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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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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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Yue P, Lv X, You J, Zou Y, Luo J, Lu Z, Cao H, Liu Z, Fan X, Ye Q. Hypothermic oxygenated perfusion attenuates DCD liver ischemia-reperfusion injury by activating the JAK2/STAT3/HAX1 pathway to regulate endoplasmic reticulum stress. Cell Mol Biol Lett 2023; 28:55. [PMID: 37438690 DOI: 10.1186/s11658-023-00466-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/14/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model. METHODS To investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted. RESULTS HOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway. CONCLUSIONS JAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation.
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Affiliation(s)
- Pengpeng Yue
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Xiaoyan Lv
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jian You
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Yongkang Zou
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Jun Luo
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Zhongshan Lu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Hankun Cao
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Zhongzhong Liu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China
| | - Xiaoli Fan
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China.
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, China.
- The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry On Transplantation Medicine Engineering and Technology, Changsha, 410013, 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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Wu S, Cheng C, Zhu W, Yang J, He BB, Li S, Wang X, Guo H, Chen D, Guo YM. Whole transcriptome analysis reveals that immune infiltration- lncRNAs are related to cellular apoptosis in liver transplantation. Front Immunol 2023; 14:1152742. [PMID: 37081883 PMCID: PMC10110847 DOI: 10.3389/fimmu.2023.1152742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 03/20/2023] [Indexed: 04/22/2023] Open
Abstract
Introduction In most instances, liver transplantation (LT) is the only available treatment for end-stage liver diseases. However, LT could also induce serious liver diseases or injury, and the underlying mechanisms of LT-induced complications remain largely unknown, especially the mechanisms of the dysfunction of the immune system mediated by long noncoding RNAs (lncRNAs). Methods In this study, we globally analyzed the proportion of immune cells by using the transcriptome sequencing data (RNA-seq) of needle-core liver biopsies from pre- and post-transplantation recipients. Dysregulated lncRNAs were found to be correlated with the altered fractions of immune cells. We finally explored the potential targets of dysregulated lncRNAs and analyzed their functions in LT. Results We found that in the samples, some immune cells changed significantly after LT, including CD4 T cells, NK cells and mast cells. The proportion of macrophages in different polarization states also changed significantly, with M0 macrophages increasing and M2 macrophages decreasing. Through weighted gene co-expression network analysis (WGCNA), 7 gene expression modules related to LT were identified. These modules were related to changes in the proportion of different immune cells. The functions of these modules represent the response modes of different functional genes after LT. Among these modules, MEtan and MEyellow modules were primarily enriched in apoptosis and inflammatory pathways. Twelve immunity-related lncRNAs were identified for the first time, and the regulatory network co-changing with immune cells was also identified. The co-expressed genes of these lncRNAs were highly enriched in apoptosis-related pathways. Many apoptosis-related genes were found to be up-regulated after LT. Discussion In summary, we speculated that the expression and regulation of these apoptotic genes may be related to the changes in the proportion of immune cells. Some of these lncRNAs and apoptosis-related genes have been reported to be related to cell proliferation and apoptosis. They are also potential biomarkers or therapeutic targets.
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Affiliation(s)
- Shile Wu
- Soochow University, Suzhou, Jiangsu, China
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Chao Cheng
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
| | - Wenjun Zhu
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Jinyu Yang
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Bei-bei He
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Song Li
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Xinsheng Wang
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Hao Guo
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
| | - Dong Chen
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
- *Correspondence: Ya-min Guo, ; Dong Chen,
| | - Ya-min Guo
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
- *Correspondence: Ya-min Guo, ; Dong Chen,
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Liang C, Peng Y, Sun H, Wang L, Jiang L, Zou S. Silencing lncRNA KCNQ1OT1 reduced hepatic ischemia reperfusion injury-induced pyroptosis by regulating miR-142a-3p/HMGB1 axis. Mol Cell Biochem 2022; 478:1293-1305. [PMID: 36308669 DOI: 10.1007/s11010-022-04586-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 10/11/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Based on pre-existing evidence, KCNQ1OT1 has been pointed out to be closely related to myocardial and cerebral ischemia reperfusion injury diseases. Herein, the objective of our study is to probe into the potential function as well as the underlying mechanism of KCNQ1OT1 on hepatic ischemia reperfusion injury (HIRI). METHODS Using C57BL/6 J mice and primary mouse hepatocytes were conducted to establish HIRI model in vivo and in vitro. Cell viability was examined using CCK-8 assay and EdU assay. Flow cytometric analysis was performed to evaluate the pyroptosis. Dual-luciferase reporter assay was employed to verify the interaction relationships. qRT-PCR and Western blot were adopted to analyze the mRNA and protein level. Histopathological alteration of liver tissue was evaluated by HE staining. Immunohistochemistry (IHC) was performed to measure NLRP3 and caspase 1. RESULTS Our data revealed that KCNQ1OT1 expression was ascending in hepatic tissue of HIRI mouse. Moreover, deprivation of KCNQ1OT1 mitigated I/R-induced hepatic injury and pyroptosis in vivo. Further experiments demonstrated that silencing KCNQ1OT1 promoted proliferation and inhibited pyroptosis in hypoxia/reoxygenation (H/R)-induced primary mouse hepatocytes. Mechanistically, KCNQ1OT1 functioned as a competing endogenous RNA which sponged miR-142a-3p, therefore promoted HMGB1 expression to activate TLR4/NF-κB signaling pathway in HIRI. CONCLUSION LncRNA KCNQ1OT1 elevated HMGB1 expression through binding to miR-142a-3p, thereby promoting pyroptosis in HIRI.
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Affiliation(s)
- Canxin Liang
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Yanhua Peng
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Huiping Sun
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Lijuan Wang
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Liubing Jiang
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China
| | - Shuangfa Zou
- Department of Anesthesiology, Hunan Cancer Hospital, Hunan Province, No. 283 Tongzipo Road, Changsha, 410013, China.
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Sun Q, Gong J, Wu J, Hu Z, Zhang Q, Zhu X. SNHG1-miR-186-5p-YY1 feedback loop alleviates hepatic ischemia/reperfusion injury. Cell Cycle 2022; 21:1267-1279. [PMID: 35275048 PMCID: PMC9132488 DOI: 10.1080/15384101.2022.2046984] [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: 04/08/2021] [Revised: 06/20/2021] [Accepted: 02/23/2022] [Indexed: 11/03/2022] Open
Abstract
As a common cause of liver injury, hepatic ischemia/reperfusion injury (HIRI) happens in various clinical conditions including trauma, hepatectomy and liver transplantation. Since transcription factor Yin Yang 1 (YY1) was reported to be downregulated after ischemia/reperfusion (I/R) injury, we focused on YY1 to explore its function in HIRI by functional assays like Cell Counting Kit-8 (CCK-8) assays and flow cytometry assays. The RT-qPCR assay revealed that YY1 was downregulated in hepatocytes after I/R injury. The function assays disclosed that YY1 facilitated cell viability and proliferation, but hindered cell apoptosis in hepatocytes after I/R injury. Through mechanism assays including luciferase reporter assay, RIP and RNA pulldown assay, miR-186-5p was found to bind with YY1 and promote hepatocyte apoptosis by targeting YY1. Subsequently, we verified that small nucleolar RNA host gene 1 (SNHG1) could sponge miR-186-5p to upregulate YY1. Importantly, we figured out that YY1 had a positive regulation on SNHG1. Along the way, YY1 was identified as the upstream transcription factor for SNHG1. In conclusion, our study unveiled a novel competing endogenous RNA (ceRNA) pattern of SNHG1/miR-186-5p/YY1 positive feedback loop in hepatic I/R injury, which might provide new insight into prevention of HIRI during liver transplantation or hepatic surgery.
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Affiliation(s)
- Qiang Sun
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Jinlong Gong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jianlong Wu
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Zhipeng Hu
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Qiao Zhang
- General Surgery Department 1, Zhongshan Hospital, Sun Yat-sen University, Zhongshan, Guangdong, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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He J, Liu D, Zhao L, Zhou D, Rong J, Zhang L, Xia Z. Myocardial ischemia/reperfusion injury: Mechanisms of injury and implications for management (Review). Exp Ther Med 2022; 23:430. [PMID: 35607376 PMCID: PMC9121204 DOI: 10.3892/etm.2022.11357] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/13/2022] [Indexed: 01/18/2023] Open
Abstract
Myocardial infarction is one of the primary causes of mortality in patients with coronary heart disease worldwide. Early treatment of acute myocardial infarction restores blood supply of ischemic myocardium and decreases the mortality risk. However, when the interrupted myocardial blood supply is recovered within a certain period of time, it causes more serious damage to the original ischemic myocardium; this is known as myocardial ischemia/reperfusion injury (MIRI). The pathophysiological mechanisms leading to MIRI are associated with oxidative stress, intracellular calcium overload, energy metabolism disorder, apoptosis, endoplasmic reticulum stress, autophagy, pyroptosis, necroptosis and ferroptosis. These interplay with one another and directly or indirectly lead to aggravation of the effect. In the past, apoptosis and autophagy have attracted more attention but necroptosis and ferroptosis also serve key roles. However, the mechanism of MIRI has not been fully elucidated. The present study reviews the mechanisms underlying MIRI. Based on current understanding of the pathophysiological mechanisms of MIRI, the association between cell death-associated signaling pathways were elaborated, providing direction for investigation of novel targets in clinical treatment.
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Affiliation(s)
- Jianfeng He
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Danyong Liu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Lixia Zhao
- Department of Anesthesiology, The Eighth Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, Guangdong 518033, P.R. China
| | - Dongcheng Zhou
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Jianhui Rong
- Department of Internal Medicine, Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, Guangdong 518057, P.R. China
| | - Liangqing Zhang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
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Xu Y, Li Z, Lu S, Wang C, Ke S, Li X, Yin B, Yu H, Zhou M, Pan S, Jiang H, Ma Y. Integrative Analysis of the Roles of lncRNAs and mRNAs in Itaconate-Mediated Protection Against Liver Ischemia-Reperfusion Injury in Mice. J Inflamm Res 2021; 14:4519-4536. [PMID: 34526799 PMCID: PMC8435882 DOI: 10.2147/jir.s327467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/19/2021] [Indexed: 12/30/2022] Open
Abstract
Purpose Itaconate is well known for its strong anti-inflammatory and antioxidant effect, but little is known about the potential role of long non-coding RNAs (lncRNAs) in the underlying mechanisms of hepatic ischemia-reperfusion (IR) injury. The aim of our study is to identify lncRNAs related to IR injury and itaconate-mediated protection and to demonstrate the mechanism by which itaconate acts in liver IR injury from the new perspective of lncRNAs. Methods 4-Octyl itaconate (OI), a membrane-permeable derivative of itaconate, was used as a substitute for itaconate in our study. By using a mouse model of hepatic IR injury, serum and liver samples were collected to measure indexes of liver injury. Then, the liver samples of the mice were subjected to RNA sequencing (RNA-seq) and subsequent bioinformatics analysis. Results Itaconate attenuated liver IR injury. A total of 138 lncRNAs and 156 messenger RNAs (mRNAs) were markedly differentially expressed in the IR-damaged liver tissues pretreated with OI compared with the matched liver tissues treated with vehicle. Functional analysis indicated that lncRNAs may indirectly participate in the effects of itaconate. Furthermore, 41 mRNAs were examined for the protein-protein interaction (PPI) network analysis, and a key gene cluster was defined. Then, combined the coexpression analysis and the cis and trans regulatory function prediction of lncRNAs, some "candidate" lncRNA-mRNA pairs which might relate to itaconate-mediated liver protection were identified, while the relationship requires future validation. Conclusion Our study revealed that itaconate could protect the liver against IR injury and that lncRNAs might play a role in this process. Our study provides a novel way to investigate the mechanism by which itaconate affects hepatic IR injury and exerts its anti-inflammatory and antioxidative stress effects.
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Affiliation(s)
- Yanan Xu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Zihao Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shounan Lu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chaoqun Wang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shanjia Ke
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Xinglong Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Bing Yin
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Hongjun Yu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Menghua Zhou
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Hongchi Jiang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Yong Ma
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
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10
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The Dietary Supplement γ-Oryzanol Attenuates Hepatic Ischemia Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress and HMGB1/NLRP3 Inflammasome. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4628050. [PMID: 34512864 PMCID: PMC8433023 DOI: 10.1155/2021/4628050] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/22/2021] [Accepted: 08/18/2021] [Indexed: 12/26/2022]
Abstract
The purpose of this study is to investigate the protective effect of γ-oryzanol (ORY) against hepatic ischemia reperfusion (HIR) injury and the potential protective mechanisms of ORY. ORY is an important biologically active ingredient isolated from rice bran oil, which has anti-inflammatory and antiapoptotic effects. However, it is still unknown whether ORY can protect the liver from the HIR damage. In this study, ORY was administered orally for seven days, after which the animals were subjected to liver ischemia for 60 minutes and reperfused for 6 hours. Related indicators were analyzed. The results showed that ORY pretreatment significantly reduced the levels of AST and ALT, relieved hepatocellular damage and apoptosis, and attenuated the exhaustion of SOD and GSH and accumulation of MDA and MPO. Interestingly, ORY treatment could significantly decreased ER stress. Furthermore, ORY pretreatment remarkably reduced the protein expressions of HMGB1, NLRP3, caspase-1 (p20), and IL-1β to protect the liver from I/R-induced inflammasome activation and apoptosis. In conclusion, we demonstrated the potential effect of ORY in modulating oxidative stress, endoplasmic reticulum stress, and inflammasome activation during HIR.
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11
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Johnson SJ, Cooper TA. Overlapping mechanisms of lncRNA and expanded microsatellite RNA. WILEY INTERDISCIPLINARY REVIEWS. RNA 2021; 12:e1634. [PMID: 33191580 PMCID: PMC7880542 DOI: 10.1002/wrna.1634] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/14/2020] [Accepted: 10/20/2020] [Indexed: 12/15/2022]
Abstract
RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3-10 nt) repeats located within coding genes. Expanded repeat-containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro-RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Sara J Johnson
- Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Thomas A Cooper
- Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA
- Department of Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA
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12
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Gong C, Zhou X, Lai S, Wang L, Liu J. Long Noncoding RNA/Circular RNA-miRNA-mRNA Axes in Ischemia-Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8838524. [PMID: 33299883 PMCID: PMC7710414 DOI: 10.1155/2020/8838524] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/30/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022]
Abstract
Ischemia-reperfusion injury (IRI) elicits tissue injury involved in a wide range of pathologies. Multiple studies have demonstrated that noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), participate in the pathological development of IRI, and they may act as biomarkers, therapeutic targets, or prognostic indicators. Nonetheless, the specific molecular mechanisms of ncRNAs in IRI have not been completely elucidated. Regulatory networks among lncRNAs/circRNAs, miRNAs, and mRNAs have been the focus of attention in recent years. Studies on the underlying molecular mechanisms have contributed to the discovery of therapeutic targets or strategies in IRI. In this review, we comprehensively summarize the current research on the lncRNA/circRNA-miRNA-mRNA axes and highlight the important role of these axes in IRI.
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Affiliation(s)
- Chengwu Gong
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xueliang Zhou
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Songqing Lai
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Lijun Wang
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Jichun Liu
- Department of Cardiothoracic Surgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China
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Ghafouri-Fard S, Shoorei H, Taheri M. Non-coding RNAs participate in the ischemia-reperfusion injury. Biomed Pharmacother 2020; 129:110419. [PMID: 32563988 DOI: 10.1016/j.biopha.2020.110419] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023] Open
Abstract
Ischemia, being defined as blood supply deficiency is involved in the pathogenesis of a number of life-threatening conditions such as myocardial infarction and cerebral stroke. Assessment of the molecular pathology of these conditions has led to identification of the role of reperfusion in induction and aggravation of tissue injury and necrosis. Thus, the term "ischemia/ reperfusion (I/R) injury" has been introduced. This process involves aberrant regulation of the mitochondrial function, apoptotic and autophagic pathways and signal transducers. More recently, non-coding RNAs including long non-coding RNAs (lncRNAs) ad microRNAs (miRNAs) have been shown to influence I/R injury. Animal studies and clinical investigations have shown up-/down-regulation of tens of lncRNAs and miRNAs in this process. In the current study, we summarize the role of these transcripts in the pathophysiology of I/R injury and their potential as biomarkers for detection of extent of tissue injury.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Luo R, Xiao F, Wang P, Hu YX. lncRNA H19 sponging miR-93 to regulate inflammation in retinal epithelial cells under hyperglycemia via XBP1s. Inflamm Res 2020; 69:255-265. [DOI: 10.1007/s00011-019-01312-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 12/19/2019] [Accepted: 12/23/2019] [Indexed: 12/20/2022] Open
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