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Huynh QDT, Phan TTT, Liu TW, Duong TLT, Hsu SJ, Kuo CC, Chu MH, Wang YH, Nguyen TV, Shen YA, Fan YJ, Nguyen DK, Vo TH, Lee CK. Cytotoxicity-guided isolation of elatostemanosides I-VI from Elatostema tenuicaudatum W. T. Wang and their cytotoxic activities. RSC Adv 2025; 15:10639-10652. [PMID: 40190632 PMCID: PMC11970508 DOI: 10.1039/d4ra09007a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 03/09/2025] [Indexed: 04/09/2025] Open
Abstract
Elatostema tenuicaudatum W. T. Wang, a medicinal plant traditionally utilized in herbal remedies, was explored for its cytotoxic properties. Bioassay-guided fractionation led to the discovery of six novel compounds, designated as elatostemanosides I-VI, with their structures elucidated through advanced spectroscopic methods and DP4+ analysis. Among these, compounds 2, 5, and 6 demonstrated moderate cytotoxicity against the human liver cancer cell line HepG2, exhibiting IC50 values of 18.2 ± 2.1, 32.1 ± 0.4, and 57.6 ± 1.3 µM, respectively. Notably, compound 6 also displayed significant activity against the human breast cancer cell line HCC1806, with an IC50 value of 35.4 ± 0.3 µM. Mechanistic studies revealed these compounds induced apoptosis by modulating the Bax/Bcl-2 ratio. Furthermore, structure-activity relationship (SAR) analysis underscored the importance of specific functional groups in mediating cytotoxic effects.
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Affiliation(s)
- Quoc-Dung Tran Huynh
- Ph. D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University Taipei 11031 Taiwan
- Institute of Pharmaceutical Education and Research, Binh Duong University Thu Dau Mot 820000 Binh Duong Vietnam
| | - Thuy-Tien Thi Phan
- Institute of Pharmaceutical Education and Research, Binh Duong University Thu Dau Mot 820000 Binh Duong Vietnam
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University Taipei 11031 Taiwan
| | - Ta-Wei Liu
- School of Pharmacy, College of Pharmacy, Taipei Medical University Taipei 11042 Taiwan
| | - Truc-Ly Thi Duong
- Faculty of Traditional Medicine, Can Tho University of Medicine and Pharmacy Can Tho 900000 Vietnam
| | - Su-Jung Hsu
- School of Pharmacy, College of Pharmacy, Taipei Medical University Taipei 11042 Taiwan
- Institute of Fisheries Science, National Taiwan University Taipei 106 Taiwan
| | - Ching-Chuan Kuo
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes Miaoli County 35053 Taiwan
| | - Man-Hsiu Chu
- School of Pharmacy, College of Pharmacy, Taipei Medical University Taipei 11042 Taiwan
| | - Yun-Han Wang
- Ph. D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University Taipei 11031 Taiwan
| | - Thanh-Vu Nguyen
- Biotechnology Center of Ho Chi Minh City Ho Chi Minh City 700000 Vietnam
| | - Yao-An Shen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University Taipei 110301 Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University Taipei 110301 Taiwan
- International Master/Ph. D. Program in Medicine, College of Medicine, Taipei Medical University Taipei 110301 Taiwan
| | - Yu-Jui Fan
- School of Biomedical Engineering, Taipei Medical University Taipei 11031 Taiwan
- International PhD Program for Biomedical Engineering, Taipei Medical University Taipei 110301 Taiwan
| | - Dang-Khoa Nguyen
- Faculty of Pharmacy, Ton Duc Thang University Ho Chi Minh 700000 Vietnam
| | - Thanh-Hoa Vo
- University of Health Sciences, Vietnam National University Ho Chi Minh City Ho Chi Minh 700000 Vietnam
- Center for Discovery and Development of Healthcare Product, Vietnam National University Ho Chi Minh City Ho Chi Minh 700000 Vietnam
| | - Ching-Kuo Lee
- Ph. D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University Taipei 11031 Taiwan
- School of Pharmacy, College of Pharmacy, Taipei Medical University Taipei 11042 Taiwan
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University Taipei 11042 Taiwan
- Department of Chemistry, Chung Yuan Christian University Zhongli District Taoyuan 32023 Taiwan
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Yao K, Shi Z, Zhao F, Tan C, Zhang Y, Fan H, Wang Y, Li X, Kong J, Wang Q, Li D. RIPK1 in necroptosis and recent progress in related pharmaceutics. Front Immunol 2025; 16:1480027. [PMID: 40007541 PMCID: PMC11850271 DOI: 10.3389/fimmu.2025.1480027] [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: 08/22/2024] [Accepted: 01/10/2025] [Indexed: 02/27/2025] Open
Abstract
Necroptosis is a programmed form of cell death. Receptor-interacting serine/threonine protein kinase l (RIPK1) is a crucial protein kinase that regulates the necroptosis pathway. Increased expression of death receptor family ligands such as tumor necrosis factor (TNF) increases the susceptibility of cells to apoptosis and necroptosis. RIPK1, RIPK3, and mixed-lineage kinase-like domain (MLKL) proteins mediate necrosis. RIPK1-mediated necroptosis further promotes cell death and inflammation in the pathogenesis of liver injury, skin diseases, and neurodegenerative diseases. The N-terminal kinase domain of RIPK1 is significant in the induction of cell death and can be used as a vital drug target for inhibitors. In this paper, we outline the pathways of necroptosis and the role RIPK1 plays in them and suggest that targeting RIPK1 in therapy may help to inhibit multiple cell death pathways.
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Affiliation(s)
- Kunhou Yao
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Zhihao Shi
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Fengya Zhao
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Cong Tan
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Yixin Zhang
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Hao Fan
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Yingzhe Wang
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Xingwang Li
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Jun Kong
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Qun Wang
- School of Basic Medicine, Henan University, Kaifeng, China
| | - Dingxi Li
- Department of Gynaecology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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Tu X, Zou Z, Li J, Zeng S, Luo Z, Li G, Gao Y, Zhang K. Artificial intelligence-enabled discovery of a RIPK3 inhibitor with neuroprotective effects in an acute glaucoma mouse model. Chin Med J (Engl) 2025; 138:172-184. [PMID: 39719694 PMCID: PMC11745860 DOI: 10.1097/cm9.0000000000003387] [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: 05/18/2024] [Indexed: 12/26/2024] Open
Abstract
BACKGROUND Retinal ganglion cell (RGC) death caused by acute ocular hypertension is an important characteristic of acute glaucoma. Receptor-interacting protein kinase 3 (RIPK3) that mediates necroptosis is a potential therapeutic target for RGC death. However, the current understanding of the targeting agents and mechanisms of RIPK3 in the treatment of glaucoma remains limited. Notably, artificial intelligence (AI) technologies have significantly advanced drug discovery. This study aimed to discover RIPK3 inhibitor with AI assistance. METHODS An acute ocular hypertension model was used to simulate pathological ocular hypertension in vivo . We employed a series of AI methods, including large language and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining) in vitro and in vivo . RESULTS AI-driven drug screening techniques have the potential to greatly accelerate drug development. A compound called HG9-91-01, identified using AI methods, exerted neuroprotective effects in acute glaucoma. Our research indicates that all five candidates recommended by AI were able to protect the morphological integrity of RGC cells when exposed to hypoxia and glucose deficiency, and HG9-91-01 showed a higher cell survival rate compared to the other candidates. Furthermore, HG9-91-01 was found to protect the retinal structure and reduce the loss of retinal layers in an acute glaucoma model. It was also observed that the neuroprotective effects of HG9-91-01 were highly correlated with the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis). Finally, we found that HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis. CONCLUSION AI-enabled drug discovery revealed that HG9-91-01 could serve as a potential treatment for acute glaucoma.
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Affiliation(s)
- Xing Tu
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510530, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510623, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zixing Zou
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510530, China
| | - Jiahui Li
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510530, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510623, China
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China
| | - Simiao Zeng
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510530, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510623, China
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China
| | - Zhengchao Luo
- Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Beijing 100871, China
| | - Gen Li
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China
| | - Yuanxu Gao
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510530, China
- Institute for Artificial Intelligence in Medicine and Faculty of Medicine, Macau University of Science and Technology, Macao Special Administrative Region 999078, China
| | - Kang Zhang
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong 510530, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510623, China
- Institute for Artificial Intelligence in Medicine and Faculty of Medicine, Macau University of Science and Technology, Macao Special Administrative Region 999078, 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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Lin W, Xue R, Ueki H, Huang P. The Necroptotic Process-related Signature Predicts Immune Infiltration and Drug Sensitivity in Kidney Renal Papillary Cell Carcinoma. Curr Cancer Drug Targets 2025; 25:244-256. [PMID: 38616744 DOI: 10.2174/0115680096286503240321040556] [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: 11/10/2023] [Revised: 03/03/2024] [Accepted: 03/12/2024] [Indexed: 04/16/2024]
Abstract
BACKGROUND It remains controversial whether the current subtypes of kidney renal papillary cell carcinoma (KIRP) can be used to predict the prognosis independently. OBJECTIVE This observational study aimed to identify a risk signature based on necroptotic process- related genes (NPRGs) in KIRP. METHODS In the training cohort, LASSO regression was applied to construct the risk signature from 158 NPRGs, followed by the analysis of Overall Survival (OS) using the Kaplan-Meier method. The signature accuracy was evaluated by the Receiver Operating Characteristic (ROC) curve, which was further validated by the test cohort. Wilcoxon test was used to compare the expressions of immune-related genes, neoantigen genes, and immune infiltration between different risk groups, while the correlation test was performed between NPRGs expressions and drug sensitivity. Gene set enrichment analysis was used to investigate the NPRGs' signature's biological functions. RESULTS We finally screened out 4-NPRGs (BIRC3, CAMK2B, PYGM, and TRADD) for constructing the risk signature with the area under the ROC curve (AUC) reaching about 0.8. The risk score could be used as an independent OS predictor. Consistent with the enriched signaling, the NPRGs signature was found to be closely associated with neoantigen, immune cell infiltration, and immune-related functions. Based on NPRGs expressions, we also predicted multiple drugs potentially sensitive or resistant to treatment. CONCLUSION The novel 4-NPRGs risk signature can predict the prognosis, immune infiltration, and therapeutic sensitivity of KIRP.
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Affiliation(s)
- Wenfeng Lin
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Department of Urology, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Ruizhi Xue
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Hideo Ueki
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Peng Huang
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Neutron Therapy Research Center (NTRC), Okayama University, Okayama, Japan
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Hu R, Liu Z, Hou H, Li J, Yang M, Feng P, Wang X, Xu D. Identification of key necroptosis-related genes and immune landscape in patients with immunoglobulin A nephropathy. BMC Nephrol 2024; 25:459. [PMID: 39696012 PMCID: PMC11653910 DOI: 10.1186/s12882-024-03885-4] [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: 04/01/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is a major cause of chronic kidney disease (CKD) and kidney failure. Necroptosis is a novel type of programmed cell death that has been proved to be associated with the pathogenesis of infectious disease, cardiovascular disease, neurological disorders and so on. However, the role of necroptosis in IgAN remains unclear. METHODS In this study, we explored the role of necroptosis-related genes in the pathogenesis of IgAN using a comprehensive bioinformatics method. Microarray datasets GSE93798 and GSE115857 were downloaded from Gene Expression Omnibus (GEO). "limma" package of R software was employed to identify necroptosis-related differentially expressed genes (NRDEGs) between IgAN and healthy controls. GO and KEGG functional enrichment analysis was performed by Clusterprofiler. Least absolute shrinkage and selection operator (LASSO) regression analysis identified hub NRDEGs. We further established a diagnostic model consisting of 7 diagnostic hub NRDEGs and validated the efficacy by an external dataset. The expression of hub genes was confirmed in sc-RNA dataset GSE171314. Immune infiltration, gene set enrichment analysis and transcription factor binding motifs enrichment analysis were conducted to further uncover their roles. RESULTS 1076 differentially expressed genes were identified between healthy individuals and IgAN patients from RNA-seq dataset GSE9379. Then we cross-linked them with necroptosis-related genes to obtain 9 NRDEGs. LASSO regression analysis screened out 7 hub genes (JUN, CD274, SERTAD1, NFKBIA, H19, UCHL1 and EZH2) of IgAN. We further conducted functional enrichment analysis and constructed the diagnostic model based on dataset GSE93798. GSE115857 was used as the independent validation cohort and indicated a great predictive efficacy. Immune infiltration, gene set enrichment analysis and transcription factor binding motifs enrichment analysis revealed their potential function. Finally, we screened out four drugs that were predicted to have therapeutic value of IgAN. CONCLUSIONS In summary, we identified 7 hub necroptosis-associated genes, which can be used as potential genetic biomarkers for IgAN prediction and treatment. Four drugs were predicted as the potential therapeutic solutions. Collectively, we provided insights into the necroptosis-related mechanisms and treatment of IgAN at the transcriptome level.
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Affiliation(s)
- Ruikun Hu
- Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Ziyu Liu
- Department of Nephrology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Huihui Hou
- Department of Nephrology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Jingyu Li
- School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Ming Yang
- Department of Nephrology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Panfeng Feng
- Department of Pharmacy, The First People's Hospital of Nantong city, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, 226001, China.
| | - Xiaorong Wang
- Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
| | - Dechao Xu
- Department of Nephrology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
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Ozgen ZE, Erdinc M, Kaya MS, Aktar F, Ozekinci SO, Erdinc L, Uyar E. Involvement of necroptosıs and apoptosıs ın protectıve effects of cyclosporın a on ischemıa-reperfusıon injury in rat kıdney. J Mol Histol 2024; 56:30. [PMID: 39630315 DOI: 10.1007/s10735-024-10281-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 11/06/2024] [Indexed: 02/07/2025]
Abstract
We aimed to investigate the protective effects of low dose cyclosporin A (CsA) on ischemia-reperfusion (IR) injury in rat the kidney and on the apoptotic and necroptotic mechanisms involved. 1. Control group (received a single intraperitoneal (i.p.) dose of 1 ml sterile saline 15 min before the surgical procedure), 2. IR group (was subjected to 30 min of bilateral kidney ischemia followed by 90 min of reperfusion; and received a single i.p. dose of 1 ml sterile saline 15 min before the IR procedure, 3. IR + CsA group (received a single i.p. dose of 3 mg/kg CsA 15 min before the IR procedure. Renal functions (renal perfusion pressures, and serum urea-creatinine levels), kidney histological scores, MDA levels, and TNF-α, caspase-3, RIP1, RIP3, MLKL, CaMKII and CypD protein expressions were also measured. Renal perfusion pressures (PP), serum urea and creatinine levels, renal tissue MDA levels, and the protein expression levels of TNF-α, caspase-3, RIP1, RIP3, MLKL, CAMKII and CypD were significantly increased in the IR group compared to the control group (p < 0.05), Additionally, there were significant decreases in all the parameters in the IR + CsA group compared to those in the IR group (p < 0.05). Furthermore, histopathological analyses revealed significantly higher kidney injury scores in the IR group compared to the control group, and low dose CsA treatment improved the injury. A single low dose of CsA injection 15 min before IR, demonstrated a protective effect on bilateral renal IR injury and a reduction in apoptotic and necroptopic markers which is resulted in improvement of renal functions.
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Affiliation(s)
- Zeynep Erdogmus Ozgen
- Department of Pharmacology, School of Pharmacy, Dicle University, Diyarbakir, Turkey.
| | - Meral Erdinc
- Department of Pharmacology, School of Medicine, Dicle University, Diyarbakir, Turkey
| | - Meryem Seyda Kaya
- Department of Pharmacology, School of Pharmacy, Dicle University, Diyarbakir, Turkey
| | - Fesih Aktar
- Department of Pediatrics, School of Medicine, Dicle University, Diyarbakir, Turkey
| | | | - Levent Erdinc
- Department of Biochemistry, School of Medicine, Dicle University, Diyarbakir, Turkey
| | - Emre Uyar
- Department of Pharmacology, School of Medicine, Uskudar University, Istanbul, Turkey
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Johnson CF, Schafer CM, Burge KY, Coon BG, Chaaban H, Griffin CT. Endothelial RIPK3 minimizes organotypic inflammation and vascular permeability in ischemia-reperfusion injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.25.625188. [PMID: 39651150 PMCID: PMC11623548 DOI: 10.1101/2024.11.25.625188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Recent studies have revealed a link between endothelial receptor-interacting protein kinase 3 (RIPK3) and vascular integrity. During mouse embryonic development, hypoxia can trigger elevated endothelial RIPK3 that contributes to lethal vascular rupture. However, it is unknown whether RIPK3 regulate endothelial barrier function in adult vasculature under hypoxic injury conditions such as ischemia-reperfusion (I/R) injury. Here we performed inducible genetic deletion of endothelial Ripk3 ( Ripk iECKO ) in mice, which led to elevated vascular permeability in the small intestine and multiple distal organs after intestinal I/R injury. Mechanistically, this vascular permeability correlated with increased endothelial secretion of IL-6 and organ-specific expression of VCAM-1 and ICAM-1 adhesion molecules. Circulating monocyte depletion with clodronate liposomes reduced permeability in organs with elevated adhesion molecules, highlighting the contribution of monocyte adhesion and extravasation to Ripk iECKO barrier dysfunction. These results elucidate mechanisms by which RIPK3 regulates endothelial inflammation to minimize vascular permeability in I/R injury. GRAPHICAL ABSTRACT
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Lee GE, Bang G, Byun J, Chen W, Jeung D, Cho H, Lee JY, Kang HC, Lee HS, Kim JY, Kim KD, Wu J, Nam SB, Kwon YJ, Lee CJ, Cho YY. SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death. Cell Mol Life Sci 2024; 81:451. [PMID: 39540935 PMCID: PMC11564579 DOI: 10.1007/s00018-024-05487-7] [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: 06/20/2024] [Revised: 09/27/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3. Two distinct degron motifs, PETST and SPTST, were identified within the linker domain of RIPK3 for SPOP. RIPK3 phosphorylations at Thr403 by PIM2 and at Thr412/Ser413 by ERK2 are essential to facilitate its interaction with SPOP. Computational docking studies and immunoprecipitation analyses showed that these PIM2 and ERK2 phosphorylations bolster the stability of the RIPK3-SPOP interaction. In particular, mutations of RIPK3 at the degron motifs extended the half-life of RIPK3 by preventing its phosphorylation and subsequent ubiquitination. The deletion of SPOP, which led to increased stability of the RIPK3 protein, intensified LPS/sMAC/zVAD-induced necroptotic cell death in colon cancer cells. These findings underscore the critical role of the SPOP-mediated RIPK3 stability regulation pathway in controlling necroptotic cell death.
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Affiliation(s)
- Ga-Eun Lee
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
- Biopharmaceutical Research Center, Ochang Institute of Biological and Environmental Sciences, Korea Basic Science Institute, 162, Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, 28119, Republic of Korea
| | - Geul Bang
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, Cheongju-si, Chungbuk, 28119, Republic of Korea
| | - Jiin Byun
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
| | - Weidong Chen
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
| | - Dohyun Jeung
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
| | - Hana Cho
- College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Joo Young Lee
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
- Research Institute for Controls and Materials of Regulated Cell Death, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Han Chang Kang
- College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
- Research Institute for Controls and Materials of Regulated Cell Death, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Hye Suk Lee
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
- Research Institute for Controls and Materials of Regulated Cell Death, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Jin Young Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, Cheongju-si, Chungbuk, 28119, Republic of Korea
| | - Kwang Dong Kim
- BK21-Four, Division of Applied Life Science, Gyeongsang National University, 501, Jinju-daero, Jinju- si, Gyeongsangnam-do, 52828, Republic of Korea
| | - Juan Wu
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
| | - Soo-Bin Nam
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea
- Biopharmaceutical Research Center, Ochang Institute of Biological and Environmental Sciences, Korea Basic Science Institute, 162, Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, 28119, Republic of Korea
| | - Young Jik Kwon
- Department of Pharmaceutical Sciences, University of California, 132, Sprague Hall, Irvine, CA, 92697, USA
| | - Cheol-Jung Lee
- Biopharmaceutical Research Center, Ochang Institute of Biological and Environmental Sciences, Korea Basic Science Institute, 162, Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, 28119, Republic of Korea.
| | - Yong-Yeon Cho
- BK21-4th, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon- si, Gyeonggi-do, 14662, Republic of Korea.
- Research Institute for Controls and Materials of Regulated Cell Death, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
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Tsai YF, Chen CH, Wu YM, Hung CL, Fang MC, Yu IS, Sheu JC, Hsu YC, Lin SW. Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation. Cell Biol Toxicol 2024; 40:80. [PMID: 39292286 PMCID: PMC11410999 DOI: 10.1007/s10565-024-09915-z] [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: 05/16/2024] [Accepted: 09/04/2024] [Indexed: 09/19/2024]
Abstract
Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.
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Affiliation(s)
- Yu-Fei Tsai
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chien-Hung Chen
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yao-Ming Wu
- Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chia-Lu Hung
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mo-Chu Fang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - I-Shing Yu
- Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jin-Chuan Sheu
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
| | - Yu-Chen Hsu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan.
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
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11
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Mazziotti V, Crescenzo F, Turano E, Guandalini M, Bertolazzo M, Ziccardi S, Virla F, Camera V, Marastoni D, Tamanti A, Calabrese M. The contribution of tumor necrosis factor to multiple sclerosis: a possible role in progression independent of relapse? J Neuroinflammation 2024; 21:209. [PMID: 39169320 PMCID: PMC11340196 DOI: 10.1186/s12974-024-03193-6] [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: 06/07/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024] Open
Abstract
Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.
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Affiliation(s)
- Valentina Mazziotti
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Francesco Crescenzo
- Neurology Unit - Multiple Sclerosis Center, Scaligera Local Unit of Health and Social Services 9, Mater Salutis Hospital, 37045, Legnago, Verona, Italy
| | - Ermanna Turano
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Maddalena Guandalini
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Maddalena Bertolazzo
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Stefano Ziccardi
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Federica Virla
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Valentina Camera
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Damiano Marastoni
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Agnese Tamanti
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Massimiliano Calabrese
- Neurology B Unit - Multiple Sclerosis Center, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy.
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Lyu P, Wen J, Zhang W, Liu N, Stolzer I, Gießl A, Jia Y, Mauro D, Zhang F, Ciccia F, Soulat D, Günther C, Schett G, Bozec A. Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery. Ann Rheum Dis 2024; 83:984-997. [PMID: 38503474 PMCID: PMC11287550 DOI: 10.1136/ard-2023-224491] [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: 06/06/2023] [Accepted: 02/28/2024] [Indexed: 03/21/2024]
Abstract
OBJECTIVES To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis. METHODS IEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α (Hif1a) in IECs (Hif1a ∆IEC) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1a ∆IEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA. RESULTS IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal necroptosis in vitro and in vivo and suppressed the development of arthritis. CONCLUSION Our results identify IEC necroptosis as a critical link between the gut and the development of arthritis.
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Affiliation(s)
- Pang Lyu
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jinming Wen
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wenshuo Zhang
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ning Liu
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Iris Stolzer
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Internal Medicine 1, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
| | - Andreas Gießl
- Department of Opthalmology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Yewei Jia
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Daniele Mauro
- Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Fulin Zhang
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Francesco Ciccia
- Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Didier Soulat
- Microbiology Institute, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Claudia Günther
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Internal Medicine 1, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
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Liu Y, Jia F, Li K, Liang C, Lin X, Geng W, Li Y. Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation. Front Pharmacol 2024; 15:1419494. [PMID: 39055494 PMCID: PMC11269110 DOI: 10.3389/fphar.2024.1419494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 06/14/2024] [Indexed: 07/27/2024] Open
Abstract
The mechanical stress environment in the temporomandibular joint (TMJ) is constantly changing due to daily mandibular movements. Therefore, TMJ tissues, such as condylar cartilage, the synovial membrane and discs, are influenced by different magnitudes of mechanical stimulation. Moderate mechanical stimulation is beneficial for maintaining homeostasis, whereas abnormal mechanical stimulation leads to degeneration and ultimately contributes to the development of temporomandibular joint osteoarthritis (TMJOA), which involves changes in critical signaling molecules. Under abnormal mechanical stimulation, compensatory molecules may prevent degenerative changes while decompensatory molecules aggravate. In this review, we summarize the critical signaling molecules that are stimulated by moderate or abnormal mechanical loading in TMJ tissues, mainly in condylar cartilage. Furthermore, we classify abnormal mechanical stimulation-induced molecules into compensatory or decompensatory molecules. Our aim is to understand the pathophysiological mechanism of TMJ dysfunction more deeply in the ever-changing mechanical environment, and then provide new ideas for discovering effective diagnostic and therapeutic targets in TMJOA.
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Affiliation(s)
| | | | | | | | | | - Wei Geng
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Yanxi Li
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
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Bak S, Kim KS, Na K. Human adipose-derived stem cells genetically programmed to induce necroptosis for cancer immunotherapy. Cancer Gene Ther 2024; 31:995-1006. [PMID: 38858535 DOI: 10.1038/s41417-024-00794-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/12/2024]
Abstract
Herein, we present human adipose-derived stem cells (ADSCs) inserted with the receptor-interacting protein kinase-3 (RIP3) gene (RP@ADSCs), which induces cell necroptosis, for tumor immunotherapy. Necroptosis has characteristics of both apoptosis, such as programmed cell death, and necrosis, such as swelling and plasma membrane rupture, during which damage-related molecular patterns are released, triggering an immune response. Therefore, necroptosis has the potential to be used as an effective anticancer immunotherapy. RP@ADSCs were programmed to necroptosis after a particular time after being injected in vivo, and various pro-inflammatory cytokines secreted during the stem cell death process stimulated the immune system, showing local and sustained anticancer effects. It was confirmed that RIP3 protein expression increased in ADSCs after RP transfection. RP@ADSCs continued to induce ADSCs death for 7 days, and various pro-inflammatory cytokines were secreted through ADSCs death. The efficacy of RP@ADSCs-mediated immunotherapy was evaluated in mouse models bearing GL-26 (glioblastoma) and K1735 (melanoma), and it was found that RP resulted in an increase in the population of long-term cytotoxic T cells and a decrease in the population of regulatory T cells. This shows that RP@ADSCs have potential and applicability as an excellent anticancer immunotherapy agent in clinical practice.
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Affiliation(s)
- Soyeon Bak
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Kyoung Sub Kim
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Kun Na
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
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15
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Hou C, Fei S, Jia F. Necroptosis and immune infiltration in hypertrophic cardiomyopathy: novel insights from bioinformatics analyses. Front Cardiovasc Med 2024; 11:1293786. [PMID: 38947229 PMCID: PMC11211569 DOI: 10.3389/fcvm.2024.1293786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 05/23/2024] [Indexed: 07/02/2024] Open
Abstract
Background Hypertrophic Cardiomyopathy (HCM), a widespread genetic heart disorder, is largely associated with sudden cardiac fatality. Necroptosis, an emerging type of programmed cell death, plays a fundamental role in several cardiovascular diseases. Aim This research utilized bioinformatics analysis to investigate necroptosis's implication in HCM. Methods The study retrieved RNA sequencing datasets GSE130036 and GSE141910 from the Gene Expression Omnibus (GEO) database. It detected necroptosis-linked differentially expressed genes (NRDEGs) by reviewing both the gene set for necroptosis and the differently expressed genes (DEGs). The enriched signaling pathway of HCM was assessed using GSEA, while common DEGs were studied through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Concurrently, the Protein-Protein Interaction network (PPI) proved useful for identifying central genes. CIBERSORT facilitated evaluating the correlation between distinct immune cell-type prevalence and NRDEGs by analyzing immune infiltration patterns. Lastly, GSE141910 dataset validated the expression ranks of NRDEGs and immune-cell penetration. Results The investigation disclosed significant enrichment and activation of the necroptosis pathway in HCM specimens. Seventeen diverse genes, including CYBB, BCL2, and JAK2 among others, were identified in the process. PPI network scrutiny classified nine of these genes as central genes. Results from GO and KEGG enrichment analyses showed substantial connections of these genes to pathways pertaining to the HIF-1 signaling track, necroptosis, and NOD-like receptor signaling process. Moreover, an imbalance in M2 macrophage cells in HCM samples was observed. Finally, CYBB, BCL2, and JAK2 emerged as vital genes and were validated using the GSE141910 dataset. Conclusion These results indicate necroptosis as a probable underlying factor in HCM, with immune cell infiltration playing a part. Additionally, CYBB, BCL2, JAK2 could act as potential biomarkers for recognizing HCM. This information forms crucial insights into the basic mechanisms of HCM and could enhance its diagnosis and management.
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Affiliation(s)
| | | | - Fang Jia
- Department of Cardiovascular Medicine, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
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16
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Yang L, Ruan Y, Xu H. HIST3H2A promotes the progression of prostate cancer through inhibiting cell necroptosis. BMC Cancer 2024; 24:544. [PMID: 38684944 PMCID: PMC11059659 DOI: 10.1186/s12885-024-12308-4] [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: 10/24/2023] [Accepted: 04/24/2024] [Indexed: 05/02/2024] Open
Abstract
In recent years, there has been an increase in the incidence and mortality rates of prostate cancer (PCa). However, the specific molecular mechanisms underlying its occurrence and development remain unclear, necessitating the identification of new therapeutic targets. Through bioinformatics analysis, we discovered a previously unstudied differential gene called HIST3H2A in prostate cancer. Our study revealed that HIST3H2A is highly expressed in PCa tissues, as confirmed by analysis of both the GEO and UALCAN databases. Further analysis using the KEGG database demonstrated that HIST3H2A regulates the pathway of programmed necroptosis in cells. Additionally, we observed significant up-regulation of HIST3H2A in PCa tissues and cell lines. HIST3H2A was found to regulate cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process in tumors. Notably, HIST3H2A's role in regulating programmed necroptosis in prostate cancer cells differs from its role in apoptosis. In vitro and in vivo experiments collectively support the key role of HIST3H2A in promoting the development of prostate cancer, highlighting its potential as a therapeutic target for patients with PCa.
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Affiliation(s)
- Lihong Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Life Sciences, Guizhou University, Guiyang, 550025, China
| | - Yong Ruan
- College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Houqiang Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Life Sciences, Guizhou University, Guiyang, 550025, China.
- College of Animal Science, Guizhou University, Guiyang, 550025, China.
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17
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Zhou Y, Xiang Y, Liu S, Li C, Dong J, Kong X, Ji X, Cheng X, Zhang L. RIPK3 signaling and its role in regulated cell death and diseases. Cell Death Discov 2024; 10:200. [PMID: 38684668 PMCID: PMC11059363 DOI: 10.1038/s41420-024-01957-w] [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: 11/10/2023] [Revised: 04/09/2024] [Accepted: 04/11/2024] [Indexed: 05/02/2024] Open
Abstract
Receptor-interacting protein kinase 3 (RIPK3), a member of the receptor-interacting protein kinase (RIPK) family with serine/threonine protein kinase activity, interacts with RIPK1 to generate necrosomes, which trigger caspase-independent programmed necrosis. As a vital component of necrosomes, RIPK3 plays an indispensable role in necroptosis, which is crucial for human life and health. In addition, RIPK3 participates in the pathological process of several infections, aseptic inflammatory diseases, and tumors (including tumor-promoting and -suppressive activities) by regulating autophagy, cell proliferation, and the metabolism and production of chemokines/cytokines. This review summarizes the recent research progress of the regulators of the RIPK3 signaling pathway and discusses the potential role of RIPK3/necroptosis in the aetiopathogenesis of various diseases. An in-depth understanding of the mechanisms and functions of RIPK3 may facilitate the development of novel therapeutic strategies.
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Affiliation(s)
- Yaqi Zhou
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Pathology, the Second People's Hospital of Jiaozuo; The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, China
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, No. 6 Gong-Ming Rd, Mazhai Town, Erqi District, Zhengzhou, Henan, 450064, China
| | - Yaxuan Xiang
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
| | - Sijie Liu
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
| | - Chenyao Li
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
| | - Jiaheng Dong
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
| | - Xiangrui Kong
- Wushu College, Henan University, Kaifeng, 475004, China
| | - Xinying Ji
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, No. 6 Gong-Ming Rd, Mazhai Town, Erqi District, Zhengzhou, Henan, 450064, China
| | - Xiaoxia Cheng
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
| | - Lei Zhang
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
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Tan W, Zhang J, Dai F, Yang D, Gu R, Tang L, Liu H, Cheng YX. Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets. Mol Cell Biochem 2024; 479:467-486. [PMID: 37097332 DOI: 10.1007/s11010-023-04736-w] [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: 02/03/2023] [Accepted: 04/07/2023] [Indexed: 04/26/2023]
Abstract
The nuclear factor κappa B (NF-κB) signaling plays a well-known function in inflammation and regulates a wide variety of biological processes. Low-grade chronic inflammation is gradually considered to be closely related to the pathogenesis of Polycystic ovary syndrome (PCOS). In this review, we provide an overview on the involvement of NF-κB in the progression of PCOS particularly, such as hyperandrogenemia, insulin resistance, cardiovascular diseases, and endometrial dysfunction. From a clinical perspective, progressive recognition of NF-κB pathway provides opportunities for therapeutic interventions aimed at inhibiting pathway-specific mechanisms. With the accumulation of basic experimental and clinical data, NF-κB signaling pathway was recognized as a therapeutic target. Although there have been no specific small molecule NF-κB inhibitors in PCOS, a plethora of natural and synthetic compound have emerged for the pharmacologic intervention of the pathway. The traditional herbs developed for NF-κB pathway have become increasingly popular in recent years. Abundant evidence elucidated that NF-κB inhibitors can significantly improve the symptoms of PCOS. Herein, we summarized evidence relating to how NF-κB pathway is involved in the development and progression of PCOS. Furthermore, we present an in-depth overview of NF-κB inhibitors for therapy interventions of PCOS. Taken together, the NF-κB signaling may be a futuristic treatment strategy for PCOS.
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Affiliation(s)
- Wei Tan
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Jie Zhang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Fangfang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Dongyong Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Ran Gu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Lujia Tang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Hua Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
| | - Yan-Xiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
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Wang L, Zhang Y, Huang M, Yuan Y, Liu X. RIP3 in Necroptosis: Underlying Contributions to Traumatic Brain Injury. Neurochem Res 2024; 49:245-257. [PMID: 37743445 DOI: 10.1007/s11064-023-04038-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/07/2023] [Accepted: 09/20/2023] [Indexed: 09/26/2023]
Abstract
Traumatic brain injury (TBI) is a global public safety issue that poses a threat to death, characterized by high fatality rates, severe injuries and low recovery rates. There is growing evidence that necroptosis regulates the pathophysiological processes of a variety of diseases, particularly those affecting the central nervous system. Thus, moderate necroptosis inhibition may be helpful in the management of TBI. Receptor-interacting protein kinase (RIP) 3 is a key mediator in the necroptosis, and its absence helps restore the microenvironment at the injured site and improve cognitive impairment after TBI. In this report, we review different domains of RIP3, multiple analyses of necroptosis, and associations between necroptosis and TBI, RIP3, RIP1, and mixed lineage kinase domain-like. Next, we elucidate the potential involvement of RIP3 in TBI and highlight how RIP3 deficiency enhances neuronal function.
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Affiliation(s)
- Lvxia Wang
- School of Life and Environmental Sciences, Shaoxing University, Zhejiang, China
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Zhejiang, China
| | - Yong Zhang
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Zhejiang, China
| | - Min Huang
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Zhejiang, China
| | - Yiling Yuan
- Department of Biosciences, Durham University, Durham, UK
| | - Xuehong Liu
- School of Life and Environmental Sciences, Shaoxing University, Zhejiang, China.
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Zhejiang, China.
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Ma Q, Wu J, Li H, Ma X, Yin R, Bai L, Tang H, Liu N. The role of TRPV4 in programmed cell deaths. Mol Biol Rep 2024; 51:248. [PMID: 38300413 DOI: 10.1007/s11033-023-09199-2] [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: 10/01/2023] [Accepted: 12/30/2023] [Indexed: 02/02/2024]
Abstract
Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.
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Affiliation(s)
- Qingjie Ma
- Department of Anesthesiology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, China
| | - Jilin Wu
- Department of Anesthesiology, Kunming Children's Hospital, Kunming, 650034, China
| | - Huixian Li
- Department of Anesthesiology, The People's Hospital of Wenshan Zhuang and Miao Minority Autonomous Prefecture, Wenshan, 663099, China
| | - Xiaoshu Ma
- The Second Clinical Medical College of Binzhou Medical College, Binzhou, 256699, China
| | - Renwan Yin
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Liping Bai
- Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Heng Tang
- Department of Anesthesiology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, China
| | - Na Liu
- Department of Anesthesiology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, China.
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21
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Zmonarski SC, Banasik M, Żabińska M, Gołębiowski T, Zmonarska JM, Krajewska M. Toll-Like Receptor 3 mRNA Expression of Peripheral Blood Mononuclear Cells Identifies Kidney Recipients with Potential for Improved Graft Performance. Ann Transplant 2023; 28:e941266. [PMID: 38013407 PMCID: PMC10693178 DOI: 10.12659/aot.941266] [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: 05/28/2023] [Accepted: 09/12/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Toll-like receptor 3 expression is detected both on the cell membrane and in endosomes of peripheral blood mononuclear cells (PBMC). Our goal in this study was to determine to what extent a single, baseline measurement of non-stimulated PBMC TLR3-mRNA can be related to baseline GFR (b-GFR) and post-follow-up-GFR (F-up-GFR) of a kidney transplant (KT) and baseline immunosuppression. MATERIAL AND METHODS In non-stimulated PBMC we investigated averaged mRNA expression of Toll-like receptor 3. A total of 133 patients were enrolled; the median of months after KT surgery was 11.4, with median F-up at 21.3 months. A favorable course (FCF) was determined if F-up-eGFR improved. An unfavorable course (UCF) was determined if F-up-eGFR was lower at the end of the observation. RESULTS The highest TLR3-mRNA expression was at b-GFR grade 3b; it was moderately higher at b-GFR grade 3a, and marginally higher at b-GFR grades 1+2. Most of the FCF group had b-GFR grade 3b, less frequent obesity, more effective immunosuppression, and much higher TLR3-mRNA (59% of cases were in the high-TLR3 area). Both delayed graft function (DGF) and TLR3-mRNA range below the median for the entire KT cohort (low-TLR3 area) had a negative association with b-GFR. The UCF group had more frequent DGFs and obesity, less effective immunosuppression, and lower TLR3-mRNA. CONCLUSIONS In patients with GFR grade 3, high levels of TLR3-mRNA are associated with improved graft efficacy. In patients with impaired graft function, low TLR3- mRNA expression reduces the likelihood of improved renal graft function.
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Affiliation(s)
- Sławomir C. Zmonarski
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Marcelina Żabińska
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Tomasz Gołębiowski
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | | | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
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Iampietro M, Amurri L, Reynard O, Bukreyev A. Interplay of Ebola Virus With Immune Cells Leading to Their Death by Diverse Mechanisms. J Infect Dis 2023; 228:S582-S586. [PMID: 37654044 PMCID: PMC10651200 DOI: 10.1093/infdis/jiad377] [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: 06/29/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/02/2023] Open
Abstract
Inflammation and cytopenia are commonly observed during Ebola virus (EBOV) infection; however, mechanisms responsible for EBOV-induced cell death remain obscure. While apoptosis and necrosis are already identified as mechanisms of cell death induced by the virus, our study demonstrates that THP-1 monocytes and SupT1 T cells exposed to EBOV undergo pyroptosis and necroptosis, respectively, through a direct contact with EBOV, and also mediate pyroptosis or necroptosis of uninfected bystander cells via indirect effects associated with secreted soluble factors. These results emphasize novel aspects of interactions between EBOV and immune cell populations and provide a better understanding of the immunopathogenesis of EBOV disease.
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Affiliation(s)
- Mathieu Iampietro
- Department of Pathology
- Galveston National Laboratory, The University of Texas Medical Branch, Galveston
- Department of Virology, Department of Immunology, International Center for Infectiology Research, Lyon, France
| | - Lucia Amurri
- Department of Virology, Department of Immunology, International Center for Infectiology Research, Lyon, France
| | - Olivier Reynard
- Department of Virology, Department of Immunology, International Center for Infectiology Research, Lyon, France
| | - Alexander Bukreyev
- Department of Pathology
- Galveston National Laboratory, The University of Texas Medical Branch, Galveston
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston
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23
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Ye Z, Zhang N, Lei H, Yao H, Fu J, Zhang N, Xu L, Zhou G, Liu Z, Lv Y. Immunogenic necroptosis in liver diseases: mechanisms and therapeutic potential. J Mol Med (Berl) 2023; 101:1355-1363. [PMID: 37740787 DOI: 10.1007/s00109-023-02363-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 08/07/2023] [Accepted: 08/18/2023] [Indexed: 09/25/2023]
Abstract
Necroptosis has received increasing attention and is extensively studied as a recently discovered mode of cell death distinct from necrosis and apoptosis. It is a programmed cell death with a necrotic morphology that occurs in various biological processes, including inflammation, immune response, embryonic development, and metabolic abnormalities. Necroptosis is indispensable in maintaining tissue homeostasis in vivo and closely correlates with the occurrence and development of various diseases. First, we outlined the etiology of necroptosis and how it affects the onset and development of prevalent liver diseases in this review. Additionally, we reviewed the therapeutic strategy by targeting the necroptosis pathway in related liver diseases. We conclude that the necroptosis signaling pathway is critical in the physiological control of liver diseases' onset, progression, and prognosis. It will likely be used as a therapeutic target in the future. Further research is required to determine the mechanisms governing the necroptosis signaling pathway and the effector molecules.
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Affiliation(s)
- Zirui Ye
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Nana Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710049, China
| | - Hong Lei
- Shaanxi Institute for Pediatric Diseases, The Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, China
| | - Huimin Yao
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710049, China
| | - Jingya Fu
- Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Nan Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Lexuan Xu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guxiang Zhou
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Zhijun Liu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710049, China.
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710049, China.
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Ke D, Zhang Z, Liu J, Chen P, Dai Y, Sun X, Chu Y, Li L. RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications. Front Immunol 2023; 14:1274654. [PMID: 37954576 PMCID: PMC10639174 DOI: 10.3389/fimmu.2023.1274654] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 10/05/2023] [Indexed: 11/14/2023] Open
Abstract
Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.
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Affiliation(s)
- Dan Ke
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Zhen Zhang
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
- School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, China
| | - Jieting Liu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Peijian Chen
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Yucen Dai
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Xinhai Sun
- Department of Thoracic Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yanhui Chu
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Luxin Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
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Li X, Tibenda JJ, Nan Y, Huang SC, Ning N, Chen GQ, Du YH, Yang YT, Meng FD, Yuan L. MiR-204-3p overexpression inhibits gastric carcinoma cell proliferation by inhibiting the MAPK pathway and RIP1/MLK1 necroptosis pathway to promote apoptosis. World J Gastroenterol 2023; 29:4542-4556. [PMID: 37621755 PMCID: PMC10445008 DOI: 10.3748/wjg.v29.i29.4542] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 05/24/2023] [Accepted: 07/05/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is the third most frequent cause of cancer-related death, highlighting the pressing need for novel clinical treatment options. In this regard, microRNAs (miRNAs) have emerged as a promising therapeutic strategy. Studies have shown that miRNAs can regulate related signaling pathways, acting as tumor suppressors or tumor promoters. AIM To explore the effect of miR-204-3p on GC cells. METHODS We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction, followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells. CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells, and the colony formation ability of GC cells was detected by the clonal formation assay. The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry. The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells. Furthermore, the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway, necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques. RESULTS Firstly, we found that the expression of miR-204-3p in GC was low. When treated with the lentivirus overexpression vector, miR-204-3p expression significantly increased, but the lentivirus knockout vector had no significant effect on miR-204-3p. In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability, promoted cell apoptosis, blocked the cell cycle, and inhibited colony formation ability. In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice. Simultaneously, our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway, as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway. CONCLUSION MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells. Thus, miR-204-3p may represent a new potential therapeutic target for GC.
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Affiliation(s)
- Xia Li
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Ningxia Chinese Medicine Reserch Center, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Joanna J Tibenda
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Nan
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Shi-Cong Huang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Na Ning
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Guo-Qing Chen
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Hua Du
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ya-Ting Yang
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Fan-Di Meng
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ling Yuan
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Horváth C, Jarabicová I, Rajtík T, Bartošová L, Ferenczyová K, Kaločayová B, Barteková M, Szobi A, Adameová A. Analysis of Signaling Pathways of Necroptotic and Pyroptotic Cell Death in the Hearts of Rats With Type 2 Diabetes Mellitus. Physiol Res 2023; 72:S23-S29. [PMID: 37294115 DOI: 10.33549/physiolres.935020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2023] Open
Abstract
Diabetes mellitus is known to produce various cell-damaging events and thereby underlie heart dysfunction and remodeling. However, very little is known about its inflammation-associated pathomechanisms due to necrosis-like cell death. For this purpose, we aimed to investigate signaling pathways of necroptosis and pyroptosis, known to produce plasma membrane rupture with the resultant promotion of inflammation. One-year old Zucker diabetic fatty (ZDF) rats did not exhibit significant heart dysfunction as revealed by echocardiographic measurement. On the other hand, there was a decrease in heart rate due to diabetes. Immunoblotting analysis showed that the left ventricles of ZDF rats overexpress neither the main necroptotic proteins including receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase-like pseudokinase (MLKL), nor the pyroptotic regulators including NLR family pyrin domain containing 3 protein (NLRP3), caspase-1, interleukin-1 beta (IL-1beta and the N-terminal gasdermin D (GSDMD-N). On the other hand, the increased activation of the RIP3 kinase due to phosphorylation was found in such hearts. In summary, we showed for the first time that the activation of cardiac RIP3 is upregulated due to disturbances in glucose metabolism which, however, did not proceed to necrosis-like cell death. These data can indicate that the activated RIP3 might also underlie other pleiotropic, non-necroptotic signaling pathways under basal conditions.
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Affiliation(s)
- C Horváth
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic.
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Tkachenko A, Onishchenko A, Myasoedov V, Yefimova S, Havranek O. Assessing regulated cell death modalities as an efficient tool for in vitro nanotoxicity screening: a review. Nanotoxicology 2023; 17:218-248. [PMID: 37083543 DOI: 10.1080/17435390.2023.2203239] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
Abstract
Nanomedicine is a fast-growing field of nanotechnology. One of the major obstacles for a wider use of nanomaterials for medical application is the lack of standardized toxicity screening protocols for assessing the safety of newly synthesized nanomaterials. In this review, we focus on less frequently studied nanomaterials-induced regulated cell death (RCD) modalities, including eryptosis, necroptosis, pyroptosis, and ferroptosis, as a tool for in vitro nanomaterials safety evaluation. We summarize the latest insights into the mechanisms that mediate these RCDs in response to nanomaterials exposure. Comprehensive data from reviewed studies suggest that ROS (reactive oxygen species) overproduction and ROS-mediated pathways play a central role in nanomaterials-induced RCDs activation. On the other hand, studies also suggest that individual properties of nanomaterials, including size, shape, or surface charge, could determine specific toxicity pathways with consequent RCD induction as well. We anticipate that the evaluation of RCDs can become one of the mechanism-based screening methods in nanotoxicology. In addition to the toxicity assessment, evaluation of necroptosis-, pyroptosis-, and ferroptosis-promoting capacity of nanomaterials could simultaneously provide useful information for specific medical applications as could be their anti-tumor potential. Moreover, a detailed understanding of molecular mechanisms driving nanomaterials-mediated induction of immunogenic RCDs will substantially aid novel anti-tumor nanodrugs development.
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Affiliation(s)
- Anton Tkachenko
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Research Institute of Experimental and Clinical Medicine, Kharkiv National Medical University, Kharkiv, Ukraine
| | - Anatolii Onishchenko
- Research Institute of Experimental and Clinical Medicine, Kharkiv National Medical University, Kharkiv, Ukraine
| | - Valeriy Myasoedov
- Department of Medical Biology, Kharkiv National Medical University, Kharkiv, Ukraine
| | - Svetlana Yefimova
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, Kharkiv, Ukraine
| | - Ondrej Havranek
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Hematology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
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Anosike NL, Adejuwon JF, Emmanuel GE, Adebayo OS, Etti-Balogun H, Nathaniel JN, Omotosho OI, Aschner M, Ijomone OM. Necroptosis in the developing brain: role in neurodevelopmental disorders. Metab Brain Dis 2023; 38:831-837. [PMID: 36964816 DOI: 10.1007/s11011-023-01203-9] [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: 07/12/2022] [Accepted: 03/17/2023] [Indexed: 03/26/2023]
Abstract
Cell death is vital to various organismal developmental processes including brain development. Apoptosis, the most recognized programmed cell death, has been linked to several developmental processes and implicated in pruning cells to provide the ultimate tissue integrity. However, more recently, other forms of non-apoptotic programmed cell death have been identified, of which necroptosis is of predominant interest. Necroptosis is a regulated form of necrosis, activated under apoptotic-deficient conditions. Tumour necrosis factor (TNF) is a major activator of necroptosis, and the process is mediated by several kinases including receptor-interacting protein kinase (RIPK) and mixed lineage kinase domain-like protein (MLKL). Potential roles for necroptosis during brain development have been muted. Necroptosis has been implicated in mediating neurological disorders, and contributing to the severity of these disorders. Here we will review the literature on the role of necroptosis in neurodevelopment, summarizing its molecular mechanisms and highlighting potential implications for disorders of the developing brain.
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Affiliation(s)
- Nnenna Loveth Anosike
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Joy Funsho Adejuwon
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
- Department of Human Anatomy, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Godslove Emeka Emmanuel
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
- Department of Human Anatomy, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Oluwatosin Samuel Adebayo
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
- Department of Human Anatomy, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Hassanat Etti-Balogun
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
- Department of Human Anatomy, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Jannie Nathaniel Nathaniel
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
- Department of Physiology, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Omolabake Ifeoluwa Omotosho
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
- Department of Human Anatomy, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Neurosciences, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Paediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Omamuyovwi Meashack Ijomone
- The Neuro- Lab, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria.
- Department of Human Anatomy, School of Basic Medical Sciences, Federal University of Technology Akure, Akure, Nigeria.
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
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Mitroshina EV, Saviuk M, Vedunova MV. Necroptosis in CNS diseases: Focus on astrocytes. Front Aging Neurosci 2023; 14:1016053. [PMID: 36778591 PMCID: PMC9911465 DOI: 10.3389/fnagi.2022.1016053] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/28/2022] [Indexed: 01/28/2023] Open
Abstract
In the last few years, necroptosis, a recently described type of cell death, has been reported to play an important role in the development of various brain pathologies. Necroptosis is a cell death mechanism that has morphological characteristics similar to necrosis but is mediated by fundamentally different molecular pathways. Necroptosis is initiated by signaling through the interaction of RIP1/RIP3/MLKL proteins (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein). RIPK1 kinase is usually inactive under physiological conditions. It is activated by stimulation of death receptors (TNFR1, TNFR2, TLR3, and 4, Fas-ligand) by external signals. Phosphorylation of RIPK1 results in the formation of its complex with death receptors. Further, complexes with the second member of the RIP3 and MLKL cascade appear, and the necroptosome is formed. There is enough evidence that necroptosis plays an important role in the pathogenesis of brain ischemia and neurodegenerative diseases. In recent years, a point of view that both neurons and glial cells can play a key role in the development of the central nervous system (CNS) pathologies finds more and more confirmation. Astrocytes play complex roles during neurodegeneration and ischemic brain damage initiating both impair and protective processes. However, the cellular and molecular mechanisms that induce pathogenic activity of astrocytes remain veiled. In this review, we consider these processes in terms of the initiation of necroptosis. On the other hand, it is important to remember that like other types of programmed cell death, necroptosis plays an important role for the organism, as it induces a strong immune response and is involved in the control of cancerogenesis. In this review, we provide an overview of the complex role of necroptosis as an important pathogenetic component of neuronal and astrocyte death in neurodegenerative diseases, epileptogenesis, and ischemic brain damage.
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Zhang Q, Hu XM, Zhao WJ, Ban XX, Li Y, Huang YX, Wan H, He Y, Liao LS, Shang L, Jiang B, Qing GP, Xiong K. Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases. Int J Biol Sci 2023; 19:658-674. [PMID: 36632450 PMCID: PMC9830514 DOI: 10.7150/ijbs.77994] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 12/15/2022] [Indexed: 01/04/2023] Open
Abstract
The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis - traditionally thought of as uncontrolled cell death - in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.
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Affiliation(s)
- Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China.,Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China
| | - Xi-min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wen-juan Zhao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xiao-xia Ban
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yan Li
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yan-xia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Hao Wan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Ye He
- Changsha Aier Eye Hospital, Changsha, China
| | - Lv-shuang Liao
- School of Physical Education, Hunan Institute of Science and Technology, Yueyang, China
| | - Lei Shang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China
| | - Bin Jiang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Guo-ping Qing
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China.,Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China.,Hunan Key Laboratory of Ophthalmology, Changsha, China.,✉ Corresponding author: E-mail:
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Zhang Q, Xiong K, Yan WT, Zhao WJ, Hu XM, Ban XX, Ning WY, Wan H. PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons. Neural Regen Res 2023; 18:357-363. [PMID: 35900430 PMCID: PMC9396479 DOI: 10.4103/1673-5374.346545] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Teng Y, Xu D, Yang X, Tang H, Tao X, Fan Y, Ding Y. The Emerging Roles of Pyroptosis, Necroptosis, and Ferroptosis in Non-Malignant Dermatoses: A Review. J Inflamm Res 2023; 16:1967-1977. [PMID: 37179755 PMCID: PMC10171792 DOI: 10.2147/jir.s409699] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Unlike apoptosis, pyroptosis, necroptosis, and ferroptosis are recently identified modes of programmed cell death (PCD) with unique molecular pathways. Increasing evidence has indicated that these PCD modes play a crucial role in the pathogenesis of various non-malignant dermatoses (a group of cutaneous disorders), including infective dermatoses, immune-related dermatoses, allergic dermatoses, benign proliferative dermatoses, etc. Moreover, their molecular mechanisms have been suggested as potential therapeutic targets for the prevention and treatment of these dermatoses. In this article, we aim to review and summarize the molecular mechanisms of pyroptosis, necroptosis, and ferroptosis and their roles in the pathogenesis of some non-malignant dermatoses.
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Affiliation(s)
- Yan Teng
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
| | - Danfeng Xu
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
| | - Xianhong Yang
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
| | - Hui Tang
- Graduate School of Clinical Medicine, Bengbu Medical College, Bengbu, People’s Republic of China
| | - Xiaohua Tao
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
| | - Yibin Fan
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
| | - Yang Ding
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China
- Correspondence: Yang Ding; Yibin Fan, Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China, Tel +86-13732261339; +86-13505811700, Email ;
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王 远, 戴 兴, 陈 春, 程 培, 陈 松, 黎 欣, 毕 炫, 程 瑶, 吴 昌, 吴 宁. [ Sidaxue, a traditional Guizhou Miao herbal medicine formula, reduces necroptosis and synovial vascular proliferation in rats with collagen-induced arthritis by inhibiting the RIPK1/RIPK3/MLKL pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1774-1782. [PMID: 36651244 PMCID: PMC9878417 DOI: 10.12122/j.issn.1673-4254.2022.12.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To explore the inhibitory effect of Sidaxue (SX), a traditional Guizhou Miao herbal medicine formula, on necrotic apoptosis and synovial angiogenesis in rats with collagen-induced arthritis (CIA) and the role of the RIPK1/RIPK3/MLKL pathway in mediating this effect. METHODS Forty-two SD rats were randomized into 6 groups (n=7), including a normal control group, a CIA model group, 3 SX treatment groups at low (10 g/kg), moderate (20 g/kg) and high (40 g/kg) doses, and a GTW treatment group. CIA rat models were established by subcutaneous injections of bovine type II collagen, and the treatments were administered daily by gavage for 21 days. The rats were observed for swelling of the hind limb joints, which was rated using the arthritis index (AI) score on a weekly basis. Serum levels of TNF-α, IL-1β and IL-17 in the rats were detected using ELISA, and the pathological changes in the synovium were observed with HE staining. Real-time PCR was performed to detect the mRNA expression levels of VEGF, MMP-9, Ang-1, RIPK1, RIPK3, and caspase-8 in the synovial tissues, and the protein expressions of VEGF, MMP9, Ang-1, Stat-3, RIPK1, RIPK3, MLKLl, p-MLKL and caspase-8 were detected using Western blotting. RESULTS Compared with those in CIA model group, the rats receiving treatment with GTW and SX showed milder swelling of the hind limb joints with significantly lower AI scores (P < 0.05). In CIA model group, a large number of inflammatory cells were observed in the synovium with obvious damages of the tissue structure. In the drug treatment groups, inflammatory cell infiltration, synovial angiogenesis and synovial hyperplasia were alleviated, and the therapeutic effects were obviously enhanced as SX dose increased. Compared with those in the model group, the rats treated with GTW and high-dose SX showed significantly decreased serum levels of IL-1β, IL-17 and TNF-α (P < 0.05), lower mRNA and protein expressions of RIPK1, RIPK3, VEGF, Ang-1, and MMP9 (P < 0.05), higher expressions of caspase-8 (P < 0.01), and obviously lowered expression of Stat-3 protein and phosphorylation level of MLKL (P < 0.05). CONCLUSION SX can improve synovial angiogenesis in CIA rats possibly by inhibiting the activation of RIP1/RIP3/MLKL signaling pathway and down-regulating the expression of the vascular growth factors VEGF, Ang-1, MMP9, and Stat-3.
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Affiliation(s)
- 远迎 王
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
| | - 兴月 戴
- 贵州医科大学麻醉医学院，贵州 贵阳 550004College of Anesthesia Medicine, Guizhou Medical University, Guiyang 55004, China
| | - 春彦 陈
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
| | - 培钧 程
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
| | - 松江 陈
- 贵州医科大学临床医学院，贵州 贵阳 550004College of Clinical Medicine, Guizhou Medical University, Guiyang 55004, China
| | - 欣悦 黎
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
| | - 炫 毕
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
| | - 瑶 程
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
| | - 昌学 吴
- 贵州医科大学医学分子生物学重点实验室，贵州 贵阳 550004Key Laboratory of Molecular Biology, Guizhou Medical University, Guiyang 55004, China
| | - 宁 吴
- 贵州医科大学基础医学院，贵州 贵阳 550004College of Basic Medical Science, Guizhou Medical University, Guiyang 55004, China
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[Tanshinone IIA alleviates lipopolysaccharide-induced renal tubular epithelial cell apoptosis by inhibiting RIP3/FUNDC1 signaling pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1852-1857. [PMID: 36651254 PMCID: PMC9878413 DOI: 10.12122/j.issn.1673-4254.2022.12.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To investigate the effect of tanshinone IIA pretreatment on acute renal injury in lipopolysaccharide (LPS)-induced septic mice and explore the possible mechanism. METHODS Thirty C57BL/6 mice were randomized for treatment with saline (control), 10 mg/kg LPS for 24 h, or 10 mg/kg tanshinone IIA 15 min before LPS treatment. After the treatments, serum creatinine and blood urea nitrogen levels of the mice were detected, renal pathologies were observed with PAS staining, and renal expressions of RIP3, cleaved caspase-3 and p18-FUNDC1 were detected with Western blotting. In the cell experiment, cultured normal human renal tubular epithelial cells (HK-2) were treated with LPS (10 mg/mL), LPS+ siNC, LPS+ siRIP3, or LPS+tanshinone IIA (10 mg/L), and the changes in cell apoptosis were examined with TUNEL staining; Western blotting was performed to detect the expression levels of RIP3, cleaved caspase-3 and p18-FUNDC1, and qRT-PCR was used to detect the expression of RIP3 mRNA. RESULTS LPS challenge for 24 h significantly increased serum creatinine and blood urea nitrogen levels in the mice, caused obviously damages in the proximal renal tubules, and increased renal expressions of RIP3, cleaved caspase-3 and p18-FUNDC1 proteins. Tanshinone IIA pretreatment significantly improved LPS-induced renal injury in the mice, alleviated apoptosis of the renal cells, and inhibited the expressions of RIP3, cleaved caspase-3 and p18-FUNDC1 proteins. In HK-2 cells, LPS stimulation significantly increased the protein expressions of RIP3, cleaved caspase-3 and p18-FUNDC1 and induced obvious cell apoptosis. Pretreatment with tanshinone IIA strongly inhibited the expression of RIP3 and p18-FUNDC1 and reduced LPS-induced apoptosis of HK-2 cells. CONCLUSION Tanshinone IIA can reduce LPS-induced apoptosis of renal tubular epithelial cells by inhibiting RIP3/FUNDC1 signal pathway.
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Primary cilia suppress Ripk3-mediated necroptosis. Cell Death Dis 2022; 8:477. [PMID: 36460631 PMCID: PMC9718801 DOI: 10.1038/s41420-022-01272-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/04/2022]
Abstract
Cilia are sensory organelles that project from the surface of almost all cells. Nephronophthisis (NPH) and NPH-related ciliopathies are degenerative genetic diseases caused by mutation of cilia-associated genes. These kidney disorders are characterized by progressive loss of functional tubular epithelial cells which is associated with inflammation, progressive fibrosis, and cyst formation, ultimately leading to end-stage renal disease. However, disease mechanisms remain poorly understood. Here, we show that targeted deletion of cilia in renal epithelial cells enhanced susceptibility to necroptotic cell death under inflammatory conditions. Treatment of non-ciliated cells with tumor necrosis factor (TNF) α and the SMAC mimetic birinapant resulted in Ripk1-dependent cell death, while viability of ciliated cells was almost not affected. Cell death could be enhanced and shifted toward necroptosis by the caspase inhibitor emricasan, which could be blocked by inhibitors of Ripk1 and Ripk3. Moreover, combined treatment of ciliated and non-ciliated cells with TNFα and cycloheximide induced a cell death response that could be partially rescued with emricasan in ciliated cells. In contrast, non-ciliated cells responded with pronounced cell death that was blocked by necroptosis inhibitors. Consistently, combined treatment with interferon-γ and emricasan induced cell death only in non-ciliated cells. Mechanistically, enhanced necroptosis induced by loss of cilia could be explained by induction of Ripk3 and increased abundance of autophagy components, including p62 and LC3 associated with the Ripk1/Ripk3 necrosome. Genetic ablation of cilia in renal tubular epithelial cells in mice resulted in TUNEL positivity and increased expression of Ripk3 in kidney tissue. Moreover, loss of Nphp1, the most frequent cause of NPH, further increased susceptibility to necroptosis in non-ciliated epithelial cells, suggesting that necroptosis might contribute to the pathogenesis of the disease. Together, these data provide a link between cilia-related signaling and cell death responses and shed new light on the disease pathogenesis of NPH-related ciliopathies.
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Chen H, Han Z, Luo Q, Wang Y, Li Q, Zhou L, Zuo H. Radiotherapy modulates tumor cell fate decisions: a review. Radiat Oncol 2022; 17:196. [PMID: 36457125 PMCID: PMC9714175 DOI: 10.1186/s13014-022-02171-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 11/29/2022] [Indexed: 12/02/2022] Open
Abstract
Cancer has always been a worldwide problem, and the application of radiotherapy has greatly improved the survival rate of cancer patients. Radiotherapy can modulate multiple cell fate decisions to kill tumor cells and achieve its therapeutic effect. With the development of radiotherapy technology, how to increase the killing effect of tumor cells and reduce the side effects on normal cells has become a new problem. In this review, we summarize the mechanisms by which radiotherapy induces tumor cell apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, autophagy, senescence, mitotic catastrophe, and cuproptosis. An in-depth understanding of these radiotherapy-related cell fate decisions can greatly improve the efficiency of radiotherapy for cancer.
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Affiliation(s)
| | - Zhongyu Han
- Chengdu Xinhua Hospital, Chengdu, China ,grid.411304.30000 0001 0376 205XSchool of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Luo
- Chengdu Xinhua Hospital, Chengdu, China
| | - Yi Wang
- Chengdu Xinhua Hospital, Chengdu, China
| | - Qiju Li
- Chengdu Xinhua Hospital, Chengdu, China
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Zhang M, Lei Q, Huang X, Wang Y. Molecular mechanisms of ferroptosis and the potential therapeutic targets of ferroptosis signaling pathways for glioblastoma. Front Pharmacol 2022; 13:1071897. [PMID: 36506514 PMCID: PMC9729877 DOI: 10.3389/fphar.2022.1071897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/16/2022] [Indexed: 11/25/2022] Open
Abstract
Ferroptosis is a newly identified form of cell death that differs from autophagy, apoptosis and necrosis, and its molecular characteristics include iron-dependent lipid reactive oxygen species accumulation, mitochondrial morphology changes, and membrane permeability damage. These characteristics are closely related to various human diseases, especially tumors of the nervous system. Glioblastoma is the most common primary malignant tumor of the adult central nervous system, and the 5-year survival rate is only 4%-5%. This study reviewed the role and mechanism of ferroptosis in glioblastoma and the research status and progress on ferroptosis as a potential therapeutic target. The mechanism of ferroptosis is related to the intracellular iron metabolism level, lipid peroxide content and glutathione peroxidase 4 activity. It is worth exploring how ferroptosis can be applied in disease treatment; however, the relation between ferroptosis and other apoptosis methods is poorly understood and methods of applying ferroptosis to drug-resistant tumors are insufficient. Ferroptosis is a promising therapeutic target for glioblastoma. In-depth studies of its mechanism of action in glioblastoma and applications for clinical treatment are expected to provide insights for glioblastoma patients.
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Affiliation(s)
- Meng Zhang
- Department of Anesthesiology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qian Lei
- Department of Anesthesiology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaobo Huang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Shi K, Zhang J, Zhou E, Wang J, Wang Y. Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities. J Med Chem 2022; 65:14971-14999. [DOI: 10.1021/acs.jmedchem.2c01518] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Kunyu Shi
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Jifa Zhang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Tianfu Jincheng Laboratory, Chengdu, 610041 Sichuan, China
| | - Enda Zhou
- West China School of Pharmacy, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Yuxi Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- Tianfu Jincheng Laboratory, Chengdu, 610041 Sichuan, China
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Role of K63-linked ubiquitination in cancer. Cell Death Dis 2022; 8:410. [PMID: 36202787 PMCID: PMC9537175 DOI: 10.1038/s41420-022-01204-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 11/08/2022]
Abstract
Ubiquitination is a critical type of post-translational modifications, of which K63-linked ubiquitination regulates interaction, translocation, and activation of proteins. In recent years, emerging evidence suggest involvement of K63-linked ubiquitination in multiple signaling pathways and various human diseases including cancer. Increasing number of studies indicated that K63-linked ubiquitination controls initiation, development, invasion, metastasis, and therapy of diverse cancers. Here, we summarized molecular mechanisms of K63-linked ubiquitination dictating different biological activities of tumor and highlighted novel opportunities for future therapy targeting certain regulation of K63-linked ubiquitination in tumor.
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Chen L, Zhang X, Ou Y, Liu M, Yu D, Song Z, Niu L, Zhang L, Shi J. Advances in RIPK1 kinase inhibitors. Front Pharmacol 2022; 13:976435. [PMID: 36249746 PMCID: PMC9554302 DOI: 10.3389/fphar.2022.976435] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/08/2022] [Indexed: 01/27/2023] Open
Abstract
Programmed necrosis is a new modulated cell death mode with necrotizing morphological characteristics. Receptor interacting protein 1 (RIPK1) is a critical mediator of the programmed necrosis pathway that is involved in stroke, myocardial infarction, fatal systemic inflammatory response syndrome, Alzheimer's disease, and malignancy. At present, the reported inhibitors are divided into four categories. The first category is the type I ATP-competitive kinase inhibitors that targets the area occupied by the ATP adenylate ring; The second category is type Ⅱ ATP competitive kinase inhibitors targeting the DLG-out conformation of RIPK1; The third category is type Ⅲ kinase inhibitors that compete for binding to allosteric sites near ATP pockets; The last category is others. This paper reviews the structure, biological function, and recent research progress of receptor interaction protein-1 kinase inhibitors.
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Affiliation(s)
- Lu Chen
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoqin Zhang
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yaqing Ou
- Department of Pharmacy, The Affiliated Chengdu 363 Hospital of Southwest Medical University, Chengdu, Sichuan, China
| | - Maoyu Liu
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Dongke Yu
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhiheng Song
- Suzhou University of Science and Technology, Suzhou, Jiangsu, China
| | - Lihong Niu
- Institute of Laboratory Animal Sciences, Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China,*Correspondence: Lihong Niu, ; Lijuan Zhang, ; Jianyou Shi,
| | - Lijuan Zhang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,*Correspondence: Lihong Niu, ; Lijuan Zhang, ; Jianyou Shi,
| | - Jianyou Shi
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,*Correspondence: Lihong Niu, ; Lijuan Zhang, ; Jianyou Shi,
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Necroptosis-Related Prognostic Signature and Nomogram Model for Predicting the Overall Survival of Patients with Lung Cancer. Genet Res (Camb) 2022; 2022:4908608. [PMID: 36101745 PMCID: PMC9452994 DOI: 10.1155/2022/4908608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/21/2022] [Indexed: 01/19/2023] Open
Abstract
Background Necroptosis is a type of programmed cell death mode and it serves an important role in the tumorigenesis and tumor metastasis. The purpose of this study is to develop a prognostic model based on necroptosis-related genes and nomogram for predicting the overall survival of patients with lung cancer. Method Differentially expressed necroptosis-related genes (NRDs) between lung cancer and normal samples were identified. Univariate and LASSO regression analyses were performed to establish a risk score (RS) model, followed by validation within TCGA and GSE37745. The correlation between RS model and tumor microenvironment, mutation status, or drug susceptibility was analyzed. By combining clinical factors, nomogram was developed to predict 1-, 3-, and 5-year survival probability of an individual. The biological function involved by different risk groups was conducted by GSEA. Results A RS model containing six NRDs (FLNC, PLK1, ID1, MYO1C, SERTAD1, and LEF1) was constructed, and patients were divieded into low-risk (LR) and high-risk (HR) groups. Patients in HR group were associated with shorter survival time than those in the LR group; this model had better prognostic performance. Nomogram based on necroptosis score, T stage, and stage had been confirmed to predict survival of patients. The number of resting NK cells and M0 macrophages was higher in HR group. In addition, higher tumor mutational burden and drug sensitivity were observed in the HR group. Patients in HR group were involved in p53 signaling pathway and cell cycle. Conclusion This study constructed a robust six-NRDs signature and established a prognostic nomogram for survival prediction of lung cancer.
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Zhu J, Wang J, Wang T, Zhou H, Xu M, Zha J, Feng C, Shen Z, Jiang Y, Chen J. Identification of molecular subtypes, risk signature, and immune landscape mediated by necroptosis-related genes in non-small cell lung cancer. Front Oncol 2022; 12:955186. [PMID: 35965497 PMCID: PMC9367639 DOI: 10.3389/fonc.2022.955186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundNon-small cell lung cancer (NSCLC) is a highly heterogeneous malignancy with an extremely high mortality rate. Necroptosis is a programmed cell death mode mediated by three major mediators, RIPK1, RIPK3, and MLKL, and has been shown to play a role in various cancers. To date, the effect of necroptosis on NSCLC remains unclear.MethodsIn The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we downloaded transcriptomes of lung adenocarcinoma (LUAD) patients and their corresponding clinicopathological parameters. We performed multi-omics analysis using consensus clustering based on the expression levels of 40 necroptosis-related genes. We constructed prognostic risk models and used the receiver operating characteristic (ROC) curves, nomograms, and survival analysis to evaluate prognostic models.ResultsWith the use of consensus clustering analysis, two distinct subtypes of necroptosis were identified based on different mRNA expression levels, and cluster B was found to have a better survival advantage. Correlation results showed that necroptosis was significantly linked with clinical features, overall survival (OS) rate, and immune infiltration. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis confirmed that these differential genes were valuable in various cellular and biological functions and were significantly enriched in various pathways such as the P53 signaling pathway and cell cycle. We further identified three genomic subtypes and found that gene cluster B patients had better prognostic value. Multivariate Cox analysis identified the 14 best prognostic genes for constructing prognostic risk models. The high-risk group was found to have a poor prognosis. The construction of nomograms and ROC curves showed stable validity in prognostic prediction. There were also significant differences in tumor immune microenvironment, tumor mutational burden (TMB), and drug sensitivity between the two risk groups. The results demonstrate that the 14 genes constructed in this prognostic risk model were used as tumor prognostic biomarkers to guide immunotherapy and chemotherapy. Finally, we used qRT-PCR to validate the genes involved in the signature.ConclusionThis study promotes our new understanding of necroptosis in the tumor microenvironment of NSCLC, mines prognostic biomarkers, and provides a potential value for guiding immunotherapy and chemotherapy.
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Affiliation(s)
- Jiaqi Zhu
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Jinjie Wang
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Tianyi Wang
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Hao Zhou
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Mingming Xu
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Jiliang Zha
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Chen Feng
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Zihao Shen
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Yun Jiang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- *Correspondence: Jianle Chen, ; Yun Jiang,
| | - Jianle Chen
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- *Correspondence: Jianle Chen, ; Yun Jiang,
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Rex DAB, Keshava Prasad TS, Kandasamy RK. Revisiting Regulated Cell Death Responses in Viral Infections. Int J Mol Sci 2022; 23:ijms23137023. [PMID: 35806033 PMCID: PMC9266763 DOI: 10.3390/ijms23137023] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/07/2023] Open
Abstract
The fate of a viral infection in the host begins with various types of cellular responses, such as abortive, productive, latent, and destructive infections. Apoptosis, necroptosis, and pyroptosis are the three major types of regulated cell death mechanisms that play critical roles in viral infection response. Cell shrinkage, nuclear condensation, bleb formation, and retained membrane integrity are all signs of osmotic imbalance-driven cytoplasmic swelling and early membrane damage in necroptosis and pyroptosis. Caspase-driven apoptotic cell demise is considered in many circumstances as an anti-inflammatory, and some pathogens hijack the cell death signaling routes to initiate a targeted attack against the host. In this review, the selected mechanisms by which viruses interfere with cell death were discussed in-depth and were illustrated by compiling the general principles and cellular signaling mechanisms of virus–host-specific molecule interactions.
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Affiliation(s)
| | - Thottethodi Subrahmanya Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
- Correspondence: (T.S.K.P.); (R.K.K.)
| | - Richard K. Kandasamy
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai P.O Box 505055, United Arab Emirates
- Correspondence: (T.S.K.P.); (R.K.K.)
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Cao J, Zhang J, Qian J, Wang X, Zhang W, Chen X. Ca 2+/Calmodulin-Dependent Protein Kinase II Regulation by RIPK3 Alleviates Necroptosis in Transverse Arch Constriction-Induced Heart Failure. Front Cardiovasc Med 2022; 9:847362. [PMID: 35571197 PMCID: PMC9097920 DOI: 10.3389/fcvm.2022.847362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/11/2022] [Indexed: 12/24/2022] Open
Abstract
Some studies have reported that the activation of Ca2+/calmodulin dependent protein kinase (CaMKII) plays a vital role in the pathogenesis of cardiovascular disease. Moreover, receptor interacting protein kinase 3 (RIPK3)-mediated necroptosis is also involved in the pathological process of various heart diseases. In the present study, we aimed to investigate the effect of RIPK3-regulated CaMKII on necroptosis in heart failure (HF) and its underlying mechanism. Wild type (WT) and RIPK3-depleted (RIPK3–/–) mice were treated with transverse arch constriction (TAC). After 6 weeks, echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK3 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure were measured. The results showed that TAC aggravated cardiac dysfunction, CaMKII activation, and necroptosis in WT mice. However, depletion of RIPK3 alleviated cardiac insufficiency, CaMKII activation, and necroptosis in TAC-treated mice. To verify the experimental results, WT mice were transfected with AAV-vector and AAV-RIPK3 shRNA, followed by TAC operation. The findings were consistent with the expected results. Collectively, our current data indicated that the activation of CaMKII, MLKL and necroptosis in HF mice were increased in a RIPK3-dependent manner, providing valuable insights into the pathogenesis and treatment strategy of HF.
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Affiliation(s)
- Ji Cao
- School of Pharmacy, Nantong University, Nantong, China
| | - Jingjing Zhang
- School of Pharmacy, Nantong University, Nantong, China.,School of Medicine, Nantong University, Nantong, China
| | - Jianan Qian
- School of Pharmacy, Nantong University, Nantong, China
| | - Xue Wang
- School of Pharmacy, Nantong University, Nantong, China
| | - Wei Zhang
- School of Pharmacy, Nantong University, Nantong, China.,School of Medicine, Nantong University, Nantong, China
| | - Xiangfan Chen
- Department of Pharmacy, Nantong First People's Hospital, The Second Affiliated Hospital of Nantong University, Nantong, China
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Qi X, Li Q, Che X, Wang Q, Wu G. Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy. Front Immunol 2022; 13:837293. [PMID: 35359956 PMCID: PMC8960167 DOI: 10.3389/fimmu.2022.837293] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/21/2022] [Indexed: 12/15/2022] Open
Abstract
The development of cancer treatment methods is constantly changing. For common cancers, our treatment methods are still based on conventional treatment methods, such as chemotherapy, radiotherapy, and targeted drug therapy. Nevertheless, the emergence of tumor resistance has a negative impact on treatment. Regulated cell death is a gene-regulated mode of programmed cell death. After receiving specific signal transduction, cells change their physical and chemical properties and the extracellular microenvironment, resulting in structural destruction and decomposition. As research accumulates, we now know that by precisely inducing specific cell death patterns, we can treat cancer with less collateral damage than other treatments. Many newly discovered types of RCD are thought to be useful for cancer treatment. However, some experimental results suggest that some RCDs are not sensitive to cancer cell death, and some may even promote cancer progression. This review summarizes the discovered types of RCDs, reviews their clinical efficacy in cancer treatment, explores their anticancer mechanisms, and discusses the feasibility of some newly discovered RCDs for cancer treatment in combination with the immune and tumor microenvironment.
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Affiliation(s)
| | | | | | - Qifei Wang
- First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Guangzhen Wu
- First Affiliated Hospital, Dalian Medical University, Dalian, China
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Chen B, Hang J, Zhao Y, Geng Y, Li X, Gu Z, Li J, Jiang C, Tao L, Yu H. Correlation between Plasma Levels of RIP3 and Acute Ischemic Stroke with Large-Artery Atherosclerosis. Curr Neurovasc Res 2022; 19:30-37. [PMID: 35156583 DOI: 10.2174/1567202619666220214105208] [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: 12/11/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Receptor-interacting serine-threonine protein kinase 3 (RIP3) was previously discovered to be an important medium in the occurrence and development of major atherosclerotic cerebral infarction. However, the role of RIP3 in acute ischemic stroke remains unclear. OBJECTIVE This study aimed to explore the correlation between plasma levels of RIP3 and acute ischemic stroke with large-artery atherosclerosis (LAA). METHODS This prospective study enrolled 116 patients with LAA, 40 healthy controls and 30 acute ischemic stroke patients with small-artery occlusion. The patients with LAA were divided according to the quartile of plasma levels of RIP3. Logistic regression model was used for comparison. The ROC curve was performed to evaluate the predictive value. RESULTS In patients with LAA, the RIP3 levels in patients with poor outcomes as well as neurological deterioration were significantly higher than those with good outcomes (P < 0.001) and without neurological deterioration (P = 0.014) respectively. Patients in the highest levels of plasma RIP3 quartile were more likely to have neurological deterioration (OR, 11.07; 95% CI, 1.990-61.582) and poor outcomes (OR, 35.970; 95% CI, 5.392-239.980) compared with the lowest. The optimal cut-off value for neurological deterioration was 1127.75 pg/mL (specificity, 66.7%; sensitivity, 69.2%), that for poor prognosis was 1181.82 pg/mL (specificity, 89.7%; sensitivity, 62.1%). CONCLUSION Elevated levels of plasma RIP3 were significantly associated with neurological deterioration and poor prognosis in patients with LAA. Significant increase in plasma RIP3 levels can predict neurological deterioration and poor prognosis of these patients.
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Affiliation(s)
- Beilei Chen
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Jing Hang
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Yuanyuan Zhao
- Department of Neurology, Bazhong Central Hospital, Bazhong, Sichuang
| | - Yang Geng
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Xiaobo Li
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Zhie Gu
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Jun Li
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Chao Jiang
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Luhang Tao
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Hailong Yu
- Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
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Zhang E, Li X. The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling. Front Immunol 2022; 13:728794. [PMID: 35197966 PMCID: PMC8860249 DOI: 10.3389/fimmu.2022.728794] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 01/14/2022] [Indexed: 12/03/2022] Open
Abstract
The Pellino family is a novel and well-conserved E3 ubiquitin ligase family and consists of Pellino1, Pellino2, and Pellino3. Each family member exhibits a highly conserved structure providing ubiquitin ligase activity without abrogating cell and structure-specific function. In this review, we mainly summarized the crucial roles of the Pellino family in pattern recognition receptor-related signaling pathways: IL-1R signaling, Toll-like signaling, NOD-like signaling, T-cell and B-cell signaling, and cell death-related TNFR signaling. We also summarized the current information of the Pellino family in tumorigenesis, microRNAs, and other phenotypes. Finally, we discussed the outstanding questions of the Pellino family in immunity.
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Affiliation(s)
- E Zhang
- Marine College, Shandong University, Weihai, China
| | - Xia Li
- Marine College, Shandong University, Weihai, China
- School of Pharmaceutical Sciences, Shandong University, Jinan, China
- *Correspondence: Xia Li,
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Huang WY, Lai YL, Liu KH, Lin S, Chen HY, Liang CH, Wu HM, Hsu KS. TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation. J Neuroinflammation 2022; 19:29. [PMID: 35109859 PMCID: PMC8809013 DOI: 10.1186/s12974-022-02406-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Systemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells). METHODS Lipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain. RESULTS Some noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection. CONCLUSIONS The findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.
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Affiliation(s)
- Wan-Yu Huang
- Institute of Basic Medical Sciences Basic Medicine, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.,Pediatrics of Kung-Ten General Hospital, Taichung City, Taiwan
| | - Yen-Ling Lai
- Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Ko-Hung Liu
- Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Shankung Lin
- Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsuan-Ying Chen
- Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Hung Liang
- Department of Food Science, Tunghai University, Taichung City, Taiwan
| | - Hung-Ming Wu
- Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan. .,Department of Neurology, Changhua Christian Hospital, Changhua City, Taiwan. .,Institute of Acupuncture, School of Chinese Medicine, China Medical University, Taichung City, Taiwan.
| | - Kuei-Sen Hsu
- Institute of Basic Medical Sciences Basic Medicine, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
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49
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Wang F, Wang JN, He XY, Suo XG, Li C, Ni WJ, Cai YT, He Y, Fang XY, Dong YH, Xing T, Yang YR, Zhang F, Zhong X, Zang HM, Liu MM, Li J, Meng XM, Jin J. Stratifin promotes renal dysfunction in ischemic and nephrotoxic AKI mouse models via enhancing RIPK3-mediated necroptosis. Acta Pharmacol Sin 2022; 43:330-341. [PMID: 33833407 PMCID: PMC8791945 DOI: 10.1038/s41401-021-00649-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/12/2021] [Indexed: 02/03/2023]
Abstract
Stratifin (SFN) is a member of the 14-3-3 family of highly conserved soluble acidic proteins, which regulates a variety of cellular activities such as cell cycle, cell growth and development, cell survival and death, and gene transcription. Acute kidney injury (AKI) is prevalent disorder characterized by inflammatory response, oxidative stress, and programmed cell death in renal tubular epithelial cells, but there is still a lack of effective therapeutic target for AKI. In this study, we investigated the role of SFN in AKI and the underlying mechanisms. We established ischemic and nephrotoxic AKI mouse models caused by ischemia-reperfusion (I/R) and cisplatin, respectively. We conducted proteomic and immunohistochemical analyses and found that SFN expression levels were significantly increased in AKI patients, cisplatin- or I/R-induced AKI mice. In cisplatin- or hypoxia/reoxygenation (H/R)-treated human proximal tubule epithelial cells (HK2), we showed that knockdown of SFN significantly reduced the expression of kidney injury marker Kim-1, attenuated programmed cell death and inflammatory response. Knockdown of SFN also significantly alleviated the decline of renal function and histological damage in cisplatin-caused AKI mice in vivo. We further revealed that SFN bound to RIPK3, a key signaling modulator in necroptosis, to induce necroptosis and the subsequent inflammation in cisplatin- or H/R-treated HK2 cells. Overexpression of SFN increased Kim-1 protein levels in cisplatin-treated MTEC cells, which was suppressed by RIPK3 knockout. Taken together, our results demonstrate that SFN that enhances cisplatin- or I/R-caused programmed cell death and inflammation via interacting with RIPK3 may serve as a promising therapeutic target for AKI treatment.
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Affiliation(s)
- Fang Wang
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Jia-nan Wang
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Xiao-yan He
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Xiao-guo Suo
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Chao Li
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Wei-jian Ni
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China ,grid.59053.3a0000000121679639Department of Pharmacy, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001 China
| | - Yu-ting Cai
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Yuan He
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Xin-yun Fang
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Yu-hang Dong
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Tian Xing
- grid.186775.a0000 0000 9490 772XHospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032 China
| | - Ya-ru Yang
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Feng Zhang
- grid.73113.370000 0004 0369 1660Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003 China
| | - Xiang Zhong
- grid.54549.390000 0004 0369 4060Department of Nephrology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072 China
| | - Hong-mei Zang
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Ming-ming Liu
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Jun Li
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Xiao-ming Meng
- grid.186775.a0000 0000 9490 772XInflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032 China
| | - Juan Jin
- grid.186775.a0000 0000 9490 772XSchool of Basic Medical Sciences, Anhui Medical University, Hefei, 230032 China
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50
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Dan W, Zhong L, Zhang Z, Wan P, Lu Y, Wang X, Liu Z, Chu X, Liu B. RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia. Int J Med Sci 2022; 19:525-536. [PMID: 35370472 PMCID: PMC8964317 DOI: 10.7150/ijms.68385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 02/22/2022] [Indexed: 11/05/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by variations in cytogenetics and molecular abnormalities, which result in variable response to therapy. Receptor-interacting serine/threonine kinase 1 (RIP1)-mediated necroptosis has been reported to have a potential role in the treatment of AML. We obtained Skp2 and RIP1 are significantly overexpressed in AML samples using original published data, and identified that Skp2-depletion in AML cells significantly suppressed RIP1. Functional analysis showed that the inhibition of RIP1 caused by necrostatin-1 (Nec-1) inhibited the proliferation, simultaneously facilitate both the apoptosis and differentiation of AML cells. Mechanistical analysis elucidated that knockdown of Skp2 suppresses RIP1 by transcriptional regulation but not by proteasome degradation. Additionally, Skp2 regulated the function of RIP1 by decreasing K63-linked ubiquitin interaction with RIP1. Moreover, the suppression of Akt/GSK3β was observed in Skp2 knockdown stable NB4 cells. Also, GSK3β inactivation via small-molecule inhibitor treatment remarkably decreased RIP1 level. RIP1 regulates differentiation by interacting with RARα, increasing RA signaling targets gene C/EBPα and C/EBPβ. In conclusion, our study provides a novel insight into the mechanism of tumorigenesis and the development of AML, for which the Skp2-Akt/GSK3β-RIP1 pathway can be developed as a promising therapeutic target.
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Affiliation(s)
- Wenran Dan
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China.,Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Liang Zhong
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Zhonghui Zhang
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Peng Wan
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China.,Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yang Lu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Xiao Wang
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Zhenyan Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China
| | - Xuan Chu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China.,Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Beizhong Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China.,Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
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