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1
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Su H, Chen G, Xie H, Li W, Xiong M, He J, Hu H, Zhao W, Shao Q, Li M, Zhao Q, Xu Y. Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro. Nat Commun 2025; 16:4288. [PMID: 40341069 PMCID: PMC12062462 DOI: 10.1038/s41467-025-59432-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 04/18/2025] [Indexed: 05/10/2025] Open
Abstract
The essential role of RIPK3 in necroptosis makes its inhibition a promising therapeutic strategy. However, the development of RIPK3 inhibitors has been hampered by on-target apoptosis and limited kinase selectivity. Inspired by the R69H mutation, which prevents on-target apoptosis by disrupting RIPK3 dimerization, we design LK-series inhibitors that effectively inhibit RIPK3 in biochemical assays and block TNF-α-induced necroptosis in both mouse L929 and human HT29 cells without inducing apoptosis. The representative compound, LK01003, shows high selectivity across a panel of 379 kinases. Our structural studies reveal that LK compounds act as Type I1/2 inhibitors, engaging a unique hydrophobic site and stabilizing an inactive conformation of RIPK3. Moreover, several type II inhibitors are also revealed to maintain RIPK3 in the inactive conformation and do not induce on-target apoptosis. These findings suggest a promising strategy for rational design of safe and selective inhibitors by locking the inactive conformation of RIPK3.
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Affiliation(s)
- Haixia Su
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Guofeng Chen
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Hang Xie
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wanchen Li
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100, China
| | - Muya Xiong
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Jian He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hangchen Hu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China
| | - Wenfeng Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China
| | - Qiang Shao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Minjun Li
- Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China
| | - Qiang Zhao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yechun Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
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Land WG, Linkermann A. Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 1: their emergence from injuries to the donor organ. FRONTIERS IN TRANSPLANTATION 2025; 4:1571516. [PMID: 40343197 PMCID: PMC12060192 DOI: 10.3389/frtra.2025.1571516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025]
Abstract
This Part 1 of a bipartite review commences with a succinct exposition of innate alloimmunity in light of the danger/injury hypothesis in Immunology. The model posits that an alloimmune response, along with the presentation of alloantigens, is driven by DAMPs released from various forms of regulated cell death (RCD) induced by any severe injury to the donor or the donor organ, respectively. To provide a strong foundation for this review, which examines RCD and DAMPs as biomarkers and therapeutic targets in normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) to improve outcomes in organ transplantation, key insights are presented on the nature, classification, and functions of DAMPs, as well as the signaling mechanisms of RCD pathways, including ferroptosis, necroptosis, pyroptosis, and NETosis. Subsequently, a comprehensive discussion is provided on major periods of injuries to the donor or donor organs that are associated with the induction of RCD and DAMPs and precede the onset of the innate alloimmune response in recipients. These periods of injury to donor organs include conditions associated with donation after brain death (DBD) and donation after circulatory death (DCD). Particular emphasis in this discussion is placed on the different origins of RCD-associated DAMPs in DBD and DCD and the different routes they use within the circulatory system to reach potential allografts. The review ends by addressing another particularly critical period of injury to donor organs: their postischemic reperfusion following implantation into the recipient-a decisive factor in determining transplantation outcome. Here, the discussion focuses on mechanisms of ischemia-induced oxidative injury that causes RCD and generates DAMPs, which initiate a robust innate alloimmune response.
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Affiliation(s)
- Walter G. Land
- German Academy for Transplantation Medicine, Munich, Germany
- Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France
- Department of Integrated Medical Sciences, Medical Science Faculty, State University of Rio De Janeiro, Cabo Frio, Brazil
| | - Andreas Linkermann
- Department of Medicine V, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
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Sun J, Chang R, Song L. The origin and evolution of necroptosis signaling pathway in metazoa. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 165:105339. [PMID: 39947503 DOI: 10.1016/j.dci.2025.105339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 01/14/2025] [Accepted: 02/10/2025] [Indexed: 02/19/2025]
Abstract
Necroptosis, a new form of cell death, is attracting significant attention as it is involved in the development and progression of many diseases in mammals. The structural domains and evolutionary principles of necroptotic components as well as the potential activation mechanism are not well understood in lower vertebrates and invertebrates. In the present study, TNFα, TNFR1, TLR3 and TLR4 are all presented in Mollusca and even higher phyla. ZBP1, TRADD and TRIF are only in some vertebrates. RIPK1/3 and MLKL are early originated from Mollusca and Echinodermata, respectively. Among which, RIPK1 with RHIM and Death domain and RIPK3 with a STYKc domain and two cRHIMs in Mollusca may fuse to be the classical RIPK1/3. More importantly, RIPK1/3 in Mollusca also provides structural domain conditions for the generation of the later ZBP1/TRADD/TRIF and MLKL, respectively. Taken together, necroptotic components in Mollusca are important fundamental for the evolution of necroptotic pathways. These findings provide insights into the evolutionary principles of necroptotic components and the possible activation mechanism of necroptosis pathways in various species.
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Affiliation(s)
- Jiejie Sun
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China.
| | - Renle Chang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology & Disease Control, Dalian Ocean University, Dalian, 116023, China.
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Ni R, Cao T, Ji X, Peng A, Zhang Z, Fan GC, Stathopulos P, Chakrabarti S, Su Z, Peng T. DNA damage-inducible transcript 3 positively regulates RIPK1-mediated necroptosis. Cell Death Differ 2025; 32:306-319. [PMID: 39362992 PMCID: PMC11802725 DOI: 10.1038/s41418-024-01385-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/05/2024] Open
Abstract
DNA damage-inducible transcript 3 (DDIT3) is a well-known transcription factor that regulates the expression of apoptosis-related genes for promoting apoptosis during endoplasmic reticulum stress. Here, we report an unrecognized role of DDIT3 in facilitating necroptosis. DDIT3 directly binds and competitively prevents the p38 MAPK-MK2 interaction and thereby blocking MK2 activation while stimulating p38 MAPK activation. This blockage of MK2 activation initially prevents RIPK1 phosphorylation at Ser320 (inactivation), subsequently relieving its suppression of RIPK1 activation. Consequently, p38 MAPK facilitates RIPK1 phosphorylation at Ser166 (activation) through DDIT3 phosphorylation-related mechanisms, leading to necroptosis. Mechanistically, a 10-amino acid segment (Glu19-Val28) within DDIT3's N-terminus is identified to account for its pro-necroptotic function. In vivo studies demonstrate that forced expression of DDIT3 induces necroptosis, whereas deletion of DDIT3 alleviates necroptosis in mouse hearts under stress. These findings shed light on a novel regulatory mechanism by which DDIT3 promotes RIPK1 activation and subsequent necroptosis.
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Affiliation(s)
- Rui Ni
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China
- Lawson Health Research Institute, London Health Sciences Centre, London, ON, N6A 5W9, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada
| | - Ting Cao
- Institute for Cardiovascular Science, Soochow University, Suzhou, 215123, China
| | - Xiaoyun Ji
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China
- Lawson Health Research Institute, London Health Sciences Centre, London, ON, N6A 5W9, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada
| | - Angel Peng
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada
| | - Zhuxu Zhang
- Lawson Health Research Institute, London Health Sciences Centre, London, ON, N6A 5W9, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada
- Department of Medicine, Western University, London, ON, N6A 5W9, Canada
| | - Guo-Chang Fan
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Peter Stathopulos
- Department of Physiology and Pharmacology, Western University, London, ON, N6A 5C1, Canada
| | - Subrata Chakrabarti
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China.
| | - Tianqing Peng
- Lawson Health Research Institute, London Health Sciences Centre, London, ON, N6A 5W9, Canada.
- Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada.
- Department of Medicine, Western University, London, ON, N6A 5W9, Canada.
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Xin L, Kanghao N, Jiacheng L, Xiaodong Y, Juhan Y, Xinyang Z, Xiangdong L. Panax Notoginseng Saponins Inhibit Apoptosis and Alleviate Renal Ischemia-Reperfusion Injury Through the ROCK2/NF-κB Pathway. Mol Biotechnol 2025:10.1007/s12033-025-01366-z. [PMID: 39820853 DOI: 10.1007/s12033-025-01366-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/27/2024] [Indexed: 01/19/2025]
Abstract
Renal ischemia-reperfusion injury (RIRI) is a primary cause of acute kidney injury (AKI), frequently resulting in high mortality rates and progression to chronic kidney disease (CKD). This study aimed to investigate the therapeutic potential of total saponins from Panax notoginseng (PNS) in the context of RIRI. Utilizing a murine RIRI model, the efficacy of PNS was evaluated, demonstrating a significant reduction in renal inflammation and cellular pyroptosis. Furthermore, PNS was found to modulate the ROCK2/NF-κB signaling pathway, thereby attenuating the inflammatory response. Importantly, in vitro experiments with hypoxia/reoxygenation cell models corroborated these findings, showing that PNS inhibited pyroptosis and regulated the ROCK2/NF-κB pathway. This research underscores the therapeutic potential of PNS in the treatment of RIRI, providing a robust scientific basis for its consideration as a prospective clinical therapy.
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Affiliation(s)
- Liu Xin
- The First Affiliated Hospital of Hebei North University Address, 12 Changqing Road, Zhangjiakou City, Hebei Province, China.
| | - Ning Kanghao
- Graduate School of Hebei North University, Zhangjiakou, China
| | - Li Jiacheng
- The First Affiliated Hospital of Hebei North University Address, 12 Changqing Road, Zhangjiakou City, Hebei Province, China
| | - Yan Xiaodong
- The First Affiliated Hospital of Hebei North University Address, 12 Changqing Road, Zhangjiakou City, Hebei Province, China
| | - Yan Juhan
- Graduate School of Hebei North University, Zhangjiakou, China
| | - Zhao Xinyang
- The First Affiliated Hospital of Hebei North University Address, 12 Changqing Road, Zhangjiakou City, Hebei Province, China
| | - Li Xiangdong
- The First Affiliated Hospital of Hebei North University Address, 12 Changqing Road, Zhangjiakou City, Hebei Province, China
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Shang H, Shi J, Zhu J, Guo Y, Wang X. Inhibition of p70 Ribosomal S6K1 Protects the Myocardium against Ischemia/Reperfusion-Induced Necrosis through Downregulation of RIP3. FRONT BIOSCI-LANDMRK 2025; 30:26186. [PMID: 39862085 DOI: 10.31083/fbl26186] [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: 08/19/2024] [Revised: 11/05/2024] [Accepted: 11/18/2024] [Indexed: 01/30/2025]
Abstract
BACKGROUND Myocardial ischemia-reperfusion (I/R) injury refers to cell damage that occurs as a consequence of the restoration of blood circulation following reperfusion therapy for cardiovascular diseases, and it is a primary cause of myocardial infarction. The search for nove therapeutic targets in the context of I/R injury is currently a highly active area of research. p70 ribosomal S6 kinase (S6K1) plays an important role in I/R induced necrosis, although the specific mechanisms remain unclear. OBJECTIVE This study aims to explore the effects of inhibiting S6K1 on myocardial I/R injury and its potential mechanisms. METHODS A rat myocardial I/R model was created and treated with the S6K1-specific inhibitor PF-4708671. Hematoxylin-eosin (H&E) staining was applied to evaluate the pathological changes in cardiac tissues. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to measure the area of myocardial infarction (MI). Left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximum rate of increase in left ventricular pressure (+dp/dtmax), and the maximum rate of the decrease in left ventricular pressure (-dp/dtmax) were measured using ultrasonic echocardiography. The expression levels of cardiac troponin-1 (cTn-1), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and aspartate aminotransferase (AST) were determined by enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and propidium iodide (PI) staining were used to examine the apoptosis and necrosis of myocardial tissues. The expressions of apoptotic-related proteins, and key molecules of necrosis were detected by western blot. The relationship between S6K1 and receptor-interacting protein kinase 3 (RIP3) was analyzed by immunoprecipitation. RESULTS Inhibition of S6K1 reduces I/R-induced myocardial tissue damage, improves myocardial function, and inhibits myocardial tissue necrosis (p < 0.05). In addition, RIP3 is a direct target of S6K1, and activation of RIP3 blocked the protective effect of the S6K1 inhibitor PF-4708671 against myocardial I/R injury (p < 0.05). CONCLUSION Inhibition of S6K1 protects against myocardial I/R injury by down-regulating RIP3, suggesting that targeting S6K1 may offer a novel approach for intervention in myocardial I/R injury.
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Affiliation(s)
- Hui Shang
- Department of Cardiology, Affiliated Hospital of Jiangnan University, 214122 Wuxi, Jiangsu, China
| | - Jinjin Shi
- Department of Cardiology, Affiliated Hospital of Jiangnan University, 214122 Wuxi, Jiangsu, China
| | - Jun Zhu
- Department of Cardiology, Affiliated Hospital of Jiangnan University, 214122 Wuxi, Jiangsu, China
| | - Yunfeng Guo
- Department of Cardiology, Affiliated Hospital of Jiangnan University, 214122 Wuxi, Jiangsu, China
| | - Xiaoyan Wang
- Department of Cardiology, Affiliated Hospital of Jiangnan University, 214122 Wuxi, Jiangsu, China
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Cheng MZ, Luo JH, Li X, Liu FY, Zhou WJ. Zinc pretreatment for protection against intestinal ischemia-reperfusion injury. World J Gastrointest Surg 2024; 16:3843-3856. [PMID: 39734451 PMCID: PMC11650234 DOI: 10.4240/wjgs.v16.i12.3843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/01/2024] [Accepted: 10/28/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND Intestinal ischemia-reperfusion (I/R) injury (II/RI) is a critical condition that results in oxidative stress, inflammation, and damage to multiple organs. Zinc, an essential trace element, offers protective benefits in several tissues during I/R injury, but its effects on intestinal II/RI remain unclear. AIM To investigate the effects of zinc pretreatment on II/RI and associated multiorgan damage. METHODS C57BL/6 mice were pretreated with zinc sulfate (ZnSO4, 10 mg/kg) daily for three days before I/R injury was induced via superior mesenteric artery occlusion (SMAO) and abdominal aortic occlusion (AAO) models. Tissue and serum samples were collected to evaluate intestinal, liver, and kidney damage using Chiu's score, Suzuki score, and histopathological analysis. Caco-2 cells and intestinal organoids were used for in vitro hypoxia-reoxygenation injury models to measure reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. RESULTS Zinc pretreatment significantly reduced intestinal damage in the SMAO and AAO models (P < 0.001). The serum levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase) and kidney markers (creatinine and urea) were lower in the zinc-treated mice than in the control mice, indicating reduced hepatic and renal injury. In vitro, zinc decreased ROS levels and increased SOD activity in Caco-2 cells subject to hypoxia-reoxygenation injury. Intestinal organoids pretreated with zinc exhibited enhanced resilience to hypoxic injury compared to controls. CONCLUSION Zinc pretreatment mitigates II/RI and reduces associated multiorgan damage. These findings suggest that zinc has potential clinical applications in protecting against I/R injuries.
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Affiliation(s)
- Ming-Zhen Cheng
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jia-Hao Luo
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xin Li
- Department of Interventional Radiology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100071, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100071, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Nishiguchi T, Kimura H, Saito Y, Ozawa T, Abe R, Hasegawa A. P2X7R-primed keratinocytes are susceptible to apoptosis via GPCR-Gβγ-pERK signal pathways. J Dermatol Sci 2024; 116:90-99. [PMID: 39438210 DOI: 10.1016/j.jdermsci.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 09/24/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND Cell death constitutes a pivotal biological phenomenon essential for the preservation of homeostasis within living organisms. In the context of maintaining a functional skin barrier, keratinocytes exert positively and negatively control cell death signals. However, in patients with severe drug eruptions, anomalous overexpression of the formyl peptide receptor 1 (FPR1) in keratinocytes elicits a distinctive mode of cell death known as necroptosis, thereby suffering a loss of the skin barrier. The precise molecular mechanisms connecting FPR1 activation to this cell death remain unclear. OBJECTIVE We have investigated the intracellular signal transduction cascade governing FPR1-mediated cell death in cultured keratinocytes. METHODS We used HaCaT cells as a model keratinocyte. The expression of FPR1 was detected with qPCR. The presence of cell death events was monitored through live-cell fluorescent staining and LDH release assays. Furthermore, the phosphorylation of ERK was assessed via Western blot analysis. Intracellular signal pathways were investigated using specific inhibitors. RESULTS Ligand stimulation of an endogenous ion channel, purinergic receptor P2X7 (P2X7R), increased the FPR1 expression level. This upregulated FPR1 demonstrated functional competence in the phosphorylation of downstream MAP kinase and the initiation of cell death. Notably, this cell death was ameliorated upon the administration of inhibitors targeting Gβγ, ERK, and caspases. CONCLUSION The induction and stimulation of FPR1 initiated apoptosis in keratinocytes via the Gβγ-pERK signaling pathway. Our findings postulate that the downstream components of FPR1 represent an alternative therapeutic target for preventing unintended keratinocyte cell death.
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Affiliation(s)
- Tomoki Nishiguchi
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Haruna Kimura
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Saito
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takeaki Ozawa
- Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
| | - Riichiro Abe
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Akito Hasegawa
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
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Lu H, Xu L, Steriopoulos J, McLeod P, Huang X, Min J, Peng T, Jevnikar AM, Zhang ZX. An acidic pH environment converts necroptosis to apoptosis. Biochem Biophys Res Commun 2024; 725:150215. [PMID: 38870845 DOI: 10.1016/j.bbrc.2024.150215] [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: 05/21/2024] [Revised: 05/24/2024] [Accepted: 06/02/2024] [Indexed: 06/15/2024]
Abstract
Cardiac ischemia results in anaerobic metabolism and lactic acid accumulation and with time, intracellular and extracellular acidosis. Ischemia and subsequent reperfusion injury (IRI) lead to various forms of programmed cell death. Necroptosis is a major form of programmed necrosis that worsens cardiac function directly and also promotes inflammation by the release of cellular contents. Potential effects of increasing acidosis on programmed cell death and their specific components have not been well studied. While apoptosis is caspase-dependent, in contrast, necroptosis is mediated by the receptor-interacting protein kinases 1 and 3 (RIPK1/3). In our study, we observed that at physiological pH = 7.4, caspase-8 inhibition did not prevent TNFα-induced cell death in mouse cardiac vascular endothelial cells (MVECs) but promoted necroptotic cell death. As expected, necroptosis was blocked by RIPK1 inhibition. However, at pH = 6.5, TNFα induced an apoptosis-like pattern which was inhibited by caspase-8 inhibition. Interestingly phosphorylation of necroptotic molecules RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) was enhanced in an acidic pH environment. However, RIPK3 and MLKL phosphorylation was self-limited which may have limited their participation in necroptosis. In addition, an acidic pH promoted apoptosis-inducing factor (AIF) cleavage and nuclear translocation. AIF RNA silencing inhibited cell death, supporting the role of AIF in this cell death. In summary, our study demonstrated that the pH of the micro-environment during inflammation can bias cell death pathways by altering the function of necroptosis-related molecules and promoting AIF-mediated cell death. Further insights into the mechanisms by which an acidic cellular micro-environment influences these and perhaps other forms of regulated cell death, may lead to therapeutic strategies to attenuate IRI.
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Affiliation(s)
- Haitao Lu
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada; Department of Pathology, Western University, London, Canada
| | - Laura Xu
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada; Department of Pathology, Western University, London, Canada
| | - Julia Steriopoulos
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada; Department of Pathology, Western University, London, Canada
| | - Patrick McLeod
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre. London, Canada
| | - Xuyan Huang
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada
| | - Jeffery Min
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada
| | - Tianging Peng
- Department of Pathology, Western University, London, Canada; Division of Nephrology, Department of Medicine, Western University. London, Canada
| | - Anthony M Jevnikar
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre. London, Canada; Division of Nephrology, Department of Medicine, Western University. London, Canada
| | - Zhu-Xu Zhang
- Matthew Mailing Centre for Translational Transplantation Studies. Lawson Health Research Institute, London, Canada; Department of Pathology, Western University, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre. London, Canada; Division of Nephrology, Department of Medicine, Western University. London, Canada.
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10
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Jin Y, Yuan H, Liu Y, Zhu Y, Wang Y, Liang X, Gao W, Ren Z, Ji X, Wu D. Role of hydrogen sulfide in health and disease. MedComm (Beijing) 2024; 5:e661. [PMID: 39156767 PMCID: PMC11329756 DOI: 10.1002/mco2.661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 08/20/2024] Open
Abstract
In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. In mammals, H2S-catalyzing enzymes, such as cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H2S. Various preclinical studies have shown that H2S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.
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Affiliation(s)
- Yu‐Qing Jin
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Hang Yuan
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Ya‐Fang Liu
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Yi‐Wen Zhu
- School of Clinical MedicineHenan UniversityKaifengHenanChina
| | - Yan Wang
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Xiao‐Yi Liang
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Wei Gao
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Zhi‐Guang Ren
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
| | - Xin‐Ying Ji
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
- Faculty of Basic Medical SubjectsShu‐Qing Medical College of ZhengzhouZhengzhouHenanChina
| | - Dong‐Dong Wu
- Henan International Joint Laboratory for Nuclear Protein RegulationSchool of Basic Medical Sciences, School of StomatologyHenan UniversityKaifengHenanChina
- School of StomatologyHenan UniversityKaifengHenanChina
- Department of StomatologyHuaihe Hospital of Henan UniversityKaifengHenanChina
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11
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Kura B, Slezak J. The Protective Role of Molecular Hydrogen in Ischemia/Reperfusion Injury. Int J Mol Sci 2024; 25:7884. [PMID: 39063126 PMCID: PMC11276695 DOI: 10.3390/ijms25147884] [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: 06/13/2024] [Revised: 07/13/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Ischemia/reperfusion injury (IRI) represents a significant contributor to morbidity and mortality associated with various clinical conditions, including acute coronary syndrome, stroke, and organ transplantation. During ischemia, a profound hypoxic insult develops, resulting in cellular dysfunction and tissue damage. Paradoxically, reperfusion can exacerbate this injury through the generation of reactive oxygen species and the induction of inflammatory cascades. The extensive clinical sequelae of IRI necessitate the development of therapeutic strategies to mitigate its deleterious effects. This has become a cornerstone of ongoing research efforts in both basic and translational science. This review examines the use of molecular hydrogen for IRI in different organs and explores the underlying mechanisms of its action. Molecular hydrogen is a selective antioxidant with anti-inflammatory, cytoprotective, and signal-modulatory properties. It has been shown to be effective at mitigating IRI in different models, including heart failure, cerebral stroke, transplantation, and surgical interventions. Hydrogen reduces IRI via different mechanisms, like the suppression of oxidative stress and inflammation, the enhancement of ATP production, decreasing calcium overload, regulating cell death, etc. Further research is still needed to integrate the use of molecular hydrogen into clinical practice.
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Affiliation(s)
- Branislav Kura
- Centre of Experimental Medicine, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia;
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12
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Li C, Yu Y, Zhu S, Hu Y, Ling X, Xu L, Zhang H, Guo K. The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives. Cell Death Discov 2024; 10:216. [PMID: 38704372 PMCID: PMC11069531 DOI: 10.1038/s41420-024-01979-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/14/2024] [Accepted: 04/18/2024] [Indexed: 05/06/2024] Open
Abstract
Renal ischemia‒reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), which is a potentially life-threatening condition with a high mortality rate. IRI is a complex process involving multiple underlying mechanisms and pathways of cell injury and dysfunction. Additionally, various types of cell death have been linked to IRI, including necroptosis, apoptosis, pyroptosis, and ferroptosis. These processes operate differently and to varying degrees in different patients, but each plays a role in the various pathological conditions of AKI. Advances in understanding the underlying pathophysiology will lead to the development of new therapeutic approaches that hold promise for improving outcomes for patients with AKI. This review provides an overview of the recent research on the molecular mechanisms and pathways underlying IRI-AKI, with a focus on regulated cell death (RCD) forms such as necroptosis, pyroptosis, and ferroptosis. Overall, targeting RCD shows promise as a potential approach to treating IRI-AKI.
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Affiliation(s)
- Chenning Li
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Ying Yu
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Shuainan Zhu
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Yan Hu
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Xiaomin Ling
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Liying Xu
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Hao Zhang
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China.
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
| | - Kefang Guo
- Department of Anesthesiology, Zhongshan Hospital, Shanghai, China.
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
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13
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Chen D, Miao S, Chen X, Wang Z, Lin P, Zhang N, Yang N. Regulated Necrosis in Glaucoma: Focus on Ferroptosis and Pyroptosis. Mol Neurobiol 2024; 61:2542-2555. [PMID: 37910286 DOI: 10.1007/s12035-023-03732-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/20/2023] [Indexed: 11/03/2023]
Abstract
Glaucoma is one of the most common causes of irreversible blindness worldwide. This neurodegenerative disease is characterized by progressive and irreversible damage to retinal ganglion cells (RGCs) and optic nerves, which can lead to permanent loss of peripheral and central vision. To date, maintaining long-term survival of RGCs using traditional treatments, such as medication and surgery, remains challenging, as these do not promote optic nerve regeneration. Therefore, it is of great clinical and social significance to investigate the mechanisms of optic nerve degeneration in depth and find reliable targets to provide pioneering methods for the prevention and treatment of glaucoma. Regulated necrosis is a form of genetically programmed cell death associated with the maintenance of homeostasis and disease progression in vivo. An increasing body of innovative evidence has recognized that aberrant activation of regulated necrosis pathways is a common feature in neurodegenerative diseases, such as Alzheimer's, Parkinson's, and glaucoma, resulting in unwanted loss of neuronal cells and function. Among them, ferroptosis and pyroptosis are newly discovered forms of regulated cell death actively involved in the pathophysiological processes of RGCs loss and optic nerve injury. This was shown by a series of in vivo and in vitro studies, and these mechanisms have been emerging as a key new area of scientific research in ophthalmic diseases. In this review, we focus on the molecular mechanisms of ferroptosis and pyroptosis and their regulatory roles in the pathogenesis of glaucoma, with the aim of exploring their implications as potential therapeutic targets and providing new perspectives for better clinical decision-making in glaucoma treatment.
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Affiliation(s)
- Duan Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China
| | - Sen Miao
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China
| | - Xuemei Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China
| | - Zhiyi Wang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China
| | - Pei Lin
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China
| | - Ningzhi Zhang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China.
| | - Ning Yang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Jiefang Road #238, Wuhan, 430060, Hubei, China.
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Abstract
Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.
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Affiliation(s)
- Junying Yuan
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, China.
- Shanghai Key Laboratory of Aging Studies, Shanghai, China.
| | - Dimitry Ofengeim
- Sanofi, Rare and Neurological Diseases Research, Cambridge, MA, USA.
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15
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Lai J, Pan Q, Chen G, Liu Y, Chen C, Pan Y, Liu L, Zeng B, Yu L, Xu Y, Tang J, Yang Y, Rao L. Triple Hybrid Cellular Nanovesicles Promote Cardiac Repair after Ischemic Reperfusion. ACS NANO 2024; 18:4443-4455. [PMID: 38193813 DOI: 10.1021/acsnano.3c10784] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
The management of myocardial ischemia/reperfusion (I/R) damage in the context of reperfusion treatment remains a significant hurdle in the field of cardiovascular disorders. The injured lesions exhibit distinctive features, including abnormal accumulation of necrotic cells and subsequent inflammatory response, which further exacerbates the impairment of cardiac function. Here, we report genetically engineered hybrid nanovesicles (hNVs), which contain cell-derived nanovesicles overexpressing high-affinity SIRPα variants (SαV-NVs), exosomes (EXOs) derived from human mesenchymal stem cells (MSCs), and platelet-derived nanovesicles (PLT-NVs), to facilitate the necrotic cell clearance and inhibit the inflammatory responses. Mechanistically, the presence of SαV-NVs suppresses the CD47-SIRPα interaction, leading to the promotion of the macrophage phagocytosis of dead cells, while the component of EXOs aids in alleviating inflammatory responses. Moreover, the PLT-NVs endow hNVs with the capacity to evade immune surveillance and selectively target the infarcted area. In I/R mouse models, coadministration of SαV-NVs and EXOs showed a notable synergistic effect, leading to a significant enhancement in the left ventricular ejection fraction (LVEF) on day 21. These findings highlight that the hNVs possess the ability to alleviate myocardial inflammation, minimize infarct size, and improve cardiac function in I/R models, offering a simple, safe, and robust strategy in boosting cardiac repair after I/R.
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Affiliation(s)
- Jialin Lai
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
- Department of Chemistry, The University of Hong Kong, Hong Kong 999077, China
| | - Qi Pan
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Guihao Chen
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Yu Liu
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
- Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China
| | - Cheng Chen
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Yuanwei Pan
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Lujie Liu
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Binglin Zeng
- Department of Chemistry, The University of Hong Kong, Hong Kong 999077, China
| | - Ling Yu
- Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Yunsheng Xu
- Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China
| | - Jinyao Tang
- Department of Chemistry, The University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong 999077, China
| | - Yuejin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Lang Rao
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China
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Prado-Acosta M, Jeong S, Utrero-Rico A, Goncharov T, Webster JD, Holler E, Morales G, Dellepiane S, Levine JE, Rothenberg ME, Vucic D, Ferrara JLM. Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects. Sci Transl Med 2023; 15:eadf8366. [PMID: 38117900 PMCID: PMC11157567 DOI: 10.1126/scitranslmed.adf8366] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 11/29/2023] [Indexed: 12/22/2023]
Abstract
Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.
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Affiliation(s)
- Mariano Prado-Acosta
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Seihwan Jeong
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Alberto Utrero-Rico
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Joshua D. Webster
- Department of Pathology, Genentech, South San Francisco, CA 94080, USA
| | - Ernst Holler
- Department of Hematology and Oncology, University of Regensburg, Regensburg 93042, Germany
| | - George Morales
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sergio Dellepiane
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - John E. Levine
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Domagoj Vucic
- Immunology Discovery, Genentech, South San Francisco, CA 94080, USA
| | - James L. M. Ferrara
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Qu Y, Liu Y, Zhang H. ALDH2 activation attenuates oxygen-glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. Clin Transl Oncol 2023; 25:3203-3216. [PMID: 37103763 DOI: 10.1007/s12094-023-03190-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: 11/25/2022] [Accepted: 04/04/2023] [Indexed: 04/28/2023]
Abstract
PURPOSE It is previously reported that aldehyde dehydrogenase 2 family member (ALDH2) shows neuroprotective effects in cerebral ischemia/reperfusion injury. However, whether the protective effects are through mediating the programmed cell death is yet to be fully elucidated. METHODS In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in HT22 cells and mouse cortical neurons. Subsequently, ALDH2 expression were assessed by qRT-PCR and western blot. The methylation status was examined by methylation-specific PCR (MS-PCR). Then, ALDH2 expression was promoted and suppressed to explore the role of ALDH2 in OGD/R-treated cells. CCK-8 assay was applied to detect cell viability, and flow cytometry was applied to evaluate cell apoptosis. Western blot was applied to detect the apoptosis-related proteins (Caspase 3, Bcl-2 and Bax), necroptosis-related proteins (RIP3 and MLKL), pyroptosis-related proteins (NLRP3 and GSDMD), ferroptosis-related protein (ACSL4 and GPX4), and autophagy-related proteins (LC3B, and p62). IL-1β and IL-18 production was evaluated by ELISA assay. Reactive oxygen species production and Fe2+ content were evaluated by the corresponding detection kit. RESULTS In OGD/R-treated cells, ALDH2 expression was decreased, which was due to the hypermethylation of ALDH2 in the promoter region. ALDH2 overexpression improved cell viability and ALDH2 knockdown suppressed cell viability in OGD/R-treated cells. We also found that ALDH2 overexpression attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy, while ALDH2 knockdown facilitated the OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. CONCLUSIONS Collectively, our results implied that ALDH2 attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy to promote cell viability in HT22 cells and mouse cortical neurons.
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Affiliation(s)
- Yun Qu
- Department of Emergency, Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, Shandong, China
| | - Yuanyuan Liu
- Department of Emergency, Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, Shandong, China
| | - Huilong Zhang
- Department of Neurology, Yuhuangding Hospital Affiliated to Qingdao University, No. 20 Yudong Road, Zhifu District, Yantai, 264000, Shandong, China.
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18
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Chen Z, Liu Y, Lin Z, Huang W. cGAS-STING pathway in ischemia-reperfusion injury: a potential target to improve transplantation outcomes. Front Immunol 2023; 14:1231057. [PMID: 37809088 PMCID: PMC10552181 DOI: 10.3389/fimmu.2023.1231057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/04/2023] [Indexed: 10/10/2023] Open
Abstract
Transplantation is an important life-saving therapeutic choice for patients with organ or tissue failure once all other treatment options are exhausted. However, most allografts become damaged over an extended period, and post-transplantation survival is limited. Ischemia reperfusion injury (IRI) tends to be associated with a poor prognosis; resultant severe primary graft dysfunction is the main cause of transplant failure. Targeting the cGAS-STING pathway has recently been shown to be an effective approach for improving transplantation outcomes, when activated or inhibited cGAS-STING pathway, IRI can be alleviated by regulating inflammatory response and programmed cell death. Thus, continuing efforts to develop selective agonists and antagonists may bring great hopes to post-transplant patient. In this mini-review, we reviewed the role of the cGAS-STING pathway in transplantation, and summarized the crosstalk between this pathway and inflammatory response and programmed cell death during IRI, aiming to provide novel insights into the development of therapies to improve patient outcome after transplantation.
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Affiliation(s)
| | | | | | - Weizhe Huang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
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19
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Li X, Peng X, Zhou X, Li M, Chen G, Shi W, Yu H, Zhang C, Li Y, Feng Z, Li J, Liang S, He W, Gou X. Small extracellular vesicles delivering lncRNA WAC-AS1 aggravate renal allograft ischemia‒reperfusion injury by inducing ferroptosis propagation. Cell Death Differ 2023; 30:2167-2186. [PMID: 37532764 PMCID: PMC10482833 DOI: 10.1038/s41418-023-01198-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 07/11/2023] [Accepted: 07/20/2023] [Indexed: 08/04/2023] Open
Abstract
Ferroptosis is a predominant contributor to renal ischemia reperfusion injury (IRI) after kidney transplant, evoking delayed graft function and poorer long-term outcomes. The wide propagation of ferroptosis among cell populations in a wave-like manner, developing the "wave of ferroptosis" causes a larger area of tubular necrosis and accordingly aggravates renal allograft IRI. In this study, we decipher a whole new metabolic mechanism underlying ferroptosis and propose a novel spreading pathway of the "wave of ferroptosis" in the renal tissue microenvironment, in which renal IRI cell-secreted small extracellular vesicles (IRI-sEVs) delivering lncRNA WAC-AS1 reprogram glucose metabolism in adjacent renal tubular epithelial cell populations by inducing GFPT1 expression and increasing hexosamine biosynthesis pathway (HBP) flux, and consequently enhances O-GlcNAcylation. Additionally, BACH2 O-GlcNAcylation at threonine 389 in renal tubular epithelial cells prominently inhibits its degradation by ubiquitination and promotes importin α5-mediated nuclear translocation. We present the first evidence that intranuclear BACH2 suppresses SLC7A11 and GPX4 transcription by binding to their proximal promoters and decreases cellular anti-peroxidation capability, accordingly facilitating ferroptosis. Inhibition of sEV biogenesis and secretion by GW4869 and knockout of lncRNA WAC-AS1 in IRI-sEVs both unequivocally diminished the "wave of ferroptosis" propagation and protected against renal allograft IRI. The functional and mechanistic regulation of IRI-sEVs was further corroborated in an allograft kidney transplant model and an in situ renal IRI model. In summary, these findings suggest that inhibiting sEV-mediated lncRNA WAC-AS1 secretion and targeting HBP metabolism-induced BACH2 O-GlcNAcylation in renal tubular epithelial cells may serve as new strategies for protecting against graft IRI after kidney transplant.
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Affiliation(s)
- Xinyuan Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Xiang Peng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Xiang Zhou
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Mao Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guo Chen
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Wei Shi
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Haitao Yu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Chunlin Zhang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Yang Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Zhenwei Feng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
| | - Jie Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Simin Liang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiyang He
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Xin Gou
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Deragon MA, McCaig WD, Truong PV, Metz KR, Carron KA, Hughes KJ, Knapp AR, Dougherty MJ, LaRocca TJ. Mitochondrial Trafficking of MLKL, Bak/Bax, and Drp1 Is Mediated by RIP1 and ROS which Leads to Decreased Mitochondrial Membrane Integrity during the Hyperglycemic Shift to Necroptosis. Int J Mol Sci 2023; 24:8609. [PMID: 37239951 PMCID: PMC10218403 DOI: 10.3390/ijms24108609] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/04/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Apoptosis and necroptosis overlap in their initial signaling but diverge to produce non-inflammatory and pro-inflammatory outcomes, respectively. High glucose pushes signaling in favor of necroptosis producing a hyperglycemic shift from apoptosis to necroptosis. This shift depends on receptor-interacting protein 1 (RIP1) and mitochondrial reactive oxygen species (ROS). Here, we show that RIP1, mixed lineage kinase domain-like (MLKL) protein, Bcl-2 agonist/killer (Bak), Bcl-2 associated x (Bax) protein, and dynamin-related protein 1 (Drp1) traffic to the mitochondria in high glucose. RIP1 and MLKL appear in the mitochondria in their activated, phosphorylated states while Drp1 appears in its activated, dephosphorylated state in high glucose. Mitochondrial trafficking is prevented in rip1 KO cells and upon treatment with N-acetylcysteine. Induction of ROS replicated the mitochondrial trafficking seen in high glucose. MLKL forms high MW oligomers in the outer and inner mitochondrial membranes while Bak and Bax form high MW oligomers in the outer mitochondrial membrane in high glucose, suggesting pore formation. MLKL, Bax, and Drp1 promoted cytochrome c release from the mitochondria as well as a decrease in mitochondrial membrane potential in high glucose. These results indicate that mitochondrial trafficking of RIP1, MLKL, Bak, Bax, and Drp1 are key events in the hyperglycemic shift from apoptosis to necroptosis. This is also the first report to show oligomerization of MLKL in the inner and outer mitochondrial membranes and dependence of mitochondrial permeability on MLKL.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Timothy J. LaRocca
- Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA; (M.A.D.)
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21
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Xu W, Yang T, Lou X, Chen J, Wang X, Hu M, An D, Gao R, Wang J, Chen X. Role of the Peli1-RIPK1 Signaling Axis in Methamphetamine-Induced Neuroinflammation. ACS Chem Neurosci 2023; 14:864-874. [PMID: 36763609 DOI: 10.1021/acschemneuro.2c00623] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Severe neurological inflammation is one of the main symptoms of methamphetamine (meth)-induced brain injury. Studies have demonstrated that meth exposure facilitates neuroinflammation via Pellino E3 ubiquitin protein ligase 1 (Peli1)-mediated signaling. However, the involved mechanisms remain incompletely understood. Herein, we used Peli1-/- mice and Peli1-knockdown microglial BV2 cells to decipher the roles of Peli1 and downstream signaling in meth-induced neuroinflammation. After meth administration for seven consecutive days, Peli1-/- mice exhibited better learning and memory behavior and dramatically lower interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels than wild-type mice. Moreover, in vitro experiments revealed that Peli1 knockdown significantly attenuated the meth-induced upregulation of cytokines. Besides, meth markedly activated and increased the levels of receptor-interacting protein kinase 1 (RIPK1), and Peli1 knockout or knockdown prevented these effects, indicating that RIPK1 participated in meth-induced Peli1-mediated inflammation. Specifically, treating the cells with necrostatin-1(Nec-1), an antagonist of RIPK1, remarkably inhibited the meth-induced increase in IL-1β, TNF-α, and IL-6 expression, confirming the involvement of RIPK1 in Peli1-mediated neuroinflammation. Finally, meth induced a dramatic transfer of the mixed lineage kinase domain-like protein, a downstream effector of RIRK1, to the cell membrane, disrupting membrane integrity and causing cytokine excretion. Therefore, targeting the Peli1-RIPK1 signaling axis is a potentially valid therapeutic approach against meth-induced neuroinflammation.
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Affiliation(s)
- Weixiao Xu
- Department of Emergency Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China
| | - Tingyu Yang
- Wujin District Center for Disease Prevention and Control, Changzhou 213100, Jiangsu, China
| | - Xinyu Lou
- The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, Jiangsu, China
| | - Jingrong Chen
- The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, Jiangsu, China
| | - Xi Wang
- The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, Jiangsu, China
| | - Miaoyang Hu
- The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, Jiangsu, China
| | - Di An
- Department of Emergency Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China
| | - Rong Gao
- Department of Hygienic Analysis and Detection, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
| | - Jun Wang
- The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, Jiangsu, China
| | - Xufeng Chen
- Department of Emergency Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China
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22
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Mohamadian M, Parsamanesh N, Chiti H, Sathyapalan T, Sahebkar A. Protective effects of curcumin on ischemia/reperfusion injury. Phytother Res 2022; 36:4299-4324. [PMID: 36123613 DOI: 10.1002/ptr.7620] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/06/2022] [Accepted: 08/24/2022] [Indexed: 12/13/2022]
Abstract
Ischemia/reperfusion (I/R) injury is a term used to describe phenomena connected to the dysfunction of various tissue damage due to reperfusion after ischemic injury. While I/R may result in systemic inflammatory response syndrome or multiple organ dysfunction syndrome, there is still a long way to improve therapeutic outcomes. A number of cellular metabolic and ultrastructural alterations occur by prolonged ischemia. Ischemia increases the expression of proinflammatory gene products and bioactive substances within the endothelium, such as cytokines, leukocytes, and adhesion molecules, even as suppressing the expression of other "protective" gene products and substances, such as thrombomodulin and constitutive nitric oxide synthase (e.g., prostacyclin, nitric oxide [NO]). Curcumin is the primary phenolic pigment derived from turmeric, the powdered rhizome of Curcuma longa. Numerous studies have shown that curcumin has strong antiinflammatory and antioxidant characteristics. It also prevents lipid peroxidation and scavenges free radicals like superoxide anion, singlet oxygen, NO, and hydroxyl. In our study, we highlight the mechanisms of protective effects of curcumin against I/R injury in various organs.
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Affiliation(s)
- Malihe Mohamadian
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Negin Parsamanesh
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hossein Chiti
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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23
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Chaouhan HS, Vinod C, Mahapatra N, Yu SH, Wang IK, Chen KB, Yu TM, Li CY. Necroptosis: A Pathogenic Negotiator in Human Diseases. Int J Mol Sci 2022; 23:12714. [PMID: 36361505 PMCID: PMC9655262 DOI: 10.3390/ijms232112714] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/25/2022] Open
Abstract
Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.
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Affiliation(s)
- Hitesh Singh Chaouhan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
| | - Ch Vinod
- Department of Biological Sciences, School of Applied Sciences, KIIT University, Bhubaneshwar 751024, India
| | - Nikita Mahapatra
- Department of Biological Sciences, School of Applied Sciences, KIIT University, Bhubaneshwar 751024, India
| | - Shao-Hua Yu
- Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - I-Kuan Wang
- School of Medicine, China Medical University, Taichung 40402, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Kuen-Bao Chen
- Department of Anesthesiology, China Medical University Hospital, Taichung 40402, Taiwan
| | - Tung-Min Yu
- School of Medicine, China Medical University, Taichung 40402, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40402, Taiwan
| | - Chi-Yuan Li
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- School of Medicine, China Medical University, Taichung 40402, Taiwan
- Department of Anesthesiology, China Medical University Hospital, Taichung 40402, Taiwan
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24
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Magusto J, Beaupère C, Afonso MB, Auclair M, Delaunay JL, Soret PA, Courtois G, Aït-Slimane T, Housset C, Jéru I, Fève B, Ratziu V, Rodrigues CM, Gautheron J. The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes. iScience 2022; 25:105166. [PMID: 36204273 PMCID: PMC9530846 DOI: 10.1016/j.isci.2022.105166] [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: 06/13/2022] [Revised: 08/02/2022] [Accepted: 09/16/2022] [Indexed: 11/28/2022] Open
Abstract
Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins are key regulators of necroptosis, a highly pro-inflammatory mode of cell death, which has been involved in various human diseases. Necroptotic-independent functions of RIPK3 and MLKL also exist, notably in the adipose tissue but remain poorly defined. Using knock-out (KO) cell models, we investigated the role of RIPK3 and MLKL in adipocyte differentiation. Mlkl-KO abolished white adipocyte differentiation via a strong expression of Wnt10b, a ligand of the Wnt/β-catenin pathway, and a downregulation of genes involved in lipid metabolism. This effect was not recapitulated by the ablation of Ripk3. Conversely, Mlkl and Ripk3 deficiencies did not block beige adipocyte differentiation. These findings indicate that RIPK3 and MLKL have distinct roles in adipogenesis. The absence of MLKL blocks the differentiation of white, but not beige, adipocytes highlighting the therapeutic potential of MLKL inhibition in obesity.
Mlkl deficiency inhibits white, but not beige, adipocyte differentiation MLKL deficiency suppresses the expression of master regulators of adipogenesis Mlkl deficiency up-regulates Wnt10b expression Ripk3 deficiency does not alter white and beige adipocyte differentiation
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25
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Zhan Y, Xu D, Tian Y, Qu X, Sheng M, Lin Y, Ke M, Jiang L, Xia Q, Kaldas FM, Farmer DG, Ke B. Novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death. JHEP Rep 2022; 4:100532. [PMID: 36035360 PMCID: PMC9404660 DOI: 10.1016/j.jhepr.2022.100532] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/04/2022] [Accepted: 06/25/2022] [Indexed: 11/16/2022] Open
Abstract
Background & Aims The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress. Methods A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice. Results The TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis. Conclusions Macrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Lay summary Liver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.
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Key Words
- ALT, alanine aminotransferase
- APAF1, apoptotic peptidase activating factor 1
- ASK1, apoptosis signal-regulating kinase 1
- AST, aspartate aminotransferase
- Apoptosis
- BMM, bone marrow-derived macrophage
- CXCL-10, C-X-C motif chemokine ligand 10
- CYLD, cyclindromatosis
- ChIP, chromatin immunoprecipitation
- DAMP, damage-associated molecular pattern
- DUB, deubiquitinating enzyme
- ER, endoplasmic reticulum
- ES, embryonic stem
- G3BP1
- G3BP1, Ras GTPase-activating protein-binding protein 1
- GCLC, glutamate-cysteine ligase catalytic subunit
- GCLM, glutamate-cysteine ligase regulatory subunit
- IHC, immunohistochemistry
- INF-β, interferon-β
- IR, ischaemia/reperfusion
- IRF3
- IRF3, interferon regulatory factor 3
- IRF7, IFN-regulating transcription factor 7
- IRI, ischaemia/reperfusion injury
- Innate immunity
- KO, knockout
- LPS, lipopolysaccharide
- Liver inflammation
- Lyz2, Lysozyme 2
- MCP-1, monocyte chemoattractant protein 1
- NOX2, NADPH oxidase 2
- NOX4, NADPH oxidase 4
- NQO1, NAD(P)H quinone dehydrogenase 1
- NRF2, nuclear factor (erythroid-derived 2)-like 2
- NS, non-specific
- Necroptosis
- OASL1, 2′,5′oligoadenylate synthetase-like 1
- PAMP, pathogen-derived molecular pattern
- RIPK3, receptor-interacting serine/threonine-protein kinase 3
- ROS, reactive oxygen species
- STING
- STING, stimulator of interferon genes
- TBK1, TANK-binding kinase 1
- TLR4, Toll-like receptor 4
- TNF-α, tumour necrosis factor-alpha
- TRX, thioredoxin
- TSS, transcription start sites
- TXNIP, thioredoxin-interacting protein
- TXNIPFL/FL, floxed TXNIP
- TXNIPM-KO, myeloid-specific TXNIP KO
- UTR, untranslated region
- sALT, serum ALT
- sAST, serum AST
- siRNA, small interfering RNA
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Affiliation(s)
- Yongqiang Zhan
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Dongwei Xu
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yizhu Tian
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Xiaoye Qu
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mingwei Sheng
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yuanbang Lin
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Michael Ke
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Longfeng Jiang
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fady M. Kaldas
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Douglas G. Farmer
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Bibo Ke
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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26
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The role of RHIM in necroptosis. Biochem Soc Trans 2022; 50:1197-1205. [PMID: 36040212 PMCID: PMC9444067 DOI: 10.1042/bst20220535] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022]
Abstract
The RIP homotypic interaction motif (RHIM) is a conserved protein domain that is approximately 18–22 amino acids in length. In humans, four proteins carrying RHIM domains have been identified: receptor-interacting serine/threonine protein kinase (RIPK) 1, RIPK3, Z-DNA-binding protein 1 (ZBP1), and TIR domain-containing adapter-inducing IFN-β (TRIF), which are all major players in necroptosis, a distinct form of regulated cell death. Necroptosis is mostly presumed to be a fail-safe form of cell death, occurring in cells in which apoptosis is compromised. Upon activation, RIPK1, ZBP1, and TRIF each hetero-oligomerize with RIPK3 and induce the assembly of an amyloid-like structure of RIPK3 homo-oligomers. These act as docking stations for the recruitment of the pseudokinase mixed-lineage kinase domain like (MLKL), the pore-forming executioner of necroptosis. As RHIM domain interactions are a vital component of the signaling cascade and can also be involved in apoptosis and pyroptosis activation, it is unsurprising that viral and bacterial pathogens have developed means of disrupting RHIM-mediated signaling to ensure survival. Moreover, as these mechanisms play an essential part of regulated cell death signaling, they have received much attention in recent years. Herein, we present the latest insights into the supramolecular structure of interacting RHIM proteins and their distinct signaling cascades in inflammation and infection. Their uncovering will ultimately contribute to the development of new therapeutic strategies in the regulation of lytic cell death.
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27
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Yan WT, Yang YD, Hu XM, Ning WY, Liao LS, Lu S, Zhao WJ, Zhang Q, Xiong K. Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies. Neural Regen Res 2022; 17:1761-1768. [PMID: 35017436 PMCID: PMC8820688 DOI: 10.4103/1673-5374.331539] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/15/2021] [Accepted: 11/01/2021] [Indexed: 11/04/2022] Open
Abstract
Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis, apoptosis and necroptosis act in consort in a multimeric protein complex, PANoptosome. This allows all the components of PANoptosis to be regulated simultaneously. PANoptosis provides a new way to study the regulation of cell death, in that different types of cell death may be regulated at the same time. To test whether PANoptosis exists in diseases other than infectious diseases, we chose cerebral ischemia/reperfusion injury as the research model, collected articles researching cerebral ischemia/reperfusion from three major databases, obtained the original research data from these articles by bibliometrics, data mining and other methods, then integrated and analyzed these data. We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion. In the cell model simulating ischemic brain injury, pyroptosis, apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons. Pyroptosis, apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury. This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.
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Affiliation(s)
- Wei-Tao Yan
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Yan-Di Yang
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Wen-Ya Ning
- Department of Human Resources, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Lyu-Shuang Liao
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Shuang Lu
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Wen-Juan Zhao
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Qi Zhang
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Kun Xiong
- Department of Neurobiology and Human Anatomy, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
- Hunan Key Laboratory of Ophthalmology, Changsha, Hunan Province, China
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28
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Zhao W, Liu Y, Xu L, He Y, Cai Z, Yu J, Zhang W, Xing C, Zhuang C, Qu Z. Targeting Necroptosis as a Promising Therapy for Alzheimer's Disease. ACS Chem Neurosci 2022; 13:1697-1713. [PMID: 35607807 DOI: 10.1021/acschemneuro.2c00172] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder featured by memory loss and cognitive default. However, there has been no effective therapeutic approach to prevent the development of AD and the available therapies are only to alleviate some symptoms with limited efficacy and severe side effects. Necroptosis is a new kind of cell death, being regarded as a genetically programmed and regulated pattern of necrosis. Increasing evidence reveals that necroptosis is tightly related to the occurrence and development of AD. This review aims to summarize the potential role of necroptosis in AD progression and the therapeutic capacity of targeting necroptosis for AD patients.
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Affiliation(s)
- Wenli Zhao
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
| | - Yue Liu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Lijuan Xu
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Yuan He
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200070, China
| | - Zhenyu Cai
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200070, China
| | - Jianqiang Yu
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
| | - Wannian Zhang
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Chengguo Xing
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Chunlin Zhuang
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Zhuo Qu
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
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29
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Jin B, Li G, Zhou L, Fan Z. Mechanism Involved in Acute Liver Injury Induced by Intestinal Ischemia-Reperfusion. Front Pharmacol 2022; 13:924695. [PMID: 35694264 PMCID: PMC9185410 DOI: 10.3389/fphar.2022.924695] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/05/2022] [Indexed: 12/28/2022] Open
Abstract
Intestinal ischemia-reperfusion (I/R) is a common pathophysiological process, which can occur in many conditions such as acute enteric ischemia, severe burns, small intestinal transplantation, etc,. Ischemia-reperfusion of the intestine is often accompanied by distal organ injury, especially liver injury. This paper outlined the signal pathways and cytokines involved in acute liver injury induced by intestinal I/R: the NF-κB Signaling Pathway, the P66shc Signaling Pathway, the HMGB1 Signaling Pathway, the Nrf2-ARE Signaling Pathway, the AMPK-SIRT-1 Signaling Pathway and other cytokines, providing new ideas for the prevention and treatment of liver injury caused by reperfusion after intestinal I/R.
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Affiliation(s)
- Binghui Jin
- Department of General Surgery, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China
- Department of Central Laboratory, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Guangyao Li
- Department of General Surgery, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China
- Department of Central Laboratory, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Lin Zhou
- Department of Outpatient, the NO. 967 Hospital of PLA Joint Logistics Support Force, Dalian Medical University, Dalian, China
| | - Zhe Fan
- Department of General Surgery, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China
- Department of Central Laboratory, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China
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30
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Zhu X, Wu C. Down-Regulation of Long Non-Coding RNA AK139328 Reduces Cell Inflammation and Apoptosis in Cerebral Ischemia Reperfusion Injury. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Cerebral ischemia-reperfusion injury (CIRI) refers to the phenomenon that the ischemic injury of brain leads to the injury of brain cells, and ischemic injury is further aggravated after the recovery of blood reperfusion. In this study, we first constructed Oxygen and glucose deprivation/reoxygenation
(OGD/R) injury model of PC12 cells, we found that the expression of LncRNA AK139328 in model cells was significantly increased through RT-qPCR. Subsequently, we interfered LncRNA AK139328 in model cells by plasmid transfection and found that interfering LncRNA AK139328 could significantly
reduce the expression of inflammatory factors, including TNF a, IL-1β, IL-6, McP-1, and oxidative stress-related factors, including ROS, MDA, LDH, while the expressions of SOD and GSHPx were significantly increased. Flow cytometry was used to detect cell apoptosis, and apoptosisrelated
proteins bcl-2, Bax, cleaved-caspase3 and cleaved PARP-1 were detected by western blot. Results show that interfering LncRNA AK139328 could reduce the apoptosis rate of OGD/R cells and the expression of Bax, cleaved caspase3 and cleaved PARP-1, while increasing the expression of bcl-2. Meanwhile,
we found that after interfering LncRNA AK139328, the expressions of Nrf2, HO-1, NQO-1 and phosphorylated-P65 increased, while P65 showed no significant changes. This may be related to Nrf2/HO-1 and NF-κB signaling pathways. In a word, our study showed that interfering with LncRNA
AK139328 can reduce cell inflammation and apoptosis in CIRI.
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Affiliation(s)
- Xuanxuan Zhu
- Nursing Department, Xinyi Hospital of Traditional Chinese Medicine, Xinyi, Jiangsu, 221400, China
| | - Changzheng Wu
- Department of Neurology, Lianyungang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine Lianyungang, Jiangsu, 222000, China
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31
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Maremonti F, Meyer C, Linkermann A. Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss. J Am Soc Nephrol 2022; 33:472-486. [PMID: 35022311 PMCID: PMC8975069 DOI: 10.1681/asn.2021101293] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
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Affiliation(s)
- Francesca Maremonti
- Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Claudia Meyer
- Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Andreas Linkermann
- Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany .,Biotechnology Center, Technical University of Dresden, Dresden, Germany
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32
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Van Slambrouck J, Van Raemdonck D, Vos R, Vanluyten C, Vanstapel A, Prisciandaro E, Willems L, Orlitová M, Kaes J, Jin X, Jansen Y, Verleden GM, Neyrinck AP, Vanaudenaerde BM, Ceulemans LJ. A Focused Review on Primary Graft Dysfunction after Clinical Lung Transplantation: A Multilevel Syndrome. Cells 2022; 11:cells11040745. [PMID: 35203392 PMCID: PMC8870290 DOI: 10.3390/cells11040745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/14/2022] [Accepted: 02/17/2022] [Indexed: 02/01/2023] Open
Abstract
Primary graft dysfunction (PGD) is the clinical syndrome of acute lung injury after lung transplantation (LTx). However, PGD is an umbrella term that encompasses the ongoing pathophysiological and -biological mechanisms occurring in the lung grafts. Therefore, we aim to provide a focused review on the clinical, physiological, radiological, histological and cellular level of PGD. PGD is graded based on hypoxemia and chest X-ray (CXR) infiltrates. High-grade PGD is associated with inferior outcome after LTx. Lung edema is the main characteristic of PGD and alters pulmonary compliance, gas exchange and circulation. A conventional CXR provides a rough estimate of lung edema, while a chest computed tomography (CT) results in a more in-depth analysis. Macroscopically, interstitial and alveolar edema can be distinguished below the visceral lung surface. On the histological level, PGD correlates to a pattern of diffuse alveolar damage (DAD). At the cellular level, ischemia-reperfusion injury (IRI) is the main trigger for the disruption of the endothelial-epithelial alveolar barrier and inflammatory cascade. The multilevel approach integrating all PGD-related aspects results in a better understanding of acute lung failure after LTx, providing novel insights for future therapies.
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Affiliation(s)
- Jan Van Slambrouck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Dirk Van Raemdonck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Robin Vos
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Respiratory Diseases, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Cedric Vanluyten
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Arno Vanstapel
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Pathology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Elena Prisciandaro
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Lynn Willems
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Pulmonary Circulation Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium;
| | - Michaela Orlitová
- Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium; (M.O.); (A.P.N.)
| | - Janne Kaes
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
| | - Xin Jin
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Yanina Jansen
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Geert M. Verleden
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Respiratory Diseases, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Arne P. Neyrinck
- Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium; (M.O.); (A.P.N.)
- Department of Anesthesiology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Bart M. Vanaudenaerde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
| | - Laurens J. Ceulemans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.V.S.); (D.V.R.); (R.V.); (C.V.); (A.V.); (E.P.); (J.K.); (X.J.); (Y.J.); (G.M.V.); (B.M.V.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
- Correspondence:
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Hira K, Sharma P, Mahale A, Prakash Kulkarni O, Sajeli Begum A. Cyclo(Val-Pro) and Cyclo(Leu-Hydroxy-Pro) from Pseudomonas sp. (ABS-36) alleviates acute and chronic renal injury under in vitro and in vivo models (Ischemic reperfusion and unilateral ureter obstruction). Int Immunopharmacol 2022; 103:108494. [PMID: 34973530 DOI: 10.1016/j.intimp.2021.108494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/12/2021] [Accepted: 12/19/2021] [Indexed: 11/16/2022]
Abstract
The study aimed to identify small molecules having potentiality in alleviating renal injury. Two natural compounds cyclo(Val-Pro) (1) and cyclo(Leu-Hydroxy-Pro) (2) were first evaluated under acute renal injury model of ischemic reperfusion at different doses of 25, 50 and 75 mg/kg body weight. Further, the compounds were subjected to antimycin A-induced ischemic in vitro study (NRK-52E cell lines). Both the compounds significantly decreased plasma IL-1β levels (P < 0.05). Also, the mRNA expression levels of inflammatory markers (TNF-α, IL-6 and IL-1β) and renal injury markers (KIM-1, NGAL, α-GST and π-GST) in the renal tissues were significantly alleviated (P < 0.01) along with the improvement in histological damage and control over neutrophil infiltration as a result of ischemic reperfusion. The in vitro study revealed the protective effect against antimycin A-induced cytotoxicity (P < 0.05) and antiapoptotic effect acting through the regulation of Bax, caspase 3 (pro and cleaved) and BCL2 with reduction in Annexin+PI+ cells. Further, the compound cyclo(Val-Pro) (1) was evaluated (50 mg/kg body weight dose) in chronic unilateral ureter obstruction model of renal injury in mice and TGF-β-induced in vitro fibrotic model (NRK-49F cell lines). Cyclo(Val-Pro) (1) significantly reduced the expression levels of fibrotic markers (collagen-1, α-SMA and TGF-β) and showed marked alleviation of renal fibrosis (sirius red staining). Also, the proliferation of TGF-β-induced NRK-49F cells was significantly reduced along with decreased levels of collagen-1 and α-SMA in immunohistochemistry studies. In conclusion, the compounds significantly abrogated ischemic injury by inhibiting renal inflammation and tubular epithelial apoptosis. Further, cyclo (Val-Pro) (1) exhibited significant anti-fibrotic activity through the inhibition of fibroblast activation and proliferation. Thus, these proline-based cyclic dipeptides are recommended as drug leads for treating renal injury.
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Affiliation(s)
- Kirti Hira
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India
| | - Pravesh Sharma
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India
| | - Ashutosh Mahale
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India
| | - Onkar Prakash Kulkarni
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India
| | - A Sajeli Begum
- Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana State, India.
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34
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Chun N, Ang RL, Chan M, Fairchild RL, Baldwin WM, Horwitz JK, Gelles JD, Chipuk JE, Kelliher MA, Pavlov VI, Li Y, Homann D, Heeger PS, Ting AT. T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death. JCI Insight 2021; 6:e148643. [PMID: 34752416 PMCID: PMC8783689 DOI: 10.1172/jci.insight.148643] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 11/03/2021] [Indexed: 12/31/2022] Open
Abstract
TNF ligation of TNF receptor 1 (TNFR1) promotes either inflammation and cell survival by (a) inhibiting RIPK1's death-signaling function and activating NF-κB or (b) causing RIPK1 to associate with the death-inducing signaling complex to initiate apoptosis or necroptosis. The cellular source of TNF that results in RIPK1-dependent cell death remains unclear. To address this, we employed in vitro systems and murine models of T cell-dependent transplant or tumor rejection in which target cell susceptibility to RIPK1-dependent cell death could be genetically altered. We show that TNF released by T cells is necessary and sufficient to activate RIPK1-dependent cell death in target cells and thereby mediate target cell cytolysis independently of T cell frequency. Activation of the RIPK1-dependent cell death program in target cells by T cell-derived TNF accelerates murine cardiac allograft rejection and synergizes with anti-PD1 administration to destroy checkpoint blockade-resistant murine melanoma. Together, the findings uncover a distinct immunological role for TNF released by cytotoxic effector T cells following cognate interactions with their antigenic targets. Manipulating T cell TNF and/or target cell susceptibility to RIPK1-dependent cell death can be exploited to either mitigate or augment T cell-dependent destruction of allografts and malignancies to improve outcomes.
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Affiliation(s)
- Nicholas Chun
- Department of Medicine and Translational Transplant Research Center and
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Rosalind L. Ang
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Mark Chan
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
| | - Robert L. Fairchild
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - William M. Baldwin
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Julian K. Horwitz
- Department of Medicine and Translational Transplant Research Center and
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jesse D. Gelles
- Graduate School of Biomedical Sciences and
- Tisch Cancer Institute and the Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jerry Edward Chipuk
- Tisch Cancer Institute and the Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michelle A. Kelliher
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Vasile I. Pavlov
- Department of Medicine and Translational Transplant Research Center and
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yansui Li
- Department of Medicine and Translational Transplant Research Center and
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dirk Homann
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Peter S. Heeger
- Department of Medicine and Translational Transplant Research Center and
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Adrian T. Ting
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
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35
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Yao D, Zhang S, Hu Z, Luo H, Mao C, Fan Y, Tang M, Liu F, Shen S, Fan L, Li M, Shi J, Li J, Ma D, Xu Y, Shi C. CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation. Aging (Albany NY) 2021; 13:25564-25577. [PMID: 34905731 PMCID: PMC8714161 DOI: 10.18632/aging.203774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/24/2021] [Indexed: 01/01/2023]
Abstract
Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.
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Affiliation(s)
- Dabao Yao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Shuo Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Zhengwei Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Haiyang Luo
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Chengyuan Mao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Yu Fan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Mibo Tang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Fen Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Si Shen
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Liyuan Fan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Mengjie Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Jingjing Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Jiadi Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Dongrui Ma
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Institute of Neuroscience, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Changhe Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China.,Institute of Neuroscience, Zhengzhou University, Zhengzhou 450000, Henan, China
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Cheng Y, Cheng A, Jia Y, Yang L, Ning Y, Xu L, Zhong Y, Zhuang Z, Guan J, Zhang X, Lin Y, Zhou T, Fan X, Li J, Liu P, Yan G, Wu R. pH-Responsive Multifunctional Theranostic Rapamycin-Loaded Nanoparticles for Imaging and Treatment of Acute Ischemic Stroke. ACS APPLIED MATERIALS & INTERFACES 2021; 13:56909-56922. [PMID: 34807583 DOI: 10.1021/acsami.1c16530] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.
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Affiliation(s)
- Yan Cheng
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Airong Cheng
- Department of Neurology, Chengwu County People's Hospital, Chengwu 274200, Shandong, China
| | - Yanlong Jia
- Department of Radiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441021, China
| | - Lin Yang
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Yan Ning
- Department of TCM, Shenzhen Maternity & Child Healthcare Hospital Affiliated to Southern Medical University, Shenzhen 518028, Guangdong, China
| | - Liang Xu
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Yazhi Zhong
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Zerui Zhuang
- Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Department of Neurosurgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, Guangdong, China
- Department of Neurosurgery, Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Jitian Guan
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Xiaolei Zhang
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Yan Lin
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Teng Zhou
- Department of Computer Science, Shantou University, Shantou 515041, China
| | - Xiusong Fan
- Department of Radiology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Jianwu Li
- Transfusion Department, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Peng Liu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong, China
| | - Gen Yan
- Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen 361023, Fujian, China
| | - Renhua Wu
- Department of Radiology, The Second Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
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Astragalin Protects against Spinal Cord Ischemia Reperfusion Injury through Attenuating Oxidative Stress-Induced Necroptosis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7254708. [PMID: 34746308 PMCID: PMC8568517 DOI: 10.1155/2021/7254708] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 09/01/2021] [Accepted: 09/03/2021] [Indexed: 01/03/2023]
Abstract
Spinal cord ischemia/reperfusion (SCI/R) injury is a devastating complication usually occurring after thoracoabdominal aortic surgery. However, it remains unsatisfactory for its intervention by using pharmacological strategies. Oxidative stress is a main pharmacological process involved in SCI/R, which will elicit downstream programmed cell death such as the novel defined necroptosis. Astragalin is a bioactive natural flavonoid with a wide spectrum of pharmacological activities. Herein, we firstly evaluated the effect of astragalin to oxidative stress as well as the possible downstream necroptosis after SCI/R in mice. Our results demonstrated that astragalin improves the ethological score and histopathological deterioration of SCI/R mice. Astragalin mitigates oxidative stress and ameliorates inflammation after SCI/R. Astragalin blocks necroptosis induced by SCI/R. That is, the amelioration of astragalin to the motoneuron injury and histopathological changes. Indicators of oxidative stress, inflammation, and necroptosis after SCI/R were significantly blocked. Summarily, we firstly illustrated the protection of astragalin against SCI/R through its blockage to the necroptosis at downstream of oxidative stress.
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Qamar A, Zhao J, Xu L, McLeod P, Huang X, Jiang J, Liu W, Haig A, Zhang ZX. Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury. Int J Mol Sci 2021; 22:11038. [PMID: 34681708 PMCID: PMC8540562 DOI: 10.3390/ijms222011038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/23/2021] [Accepted: 10/08/2021] [Indexed: 12/26/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival.
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Affiliation(s)
- Adnan Qamar
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
- Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada; (W.L.); (A.H.)
| | - Jianqi Zhao
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
- Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada; (W.L.); (A.H.)
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, 3808 Jiefang Road, Changchun 130021, China
| | - Laura Xu
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
- Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada; (W.L.); (A.H.)
| | - Patrick McLeod
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
| | - Xuyan Huang
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
| | - Jifu Jiang
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
| | - Weihua Liu
- Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada; (W.L.); (A.H.)
| | - Aaron Haig
- Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada; (W.L.); (A.H.)
| | - Zhu-Xu Zhang
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada; (A.Q.); (J.Z.); (L.X.); (P.M.); (X.H.); (J.J.)
- Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada; (W.L.); (A.H.)
- Multi-Organ Transplant Program, London Health Sciences Centre, London, ON N6A 5A5, Canada
- Division of Nephrology, Department of Medicine, Western University, London, ON N6A 3K7, Canada
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Li Z, Wang-Heaton H, Cartwright BM, Makinwa Y, Hilton BA, Musich PR, Shkriabai N, Kvaratskhelia M, Guan S, Chen Q, Yu X, Zou Y. ATR prevents Ca 2+ overload-induced necrotic cell death through phosphorylation-mediated inactivation of PARP1 without DNA damage signaling. FASEB J 2021; 35:e21373. [PMID: 33811702 PMCID: PMC8252533 DOI: 10.1096/fj.202001636rrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 12/10/2020] [Accepted: 12/31/2020] [Indexed: 12/19/2022]
Abstract
Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+/ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid‐induced necrotic death of cells including SH‐SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site‐specific phosphorylation inactivates PARP1, inhibiting ionophore‐induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR‐mediated anti‐necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.
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Affiliation(s)
- Zhengke Li
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Hui Wang-Heaton
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Brian M Cartwright
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Yetunde Makinwa
- Department of Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA
| | - Benjamin A Hilton
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Phillip R Musich
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Nikolozi Shkriabai
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mamuka Kvaratskhelia
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Shengheng Guan
- Department of Pharmaceutical Chemistry and Mass Spectrometry Facility, University of California, San Francisco, CA, USA
| | - Qian Chen
- Department of Cancer Genetics and Epigenetics, City of Hope, Duarte, CA, USA
| | - Xiaochun Yu
- Department of Cancer Genetics and Epigenetics, City of Hope, Duarte, CA, USA
| | - Yue Zou
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Department of Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA
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40
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Drysch M, Schmidt SV, Becerikli M, Reinkemeier F, Dittfeld S, Wagner JM, Dadras M, Sogorski A, von Glinski M, Lehnhardt M, Behr B, Wallner C. Myostatin Deficiency Protects C2C12 Cells from Oxidative Stress by Inhibiting Intrinsic Activation of Apoptosis. Cells 2021; 10:cells10071680. [PMID: 34359850 PMCID: PMC8305813 DOI: 10.3390/cells10071680] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 01/09/2023] Open
Abstract
Ischemia reperfusion (IR) injury remains an important topic in clinical medicine. While a multitude of prophylactic and therapeutic strategies have been proposed, recent studies have illuminated protective effects of myostatin inhibition. This study aims to elaborate on the intracellular pathways involved in myostatin signaling and to explore key proteins that convey protective effects in IR injury. We used CRISPR/Cas9 gene editing to introduce a myostatin (Mstn) deletion into a C2C12 cell line. In subsequent experiments, we evaluated overall cell death, activation of apoptotic pathways, ROS generation, lipid peroxidation, intracellular signaling via mitogen-activated protein kinases (MAPKs), cell migration, and cell proliferation under hypoxic conditions followed by reoxygenation to simulate an IR situation in vitro (hypoxia reoxygenation). It was found that mitogen-activated protein kinase kinase 3/6, also known as MAPK/ERK Kinase 3/6 (MEK3/6), and subsequent p38 MAPK activation were blunted in C2C12-Mstn−/− cells in response to hypoxia reoxygenation (HR). Similarly, c-Jun N-terminal kinase (JNK) activation was negated. We also found the intrinsic activation of apoptosis to be more important in comparison with the extrinsic activation. Additionally, intercepting myostatin signaling mitigated apoptosis activation. Ultimately, this research validated protective effects of myostatin inhibition in HR and identified potential mediators worth further investigation. Intercepting myostatin signaling did not inhibit ROS generation overall but mitigated cellular injury. In particular, intrinsic activation of apoptosis origination from mitochondria was alleviated. This was presumably mediated by decreased activation of p38 caused by the diminished kinase activity increase of MEK3/6. Overall, this work provides important insights into HR signaling in C2C12-Mstn−/− cells and could serve as basis for further research.
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Shepherd HM, Gauthier JM, Li W, Krupnick AS, Gelman AE, Kreisel D. Innate immunity in lung transplantation. J Heart Lung Transplant 2021; 40:562-568. [PMID: 34020867 PMCID: PMC10977655 DOI: 10.1016/j.healun.2021.03.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 01/11/2023] Open
Abstract
Innate immune pathways early after pulmonary transplantation have been shown to cause primary graft dysfunction (PGD) and also predispose to late graft failure. Recent studies in animal models have elucidated critical mechanisms governing such innate immune responses. Here, we discuss pathways of inflammatory cell death, triggers for sterile and infectious inflammation, and signaling cascades that mediate lung injury early after transplantation. These studies highlight potential avenues for lung-specific therapies early following lung transplantation to dampen innate immune responses and improve outcomes.
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Affiliation(s)
- Hailey M Shepherd
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Jason M Gauthier
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Wenjun Li
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | | | - Andrew E Gelman
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Daniel Kreisel
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri.
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Abstract
In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death." We hypothesize that necroptosis might initiate cell death propagation through ferroptosis. The remaining necrotic debris requires effective removal processes to prevent a secondary inflammatory response, referred to as necroinflammation. Open questions include the differences in the immunogenicity of ferroptosis and necroptosis, and the specificity of necrostatins and ferrostatins to therapeutically target these processes to prevent AKI-to-CKD progression and end-stage renal disease.
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Lee JY, Arumugarajah S, Lian D, Maehara N, Haig AR, Suri RS, Miyazaki T, Gunaratnam L. Recombinant apoptosis inhibitor of macrophage protein reduces delayed graft function in a murine model of kidney transplantation. PLoS One 2021; 16:e0249838. [PMID: 33891625 PMCID: PMC8064555 DOI: 10.1371/journal.pone.0249838] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 03/25/2021] [Indexed: 12/03/2022] Open
Abstract
Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. HMGB1), propagating further inflammation (necroinflammation) and tissue damage. Kidney Injury Molecule-1 (KIM-1) is a phagocytic receptor upregulated on proximal TECs during acute kidney injury. We have previously shown that renal KIM-1 protects the graft against transplant associated IRI by enabling TECs to clear apoptotic and necrotic cells, and that recognition of necrotic cells by KIM-1 is augmented in the presence of the opsonin, apoptosis inhibitor of macrophages (AIM). Here, we tested whether recombinant AIM (rAIM) could be used to mitigate transplant associated IRI. We administered rAIM or vehicle control to nephrectomised B6 mice transplanted with a single B6 donor kidney. Compared to grafts in vehicle-treated recipients, grafts from rAIM-treated mice exhibited significantly less renal dysfunction, tubular cell death, tissue damage, tubular obstruction, as well as local and systemic inflammation. Both mouse and human rAIM enhanced the clearance of necrotic cells by murine and human TECs, respectively in vitro. These data support testing of rAIM as a potential therapeutic agent to reduce DGF following kidney transplantation.
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Affiliation(s)
- Ji Yun Lee
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Shabitha Arumugarajah
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Dameng Lian
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Natsumi Maehara
- Centre for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan
| | - Aaron R. Haig
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Rita S. Suri
- Faculty of Medicine, Division of Nephrology, McGill University, Montreal, Quebec, Canada
| | - Toru Miyazaki
- Centre for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan
| | - Lakshman Gunaratnam
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
- Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- * E-mail:
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Wang WY, Xie L, Zou XS, Li N, Yang YG, Wu ZJ, Tian XY, Zhao GY, Chen MH. Inhibition of extracellular signal-regulated kinase/calpain-2 pathway reduces neuroinflammation and necroptosis after cerebral ischemia-reperfusion injury in a rat model of cardiac arrest. Int Immunopharmacol 2021; 93:107377. [PMID: 33517223 DOI: 10.1016/j.intimp.2021.107377] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/06/2021] [Accepted: 01/06/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Cerebral ischemia-reperfusion injury (CIRI) is the leading cause of poor neurological prognosis after cardiopulmonary resuscitation (CPR). We previously reported that the extracellular signal-regulated kinase (ERK) activation mediates CIRI. Here, we explored the potential ERK/calpain-2 pathway role in CIRI using a rat model of cardiac arrest (CA). METHODS Adult male Sprague-Dawley rats suffered from CA/CPR-induced CIRI, received saline, DMSO, PD98059 (ERK1/2 inhibitor, 0.3 mg/kg), or MDL28170 (calpain inhibitor, 3.0 mg/kg) after spontaneous circulation recovery. The survival rate and the neurological deficit score (NDS) were utilized to assess the brain function. Hematoxylin stain, Nissl staining, and transmission electron microscopy were used to evaluate the neuron injury. The expression levels of p-ERK, ERK, calpain-2, neuroinflammation-related markers (GFAP, Iba1, IL-1β, TNF-α), and necroptosis proteins (TNFR1, RIPK1, RIPK3, p-MLKL, and MLKL) in the brain tissues were determined by western blotting and immunohistochemistry. Fluorescent multiplex immunohistochemistry was used to analyze the p-ERK, calpain-2, and RIPK3 co-expression in neurons, and RIPK3 expression levels in microglia or astrocytes. RESULTS At 24 h after CA/CPR, the rats in the saline-treated and DMSO groups presented with injury tissue morphology, low NDS, ERK/calpain-2 pathway activation, and inflammatory cytokine and necroptosis protein over-expression in the brain tissue. After PD98059 and MDL28170 treatment, the brain function was improved, while inflammatory response and necroptosis were suppressed by ERK/calpain-2 pathway inhibition. CONCLUSION Inflammation activation and necroptosis involved in CA/CPR-induced CIRI were regulated by the ERK/calpain-2 signaling pathway. Inhibition of that pathway can reduce neuroinflammation and necroptosis after CIRI in the CA model rats.
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Affiliation(s)
- Wen-Yan Wang
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Lu Xie
- Department of Physiology, Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Xin-Sen Zou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Nuo Li
- Department of Physiology, Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Ye-Gui Yang
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Zhi-Jiang Wu
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Xin-Yue Tian
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Gao-Yang Zhao
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China
| | - Meng-Hua Chen
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China.
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Intestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies. Biomed Pharmacother 2021; 138:111482. [PMID: 33740527 DOI: 10.1016/j.biopha.2021.111482] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/01/2021] [Accepted: 03/06/2021] [Indexed: 12/17/2022] Open
Abstract
Intestinal ischemic reperfusion injury (IIRI) is a life-threatening condition with high morbidity and mortality in the clinic. IIRI was induced by intestinal ischemic diseases such as, small bowel transplantation, aortic aneurysm surgery, and strangulated hernias. Although related mechanisms have not been fully elucidated, during the last decade, researches have demonstrated that many factors are crucial in the pathological process, including oxidative stress (OS), epithelial barrier function disorder, and so on. Rats model, as the most applied animal IIRI model, provides specific targets for researches and therapeutic strategies. Moreover, various treatment strategies such as, anti-oxidative stress, anti-apoptosis, and anti-inflammation, have shown promising effects in alleviating IIRI. However, current researches cannot solve the clinical problems of IIRI, and specific treatment strategies are still needed to be exploited. This review focuses on a recommended experimental IIRI rat model and understanding of the involved mechanisms such as, OS, gut bacteria translocation, apoptosis, and necroptosis, aim at providing novel ideas for therapeutic strategies of IIRI.
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The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation-Where Have We Gone So Far? Int J Mol Sci 2021; 22:ijms22042157. [PMID: 33671524 PMCID: PMC7926299 DOI: 10.3390/ijms22042157] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 02/07/2023] Open
Abstract
The damage of the endothelial glycocalyx as a consequence of ischemia and/or reperfusion injury (IRI) following kidney transplantation has come at the spotlight of research due to potential associations with delayed graft function, acute rejection as well as long-term allograft dysfunction. The disintegration of the endothelial glycocalyx induced by IRI is the crucial event which exposes the denuded endothelial cells to further inflammatory and oxidative damage. The aim of our review is to present the currently available data regarding complex links between shedding of the glycocalyx components, like syndecan-1, hyaluronan, heparan sulphate, and CD44 with the activation of intricate immune system responses, including toll-like receptors, cytokines and pro-inflammatory transcription factors. Evidence on modes of protection of the endothelial glycocalyx and subsequently maintenance of endothelial permeability as well as novel nephroprotective molecules such as sphingosine-1 phosphate (S1P), are also depicted. Although advances in technology are making the visualization and the analysis of the endothelial glycocalyx possible, currently available evidence is mostly experimental. Ongoing progress in understanding the complex impact of IRI on the endothelial glycocalyx, opens up a new era of research in the field of organ transplantation and clinical studies are of utmost importance for the future.
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Shanmugam N, Baker MODG, Sanz-Hernandez M, Sierecki E, Gambin Y, Steain M, Pham CLL, Sunde M. Herpes simplex virus encoded ICP6 protein forms functional amyloid assemblies with necroptosis-associated host proteins. Biophys Chem 2021; 269:106524. [PMID: 33348174 DOI: 10.1016/j.bpc.2020.106524] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/31/2022]
Abstract
The viral protein ICP6, encoded by herpes simplex virus 1 (HSV-1), harbours a RIP-homotypic interaction motif (RHIM), that plays a role in viral inhibition of host cell death pathways. Other members of the Herpesviridae family also encode RHIM-containing proteins that interfere with host-cell death pathways, including the M45 protein from murine cytomegalovirus, and ORF20 protein from varicella zoster virus. We have used amyloid assembly assays, electron microscopy and single molecule fluorescence spectroscopy to show that the ICP6 RHIM is amyloidogenic and can interact with host RHIM-containing proteins to form heteromeric amyloid complexes, in a manner similar to that of M45 and ORF20 RHIMs. The core tetrad sequence of the ICP6 RHIM is important for both amyloid formation and interaction with host RHIM-containing proteins. Notably, we show that the amyloid forming capacity of the ICP6 RHIM is affected by the redox environment. We propose that the formation of an intramolecular disulfide bond within ICP6 triggers the formation of amyloid assemblies that are distinct from previously characterised viral amyloids M45 and ORF20. Formation of viral-host heteromeric amyloid assemblies may underlie a general mechanism of viral adaptation against host immune machineries.
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Affiliation(s)
- Nirukshan Shanmugam
- Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia
| | - Max O D G Baker
- Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia
| | - Maximo Sanz-Hernandez
- Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ London, United Kingdom
| | - Emma Sierecki
- EMBL Australia Node in Single Molecule Science, School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia
| | - Yann Gambin
- EMBL Australia Node in Single Molecule Science, School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia
| | - Megan Steain
- Immunology and Infectious Diseases, School of Medical Sciences, University of Sydney, NSW 2006, Australia
| | - Chi L L Pham
- Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia
| | - Margaret Sunde
- Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
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Protective effect of necrosulfonamide on rat pulmonary ischemia-reperfusion injury via inhibition of necroptosis. J Thorac Cardiovasc Surg 2021; 163:e113-e122. [PMID: 33612303 DOI: 10.1016/j.jtcvs.2021.01.037] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/22/2020] [Accepted: 01/10/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Necroptosis plays an important role in cell death during pulmonary ischemia-reperfusion injury (IRI). We hypothesized that therapy with necrosulfonamide (NSA), a mixed-lineage kinase domain-like protein inhibitor, would attenuate lung IRI. METHODS Rats were assigned at random into the sham operation group (n = 6), vehicle group (n = 8), or NSA group (n = 8). In the NSA and vehicle groups, the animals were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes, followed by reperfusion for 120 minutes. NSA (0.5 mg/body) and a solvent were administered i.p. in the NSA group and the vehicle group, respectively. The sham group underwent 210 minutes of perfusion without ischemia. After reperfusion, arterial blood gas analysis, physiologic data, lung wet-to-dry weight ratio, histologic changes, and cytokine levels were assessed. Fluorescence double immunostaining was performed to evaluate necroptosis and apoptosis. RESULTS Arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) was better, dynamic compliance was higher, and mean airway pressure and lung edema were lower in the NSA group compared with the vehicle group. Moreover, in the NSA group, lung injury was significantly alleviated, and the mean number of necroptotic cells (55.3 ± 4.06 vs 78.2 ± 6.87; P = .024), but not of apoptotic cells (P = .084), was significantly reduced compared with the vehicle group. Interleukin (IL)-1β and IL-6 levels were significantly lower with NSA administration. CONCLUSIONS In a rat model, our results suggest that NSA may have a potential protective role in lung IRI through the inhibition of necroptosis.
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Cardiac Shock Wave Therapy Alleviates Hypoxia/Reoxygenation-Induced Myocardial Necroptosis by Modulating Autophagy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8880179. [PMID: 33532500 PMCID: PMC7837773 DOI: 10.1155/2021/8880179] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 12/15/2020] [Accepted: 12/24/2020] [Indexed: 12/25/2022]
Abstract
Regulated necrosis (necroptosis) is crucially involved in cardiac ischaemia-reperfusion injury (MIRI). The aim of our study is to investigate whether shock wave therapy (SWT) is capable of exerting protective effects by inhibiting necroptosis during myocardial ischaemia-reperfusion (I/R) injury and the possible role of autophagy in this process. We established a hypoxia/reoxygenation (H/R) model in vitro using HL-1 cells to simulate MIRI. MTS assays and LDH cytotoxicity assay were performed to measure cell viability and cell damage. Annexin V/PI staining was used to determine apoptosis and necrosis. Western blotting was performed to assess the changes in cell signaling pathways associated with autophagy, necroptosis, and apoptosis. Reactive oxygen species (ROS) production was detected using DHE staining. Autophagosome generation and degradation (autophagic flux) were analysed using GFP and RFP tandemly tagged LC3 (tfLC3). HL-1 cells were then transfected with p62/SQSTM1 siRNA in order to analyse its role in cardioprotection. Our results revealed that SWT increased cell viability in the H/R model and decreased receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 expression. ROS production was also inhibited by SWT. Moreover, SWT decreased Beclin1 expression and the ratio of LC3-II/LC3-I following H/R. Simultaneously, in the tfLC3 assay, the SWT provoked a decrease in the cumulative autophagosome abundance. siRNA-mediated knockdown of p62 attenuated H/R-induced necroptosis, and SWT did not exert additive effects. Taken together, SWT ameliorated H/R injury by inhibiting necroptosis. SWT also relieved the blockade of autophagic flux in response to H/R injury. The restoration of autophagic flux by SWT might contribute to its cardioprotective effect on necroptosis following H/R injury.
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Abstract
Necroptosis is a noncaspase-dependent and precisely regulated mechanism of cell death. Necroptosis is mainly initiated by members of the tumor necrosis factor receptor (TNFR) and Toll-like receptor (TLR) families, interferon, intracellular RNA and DNA sensors and other mediators. Subsequently, the protein kinase RIPK1 (receptor-interacting protein kinase 1) and RIPK3 interact with the receptor protein, which transduces death signals and further recruits and phosphorylates MLKL (mixed lineage kinase domain-like protein). MLKL serves as the initiator of cell death and eventually induces necroptosis. It was found that necroptosis is not only involved in the physiological regulation but also in the occurrence, development and prognosis of some necrotic diseases, especially infectious diseases. Intervention in the necroptosis signaling pathway is helpful for removing pathogens, inhibiting the development of lesions, and promoting the remodeling of tissue. In-depth study of the molecular regulation mechanism of necroptosis and its relationship with the pathogenesis of infectious diseases will help to provide new ideas and directions for research of the pathological mechanisms and clinical prevention of infectious diseases.
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Affiliation(s)
- Xiaojing Xia
- Post-Doctoral Research Station, Henan Agriculture University, No. 63, Nonye Road, Zhengzhou, 450002, People's Republic of China.,College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, 453003, People's Republic of China.,Postdoctoral Research Base, Henan Institute of Science and Technology, No. 90, Hualan Street, Xinxiang, 453003, Henan, People's Republic of China
| | - Liancheng Lei
- College of Veterinary Medicine, Jilin University, Changchun, 130062, People's Republic of China
| | - Song Wang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, 453003, People's Republic of China.,Postdoctoral Research Base, Henan Institute of Science and Technology, No. 90, Hualan Street, Xinxiang, 453003, Henan, People's Republic of China
| | - Jianhe Hu
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, 453003, People's Republic of China. .,Postdoctoral Research Base, Henan Institute of Science and Technology, No. 90, Hualan Street, Xinxiang, 453003, Henan, People's Republic of China.
| | - Gaiping Zhang
- Post-Doctoral Research Station, Henan Agriculture University, No. 63, Nonye Road, Zhengzhou, 450002, People's Republic of China.
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