. MiR-146a and miR-146b inhibited IRAK1 and TRAF6 expression by binding to the 3'UTR of IRAK1 or TRAF6, respectively, in the rat macrophage cell line NR8383. The administration of miR-146a mimics and miR-146b mimics prevented liver graft injury in small-for-size liver graft injury via the inactivation of IRAK1 and TRAF6 in vivo. CONCLUSIONS miR-146a and miR-146b prevent liver injury in small-for-size liver graft injury via the inactivation of IRAK1 and TRAF6.
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Affiliation(s)
- Weiwei Jiang
- Department of Neonatal Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China
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Lin WB, Liang MY, Chen GX, Yang X, Qin H, Yao JP, Feng KN, Wu ZK. MicroRNA profiling of the intestine during hypothermic circulatory arrest in swine. World J Gastroenterol 2015; 21:2183-2190. [PMID: 25717255 PMCID: PMC4326157 DOI: 10.3748/wjg.v21.i7.2183] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 08/12/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To perform a profiling analysis of changes in intestinal microRNA (miRNA) expression during hypothermic circulatory arrest (HCA).
METHODS: A total of eight piglets were randomly divided into HCA and sham operation (SO) groups. Under general anesthesia, swine in the HCA group were subjected to hypothermic cardiopulmonary bypass at 24 °C followed by 80 min of circulatory arrest, and the reperfusion lasted for 180 min after cross-clamp removal. The counterparts in the SO group were only subjected to median sternotomy. Histopathological analysis was used to detect mucosal injury, and Pick-and-Mix custom miRNA real-time polymerase chain reaction (PCR) panels containing 306 unique primer sets were utilized to assay unpooled intestinal samples harvested from the two groups.
RESULTS: The intestinal mucosa of the animals that were subjected to 24 °C HCA exhibited representative ischemic reperfusion injury of grade 2 or 3 according to the Chiu score. Such intestinal mucosal injuries, with the subepithelial space and epithelial layer lifting away from the lamina propria, were accompanied by shortened and irregular villi. On the contrary, the intestinal mucosa remained normal in the sham-operated animals. In total, twenty-five miRNAs were differentially expressed between the two groups (15 upregulated and 10 downregulated in the HCA group). Among these, eight miRNAs (miR-122, miR-221-5p, miR-31, miR-421-5p, miR-4333, miR-499-3p, miR-542 and let-7d-3p) were significantly dysregulated (four higher and four lower). The expression of miR-122 was significantly (5.37-fold) increased in the HCA group vs the SO group, indicating that it may play a key role in HCA-induced mucosal injury.
CONCLUSION: Exposure to HCA caused intestinal miRNA dysregulation and barrier dysfunction in swine. These altered miRNAs might be related to the protection or destruction of the intestinal barrier.
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Triptolide Attenuates Acute Small-for-Size Liver Graft Injury in Rats by Inhibition of Toll-like Receptor 4. Transplant Proc 2014; 46:3303-8. [DOI: 10.1016/j.transproceed.2014.07.077] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 06/19/2014] [Accepted: 07/15/2014] [Indexed: 01/19/2023]
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Hu H, Jiang W, Xi X, Zou C, Ye Z. MicroRNA-21 attenuates renal ischemia reperfusion injury via targeting caspase signaling in mice. Am J Nephrol 2014; 40:215-23. [PMID: 25322693 DOI: 10.1159/000368202] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 08/29/2014] [Indexed: 01/01/2023]
Abstract
BACKGROUND MicroRNAs (miR) have come into focus as powerful regulators of gene expression and potential diagnostic tools during renal ischemia reperfusion injury (IRI). The aim of this study was to investigate the molecular regulation and function of miR-21, and to analyze the relationship between caspases and miR-21 expression levels in an experimental model of renal IRI. METHODS IRI was induced by bilateral renal ischemia for 45 min followed by reperfusion. The male BALB/c mice were randomly assigned to the following groups: pre-miR-21 + IRI group, antagomiR-21 + IRI group, PBS + IRI group, pre-miR-21 + sham operation group, antagomiR-21 + sham operation group, PBS + sham operation group. The pre-miR-21 or antagomiR-21 was administered intraperitoneally (200 ng/kg weight) 24 and 6 h before induction of ischemia. Renal function, histological damage, renal cell apoptosis proteins were evaluated at 24 h after reperfusion. RESULTS Mice upregulated miR-21 had lower plasma levels of blood urea nitrogen (BUN) and creatinine, lower histopathological scores and a decrease in programmed cell death 4 (PDCD4) mRNA and active caspase-3, caspase-8 proteins expressions. CONCLUSIONS miR-21 is endowed with anti-apoptotic properties by suppressing the expression of PDCD4 gene and active caspase 3/8 fragments in the condition of renal IRI. miR-21 exerts significant functional protection in our renal murine model of IRI.
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Affiliation(s)
- Honglin Hu
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, PR China
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Jiang W, Kong L, Ni Q, Lu Y, Ding W, Liu G, Pu L, Tang W, Kong L. miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6. PLoS One 2014; 9:e101530. [PMID: 24987958 PMCID: PMC4079695 DOI: 10.1371/journal.pone.0101530] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 06/09/2014] [Indexed: 12/26/2022] Open
Abstract
A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor- associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.
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Affiliation(s)
- Weiwei Jiang
- Department of Neonatal Surgery, Nanjing Children’s Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Liangliang Kong
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qingfeng Ni
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yeting Lu
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenzhou Ding
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoqing Liu
- Department of Neonatal Surgery, Nanjing Children’s Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Liyong Pu
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weibing Tang
- Department of Neonatal Surgery, Nanjing Children’s Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Lianbao Kong
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Li X, Yi S, Deng Y, Cheng J, Wu X, Liu W, Tai Y, Chen G, Zhang Q, Yang Y. MiR-124 protects human hepatic L02 cells from H2O2-induced apoptosis by targeting Rab38 gene. Biochem Biophys Res Commun 2014; 450:148-53. [PMID: 24875359 DOI: 10.1016/j.bbrc.2014.05.085] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Accepted: 05/19/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgeons. Because microRNAs (miRNAs) participate in various hepatic pathophysiological processes, this study aimed to explore the role and potential mechanism of miR-124 in hepatic IRI. METHODS A liver IRI model was established in rats. The differential expression of miRNAs was detected using microarrays, and the expression of miR-124 was measured by qRT-PCR. A hydrogen peroxide (H2O2)-induced oxidative stress apoptosis model was also established. Cell apoptosis was detected by flow cytometry, and viability was detected by CCK8. The expression of Rab38 was detected by Western blotting and qRT-PCR, and a luciferase reporter assay was used to verify the expression of the miR-124 target gene. RESULTS The miRNA spectrum changes dramatically after hepatic IRI in rats, and miR-124 is significantly down-regulated after liver IRI. MiR-124 decreases the H2O2-induced apoptosis of human hepatic L02 cells by up-regulating the activation of the AKT pathway. Rab38 is a target gene of miR-124 and is involved in H2O2-induced apoptosis. Interference with the expression of the Rab38 gene can protect hepatic L02 from H2O2-induced apoptosis by increasing the phosphorylation of AKT. These protective effects of miR-124 are attenuated by over-expression of Rab38. CONCLUSIONS Many miRNAs are involved in hepatic IRI in rats, and miR-124 is significantly decreased in this model. MiR-124 significantly decreases the H2O2-induced apoptosis of human hepatic L02 cells by targeting the Rab38 gene and activating the AKT pathway.
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Affiliation(s)
- Xiaohua Li
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Shuhong Yi
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yinan Deng
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Jintao Cheng
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Xiaocai Wu
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Wei Liu
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Yan Tai
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Guihua Chen
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Qi Zhang
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Yang Yang
- Liver Surgery Center, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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28
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Zhou L, Zang G, Zhang G, Wang H, Zhang X, Johnston N, Min W, Luke P, Jevnikar A, Haig A, Zheng X. MicroRNA and mRNA signatures in ischemia reperfusion injury in heart transplantation. PLoS One 2013; 8:e79805. [PMID: 24278182 PMCID: PMC3835872 DOI: 10.1371/journal.pone.0079805] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 10/04/2013] [Indexed: 11/19/2022] Open
Abstract
Ischemia reperfusion (I/R) injury is an unavoidable event occurring during heart transplantation, leading to graft failures and lower long-term survival rate of the recipient. Several studies have demonstrated that microRNAs (miRNAs) are vital regulators of signalling pathways involved in I/R injury. The present study aims to quantify the altered expression levels of miRNA and mRNA upon I/R injury in a mouse heart transplantation model, and to investigate whether these miRNA can regulate genes involved in I/R injury. We performed heterotopic heart transplantation on mouse models to generate heart tissue samples with I/R and non-I/R (control). The expression levels of miRNAs as well as genes were measured in heart grafts by microarray and real time RT-PCR. miRNA alteration in cardiomyocytes exposed to hypoxia was also detected by qRT-PCR. We observed significant alterations in miRNA and gene expression profile after I/R injury. There were 39 miRNAs significantly downregulated and 20 upregulated up to 1.5 fold in heart grafts with I/R injury compared with the grafts without I/R. 48 genes were observed with 3 fold change and p<0.05 and 18 signalling pathways were enriched using Keggs pathway library. Additionally, hypoxia/reperfusion induced primary cardiomyocyte apoptosis and altered miRNA expression profiles. In conclusion, this is the first report on miRNA expression profile for heart transplantation associated with I/R injury. These findings provide us with an insight into the role of miRNA in I/R injury in heart transplantation.
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Affiliation(s)
- Liangyi Zhou
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Guoyao Zang
- Sir Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guangfeng Zhang
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Hansong Wang
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Xusheng Zhang
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Nathan Johnston
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Weiping Min
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
- Lawson Health Research Institute, London Ontario, Canada
- Multiple Organ Transplant Program, London Ontario, Canada
| | - Patrick Luke
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
- Multiple Organ Transplant Program, London Ontario, Canada
| | - Anthony Jevnikar
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
- Lawson Health Research Institute, London Ontario, Canada
- Multiple Organ Transplant Program, London Ontario, Canada
| | - Aaron Haig
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Xiufen Zheng
- Department of Pathology, Surgery, Medicine, and Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
- Lawson Health Research Institute, London Ontario, Canada
- * E-mail:
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Ouyang YB, Xu L, Yue S, Liu S, Giffard RG. Neuroprotection by astrocytes in brain ischemia: importance of microRNAs. Neurosci Lett 2013; 565:53-8. [PMID: 24269978 DOI: 10.1016/j.neulet.2013.11.015] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 10/25/2013] [Accepted: 11/10/2013] [Indexed: 01/25/2023]
Abstract
Astrocytes have been shown to protect neurons and increase their survival in many pathological settings. Manipulating astrocyte functions is thus an important strategy to enhance neuronal survival and improve outcome following cerebral ischemia. Increasing evidence supports the involvement of microRNAs (miRNA), some of them being astrocyte-enriched, in the regulation of cerebral ischemia. This mini review will focus on several recently reported astrocyte-enriched miRNAs (miR-181 and miR-29 families and miR-146a), their validated targets, regional expression and effects on outcome after cerebral ischemia.
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Affiliation(s)
- Yi-Bing Ouyang
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Lijun Xu
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sibiao Yue
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Siwei Liu
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Rona G Giffard
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA.
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