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Jiang SM, Li XJ, Wang ZL, Chen ZW, Liu ZL, Li Q, Chen XL. Role of autophagy in rejection after solid organ transplantation: A systematic review of the literature. World J Transplant 2025; 15:103163. [DOI: 10.5500/wjt.v15.i3.103163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 04/18/2025] Open
Abstract
Organ transplantation has long been recognized as an effective treatment for end-stage organ failure, metabolic diseases, and malignant tumors. However, graft rejection caused by major histocompatibility complex mismatch remains a significant challenge. While modern immunosuppressants have made significant strides in reducing the incidence and risk of rejection, they have not been able to eliminate it completely. The intricate mechanisms underlying transplant rejection have been the subject of intense investigation by transplant immunologists. Among these factors, autophagy has emerged as a key player. Autophagy is an evolutionarily conserved mechanism in eukaryotic cells that mediates autophagocytosis and cellular protection. This process is regulated by autophagy-related genes and their encoded protein families, which maintain the material and energetic balance within cells. Additionally, autophagy has been reported to play crucial roles in the development, maturation, differentiation, and responses of immune cells. In the complex immune environment following transplantation, the role and mechanisms of autophagy are gradually being revealed. In this review, we aim to explore the current understanding of the role of autophagy in solid organ rejection after transplantation. Furthermore, we delve into the therapeutic advancements achieved by targeting autophagy involved in the rejection process.
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Affiliation(s)
- Shu-Min Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Xue-Jiao Li
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Zi-Lin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Wei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Long Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Long Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
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Liu Z, Chu A, Bai Z, Yang C. Nobiletin ameliorates monosodium urate-induced gouty arthritis in mice by enhancing AMPK/mTOR-mediated autophagy to inhibit NF-κB/NLRP3 inflammasome activation. Immunol Lett 2025; 274:106982. [PMID: 39965668 DOI: 10.1016/j.imlet.2025.106982] [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: 07/23/2024] [Revised: 01/06/2025] [Accepted: 02/09/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Gouty arthritis (GA) is a common rheumatic disease caused by the release of monosodium urate crystal (MSU) deposits into joint space. Nobiletin is a polymethoxylated flavonoid isolated from citrus fruits and has many beneficial activities. This study aimed to elucidate the therapeutic efficacy of nobiletin in GA and to reveal its potential mechanisms. METHODS Phorbol-12-myristate-13-acetate (PMA)-differentiated THP-1 macrophages were primed with lipopolysaccharide (LPS) and then stimulated with MSU crystals in the presence or absence of nobiletin. Cell viability as well as the levels of proinflammatory cytokines, pathway-related proteins, NLRP3 inflammasomes, and autophagy-related proteins were evaluated. MSU was used to induce GA in mice. Hematoxylin-eosin staining was conducted to assess histological morphology changes. Immunofluorescence staining was performed to measure LC3 expression in THP-1 cells and ankle joint tissues. RESULTS For in vitro analysis, nobiletin reduced LPS and MSU-induced cell viability inhibition. Additionally, nobiletin inhibited inflammation and NF-κB/NLRP3 pathway in THP-1 cells. Moreover, nobiletin inhibited the activation of NLRP3 inflammasome by promoting AMPK/mTOR-mediated autophagy. For in vivo analysis, nobiletin attenuated MSU-induced GA in mice. Additionally, nobiletin suppressed inflammation and NF-κB/NLRP3 pathway and promoted tissue autophagy in GA mice. CONCLUSION Nobiletin prevents MSU-induced GA in mice by inhibiting NF-κB/NLRP3 inflammasome activation through AMPK/mTOR-mediated autophagy.
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Affiliation(s)
- Zhiyong Liu
- Department of Rheumatology and Immunology, Wuhan University, Renmin Hospital, 238 Jiefang Road, Wuchang District, Wuhan, Hubei 430060, China
| | - Aichun Chu
- Department of Rheumatology and Immunology, Wuhan University, Renmin Hospital, 238 Jiefang Road, Wuchang District, Wuhan, Hubei 430060, China
| | - Zhiqian Bai
- Department of Rheumatology and Immunology, Wuhan University, Renmin Hospital, 238 Jiefang Road, Wuchang District, Wuhan, Hubei 430060, China
| | - Chao Yang
- Department of Orthopedics, Maternal and Child Health Hospital of Hubei Province, No 745 Wuluo Road, Hongshan District, Wuhan, Hubei 430070, China.
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Wang F, Liu Y, Wen J, Tan A, Deng Y, Wang L, Gong H, Lai Y, Huang Z, Zhao F. Autophagy enhances the antibacterial response in Macrobrachium rosenbergii by modulating cellular metabolism and immune pathways. FISH & SHELLFISH IMMUNOLOGY 2025; 161:110258. [PMID: 40058674 DOI: 10.1016/j.fsi.2025.110258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 03/02/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
Autophagy plays a crucial role in innate and adaptive immunity against invading microorganisms. However, the mechanism underlying autophagy in Macrobrachium rosenbergii remains largely unknown. Here, we demonstrate that Aeromonas hydrophila activates autophagy in M. rosenbergii, according to Western blot, qRT-PCR, and transmission electron microscopy observations. Rapamycin treatment to activate autophagy in M. rosenbergii followed by stimulation with A. hydrophila significantly decreased the A. hydrophila OmpA copy number in the gills of M. rosenbergii. Furthermore, high-throughput RNA-seq analysis of M. rosenbergii gills treated with rapamycin revealed 1684 upregulated and 1500 downregulated differentially expressed genes (DEGs), most of which regulate metabolic pathways. A comprehensive joint analysis of the two transcriptomic databases for A. hydrophila infection and rapamycin treatment identified 15 upregulated and 25 downregulated DEGs, respectively. These genes enhance the immune defense of M. rosenbergii by negatively regulating metabolic pathways and promoting immune pathways. Our results provide a theoretical basis for further exploration of the antibacterial mechanism of M. rosenbergii.
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Affiliation(s)
- Feifei Wang
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Yang Liu
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Jing Wen
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Aiping Tan
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Yuting Deng
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Ling Wang
- Zhaoqing Branch Center of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing, 526238, China
| | - Hua Gong
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Yingtiao Lai
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Zhibin Huang
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China
| | - Fei Zhao
- Key Laboratory of Fishery Drug Development, Ministry Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Aquatic Animal Immunology and Sustainable Aquaculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, 510380, China.
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Bezrukova AI, Basharova KS, Emelyanov AK, Rybakov AV, Miliukhina IV, Pchelina SN, Usenko TS. Autophagy Process in Parkinson's Disease Depends on Mutations in the GBA1 and LRRK2 Genes. Biochem Genet 2025:10.1007/s10528-025-11125-z. [PMID: 40388077 DOI: 10.1007/s10528-025-11125-z] [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: 01/09/2025] [Accepted: 04/28/2025] [Indexed: 05/20/2025]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and abnormal aggregation of the alpha-synuclein protein. Disruption of the autophagy-lysosomal pathway is closely associated with PD pathogenesis. Here, using western-blot analysis we assessed the level of autophagy-related proteins, including phosphorylated mTOR (p-mTOR), phosphorylated RPS6 (p-RPS6), beclin-1 (BECN1), LC3B, p62, and cathepsin D (CTSD) in macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages) of GBA1-PD (p.N370S/N, p.L444P/N), LRRK2-PD (p.G2019S/N), idiopathic PD (iPD) patients, and healthy controls. Our findings revealed mutation-specific disruptions in autophagy pathways among PD patients. In p.N370S-GBA1-PD, PBMC-derived macrophages exhibited elevated levels of p-RPS6, BECN1, LC3B-II and decreased mature form of CTSD levels suggesting more active mTOR-dependent autophagy initiation alongside potential autophagosome accumulation that may lead to downregulation of lysosomal degradation. p.L444P-GBA1-PD PBMC-derived macrophages showed increased levels of p-RPS6 and BECN1, coupled with decreased p62 levels and stable mature form of CTSD and LC3B-II, indicative of enhanced autophagy flux driven by mTOR activity without evident lysosomal dysfunction. In p.G2019S-LRRK2-PD patients, PBMC-derived macrophages demonstrated elevated p-RPS6, LC3B-II, and mature CTSD levels, alongside reduced p62 levels. These changes suggest higher basal autophagosome abundance in steady-state autophagy and turnover, potentially driven by lysosomal alterations rather than direct mTOR dysregulation. These mutation-dependent differences highlight distinct autophagy dynamics in GBA1-PD and LRRK2-PD, underscoring the critical role of genetic mutations in modulating PD pathogenesis. Our results emphasize the necessity for subtype-specific therapeutic strategies targeting autophagy and other mTOR-regulated pathways to address the heterogeneity of PD mechanisms.
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Affiliation(s)
- A I Bezrukova
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - K S Basharova
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - A K Emelyanov
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - A V Rybakov
- Institute of the Human Brain, Russian Academy of Sciences (RAS), 9 Akademika Pavlova Street, Saint Petersburg, Russia
| | - I V Miliukhina
- Institute of the Human Brain, Russian Academy of Sciences (RAS), 9 Akademika Pavlova Street, Saint Petersburg, Russia
| | - S N Pchelina
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - T S Usenko
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia.
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia.
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Zhao Y, He Z, Liu Y, Ren Y, Ren J, Zhang Y, Wang Y, Wang G, San L, Hou J. Isolation, identification and the pathogenicity characterization of Pseudomonas putida 1C3 and its activation on immune responses in Japanese flounder (Paralichthys olivaceus). FISH & SHELLFISH IMMUNOLOGY 2025; 160:110208. [PMID: 39988218 DOI: 10.1016/j.fsi.2025.110208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 01/30/2025] [Accepted: 02/18/2025] [Indexed: 02/25/2025]
Abstract
The outbreak of mass mortality of Japanese flounder occurred in an aquaculture farm in Hebei province of China. This study isolated and identified Pseudomonas putida as the dominant bacterium from diseased Japanese flounder (Paralichthys olivaceus) based on morphological, physiological, biochemical characteristics, 16S rRNA gene sequencing, and whole-genome sequencing. Pathogenicity assessment, histopathological analysis, and host immune response were investigated. Results demonstrated that P. putida was pathogenic, causing acute enteritis and multiple organ damage in infected fish. The median lethal dose (LD50) was determined as 2.66 × 106 CFU/g. Transcriptome analysis of the spleen at three post-infection timepoints revealed a robust immune response, with significantly upregulation of immune pathways and downregulation of metabolic functions. Key cytokines (il-1β, il-6, tnf, il-8, il-12, cxcl10, ccl2) were significantly upregulated, indicating intense immune activation. Notably, the P. putida strain exhibited a multidrug-resistant phenotype and harbored multiple drug resistance genes and virulence factors. This is the first report linking P. putida to disease in P. olivaceus, comprehensively elucidating its causative role and the host immune response in Japanese flounder culture.
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Affiliation(s)
- Yaxian Zhao
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Zhongwei He
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Yufeng Liu
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Yuqin Ren
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Jiangong Ren
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Yitong Zhang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Yufen Wang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Guixing Wang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Lize San
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China
| | - Jilun Hou
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Hebei Key Laboratory of the Bohai Sea Fish Germplasm Resources Conservation and Utilization, Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China; Bohai Sea Fishery Research Center, Chinese Academy of Fishery Sciences, Qinhuangdao, 066100, China.
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Yan W, Xiang S, Feng J, Zu X. Role of ubiquitin-specific proteases in programmed cell death of breast cancer cells. Genes Dis 2025; 12:101341. [PMID: 40083330 PMCID: PMC11904532 DOI: 10.1016/j.gendis.2024.101341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 03/26/2024] [Accepted: 04/11/2024] [Indexed: 03/16/2025] Open
Abstract
Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related deaths among women worldwide. Great progress has been recently achieved in controlling breast cancer; however, mortality from breast cancer remains a substantial challenge, and new treatment mechanisms are being actively sought. Programmed cell death (PCD) is associated with the progression and treatment of many types of human cancers. PCD can be divided into multiple pathways including autophagy, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis, and anoikis. Ubiquitination is a post-translational modification process in which ubiquitin, a 76-amino acid protein, is coupled to the lysine residues of other proteins. Ubiquitination is involved in many physiological events and promotes cancer development and progression. This review elaborates the role of ubiquitin-specific protease (USP) in programmed cell death, which is common in breast cancer cells, and lays the foundation for tumor diagnosis and targeted therapy.
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Affiliation(s)
| | | | - Jianbo Feng
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001 Hunan, China
| | - Xuyu Zu
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001 Hunan, China
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Su W, Gong S, Luo Y, Ma X, Wei X, Song Y, Chen Q, Xu H, Ke C, He H, Shen F, Li J. Puerarin alleviates silicon dioxide-induced pulmonary inflammation and fibrosis via improving Autophagolysosomal dysfunction in alveolar macrophages of murine mice. Int Immunopharmacol 2025; 152:114375. [PMID: 40043356 DOI: 10.1016/j.intimp.2025.114375] [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: 01/10/2025] [Revised: 02/16/2025] [Accepted: 02/24/2025] [Indexed: 03/24/2025]
Abstract
Silicosis, caused by the inhalation of silicon dioxide (SiO2), is one of the most pressing public health problems. Nevertheless, there is currently no effective treatment. This study employed male C57BL/6 J mice and mouse alveolar macrophage cell line MH-S to investigate the biological mechanism in the development of silicosis, with a view to exploring the potential applications of puerarin (Pue) in the improvement of pulmonary inflammation and fibrosis in SiO2-exposed mice. This study elucidated that SiO2 could induce expression of inflammatory factors, accompanied by autophagy flux block, lysosome alkalization and membrane permeability in MH-S cells. Pue pretreatment could effectively inhibit expression of inflammatory factors in SiO2-exposed MH-S cells via alleviating autophagolysosomal dysfunction, and suppress TGF-β-induced myofibroblast differentiation. In addition, Pue was also been demonstrated to mitigate autophagolysosomal dysfunction, pulmonary inflammation and fibrosis in SiO2-exposed C57BL/6 J mice. Furthermore, the ingestion of Pue-enriched pueraria lobata tea (Plt), a traditional Chinese tea substitute that possesses anti-inflammatory, antioxidant, and cardiovascular benefits, was determined to improve imbalance of lysosome homeostasis, pulmonary inflammation and fibrosis in SiO2-exposed mice. This study illustrates the anti-inflammatory and antifibrotic properties of Pue and Plt by alleviating autophagolysosomal dysfunction and, consequently, reducing pulmonary inflammation and fibrosis. These findings provide insights into the pathogenesis mechanism of silicosis and indicate potential avenues for application of Pue and Plt in the mitigation of silicosis.
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Affiliation(s)
- Wei Su
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Shuwen Gong
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Yi Luo
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Xinyu Ma
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Xiaoxi Wei
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Yining Song
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Qiuyi Chen
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Hong Xu
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China; Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China
| | - Changyong Ke
- Shanxi Qin Dashan Kudzu Industry Co., Qin Dashan Ecological Park, Baihe County, Ankang City, Shaanxi Province, PR China
| | - Hailan He
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China; Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China.
| | - Fuhai Shen
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China; Hebei Coordinated Innovation Center of Occupational Health and Safety, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China.
| | - Jinlong Li
- School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China; Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China; Hebei Coordinated Innovation Center of Occupational Health and Safety, North China University of Science and Technology, Tangshan, Hebei Province 063210, PR China.
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8
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Yang B, Shen M, Lu C, Wang Y, Zhao X, Zhang Q, Qin X, Pei J, Wang H, Wang J. RNF144A inhibits autophagy by targeting BECN1 for degradation during L. monocytogenes infection. Autophagy 2025; 21:789-806. [PMID: 39608349 PMCID: PMC11925115 DOI: 10.1080/15548627.2024.2429380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/30/2024] Open
Abstract
Listeria monocytogenes (L. monocytogenes, Lm) is widely used in the laboratory as an infection model for the research on pathogenesis and host defense against gram-positive intracellular bacteria. Macroautophagy (called simply "autophagy" hereafter), is important in the host defense against pathogens, such as bacteria, viruses, and parasites. BECN1 plays a pivotal role in the initiation of autophagy and accumulating evidence indicates that post-translational modifications of BECN1 provide multiple strategies for autophagy regulation. In this study, we demonstrated that the RING1-IBR-RING2 (RBR) family member RNF144A (ring finger protein 144A), which was induced by Lm infection, promoted Lm infection in an autophagy-dependent but STING1-independent pattern. rnf144a deficiency in mice protected mice from Lm infection with inhibited innate immune responses. Interestingly, RNF144A decreased Lm-induced autophagosome accumulation. Mechanistic investigation indicated that RNF144A interacted with BECN1 and promoted its K48-linked ubiquitination, leading to the subsequent proteasome-dependent degradation of BECN1 and reduced autophagosome accumulation. Further study demonstrated that RNF144A promoted the ubiquitination of BECN1 at K117 and K427, and these two ubiquitination sites were essential to the role of BECN1 in autophagy and Lm infection. Thus, our findings suggested a new regulator in intracellular bacterial infection and autophagy, which may contribute to our understanding of host defense against intracellular bacterial infection via autophagy.Abbreviations: ATG3: autophagy related 3; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG10: autophagy related 10; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; Baf A1: bafilomycin A1; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cell; BMDM: bone marrow-derived macrophage; CFUs: colony-forming units; CHX: cycloheximide; CQ: chloroquine; CXCL10/IP-10: C-X-C motif chemokine ligand 10; EBSS: Earle's balanced salt solution; ELISA: enzyme-linked immunosorbent assay; IFIT1/ISG56: interferon induced protein with tetratricopeptide repeats 1; IFNB/IFN-β: interferon beta; IL6: interleukin 6; IRF3, interferon regulatory factor 3; Lm: L. monocytogenes; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MOI: multiplicity of infection; PLA: proximity ligation assay; PMA: phorbol myristate acetate; PMA-THP1, PMA-differentiated THP1; PMs: peritoneal macrophages; PTMs: posttranslational modifications; RBR: RING1-IBR-RING2; RNF144A: ring finger protein 144A; STING1, stimulator of interferon response cGAMP interactor 1; TBK1, TANK binding kinase 1; TNF/TNF-α: tumor necrosis factor.
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Affiliation(s)
- Bo Yang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Mengyang Shen
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Chen Lu
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yi Wang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xin Zhao
- Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Qunmei Zhang
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
| | - Xiao Qin
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Jinyong Pei
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hui Wang
- Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, Henan, China
| | - Jie Wang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
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Huang X, Yan H, Xu Z, Yang B, Luo P, He Q. The inducible role of autophagy in cell death: emerging evidence and future perspectives. Cell Commun Signal 2025; 23:151. [PMID: 40140912 PMCID: PMC11948861 DOI: 10.1186/s12964-025-02135-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/02/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague. AIM OF REVIEW This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate. KEY SCIENTIFIC CONCEPTS OF REVIEW This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.
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Affiliation(s)
- Xiangliang Huang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
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10
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Barbeau LMO, Beelen NA, Savelkouls KG, Keulers TGH, Wieten L, Rouschop KMA. MAP1LC3C repression reduces CIITA- and HLA class II expression in non-small cell lung cancer. PLoS One 2025; 20:e0316716. [PMID: 39928678 PMCID: PMC11809862 DOI: 10.1371/journal.pone.0316716] [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: 06/12/2024] [Accepted: 12/15/2024] [Indexed: 02/12/2025] Open
Abstract
In the last decade, advancements in understanding the genetic landscape of lung squamous cell carcinoma (LUSC) have significantly impacted therapy development. Immune checkpoint inhibitors (ICI) have shown great promise, improving overall and progression-free survival in approximately 25% of the patients. However, challenges remain, such as the lack of predictive biomarkers, difficulties in patient stratification, and identifying mechanisms that cancers use to become immune-resistant ("immune-cold"). Analysis of TCGA datasets reveals reduced MAP1LC3C expression in cancer. Further analysis indicates that low MAP1LC3C is associated with reduced CIITA and HLA expression and with decreased immune cell infiltration. In tumor cells, silencing MAP1LC3C inhibits CIITA expression and suppresses HLA class II production. These findings suggest that cancer cells are selected for low MAP1LC3C expression to evade efficient immune responses.
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Affiliation(s)
- Lydie M. O. Barbeau
- Department of Radiation Oncology (Maastro), GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Nicky A. Beelen
- Department of Internal Medicine, GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
- Department of Transplantation Immunology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Kim G. Savelkouls
- Department of Radiation Oncology (Maastro), GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Tom G. H. Keulers
- Department of Radiation Oncology (Maastro), GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Lotte Wieten
- Department of Transplantation Immunology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Kasper M. A. Rouschop
- Department of Radiation Oncology (Maastro), GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
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Ibrahim D, Khater SI, Sherkawy HS, Elgamal A, Hasan AA, Muhammed AA, Farag MFM, Eissa SA, Ismail TA, Eissa HM, Eskandrani AA, Alansari WS, El-Emam MMA. Protective Role of Nano-encapsulated Bifidobacterium breve, Bacilllus coagulans, and Lactobacillus plantarum in Colitis Model: Insights Toward Propagation of Short-Chain Fatty Acids and Reduction of Exaggerated Inflammatory and Oxidative Response. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10472-y. [PMID: 39900879 DOI: 10.1007/s12602-025-10472-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2025] [Indexed: 02/05/2025]
Abstract
Irritable bowel disease (IBD), also known as ulcerative colitis and Crohn's disease, is a chronic inflammatory disorder affecting millions of people worldwide. Herein, nano-encapsulated multi-strain probiotics formulation, comprising Bifidobacterium breve DSM24732 and B. coagulans SANK 70258 and L. plantarum DSM24730 (BBLNPs) is used as an effective intervention technique for attenuating IBD through gut microenvironment regulation. The efficacy of the prophylactic role of BBLNPs in alleviating injury induced by dextran sulfate sodium (DSS) was evaluated by assessing oxidative and inflammatory responses, levels of short-chain fatty acids (SCFAs) and their regulation on GPR41/43 pathway, expression of genes related to tight-junctions and autophagy, immunohistochemistry of IL1β and GPR43, and histological examination of inflamed colonic tissue. The severity of clinical signs and paracellular permeability to FITC (fluorescein isothiocyanate)-labeled dextran was significantly decreased after BBLNP treatment. Reduction of oxidative stress-associated biomarkers (MDA, ROS, and H2O2) and acceleration of antioxidant enzyme activities (SOD, CAT, and GSH-Px) were noted in the BBLNP-treated group. Subsiding of inflammatory markers (TNF-α, IL-18, IL-6, TRL-4, CD-8, NLRP3, and caspase 1) and upregulation of tight-junction-related genes (occludin and JAM) was detected in BBLNPs. Administration of BBLNPs remarkably resulted in a higher level of SCFAs which parrel with colonic upregulation of GPR41 and GPR43 expression compared to DSS-treated rats. Notable modulation of autophagy-related genes (p62, mTOR, LC3, and Beclin-1) was identified post BBLNP treatment. The mRNA expressions of p62 and mTOR were significantly downregulated, while LC3 and Beclin-1 were upregulated after prophylactic treatment with BBLNPs. Immune-stained labeled cells showed lower expression of IL-1β and higher expression levels of GPR43 in BBLNPs compared to the DSS-induced group. The intestinal damage caused by DSSwas effectively mitigated by oral BBLNP treatment, as supported by the restoration of healthy colonic tissue architecture. The findings suggest that BBLNPs have a promising avenue in the remission of IBD by modulating inflammation, oxidative stress, microbial metabolites such as SCFAs, and autophagy.
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Affiliation(s)
- Doaa Ibrahim
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt.
| | - Safaa I Khater
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Hoda S Sherkawy
- Department of Medical Biochemistry, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - Aya Elgamal
- Department of Animal Histology and Anatomy, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Cairo, Egypt
| | - Asmaa A Hasan
- Department of Human Anatomy and Embryology, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - Asmaa A Muhammed
- Department of Medical Physiology, Faculty of Medicine, Aswan University, Aswan, 81511, Egypt
| | - Mohamed F M Farag
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Samar A Eissa
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Tamer Ahmed Ismail
- Department of Clinical Laboratory Sciences, Turabah University College, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Hemmat M Eissa
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Areej A Eskandrani
- Chemistry Department, College of Science, Taibah University, Medina, Saudi Arabia
| | - Wafa S Alansari
- Biochemistry Department, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Mahran Mohamed Abd El-Emam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
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12
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Xin Y, Wang Y. Programmed Cell Death Tunes Periodontitis. Oral Dis 2025. [PMID: 39846400 DOI: 10.1111/odi.15248] [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: 08/14/2024] [Revised: 11/25/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
OBJECTIVE To review current knowledge of the various processes of programmed cell death and their roles in immunoregulation in periodontitis. METHODS Relevant literature in the PubMed, Medline, and Scopus databases was searched, and a narrative review was performed. Programmed cell death and the regulation of its various pathways implicated in periodontal infection were reviewed. RESULTS Multicellular organisms dispose of unnecessary or damaged cells via programmed cell death. Programmed cell death lies at the core of the balance of cell death and survival in pathological progress and infection. Periodontitis is a complex infectious disease involving virulence factors of periodontal pathogens and tightly regulated immune responses of the host. Different types of programmed cell death can play opposite roles in periodontitis or exert their action combinatorially. CONCLUSION The coordinated system of various programmed cell death pathways and the extensive crosstalk among them play a fundamental role in the pathophysiology of periodontitis. Illuminating the precise roles and mechanisms of programmed cell death in periodontitis could open up novel therapeutic approaches.
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Affiliation(s)
- Yuejiao Xin
- Department of Periodontics, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, China
| | - Yixiang Wang
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
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13
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Xia Q, Zhang J. Interaction Between Autophagy and the Inflammasome in Human Tumors: Implications for the Treatment of Human Cancers. Cell Biochem Funct 2025; 43:e70035. [PMID: 39722223 DOI: 10.1002/cbf.70035] [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: 09/27/2024] [Revised: 10/10/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024]
Abstract
Autophagy is a physiologically regulated cellular process orchestrated by autophagy-related genes (ATGs) that, depending on the tumor type and stage, can either promote or suppress tumor growth and progression. It can also modulate cancer stem cell maintenance and immune responses. Therefore, targeted manipulation of autophagy may inhibit tumor development by overcoming tumor-promoting mechanisms. The inflammasome is another multifunctional bioprocess that induces a form of pro-inflammatory programmed cell death, called pyroptosis. Dysregulation or overactivation of the inflammasome has been implicated in tumor pathogenesis and development. Additionally, autophagy can inhibit the NLRP3 inflammasome by removing inflammatory drivers. Recent research suggests that the NLRP3 inflammasome, in turn, affects autophagy. Understanding the complex interplay between autophagy and inflammasomes could lead to more precise and effective strategies for cancer treatments. In this review, we summarize the impact of autophagy and inflammasome dysregulation on tumor progression or suppression. We then highlight their targeting for cancer treatment as monotherapy or in combination with other therapies. Furthermore, we discuss the interaction between autophagy and tumor-promoting inflammation or the NLRP3 inflammasome. Finally, based on recent findings, we review the potential of this interaction for cancer treatment.
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Affiliation(s)
- Qing Xia
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingzhou Zhang
- Peking Union Medical College, Graduate School of Peking Union Medical College, Beijing, China
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14
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Hu Y, Yu Q, Li X, Wang J, Guo L, Huang L, Gao W. Nanoformula Design for Inducing Non-Apoptotic Cell Death Regulation: A Powerful Booster for Cancer Immunotherapy. Adv Healthc Mater 2025; 14:e2403493. [PMID: 39632361 DOI: 10.1002/adhm.202403493] [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: 11/03/2024] [Indexed: 12/07/2024]
Abstract
Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.
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Affiliation(s)
- Yi Hu
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Qing Yu
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Xia Li
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Juan Wang
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Wenyuan Gao
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
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15
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Guo N, Xia Y, He N, Cheng H, Zhang L, Liu J. IRGM Deficiency Exacerbates Sepsis-Induced Acute Lung Injury by Inhibiting Autophagy Through the AKT/mTOR Signaling Pathway. J Inflamm Res 2024; 17:10255-10272. [PMID: 39654860 PMCID: PMC11626208 DOI: 10.2147/jir.s496687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024] Open
Abstract
Background Sepsis is a life-threatening condition characterized by organ dysfunction due to an impaired immune response to infection. The lungs are highly susceptible to infection, often resulting in acute lung injury (ALI). The immune-related GTPase M (IRGM) and its murine homolog Irgm1 mediate autophagy and are implicated in inflammatory diseases, yet their roles in sepsis-induced ALI remain unclear. Methods We used RNA sequencing and bioinformatics to explore IRGM regulation. Sepsis-induced ALI was modeled in mice using cecal ligation and puncture (CLP). An in vitro model was created by stimulating A549 cells with lipopolysaccharide (LPS). Results In A549 cells, LPS treatment induced upregulation of IRGM expression and enhanced autophagy levels. IRGM knockdown exacerbated LPS-induced ALI, characterized by suppressed autophagy and increased apoptosis, along with significantly elevated levels of p-AKT and p-mTOR. Further investigation revealed that treatment with the AKT inhibitor MK2206 effectively reversed the autophagy inhibition caused by IRGM knockdown and reduced apoptosis. These findings suggest that the AKT/mTOR signaling pathway plays a crucial role in IRGM-mediated protection against sepsis-related ALI. Conclusion This study identifies the protective role of IRGM in sepsis-induced ALI and reveals that IRGM mitigates ALI by promoting autophagy through inhibition of the AKT/mTOR pathway. These findings provide insights into the pathogenesis of sepsis-related ALI and highlight IRGM as a potential therapeutic target.
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Affiliation(s)
- Na Guo
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Yu Xia
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Nannan He
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Huixin Cheng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
| | - Lei Zhang
- Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, People’s Republic of China
| | - Jian Liu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China
- Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, People’s Republic of China
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16
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Feng Y, Liu M, Liu Y, Li H. Invasion of human dental pulp fibroblasts by Porphyromonas gingivalis leads to autophagy via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling pathway. J Oral Biosci 2024; 66:10-18. [PMID: 39179205 DOI: 10.1016/j.job.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 08/26/2024]
Abstract
OBJECTIVES Porphyromonas gingivalis is a pathogenic bacterium that causes periodontitis and dental pulp infection. Autophagy is a potential mechanism involved in inflammatory disease. This study established an in vitro model of P. gingivalis intracellular infection in human dental pulp fibroblasts (HDPFs) to investigate the effects of live P. gingivalis on HDPFs. METHODS Morphological and quantification techniques such as fluorescence microscopy, transmission electron microscopy (TEM), indirect immunofluorescence analysis, enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR), and western blotting were used in this study. RESULTS After cell invasion, P. gingivalis is mainly localized in the cytoplasm and lysosomes. Additionally, P. gingivalis activates autophagy in HDPFs by upregulating the expression of autophagy-related gene Beclin-1, activate autophagy-related gene12 (ATG12), and microtubule-associated protein light chain 3 (LC3). Furthermore, the invasion of P. gingivalis leads to increased phosphorylation of PI3K, Akt, and mTOR with the addition of rapamycin, whereas the addition of wortmannin decreased phosphorylation. This invasion of P. gingivalis, also causes an inflammatory response, leading to the upregulation of IL-1β, IL-6, and TNF-α. Rapamycin helps decrease levels of pro-inflammatory cytokines, but the addition of wortmannin increases them. These results show that the invasion of P. gingivalis can cause excessive inflammation and promote the autophagy of HDPFs, which is regulated by PI3K/Akt/mTOR. CONCLUSIONS P. gingivalis escapes the immune system by inducing autophagy in the host cells, causing excessive inflammation. P. gingivalis regulates autophagy in HDPFs through the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway.
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Affiliation(s)
- Ying Feng
- Department of General Dentistry and Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Mingxiang Liu
- Department of Endodontics, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Hong Li
- Department of Endodontics, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China.
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Cheng Y, Liu G, Huang X, Xiong Y, Song N, An Z, Hong W, Leethanakul C, Samruajbenjakun B, Liao J. Zoledronic Acid Inhibits Lipopolysaccharide-Induced Osteoclastogenesis by Suppressing Macrophage NLRP3-Mediated Autophagy Pathway. Immun Inflamm Dis 2024; 12:e70094. [PMID: 39679857 PMCID: PMC11647992 DOI: 10.1002/iid3.70094] [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: 04/30/2024] [Revised: 10/19/2024] [Accepted: 11/20/2024] [Indexed: 12/17/2024] Open
Abstract
INTRODUCTION Inflammatory factors leading to bone loss significantly increase the risk of tooth loosening or implantation failure. Zoledronic acid (ZOL) is a widely used medication for effectively inhibiting excessive bone destruction, but its effect on alleviating inflammatory bone loss remains to be elucidated. In this study, we investigated whether ZOL alleviates inflammatory bone resorption through immunomodulatory effect. METHODS The viability of the cells was evaluated by Cell Counting Kit 8 (CCK8) assay. Osteoclast (OC) differentiation and function were determined by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption pits assays, respectively. Autophagosomes and actin ring structures of OC were observed using transmission electron microscopy (TEM) and F-actin ring staining, respectively. The microstructure in mice maxillary alveolar bone model was observed by micro computed tomography (Miro-CT). Reverse transcription-quantitative PCR (RT-qPCR) to detect the mRNA expression of osteoclast-related genes and Western blot (WB) analysis to evaluate the protein expression levels of autophagy-related proteins and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3)-related proteins in pre-OCs. RESULTS The findings indicated that ZOL hindered lipopolysaccharide (LPS)-mediated OC differentiation, formation, bone resorption activity and autophagosome levels. Furthermore, ZOL diminished the expression of genes associated with OC. And the expression of proteins ATG7, LC3II, Beclin1, NLRP3-related proteins and tumor necrosis factor-α (TNF-α) protein were markedly decreased while P62 was increased, especially in the 1 μM ZOL group or MCC950 + ZOL group. CONCLUSIONS ZOL has a certain immunomodulatory effect that exhibits anti-inflammatory properties at lower concentrations, which can weaken LPS-induced OCs differentiation and function, and NLRP3-mediated autophagy pathway may participate in this process.
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Affiliation(s)
- Yuting Cheng
- School/Hospital of StomatologyGuizhou Medical UniversityGuiyangChina
- Faculty of DentistryPrince of Songkla UniversityHat YaiThailand
| | - Guanjuan Liu
- School/Hospital of StomatologyGuizhou Medical UniversityGuiyangChina
| | - Xiaolin Huang
- Hospital of Stomatology, Zhongshan CityZhongshanChina
| | - Yue Xiong
- School/Hospital of StomatologyGuizhou Medical UniversityGuiyangChina
| | - Na Song
- School/Hospital of StomatologyGuizhou Medical UniversityGuiyangChina
| | - Zheqing An
- School/Hospital of StomatologyGuizhou Medical UniversityGuiyangChina
| | - Wei Hong
- Key Laboratory of Endemic and Ethnic DiseasesGuizhou Medical University, Ministry of EducationGuiyangChina
| | | | | | - Jian Liao
- School/Hospital of StomatologyGuizhou Medical UniversityGuiyangChina
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18
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Bai R, Yang D, Sun R, Zhang X, Shi L, Liu J, Sun H, Yao L, Tang Y. A supramolecular fluorescence probe that simultaneously responds to viscosity and G-quadruplex for autophagy detection. Anal Chim Acta 2024; 1329:343245. [PMID: 39396306 DOI: 10.1016/j.aca.2024.343245] [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: 07/03/2024] [Revised: 08/20/2024] [Accepted: 09/13/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Autophagy, as an essential physiological process in eukaryotes, has been revealed to be closely related to aging and many major diseases. Real-time in situ imaging of autophagy processes in living cells is necessary for timely detection of autophagy defects and the development of treatment methods. Currently, many studies are dedicated to the design of autophagy probes, and various types of fluorescent probes for autophagy detection have been reported. However, most of them are single fluorescence signal outputs, which may lead to non-specific signals. Nowadays a reliable and sensitive autophagy monitoring probe is still essential. RESULTS A supramolecular fluorescent probe was prepared via the controllable self-assembly of a thiacyanine dye named PTC for tracking autophagy in living cells. PTC was very sensitive to viscosity, and its aggregates were completely converted into monomers as viscosity increased. This process led to a significant increase of over 2000 times in the fluorescence intensity ratio between monomers and aggregates. PTC also exhibited selective affinity for G-quadruplex (G4) structure, which decomposed PTC aggregates into monomers, resulting in a fluorescence ratio increase of up to tens of folds. In living cells, PTC existed as aggregates in lysosomes, maintaining sensitivity to viscosity and G4s. In confocal imaging experiments, PTC sensitively responded to the induction and inhibition of cellular autophagy, displaying opposite changes in the monomer and aggregate fluorescent channels. SIGNIFICANCE This work provides a reliable fluorescent probe for autophagy detection in live cells, which has the advantages of high sensitivity, low cost, and ease of use, making it have the potential for widespread application. This study also offers a new strategy for designing autophagy probes with both high sensitivity and high specificity.
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Affiliation(s)
- Ruiyang Bai
- College of Chemistry Engineering, North China University of Science and Technology, Tangshan, 063210, PR China; Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, PR China
| | - Dawei Yang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Ranran Sun
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Xiufeng Zhang
- College of Chemistry Engineering, North China University of Science and Technology, Tangshan, 063210, PR China.
| | - Lei Shi
- College of Chemistry Engineering, North China University of Science and Technology, Tangshan, 063210, PR China
| | - Jing Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, PR China
| | - Hongxia Sun
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
| | - Li Yao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
| | - Yalin Tang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry Chinese Academy of Sciences, Beijing, 100190, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
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Song Y, Tang L, Li N, Xu J, Zhang Z, Ma H, Liao Y, Chu Y. Mycoplasma bovis activates apoptotic caspases to suppress xenophagy for its intracellular survival. Vet Microbiol 2024; 298:110298. [PMID: 39509837 DOI: 10.1016/j.vetmic.2024.110298] [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: 06/18/2024] [Revised: 10/30/2024] [Accepted: 11/03/2024] [Indexed: 11/15/2024]
Abstract
Mammalian caspases are categorized into apoptotic and inflammatory types. Apoptotic caspases mediate apoptosis activation, while inflammatory caspases participate in inflammasome activation. Previous studies have shown that apoptotic caspases regulate autophagy in both cancer and pharmacological treatment models. However, the relationship between apoptotic caspases and xenophagy during pathogen infection remains elusive. In the current study, we used Mycoplasma bovis (M. bovis) as a model pathogen investigating the relationship between apoptotic caspases and xenophagy during infection. We found that M. bovis activated apoptotic caspases by triggering mitochondrial damage in macrophages, and the intracellular survival of M. bovis was enhanced by the activation of apoptotic caspases and restricted by the inhibition of apoptotic caspases. Moreover, confocal microscopy and Western blot analysis revealed that the activation of apoptotic caspases impedes host xenophagy by cleaving autophagy-related protein Beclin 1. Our findings indicate that M. bovis utilizes host apoptotic caspases to suppress xenophagy, thereby enhancing its intracellular survival. This research contributes to understanding the interplay between apoptotic caspases and xenophagy during pathogen infection, offering novel insights into the intracellular survival mechanisms of mycoplasma in macrophages.
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Affiliation(s)
- Yinjuan Song
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Li Tang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Na Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Jian Xu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Zhengyang Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Hui Ma
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
| | - Yi Liao
- Key Laboratory of Veterinary Medicine of Universities in Sichuan, College of Animal and Veterinary Sciences, Southwest Minzu University, Sichuan 610041, China
| | - Yuefeng Chu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou 730046, China.
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20
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Luo R, Wang T, Lan J, Lu Z, Chen S, Sun Y, Qiu HJ. The multifaceted roles of selective autophagy receptors in viral infections. J Virol 2024; 98:e0081424. [PMID: 39212450 PMCID: PMC11494948 DOI: 10.1128/jvi.00814-24] [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] [Indexed: 09/04/2024] Open
Abstract
Selective autophagy is a protein clearance mechanism mediated by evolutionarily conserved selective autophagy receptors (SARs), which specifically degrades misfolded, misassembled, or metabolically regulated proteins. SARs help the host to suppress viral infections by degrading viral proteins. However, viruses have evolved sophisticated mechanisms to counteract, evade, or co-opt autophagic processes, thereby facilitating viral replication. Therefore, this review aims to summarize the complex mechanisms of SARs involved in viral infections, specifically focusing on how viruses exploit strategies to regulate selective autophagy. We present an updated understanding of the various critical roles of SARs in viral pathogenesis. Furthermore, newly discovered evasion strategies employed by viruses are discussed and the ubiquitination-autophagy-innate immune regulatory axis is proposed to be a crucial pathway to control viral infections. This review highlights the remarkable flexibility and plasticity of SARs in viral infections.
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Affiliation(s)
- Rui Luo
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Tao Wang
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Jing Lan
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
- College of Animal Sciences, Yangtze University, Jingzhou, China
| | - Zhanhao Lu
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Shengmei Chen
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
- School of Life Science Engineering, Foshan University, Foshan, China
| | - Yuan Sun
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Hua-Ji Qiu
- State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
- College of Animal Sciences, Yangtze University, Jingzhou, China
- School of Life Science Engineering, Foshan University, Foshan, China
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21
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Amini J, Sanchooli N, Milajerdi MH, Baeeri M, Haddadi M, Sanadgol N. The interplay between tauopathy and aging through interruption of UPR/Nrf2/autophagy crosstalk in the Alzheimer's disease transgenic experimental models. Int J Neurosci 2024; 134:1049-1067. [PMID: 37132251 DOI: 10.1080/00207454.2023.2210409] [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: 02/13/2022] [Revised: 10/14/2022] [Accepted: 04/24/2023] [Indexed: 05/04/2023]
Abstract
PURPOSE Alzheimer's disease (AD) is the most common form of tauopathy that usually occursduring aging and unfolded protein response (UPR), oxidative stress and autophagy play a crucialrole in tauopathy-induced neurotoxicity. The aim of this study was to investigate the effects oftauopathy on normal brain aging in a Drosophila model of AD. METHOD We investigated the interplay between aging (10, 20, 30, and 40 days) and human tauR406W (htau)-induced cell stress in transgenic fruit flies. RESULTS Tauopathy caused significant defects in eye morphology, a decrease in motor function and olfactory memory performance (after 20 days), and an increase in ethanol sensitivity (after 30 days). Our results showed a significant increase in UPR (GRP78 and ATF4), redox signalling (p-Nrf2, total GSH, total SH, lipid peroxidation, and antioxidant activity), and regulatory associated protein of mTOR complex 1 (p-Raptor) activity in the control group after 40 days, while the tauopathy model flies showed an advanced increase in the above markers at 20 days of age. Interestingly, only the control flies showed reduced autophagy by a significant decrease in the autophagosome formation protein (dATG1)/p-Raptor ratio at 40 days of age. Our results were also confirmed by bioinformatic analysis of microarray data from tauPS19 transgenic mice (3, 6, 9, and 12 months), in which tauopathy increased expression of heme oxygenase 1, and glutamate-cysteine ligase catalytic subunit and promote aging in transgenic animals. CONCLUSIONS Overall, we suggest that the neuropathological effects of tau aggregates may be accelerated brain aging, where redox signaling and autophagy efficacy play an important role.
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Affiliation(s)
- Javad Amini
- Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran
| | - Naser Sanchooli
- Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran
| | | | - Maryam Baeeri
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences, and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Science, Tehran, Iran
| | - Mohammad Haddadi
- Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran
| | - Nima Sanadgol
- Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran
- Institute of Neuroanatomy, RWTH University Hospital Aachen, Aachen, Germany
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22
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Luo L, Deng J, Tang Q. A Four-Gene Autophagy-Related Prognostic Model Signature and Its Association With Immune Phenotype in Lung Squamous Cell Carcinoma. Cancer Rep (Hoboken) 2024; 7:e70000. [PMID: 39443755 PMCID: PMC11499073 DOI: 10.1002/cnr2.70000] [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: 12/14/2023] [Revised: 07/21/2024] [Accepted: 08/10/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND In the era of immunotherapy, there is a critical need for effective biomarkers to improve outcome prediction and guide treatment decisions for patients with lung squamous cell carcinoma (LUSC). We hypothesized that the immune contexture of LUSC may be influenced by tumor intrinsic events, such as autophagy. AIMS We aimed to develop an autophagy-related risk signature and assess its predictive value for immune phenotype. METHODS AND RESULTS Expression profiles of autophagy-related genes (ARGs) in LUSC samples were obtained from the TCGA and GEO databases. Survival analyses were conducted to identify survival-related ARGs and construct a risk signature using the Random Forest algorithm. Four ARGs (CFLAR, RGS19, PINK1, and CTSD) with the most significant prognostic value were selected to construct the risk signature. Patients in the high-risk group exhibited worse prognosis than those in the low-risk group (p < 0.0001 in TCGA; p < 0.01 in GEO) and the risk score was identified as an independent prognostic factor. We observed that the high-risk group displayed an immune-suppressive status and showed higher levels of infiltrating regulatory T cells and macrophages, which are associated with poorer outcomes. Additionally, the risk score exhibited a significantly positive correlation with the expression of PD-1 and CTLA4, as well as the estimate score and immune score. CONCLUSION This study provided an effective autophagy-related prognostic signature, which could also predict the immune phenotype.
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Affiliation(s)
- Lumeng Luo
- Department of Radiation OncologyWomen's Hospital, School of Medicine, Zhejiang UniversityZhejiangChina
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of MedicineHangzhouPeople's Republic of China
- Zhejiang Provincial Clinical Research Center for Obstetrics and GynecologyZhejiangChina
| | - Jiaying Deng
- Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
| | - Qiu Tang
- Department of Radiation OncologyWomen's Hospital, School of Medicine, Zhejiang UniversityZhejiangChina
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of MedicineHangzhouPeople's Republic of China
- Zhejiang Provincial Clinical Research Center for Obstetrics and GynecologyZhejiangChina
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23
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Du L, Zhang Q, Li Y, Li T, Deng Q, Jia Y, Lei K, Kan D, Xie F, Huang S. Research progress on the role of PTEN deletion or mutation in the immune microenvironment of glioblastoma. Front Oncol 2024; 14:1409519. [PMID: 39206155 PMCID: PMC11349564 DOI: 10.3389/fonc.2024.1409519] [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: 03/30/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma.
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Affiliation(s)
- Leiya Du
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Qian Zhang
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yi Li
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Ting Li
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Qingshan Deng
- Department of Neurosurgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yuming Jia
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Kaijian Lei
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Daohong Kan
- Department of Burn and Plastic Surgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Fang Xie
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Shenglan Huang
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
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Cai K, Jiang H, Zou Y, Song C, Cao K, Chen S, Wu Y, Zhang Z, Geng D, Zhang N, Liu B, Sun G, Tang M, Li Z, Zhang Y, Sun Y, Zhang Y. Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches. Pharmacol Res 2024; 206:107281. [PMID: 38942341 DOI: 10.1016/j.phrs.2024.107281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 06/30/2024]
Abstract
Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.
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Affiliation(s)
- Kexin Cai
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Haoyue Jiang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Yuanming Zou
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Chunyu Song
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Kexin Cao
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Shuxian Chen
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Yanjiao Wu
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Zhaobo Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Danxi Geng
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China
| | - Naijin Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China; Institute of health sciences, China medical university, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110001, People's Republic of China; Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110001, People's Republic of China
| | - Bo Liu
- The first hospital of China Medical University, Department of cardiac surgery, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China.
| | - Guozhe Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China.
| | - Man Tang
- Department of clinical pharmacology, College of Pharmacy, China medical university, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110001, People's Republic of China.
| | - Zhao Li
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China.
| | - Yixiao Zhang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, Liaoning 110004, People's Republic of China.
| | - Yingxian Sun
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China; Institute of health sciences, China medical university, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110001, People's Republic of China; Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110001, People's Republic of China.
| | - Ying Zhang
- Department of Cardiology, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, People's Republic of China; Institute of health sciences, China medical university, 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110001, People's Republic of China.
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Zhao C, Changhong Lin, Zhang B, Wang P, Zhang B, Yan L, Wang C, Qiu L. Study on the mechanism of miR-7562 regulating ATG5 and ATG12 genes in Penaeus monodon under Vibrio harveyi infection. FISH & SHELLFISH IMMUNOLOGY 2024; 151:109670. [PMID: 38838838 DOI: 10.1016/j.fsi.2024.109670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/01/2024] [Accepted: 06/02/2024] [Indexed: 06/07/2024]
Abstract
MicroRNAs (miRNAs) play a fundamental role in the post-transcriptional regulation of genes and are pivotal in modulating immune responses in marine species, particularly during pathogen assaults. This study focused on the function of miR-7562 and its regulatory effects on autophagy against Vibrio harveyi infection in the black tiger shrimp (Penaeus monodon), an economically important aquatic species. We successfully cloned and characterized two essential autophagy-related genes (ATGs) from P. monodon, PmATG5 and PmATG12, and then identified the miRNAs potentially involved in co-regulating these genes, which were notably miR-7562, miR-8485, and miR-278. Subsequent bacterial challenge experiments and dual-luciferase reporter assays identified miR-7562 as the principal regulator of both genes, particularly by targeting the 3'UTR of each gene. By manipulating the in vivo levels of miR-7562 using mimics and antagomirs, we found significant differences in the expression of PmATG5 and PmATG12, which corresponded to alterations in autophagic activity. Notably, miR-7562 overexpression resulted in the downregulation of PmATG5 and PmATG12, leading to a subdued autophagic response. Conversely, miR-7562 knockdown elevated the expression levels of these genes, thereby enhancing autophagic activity. Our findings further revealed that during V. harveyi infection, miR-7562 continued to influence the autophagic pathway by specifically targeting the ATG5-ATG12 complex. This research not only sheds light on the miRNA-dependent mechanisms governing autophagic immunity in shrimp but also proposes miR-7562 as a promising target for therapeutic strategies intended to strengthen disease resistance within the crustacean aquaculture industry.
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Affiliation(s)
- Chao Zhao
- Key Laboratory of Applied Marine Biotechnology, Ningbo University, Chinese Ministry of Education, Ningbo, PR China; South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, Guangzhou, PR China; Sanya Tropical Fisheries Research Institute, Sanya, PR China
| | - Changhong Lin
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; College of Aqua-life Science and Technology, Shanghai Ocean University, Shanghai, PR China
| | - Bo Zhang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, Guangzhou, PR China.
| | - Pengfei Wang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, Guangzhou, PR China; Sanya Tropical Fisheries Research Institute, Sanya, PR China
| | - Bo Zhang
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, Guangzhou, PR China.
| | - Lulu Yan
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, Guangzhou, PR China
| | - Chunlin Wang
- Key Laboratory of Applied Marine Biotechnology, Ningbo University, Chinese Ministry of Education, Ningbo, PR China
| | - Lihua Qiu
- South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, PR China; Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, Guangzhou, PR China; Sanya Tropical Fisheries Research Institute, Sanya, PR China.
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Zhou C, Qiu SW, Wang FM, Liu YC, Hu W, Yang ML, Liu WH, Li H. Gasdermin D could be lost in the brain parenchyma infarct core and a pyroptosis-autophagy inhibition effect of Jie-Du-Huo-Xue decoction after stroke. Front Pharmacol 2024; 15:1449452. [PMID: 39139639 PMCID: PMC11320715 DOI: 10.3389/fphar.2024.1449452] [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: 06/15/2024] [Accepted: 07/15/2024] [Indexed: 08/15/2024] Open
Abstract
Background The Chinese ethnic medicine Jie-Du-Huo-Xue Decoction (JDHXD) is used to alleviate neuroinflammation in cerebral ischemia (CI). Our previous studies have confirmed that JDHXD can inhibit microglial pyroptosis in CI. However, the pharmacological mechanism of JDHXD in alleviating neuroinflammation and pyroptosis needs to be further elucidated. New research points out that there is an interaction between autophagy and inflammasome NLRP3, and autophagy can help clear NLRP3. The NLRP3 is a key initiator of pyroptosis and autophagy. The effect of JDHXD promoting autophagy to clear NLRP3 to inhibit pyroptosis on cerebral ischemia-reperfusion inflammatory injury is currently unknown. We speculate that JDHXD can inhibit pyroptosis in CI by promoting autophagy to clear NLRP3. Methods Chemical characterization of JDHXD was performed using LC-MS. Model of middle cerebral artery occlusion/reperfusion (MCAO/R) was established in SD rats. Neurological deficits, neuron damage, and cerebral infarct volume were evaluated. Western Blot and immunofluorescence were used to detect neuronal pyroptosis and autophagy. Results 30 possible substance metabolites in JDHXD medicated serum were analyzed by LC-MS (Composite Score > 0.98). Furthermore, JDHXD protects rat neurological function and cerebral infarct size after CI. JDHXD inhibited the expression of pyroptosis and autophagy after CI. Our western blot and immunofluorescence results showed that JDHXD treatment can reduce the expression of autophagy-related factors ULK1, beclin1, and LC3-Ⅱ. The expression of NLRP3 protein was lower in the JDHXD group than in the I/R group. Compared with the I/R group, the expressions of pyroptosis-related factors caspase-1 P 10, GSDMD-NT, IL-18, and IL-1β decreased in the JDHXD group. Furthermore, we observed an unexpected result: immunofluorescence demonstrated that Gasdermin D (GSDMD) was significantly absent in the infarct core, and highly expressed in the peri-infarct and contralateral cerebral hemispheres. This finding challenges the prevailing view that GSDMD is elevated in the ischemic cerebral hemisphere. Conclusion JDHXD inhibited pyroptosis and autophagy after MCAO/R. JDHXD suppressed pyroptosis and autophagy by inhibiting NLRP3, thereby alleviating CI. In addition, we present a different observation from previous studies that the expression of GSDMD in the infarct core was lower than that in the peri-infarct and contralateral non-ischemic hemispheres on day 3 of CI.
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Affiliation(s)
- Chang Zhou
- Hunan University of Chinese Medicine, Changsha, Hunan, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Changsha, Hunan, China
| | - Shi-wei Qiu
- Hunan University of Chinese Medicine, Changsha, Hunan, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Feng-ming Wang
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yu-chen Liu
- Hunan University of Chinese Medicine, Changsha, Hunan, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Wei Hu
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Mei-lan Yang
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Wang-hua Liu
- Hunan University of Chinese Medicine, Changsha, Hunan, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Key Laboratory of TCM Heart and Lung Syndrome Differentiation & Medicated Diet and Dietotherapy, University of Chinese Medicine, Changsha, Hunan, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Hua Li
- Hunan University of Chinese Medicine, Changsha, Hunan, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan, China
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Mishra A, Khan A, Singh VK, Glyde E, Saikolappan S, Garnica O, Das K, Veerapandian R, Dhandayuthapani S, Jagannath C. The ΔfbpAΔsapM candidate vaccine derived from Mycobacterium tuberculosis H37Rv is markedly immunogenic in macrophages and induces robust immunity to tuberculosis in mice. Front Immunol 2024; 15:1321657. [PMID: 38975346 PMCID: PMC11224292 DOI: 10.3389/fimmu.2024.1321657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 06/03/2024] [Indexed: 07/09/2024] Open
Abstract
Tuberculosis (TB) remains a significant global health challenge, with approximately 1.5 million deaths per year. The Bacillus Calmette-Guérin (BCG) vaccine against TB is used in infants but shows variable protection. Here, we introduce a novel approach using a double gene knockout mutant (DKO) from wild-type Mycobacterium tuberculosis (Mtb) targeting fbpA and sapM genes. DKO exhibited enhanced anti-TB gene expression in mouse antigen-presenting cells, activating autophagy and inflammasomes. This heightened immune response improved ex vivo antigen presentation to T cells. Subcutaneous vaccination with DKO led to increased protection against TB in wild-type C57Bl/6 mice, surpassing the protection observed in caspase 1/11-deficient C57Bl/6 mice and highlighting the critical role of inflammasomes in TB protection. The DKO vaccine also generated stronger and longer-lasting protection than the BCG vaccine in C57Bl/6 mice, expanding both CD62L-CCR7-CD44+/-CD127+ effector T cells and CD62L+CCR7+/-CD44+CD127+ central memory T cells. These immune responses correlated with a substantial ≥ 1.7-log10 reduction in Mtb lung burden. The DKO vaccine represents a promising new approach for TB immunization that mediates protection through autophagy and inflammasome pathways.
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Affiliation(s)
- Abhishek Mishra
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell Medicine, Houston, TX, United States
| | - Arshad Khan
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell Medicine, Houston, TX, United States
| | - Vipul Kumar Singh
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell Medicine, Houston, TX, United States
| | - Emily Glyde
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell Medicine, Houston, TX, United States
| | - Sankaralingam Saikolappan
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Omar Garnica
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Kishore Das
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Raja Veerapandian
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Subramanian Dhandayuthapani
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Chinnaswamy Jagannath
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Weill-Cornell Medicine, Houston, TX, United States
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Fan HL, Han ZT, Gong XR, Wu YQ, Fu YJ, Zhu TM, Li H. Macrophages in CRSwNP: Do they deserve more attention? Int Immunopharmacol 2024; 134:112236. [PMID: 38744174 DOI: 10.1016/j.intimp.2024.112236] [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: 01/17/2024] [Revised: 05/05/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024]
Abstract
Chronic rhinosinusitis (CRS) represents a heterogeneous disorder primarily characterized by the persistent inflammation of the nasal cavity and paranasal sinuses. The subtype known as chronic rhinosinusitis with nasal polyposis (CRSwNP) is distinguished by a significantly elevated recurrence rate and augmented challenges in the management of nasal polyps. The pathogenesis underlying this subtype remains incompletely understood. Macrophages play a crucial role in mediating the immune system's response to inflammatory stimuli. These cells exhibit remarkable plasticity and heterogeneity, differentiating into either the pro-inflammatory M1 phenotype or the anti-inflammatory and reparative M2 phenotype depending on the surrounding microenvironment. In CRSwNP, macrophages demonstrate reduced production of Interleukin 10 (IL-10), compromised phagocytic activity, and decreased autophagy. Dysregulation of pro-resolving mediators may occur during the inflammatory resolution process, which could potentially hinder the adequate functioning of anti-inflammatory macrophages in facilitating resolution. Collectively, these factors may contribute to the prolonged inflammation observed in CRSwNP. Additionally, macrophages may enhance fibrin cross-linking through the release of factor XIII-A (FAXIII), promoting fibrin deposition and plasma protein retention. Macrophages also modulate vascular permeability by releasing Vascular endothelial growth factor (VEGF). Moreover, they may disrupt the balance between Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs), which favors extracellular matrix (ECM) degradation, edema formation, and pseudocyst development. Accumulating evidence suggests a close association between macrophage infiltration and CRSwNP; however, the precise mechanisms underlying this relationship warrant further investigation. In different subtypes of CRSwNP, different macrophage phenotypic aggregations trigger different types of inflammatory features. Increasing evidence suggests that macrophage infiltration is closely associated with CRSwNP, but the mechanism and the relationship between macrophage typing and CRSwNP endophenotyping remain to be further explored. This review discusses the role of different types of macrophages in the pathogenesis of different types of CRSwNP and their contribution to polyp formation, in the hope that a better understanding of the role of macrophages in specific CRSwNP will contribute to a precise and individualized understanding of the disease.
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Affiliation(s)
- Hong-Li Fan
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhou-Tong Han
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xin-Ru Gong
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yu-Qi Wu
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yi-Jie Fu
- School of Preclinical Medicine, Chengdu University, Chengdu, Sichuan, China
| | - Tian-Min Zhu
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Hui Li
- School of Preclinical Medicine, Chengdu University, Chengdu, Sichuan, China.
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Chen Q, Zhou Y, Yu M, Zhu S, Sun J, Du W, Chen Z, Tao J, Feng X, Zhang Q, Zhao Y. Transcription factor EB-mediated autophagy affects cell migration and inhibits apoptosis to promote endometriosis. Apoptosis 2024; 29:757-767. [PMID: 38358580 DOI: 10.1007/s10495-024-01939-4] [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] [Accepted: 01/29/2024] [Indexed: 02/16/2024]
Abstract
Autophagy has emerged as an important process of cell metabolism. With continuous in-depth research on autophagy, TFEB has been a key transcription factor regulating autophagy levels in recent years. Studies have established that TFEB regulates autophagy and apoptosis in various diseases. However, the relationship between TFEB and the pathogenesis of endometriosis remains unclear. This study aimed to investigate the effect of TFEB on the mechanism of endometriosis progression. The results showed that TFEB and autophagy-related protein LC3 are highly expressed in ectopic endometrium of patients with endometriosis, overexpression of TFEB in cultured human endometrial stromal cells (HESCs) by lentivirus not only promoted autophagy but also inhibited apoptosis. In addition, the migration and invasion ability of HESCs were enhanced by TFEB overexpression. Furthermore, inhibiting autophagy with specific inhibitors can attenuate migration and invasion of HESCs induced by TFEB. The rat models of endometriosis show that TFEB knockdown can suppress lesion growth in vivo. Our results suggest that autophagy may be involved in the progression mechanism of endometriosis, and the mechanism of autophagy disorder in endometriosis is probably related to TFEB. TFEB may be a key molecule in promoting endometriosis.
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Affiliation(s)
- Qiuyu Chen
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yi Zhou
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Mengqi Yu
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Sennan Zhu
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Jindan Sun
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Wenzhuo Du
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Ziqi Chen
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Jiayu Tao
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Xiao Feng
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China
| | - Qiong Zhang
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China.
| | - Yu Zhao
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 306 Hualongqiao Road, Wenzhou, Zhejiang, 325000, China.
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Montardi C, Gaudemer A, Zuber M, Vuillemet F, Alexandra J, Lidove O, Mauhin W. Aseptic meningitis and Fabry disease. Ann Clin Transl Neurol 2024; 11:1430-1441. [PMID: 38717582 PMCID: PMC11187954 DOI: 10.1002/acn3.52043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/16/2024] [Accepted: 02/28/2024] [Indexed: 06/20/2024] Open
Abstract
OBJECTIVE Fabry disease is caused by enzymatic defects in alpha-galactosidase A that leads to the accumulation of glycosphingolipids throughout the body, resulting in a multisystemic disorder. The most common neurological manifestations are neuropathic pain, autonomic nervous system dysfunction and strokes, but some rarer neurological manifestations exist. Among these, aseptic meningitis is a possible complication. Our objectives were to measure the prevalence of this complication in a cohort of patients with Fabry disease, and to describe its clinical features. METHODS We conducted a retrospective review of Fabry disease patients followed at our tertiary referral center between 1995 and September 2023 with at least one episode of meningitis, and performed a systematic review to identify similar published cases. RESULTS Four patients out of 107 (3.7%) had at least one episode of aseptic meningitis. Our systematic review identified 25 other observations. The median age of these 29 patients was 29.0 years, the median cerebrospinal fluid leukocyte count was 24 cells/mm3 with a predominance of lymphocytes in 64.7% of cases. In 82.8% of the patients, the diagnosis of Fabry disease was unknown before the meningitis. Large artery stenosis was present in 17.2% of patients and 57.1% of patients had a recent stroke concomitant with the meningitis. Several differential diagnoses were evoked, such as multiple sclerosis or central nervous system vasculitis. INTERPRETATION Our study suggests that Fabry disease should be considered as a cause of aseptic meningitis. The pathophysiological mechanisms underlying meningeal inflammation remain largely unknown but may reflect the dysregulation of pro-inflammatory signaling pathways.
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Affiliation(s)
- Camille Montardi
- Internal Medicine DepartmentReference Centre for Lysosomal Diseases, Groupe Hospitalier Diaconesses Croix Saint‐SimonParisFrance
| | - Augustin Gaudemer
- Radiology DepartmentBichat University Hospital, Assistance Publique Hôpitaux de ParisParisFrance
- IAME UMR‐1137, INSERM, Université Paris CitéParisFrance
| | - Mathieu Zuber
- Neurology DepartmentParis Saint‐Joseph HospitalParisFrance
- UMR‐S U1237, GIP Cycéron, INSERM, Université Paris CitéParisFrance
| | - Francis Vuillemet
- Neurology DepartmentLouis Pasteur Civil Hospital of ColmarColmarFrance
| | - Jean‐François Alexandra
- Internal Medicine DepartmentBichat University Hospital, Assistance Publique Hôpitaux de ParisParisFrance
| | - Olivier Lidove
- Internal Medicine DepartmentReference Centre for Lysosomal Diseases, Groupe Hospitalier Diaconesses Croix Saint‐SimonParisFrance
| | - Wladimir Mauhin
- Internal Medicine DepartmentReference Centre for Lysosomal Diseases, Groupe Hospitalier Diaconesses Croix Saint‐SimonParisFrance
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Gao Y, Chen S, Jiao S, Fan Y, Li X, Tan N, Fang J, Xu L, Huang Y, Zhao J, Guo S, Liu T, Xu W. ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4 + Th1 responses. Autophagy 2024; 20:1398-1417. [PMID: 38368631 PMCID: PMC11210915 DOI: 10.1080/15548627.2024.2319512] [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: 09/28/2023] [Revised: 02/06/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024] Open
Abstract
Parasite-specific CD4+ Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4+ Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G- ITGAM/CD11b+ ADGRE1/F4/80- cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G- ITGAM+ ADGRE1- cell-derived CCL2 selectively interacted with CCR2 on CD4+ Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4+ Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4+ Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines.Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1.
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Affiliation(s)
- Yuanli Gao
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Suilin Chen
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- Clinical Laboratory Diagnostic Center, General Hospital of Xinjiang Military Region, Urumqi, China
| | - Shiming Jiao
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yongling Fan
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiuxiu Li
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- The School of Medicine, Chongqing University, Chongqing, China
| | - Nie Tan
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiaqin Fang
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Luming Xu
- Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yi Huang
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jing Zhao
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shuai Guo
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Taiping Liu
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
| | - Wenyue Xu
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- The School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
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Song A, Wang W, Wang H, Ji Y, Zhang Y, Ren J, Qu X. An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis. ACS APPLIED MATERIALS & INTERFACES 2024. [PMID: 38697643 DOI: 10.1021/acsami.4c02620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Pyroptosis has garnered increasing attention because of its ability to trigger robust antitumor immunity. Pyroptosis is initiated by the activation of inflammasomes, which are regulated by various organelles. The collaboration among organelles offers several protective mechanisms to prevent activation of the inflammasome, thereby limiting the induction of efficient pyroptosis. Herein, a multiorganelle homeostasis disruptor (denoted BLL) is constructed by encapsulating liposomes and bortezomib (BTZ) within a layered double hydroxide (LDH) nanocage to continuously activate inflammasomes for inducing efficient pyroptosis. In lysosomes, the negatively charged liposomes are released to recruit the NLRP3 inflammasomes through electrostatic interactions. ER stress is induced by BTZ to enhance the activation of the NLRP3 inflammasome. Meanwhile, the BLL nanocage exhibited H+-scavenging ability due to the weak alkalinity of LDH, thus disrupting the homeostasis of the lysosome and alleviating the degradation of the NLRP3 inflammasome by lysosomal-associated autophagy. Our results suggest that the BLL nanocage induces homeostatic imbalance in various organelles and efficient pyroptosis. We hope this work can provide new insights into the design of an efficient pyroptosis inducer by disrupting the homeostatic balance of multiple organelles and promote the development of novel antineoplastic platforms.
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Affiliation(s)
- Anjun Song
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
| | - Wenjie Wang
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
| | - Huan Wang
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
| | - Yanjun Ji
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
| | - Yanjie Zhang
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
| | - Jinsong Ren
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
| | - Xiaogang Qu
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230029, P. R. China
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Kim YS. Cardiomyocyte Autophagy: A Novel Therapeutic Target by LncRNA PART1. Korean Circ J 2024; 54:253-255. [PMID: 38767338 PMCID: PMC11109836 DOI: 10.4070/kcj.2024.0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 05/07/2024] [Indexed: 05/22/2024] Open
Affiliation(s)
- Yong Sook Kim
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju, Korea.
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Wan X, Li C, Tan YH, Zuo SQ, Deng FM, Sun J, Liu YL. Dihydroartemisinin eliminates senescent cells by promoting autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway. Cell Biol Int 2024; 48:726-736. [PMID: 38439187 DOI: 10.1002/cbin.12143] [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: 10/06/2023] [Revised: 12/30/2023] [Accepted: 02/11/2024] [Indexed: 03/06/2024]
Abstract
Cellular senescence is an irreversible cell-cycle arrest in response to a variety of cellular stresses, which contribute to the pathogenesis of a variety of age-related degenerative diseases. However, effective antisenescence strategies are still lacking. Drugs that selectively target senescent cells represent an intriguing therapeutic strategy to delay aging and age-related diseases. Thus, we thought to investigate the effects of dihydroartemisinin (DHA) on senescent cells and elucidated its mechanisms underlying aging. Stress-induced premature senescence (SIPS) model was built in NIH3T3 cells using H2O2 and evaluated by β-galactosidase staining. Cells were exposed to DHA and subjected to cellular activity assays including viability, ferroptosis, and autophagy. The number of microtubule-associated protein light-chain 3 puncta was detected by immunofluorescence staining. The iron content was assessed by spectrophotometer and intracellular reactive oxygen species (ROS) was measured by fluorescent probe dichlorodihydrofluorescein diacetate. We found that DHA triggered senescent cell death via ferroptosis. DHA accelerated ferritin degradation via promoting autophagy, increasing the iron contents, promoting ROS accumulation, thus leading to ferroptotic cell death in SIPS cells. In addition, autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. Moreover, Atg5 silencing and autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. We also revealed that the expression of p-AMP-activated protein kinase (AMPK) and p-mammalian target of rapamycin (mTOR) in senescent cells was downregulated. These results suggested that DHA may be a promising drug candidate for clearing senescent cells by inducing autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway.
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Affiliation(s)
- Xing Wan
- Department of Pediatrics, School of Clinical Medicine, Southwest Medical University, Luzhou, China
- Department of Pediatrics, Chengdu Third People's Hospital, Chengdu, Sichuan, China
| | - Can Li
- Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yue Hao Tan
- Department of Inspection Technology, Sichuan Nursing Vocational College, Chengdu, China
| | - Shi Qi Zuo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Feng Mei Deng
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Jing Sun
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Yi Lun Liu
- Department of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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35
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Morito D. Molecular structure and function of mysterin/RNF213. J Biochem 2024; 175:495-505. [PMID: 38378744 DOI: 10.1093/jb/mvae020] [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: 12/05/2023] [Revised: 01/19/2024] [Accepted: 01/24/2024] [Indexed: 02/22/2024] Open
Abstract
Mysterin is a large intracellular protein harboring a RING finger ubiquitin ligase domain and is also referred to as RING finger protein 213 (RNF213). The author performed the first molecular cloning of the mysterin gene as the final step in genetic exploration of cerebrovascular moyamoya disease (MMD) and initiated the next round of exploration to understand its molecular and cellular functions. Although much remains unknown, accumulating findings suggest that mysterin functions in cells by targeting massive intracellular structures, such as lipid droplets (LDs) and various invasive pathogens. In the latter case, mysterin appears to directly surround and ubiquitylate the surface of pathogens and stimulate cell-autonomous antimicrobial reactions, such as xenophagy and inflammatory response. To date, multiple mutations causing MMD have been identified within and near the RING finger domain of mysterin; however, their functional relevance remains largely unknown. Besides the RING finger, mysterin harbors a dynein-like ATPase core and an RZ finger, another ubiquitin ligase domain unique to mysterin, while functional exploration of these domains has also just commenced. In this review, the author attempts to summarize the core findings regarding the molecular structure and function of the mysterin protein, with an emphasis on the perspective of MMD research.
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Affiliation(s)
- Daisuke Morito
- Department of Biochemistry, Showa University School of Medicine, Hatanodai 1-5-8, Shinagawa, Tokyo 142-0064, Japan
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36
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Chen Y, Cao W, Li B, Qiao X, Wang X, Yang G, Li S. The potential role of hydrogen sulfide in regulating macrophage phenotypic changes via PINK1/parkin-mediated mitophagy in sepsis-related cardiorenal syndrome. Immunopharmacol Immunotoxicol 2024; 46:139-151. [PMID: 37971696 DOI: 10.1080/08923973.2023.2281901] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 11/04/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVE Sepsis is one of major reasons of cardiorenal syndrome type 5 (CRS-5), resulting in irreversible tissue damage and organ dysfunction. Macrophage has been demonstrated to play key role in the pathophysiology of sepsis, highlighting the need to identify therapeutic targets for modulating macrophage phenotype in sepsis. METHODS AND RESULTS In this study, a rapid-releasing hydrogen sulfide (H2S) donor NaSH, and a slow-releasing H2S compound S-propargyl-cysteine (SPRC) which is derived from garlic, have been studied for the immune-regulatory effects on macrophages. The NaSH and SPRC showed the potential to protect the heart and kidney from tissue injury induced by LPS. The immunohistochemistry of F4/80+ revealed that the infiltration of macrophages in the heart and kidney tissues of LPS-treated mice was reduced by NaSH and SPRC. In addition, in the LPS-triggered inflammatory cascade of RAW264.7 macrophage cells, NaSH and SPRC exhibited significantly inhibitory effects on the secretion of inflammatory cytokines, production of reactive oxygen species (ROS), and regulation of the macrophage phenotype from M1-like to M2-like. Moreover, autophagy, a crucial process involved in the elimination of impaired proteins and organelles during oxidative stress and immune response, was induced by NaSH and SPRC in the presence of LPS stimulation. Consequently, there was an increase in the number of mitochondria and an improvement in mitochondrial membrane potential. This process was mainly mediated by PINK1/Parkin pathway mediated mitophagy. DISCUSSION These results demonstrated that the immunoregulatory effects of H2S donors were through the PINK1/Parkin-mediated mitophagy pathway. Overall, our study provided a new therapeutic direction in LPS-induced cardiorenal injury.
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Affiliation(s)
- Yuxuan Chen
- Department of Cell Biology, Shandong University, Jinan, China
- Shandong Institute of Endocrinology and Metabolic Diseases, Shandong First Medical University, Jinan, China
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wei Cao
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Bin Li
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xiaofei Qiao
- Department of Cell Biology, Shandong University, Jinan, China
| | - Xiangdong Wang
- Department of Cell Biology, Shandong University, Jinan, China
| | - Guang Yang
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Siying Li
- Department of Cell Biology, Shandong University, Jinan, China
- Shandong Institute of Endocrinology and Metabolic Diseases, Shandong First Medical University, Jinan, China
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Provincial Key Laboratory of Cardiovascular Disease Proteomics, Qilu Hospital of Shandong University, Jinan, China
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37
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Talebi Taheri A, Golshadi Z, Zare H, Alinaghipour A, Faghihi Z, Dadgostar E, Tamtaji Z, Aschner M, Mirzaei H, Tamtaji OR, Nabavizadeh F. The Potential of Targeting Autophagy-Related Non-coding RNAs in the Treatment of Alzheimer's and Parkinson's Diseases. Cell Mol Neurobiol 2024; 44:28. [PMID: 38461204 PMCID: PMC10924707 DOI: 10.1007/s10571-024-01461-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 01/29/2024] [Indexed: 03/11/2024]
Abstract
Clearance of accumulated protein aggregates is one of the functions of autophagy. Recently, a clearer understanding of non-coding RNAs (ncRNAs) functions documented that ncRNAs have important roles in several biological processes associated with the development and progression of neurodegenerative disorders. Subtypes of ncRNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), are commonly dysregulated in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dysregulation of these non-coding RNAs has been associated with inhibition or stimulation of autophagy. Decreased miR-124 led to decreased/increased autophagy in experimental model of Alzheimer and Parkinson diseases. Increased BACE1-AS showed enhanced autophagy in Alzheimer disease by targeting miR-214-3p, Beclin-1, LC3-I/LC3-II, p62, and ATG5. A significant increase in NEAT1led to stimulated autophagy in experimental model of PD by targeting PINK1, LC3-I, LC3-II, p62 and miR-374c-5p. In addition, increased BDNF-AS and SNHG1 decreased autophagy in MPTP-induced PD by targeting miR-125b-5p and miR-221/222, respectively. The upregulation of circNF1-419 and circSAMD4A resulted in an increased autophagy by regulating Dynamin-1 and miR-29c 3p, respectively. A detailed discussion of miRNAs, circRNAs, and lncRNAs in relation to their autophagy-related signaling pathways is presented in this study.
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Affiliation(s)
- Abdolkarim Talebi Taheri
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zakieh Golshadi
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Azam Alinaghipour
- School of Medical Sciences, Yazd Branch, Islamic Azad University, Yazd, Iran
| | - Zahra Faghihi
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran
| | - Ehsan Dadgostar
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. of Iran
- Student Research Committee, Isfahan University of Medical Sciences, Isfahan, I.R. of Iran
| | - Zeinab Tamtaji
- Student Research Committee, Kashan University of Medical Sciences, Kashan, I.R. of Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. of Iran.
| | - Omid Reza Tamtaji
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
| | - Fatemeh Nabavizadeh
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
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38
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Deng W, Shang H, Tong Y, Liu X, Huang Q, He Y, Wu J, Ba X, Chen Z, Chen Y, Tang K. The application of nanoparticles-based ferroptosis, pyroptosis and autophagy in cancer immunotherapy. J Nanobiotechnology 2024; 22:97. [PMID: 38454419 PMCID: PMC10921615 DOI: 10.1186/s12951-024-02297-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 01/02/2024] [Indexed: 03/09/2024] Open
Abstract
Immune checkpoint blockers (ICBs) have been applied for cancer therapy and achieved great success in the field of cancer immunotherapy. Nevertheless, the broad application of ICBs is limited by the low response rate. To address this issue, increasing studies have found that the induction of immunogenic cell death (ICD) in tumor cells is becoming an emerging therapeutic strategy in cancer treatment, not only straightly killing tumor cells but also enhancing dying cells immunogenicity and activating antitumor immunity. ICD is a generic term representing different cell death modes containing ferroptosis, pyroptosis, autophagy and apoptosis. Traditional chemotherapeutic agents usually inhibit tumor growth based on the apoptotic ICD, but most tumor cells are resistant to the apoptosis. Thus, the induction of non-apoptotic ICD is considered to be a more efficient approach for cancer therapy. In addition, due to the ineffective localization of ICD inducers, various types of nanomaterials have been being developed to achieve targeted delivery of therapeutic agents and improved immunotherapeutic efficiency. In this review, we briefly outline molecular mechanisms of ferroptosis, pyroptosis and autophagy, as well as their reciprocal interactions with antitumor immunity, and then summarize the current progress of ICD-induced nanoparticles based on different strategies and illustrate their applications in the cancer therapy.
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Affiliation(s)
- Wen Deng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haojie Shang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yonghua Tong
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiao Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qiu Huang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yu He
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jian Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaozhuo Ba
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhiqiang Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuan Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Kun Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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39
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Münz C. Degrade to stay healthy-Proteolytic interplay during inflammation. PLoS Biol 2024; 22:e3002548. [PMID: 38452120 PMCID: PMC10919839 DOI: 10.1371/journal.pbio.3002548] [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] [Indexed: 03/09/2024] Open
Abstract
Proteasomes and autophagy constitute the 2 main proteolytic machineries for cytoplasmic content. A new study in PLOS Biology now demonstrates that autophagy stimulation alters proteasome composition, degrading hyperactive immunoproteasomes and thereby limiting inflammation.
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Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
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40
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Wang D, Liu Y, Yang B, Zhang Z, El-Ashram S, Liu X, Li B. Toxoplasma gondii surface antigen 1 (SAG1) interacts in vitro with host cell receptor for activated C kinase 1 (RACK1). Acta Trop 2024; 251:107112. [PMID: 38157925 DOI: 10.1016/j.actatropica.2023.107112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024]
Abstract
Toxoplasma gondii (T. gondii) surface antigen 1 (SAG1) is crucial for tachyzoite invasion into host cells. However, the role of SAG1 in interaction with host cells remains unknown. The primary objective of this study was to analyze and validate the interaction between SAG1 and host cells. RACK1, an intracellular multifunctional protein, was identified as a SAG1 binding partner in host cells. Furthermore, the expression of RACK1 is manipulated by SAG1, and depletion of RACK1 negatively regulated host cell viability. These results imply that through interaction with RACK1, SAG1 preserves the viability of host cells to satisfy the survival needs of T. gondii. Our findings suggest a novel role for SAG1 in intracellular parasitism.
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Affiliation(s)
- Dawei Wang
- College of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University, Jinzhou, Liaoning Province, China; Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Yuming Liu
- College of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University, Jinzhou, Liaoning Province, China; Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Baoling Yang
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning Province, China; Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Zixuan Zhang
- College of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University, Jinzhou, Liaoning Province, China; Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Saeed El-Ashram
- College of Life Science and Engineering, Foshan University, 18 Jiangwan Street, Foshan, Guangdong Province, China; Faculty of Science, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Xiaogang Liu
- College of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University, Jinzhou, Liaoning Province, China; Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning Province, China.
| | - Bing Li
- College of Animal Husbandry and Veterinary Medicine, Jinzhou Medical University, Jinzhou, Liaoning Province, China; Collaborative Innovation Center for Prevention and Control of Zoonoses, Jinzhou Medical University, Jinzhou, Liaoning Province, China.
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41
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Jasim SA, Almajidi YQ, Al-Rashidi RR, Hjazi A, Ahmad I, Alawadi AHR, Alwaily ER, Alsaab HO, Haslany A, Hameed M. The interaction between lncRNAs and transcription factors regulating autophagy in human cancers: A comprehensive and therapeutical survey. Cell Biochem Funct 2024; 42:e3971. [PMID: 38509767 DOI: 10.1002/cbf.3971] [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: 12/31/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/22/2024]
Abstract
Autophagy, as a highly conserved cellular process, participates in cellular homeostasis by degradation and recycling of damaged organelles and proteins. Besides, autophagy has been evidenced to play a dual role through cancer initiation and progression. In the early stage, it may have a tumor-suppressive function through inducing apoptosis and removing damaged cells and organelles. However, late stages promote tumor progression by maintaining stemness features and induction of chemoresistance. Therefore, identifying and targeting molecular mechanisms involved in autophagy is a potential therapeutic strategy for human cancers. Multiple transcription factors (TFs) are involved in the regulation of autophagy by modulating the expression of autophagy-related genes (ATGs). In addition, a wide array of long noncoding RNAs (lncRNAs), a group of regulatory ncRNAs, have been evidenced to regulate the function of these autophagy-related TFs through tumorigenesis. Subsequently, the lncRNAs/TFs/ATGs axis shows great potential as a therapeutic target for human cancers. Therefore, this review aimed to summarize new findings about the role of lncRNAs in regulating autophagy-related TFs with therapeutic perspectives.
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Affiliation(s)
| | - Yasir Qasim Almajidi
- Department of Pharmacy (Pharmaceutics), Baghdad College of Medical Sciences, Baghdad, Iraq
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ahmed Hussien Radie Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Hashem O Alsaab
- Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - Ali Haslany
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Mohamood Hameed
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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42
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Zhou J, Li C, Lu M, Jiang G, Chen S, Li H, Lu K. Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits. PLoS Biol 2024; 22:e3002537. [PMID: 38447109 PMCID: PMC10917451 DOI: 10.1371/journal.pbio.3002537] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 02/05/2024] [Indexed: 03/08/2024] Open
Abstract
Defective autophagy is linked to proinflammatory diseases. However, the mechanisms by which autophagy limits inflammation remain elusive. Here, we found that the pan-FGFR inhibitor LY2874455 efficiently activated autophagy and suppressed expression of proinflammatory factors in macrophages stimulated by lipopolysaccharide (LPS). Multiplex proteomic profiling identified the immunoproteasome, which is a specific isoform of the 20s constitutive proteasome, as a substrate that is degraded by selective autophagy. SQSTM1/p62 was found to be a selective autophagy-related receptor that mediated this degradation. Autophagy deficiency or p62 knockdown blocked the effects of LY2874455, leading to the accumulation of immunoproteasomes and increases in inflammatory reactions. Expression of proinflammatory factors in autophagy-deficient macrophages could be reversed by immunoproteasome inhibitors, confirming the pivotal role of immunoproteasome turnover in the autophagy-mediated suppression on the expression of proinflammatory factors. In mice, LY2874455 protected against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis and caused low levels of proinflammatory cytokines and immunoproteasomes. These findings suggested that selective autophagy of the immunoproteasome was a key regulator of signaling via the innate immune system.
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Affiliation(s)
- Jiao Zhou
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and the Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Chunxia Li
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and the Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China
| | - Meng Lu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and the Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China
| | - Gaoyue Jiang
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and the Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China
| | - Shanze Chen
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen Institute of Respiratory Diseases, Shenzhen, China
| | - Huihui Li
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Kefeng Lu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and the Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China
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43
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Liu LK, Jian JT, Jing SS, Gao RL, Chi XD, Tian G, Liu HP. The crustacean DNA virus tegument protein VP26 binds to SNAP29 to inhibit SNARE complex assembly and autophagic degradation. J Virol 2024; 98:e0140823. [PMID: 38189252 PMCID: PMC10878264 DOI: 10.1128/jvi.01408-23] [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: 09/09/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Autophagy generally functions as a cellular surveillance mechanism to combat invading viruses, but viruses have evolved various strategies to block autophagic degradation and even subvert it to promote viral propagation. White spot syndrome virus (WSSV) is the most highly pathogenic crustacean virus, but little is currently known about whether crustacean viruses such as WSSV can subvert autophagic degradation for escape. Here, we show that even though WSSV proliferation triggers the accumulation of autophagosomes, autophagic degradation is blocked in the crustacean species red claw crayfish. Interestingly, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex including CqSNAP29, CqVAMP7, and the novel autophagosome SNARE protein CqSyx12 is required for autophagic flux to restrict WSSV replication, as revealed by gene silencing experiments. Simultaneously, the expressed WSSV tegument protein VP26, which likely localizes on autophagic membrane mediated by its transmembrane region, binds the Qb-SNARE domain of CqSNAP29 to competitively inhibit the binding of CqSyx12-Qa-SNARE with CqSNAP29-Qb-SNARE; this in turn disrupts the assembly of the CqSyx12-SNAP29-VAMP7 SNARE complex, which is indispensable for the proposed fusion of autophagosomes and lysosomes. Consequently, the autophagic degradation of WSSV is likely suppressed by the expressed VP26 protein in vivo in crayfish, thus probably protecting WSSV components from degradation via the autophagosome-lysosome pathway, resulting in evasion by WSSV. Collectively, these findings highlight how a DNA virus can subvert autophagic degradation by impairing the assembly of the SNARE complex to achieve evasion, paving the way for understanding host-DNA virus interactions from an evolutionary point of view, from crustaceans to mammals.IMPORTANCEWhite spot syndrome virus (WSSV) is one of the largest animal DNA viruses in terms of its genome size and has caused huge economic losses in the farming of crustaceans such as shrimp and crayfish. Detailed knowledge of WSSV-host interactions is still lacking, particularly regarding viral escape from host immune clearance. Intriguingly, we found that the presence of WSSV-VP26 might inhibit the autophagic degradation of WSSV in vivo in the crustacean species red claw crayfish. Importantly, this study is the first to show that viral protein VP26 functions as a core factor to benefit WSSV escape by disrupting the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which is necessary for the proposed fusion of autophagosomes with lysosomes for subsequent degradation. These findings highlight a novel mechanism of DNA virus evasion by blocking SNARE complex assembly and identify viral VP26 as a key candidate for anti-WSSV targeting.
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Affiliation(s)
- Ling-Ke Liu
- State Key Laboratory of Marine Environmental Science, State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jiu-Ting Jian
- State Key Laboratory of Marine Environmental Science, State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Shan-Shan Jing
- State Key Laboratory of Marine Environmental Science, State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Rui-Lin Gao
- State Key Laboratory of Marine Environmental Science, State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
| | - Xiao-Dong Chi
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China
| | - Geng Tian
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China
| | - Hai-Peng Liu
- State Key Laboratory of Marine Environmental Science, State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, China
- Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong, China
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44
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Zhang X, Zhang M, Cui H, Zhang T, Wu L, Xu C, Yin C, Gao J. Autophagy-modulating biomembrane nanostructures: A robust anticancer weapon by modulating the inner and outer cancer environment. J Control Release 2024; 366:85-103. [PMID: 38142964 DOI: 10.1016/j.jconrel.2023.12.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/09/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023]
Abstract
Recently, biomembrane nanostructures, such as liposomes, cell membrane-coated nanostructures, and exosomes, have demonstrated promising anticancer therapeutic effects. These nanostructures possess remarkable biocompatibility, multifunctionality, and low toxicity. However, their therapeutic efficacy is impeded by chemoresistance and radiotherapy resistance, which are closely associated with autophagy. Modulating autophagy could enhance the therapeutic sensitivity and effectiveness of these biomembrane nanostructures by influencing the immune system and the cancer microenvironment. For instance, autophagy can regulate the immunogenic cell death of cancer cells, antigen presentation of dendritic cells, and macrophage polarization, thereby activating the inflammatory response in the cancer microenvironment. Furthermore, combining autophagy-regulating drugs or genes with biomembrane nanostructures can exploit the targeting and long-term circulation properties of these nanostructures, leading to increased drug accumulation in cancer cells. This review explores the role of autophagy in carcinogenesis, cancer progression, metastasis, cancer immune responses, and resistance to treatment. Additionally, it highlights recent research advancements in the synergistic anticancer effects achieved through autophagy regulation by biomembrane nanostructures. The review also discusses the prospects and challenges associated with the future clinical translation of these innovative treatment strategies. In summary, these findings provide valuable insights into autophagy, autophagy-modulating biomembrane-based nanostructures, and the underlying molecular mechanisms, thereby facilitating the development of promising cancer therapeutics.
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Affiliation(s)
- Xinyi Zhang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| | - Mengya Zhang
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| | - Hengqing Cui
- Department of Burns and Plastic Surgery, Shanghai Changzheng Hospital, Shanghai 200003, China; Tongji Hospital,School of Medicine, Tongji University, Shanghai 200092, China
| | - Tinglin Zhang
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| | - Lili Wu
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| | - Can Xu
- Department of Gastroenterology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| | - Chuan Yin
- Department of Gastroenterology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
| | - Jie Gao
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
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45
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Chen L, Gao T, Zhou P, Xia W, Yao H, Xu S, Xu J. Recent advances of vacuolar protein-sorting 34 inhibitors targeting autophagy. Bioorg Chem 2024; 143:107039. [PMID: 38134519 DOI: 10.1016/j.bioorg.2023.107039] [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: 11/02/2023] [Revised: 11/21/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023]
Abstract
Autophagy is a ubiquitous pathological/physiological antioxidant cellular reaction in eukaryotic cells. Vacuolar protein sorting 34 (Vps34 or PIK3C3), which plays a crucial role in autophagy, has received much attention. As the only Class III phosphatidylinositol-3 kinase in mammals, Vps34 participates in vesicular transport, nutrient signaling and autophagy. Dysfunctionality of Vps34 induces carcinogenesis, and abnormal autophagy mediated by dysfunction of Vps34 is closely related to the pathological progression of various human diseases, which makes Vps34 a novel target for tumor immunotherapy. In this review, we summarize the molecular mechanisms underlying macroautophagy, and further discuss the structure-activity relationship of Vps34 inhibitors that have been reported in the past decade as well as their potential roles in anticancer immunotherapy to better understand the antitumor mechanism underlying the effects of these inhibitors.
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Affiliation(s)
- Long Chen
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Tian Gao
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Pijun Zhou
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wenxuan Xia
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Hong Yao
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Shengtao Xu
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China; Shenzhen Research Institute of China Pharmaceutical University, Nanshan District, Shenzhen 518052, PR China.
| | - Jinyi Xu
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China; Shenzhen Research Institute of China Pharmaceutical University, Nanshan District, Shenzhen 518052, PR China.
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46
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Zhou Y, Yuan J, Xu K, Li S, Liu Y. Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy. ACS NANO 2024; 18:1846-1864. [PMID: 38180952 DOI: 10.1021/acsnano.3c11260] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2024]
Abstract
Mutation burden, hypoxia, and immunoediting contribute to altered metabolic profiles in tumor cells, resulting in a tumor microenvironment (TME) characterized by accumulation of toxic metabolites and depletion of various nutrients, which significantly hinder the antitumor immunity via multiple mechanisms, hindering the efficacy of tumor immunotherapies. In-depth investigation of the mechanisms underlying these phenomena are vital for developing effective antitumor drugs and therapies, while the therapeutic effects of metabolism-targeting drugs are restricted by off-target toxicity toward effector immune cells and high dosage-mediated side effects. Nanotechnologies, which exhibit versatility and plasticity in targeted delivery and metabolism modulation, have been widely applied to boost tumor immunometabolic therapies via multiple strategies, including targeting of metabolic pathways. In this review, recent advances in understanding the roles of tumor cell metabolism in both immunoevasion and immunosuppression are reviewed, and nanotechnology-based metabolic reprogramming strategies for enhanced tumor immunotherapies are discussed.
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Affiliation(s)
- Yangkai Zhou
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Yuan
- First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Ke Xu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shilin Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ying Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
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47
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Jiang H, Xie Y, Lu J, Li H, Zeng K, Hu Z, Wu D, Yang J, Yao Z, Chen H, Gong X, Yu X. Pristimerin suppresses AIM2 inflammasome by modulating AIM2-PYCARD/ASC stability via selective autophagy to alleviate tendinopathy. Autophagy 2024; 20:76-93. [PMID: 37647255 PMCID: PMC10761048 DOI: 10.1080/15548627.2023.2249392] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 08/09/2023] [Accepted: 08/11/2023] [Indexed: 09/01/2023] Open
Abstract
Macroautophagy/autophagy plays an important role in regulating cellular homeostasis and influences the pathogenesis of degenerative diseases. Tendinopathy is characterized by tendon degeneration and inflammation. However, little is known about the role of selective autophagy in tendinopathy. Here, we find that pristimerin (PM), a quinone methide triterpenoid, is more effective in treating tendinopathy than the first-line drug indomethacin. PM inhibits the AIM2 inflammasome and alleviates inflammation during tendinopathy by promoting the autophagic degradation of AIM2 through a PYCARD/ASC-dependent manner. A mechanistic study shows that PM enhances the K63-linked ubiquitin chains of PYCARD/ASC at K158/161, which serves as a recognition signal for SQSTM1/p62-mediated autophagic degradation of the AIM2-PYCARD/ASC complex. We further identify that PM binds the Cys53 site of deubiquitinase USP50 through the Michael-acceptor and blocks the binding of USP50 to PYCARD/ASC, thereby reducing USP50-mediated cleavage of K63-linked ubiquitin chains of PYCARD/ASC. Finally, PM treatment in vivo generates an effect comparable to inflammasome deficiency in alleviating tendinopathy. Taken together, these findings demonstrate that PM alleviates the progression of tendinopathy by modulating AIM2-PYCARD/ASC stability via SQSTM1/p62-mediated selective autophagic degradation, thus providing a promising autophagy-based therapeutic for tendinopathy.Abbreviations: 3-MA: 3-methyladenine; AIM2: absent in melanoma 2; AT: Achilles tenotomy; ATP: adenosine triphosphate; BMDMs: bone marrow-derived macrophages; CHX: cycloheximide; Col3a1: collagen, type III, alpha 1; CQ: chloroquine; Cys: cysteine; DARTS: drug affinity responsive target stability; DTT: dithiothreitol; DUB: deubiquitinase; gDNA: genomic DNA; GSH: glutathione; His: histidine; IL1B/IL-1β: interleukin 1 beta; IND: indomethacin; IP: immunoprecipitation; LPS: lipopolysaccharide; MMP: mitochondrial membrane potential; NLRP3: NLR family, pyrin domain containing 3; PM: pristimerin; PYCARD/ASC: PYD and CARD domain containing; SN: supernatants; SOX9: SRY (sex determining region Y)-box 9; SQSTM1: sequestosome 1; Tgfb: transforming growth factor, beta; TIMP3: tissue inhibitor of metalloproteinase 3; TNMD: tenomodulin; TRAF6: TNF receptor-associated factor 6; Ub: ubiquitin; USP50: ubiquitin specific peptidase 50; WCL: whole cell lysates.
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Affiliation(s)
- Huaji Jiang
- Yue Bei People’s Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou, Guangdong, China
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yingchao Xie
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Joint Surgery, the Fifth Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Jiansen Lu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Lab of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongyu Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Ke Zeng
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhiqiang Hu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Dan Wu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianwu Yang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhenxia Yao
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Huadan Chen
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoqian Gong
- Yue Bei People’s Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiao Yu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Lab of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China
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48
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Voss OH, Gaytan H, Ullah S, Sadik M, Moin I, Rahman MS, Azad AF. Autophagy facilitates intracellular survival of pathogenic rickettsiae in macrophages via evasion of autophagosomal maturation and reduction of microbicidal pro-inflammatory IL-1 cytokine responses. Microbiol Spectr 2023; 11:e0279123. [PMID: 37819111 PMCID: PMC10715094 DOI: 10.1128/spectrum.02791-23] [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: 07/07/2023] [Accepted: 09/01/2023] [Indexed: 10/13/2023] Open
Abstract
IMPORTANCE Rickettsia spp. are intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some rickettsiae are responsible for several severe human diseases globally. One interesting feature of these pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia spp. elude host defense responses remains unclear. Here, we observed that pathogenic Rickettsia typhi and Rickettsia rickettsii (Sheila Smith [SS]), but not non-pathogenic Rickettsia montanensis, become ubiquitinated and induce autophagy upon entry into macrophages. Moreover, unlike R. montanensis, R. typhi and R. rickettsii (SS) colocalized with LC3B but not with Lamp2 upon host cell entry. Finally, we observed that both R. typhi and R. rickettsii (SS), but not R. montanensis, reduce pro-inflammatory interleukin-1 (IL-1) responses, likely via an autophagy-mediated mechanism. In summary, we identified a previously unappreciated pathway by which both pathogenic R. typhi and R. rickettsii (SS) become ubiquitinated, induce autophagy, avoid autolysosomal destruction, and reduce microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages.
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Affiliation(s)
- Oliver H. Voss
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Hodalis Gaytan
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Saif Ullah
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Mohammad Sadik
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Imran Moin
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - M. Sayeedur Rahman
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Abdu F. Azad
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Wang C, Zou K, Diao Y, Zhou C, Zhou J, Yang Y, Zeng Z. Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway. Biomed Pharmacother 2023; 168:115813. [PMID: 37922654 DOI: 10.1016/j.biopha.2023.115813] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/16/2023] [Accepted: 10/27/2023] [Indexed: 11/07/2023] Open
Abstract
Acute lung injury (ALI) is a major pathological problem characterized by severe inflammatory reactions and is a critical disease with high clinical morbidity and mortality. Liensinine, a major isoquinoline alkaloid, is extracted from the green embryos of mature Nelumbonaceae seeds. It has been reported to have an inhibitory effect on tumors. However, the effects of liensinine on ALI have not been reported to-date. The aim of this study was to explore the inhibitory effects of liensinine on lipopolysaccharide (LPS)-induced ALI and its possible mechanism. We found that liensinine significantly reduced LPS-induced ALI and reduced the production of inflammatory factors IL-6, IL-8, and TNF-α. In addition, liensinine blocked autophagic flux and increased the number of autophagosomes by upregulating LC3-II/I and p62 protein levels. More importantly, pretreatment with the early stages autophagy inhibitor 3-Methyladenine (3-MA) can reverse the inhibitory effects of liensinine on the secretion of inflammatory factors in ALI. The PI3K/AKT/mTOR pathway is involved in LPS-induced autophagy regulated by liensinine in ALI. In summary, this study suggests that liensinine inhibits the production of inflammatory factors in LPS-induced ALI by regulating autophagy via the PI3K/AKT/mTOR pathway, which may provide a new therapeutic strategy to alleviate ALI.
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Affiliation(s)
- Cheng Wang
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Jiangxi Institute of Respiratory Disease, Nanchang 330052, China
| | - Kang Zou
- Department of Critical Care Medicine, the First Affiliated Hospital of Gannan Medical College, Gannan Medical College, Ganzhou 341000, China
| | - Yunlian Diao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Jiangxi Institute of Respiratory Disease, Nanchang 330052, China
| | - Chaoqi Zhou
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Jia Zhou
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Jiangxi Institute of Respiratory Disease, Nanchang 330052, China
| | - Yuting Yang
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Zhenguo Zeng
- Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
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50
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Won J, Lee S, Ahmad Khan Z, Choi J, Ho Lee T, Hong Y. Suppression of DAPK1 reduces ischemic brain injury through inhibiting cell death signaling and promoting neural remodeling. Brain Res 2023; 1820:148588. [PMID: 37742938 DOI: 10.1016/j.brainres.2023.148588] [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: 05/17/2023] [Revised: 08/11/2023] [Accepted: 09/10/2023] [Indexed: 09/26/2023]
Abstract
The role of death-associated protein kinase1 (DAPK1) in post-stroke functional recovery is controversial, as is its mechanism of action and any neural remodeling effect after ischemia. To assess the debatable role of DAPK1, we established the middle cerebral artery occlusion (MCAo) model in DAPK1 knockout mice and Sprague-Dawley (SD) rats. We identified that the genetic deletion of the DAPK1 as well as pharmacological inhibition of DAPK1 showed reduced brain infarct volume and neurological deficit. We report that DAPK1 inhibition (DI) reduces post-stroke neuronal death by inhibiting BAX/BCL2 and LC3/Beclin1 mediated apoptosis and autophagy, respectively. Histological analysis displayed a reduction in nuclear condensation, neuronal dissociation, and degraded cytoplasm in the DI group. The DI treatment showed enhanced dendrite spine density and neurite outgrowth, upregulated neural proliferation marker proteins like brain-derived neurotrophic factor, and reduced structural abnormalities of the cortical pyramidal neurons. This research shows that DAPK1 drives cell death, its activation exacerbates functional recovery after cerebral ischemia and shows that oxazolone-based DI could be an excellent candidate for stroke and ischemic injury intervention.
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Affiliation(s)
- Jinyoung Won
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, South Korea; Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea
| | - Seunghoon Lee
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea; Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, South Korea
| | - Zeeshan Ahmad Khan
- Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea; Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, South Korea
| | - Jeonghyun Choi
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, South Korea; Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea
| | - Tae Ho Lee
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Science, Fujian Medical University, Fuzhou, China
| | - Yonggeun Hong
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, South Korea; Biohealth Products Research Center (BPRC), Inje University, Gimhae, South Korea; Research Center for Aged-life Redesign (RCAR), Inje University, Gimhae, South Korea; Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, South Korea.
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