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Zhang Z, Wang X, Zhao C, Zhu H, Liao X, Tsai HI. STING and metabolism-related diseases: Roles, mechanisms, and applications. Cell Signal 2025; 132:111833. [PMID: 40294833 DOI: 10.1016/j.cellsig.2025.111833] [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: 01/23/2025] [Revised: 04/08/2025] [Accepted: 04/22/2025] [Indexed: 04/30/2025]
Abstract
The stimulator of interferon genes (STING) pathway plays a critical role in innate immunity, acting as a central mediator that links cytosolic DNA sensing to inflammatory signaling. STING not only responds to cellular metabolic states but also actively regulates key metabolic processes, including glycolysis, lipid metabolism, and redox balance. This bidirectional interaction underscores the existence of a dynamic feedback mechanism between STING signaling and metabolic pathways, which is essential for maintaining cellular homeostasis. This review provides a comprehensive analysis, beginning with an in-depth overview of the classical STING signaling pathway, followed by a detailed examination of its reciprocal regulation of various metabolic pathways. Additionally, it explores the role and mechanisms of STING signaling in metabolic disorders, including obesity, diabetes, and atherosclerosis. By integrating these insights into the mutual regulation between STING and its metabolism, novel therapeutic strategies targeting this pathway in metabolic diseases have been proposed.
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Affiliation(s)
- Zhengyang Zhang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Xirui Wang
- Department of Biomedical Engineering, School of Medical Imaging, Xuzhou Medical University, Xuzhou 221000, China
| | - Chuangchuang Zhao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Haitao Zhu
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Xiang Liao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China.
| | - Hsiang-I Tsai
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
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2
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Giordano L, Ware SA, Lagranha CJ, Kaufman BA. Mitochondrial DNA signals driving immune responses: Why, How, Where? Cell Commun Signal 2025; 23:192. [PMID: 40264103 PMCID: PMC12012978 DOI: 10.1186/s12964-025-02042-0] [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: 10/29/2024] [Accepted: 01/14/2025] [Indexed: 04/24/2025] Open
Abstract
There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
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Affiliation(s)
- Luca Giordano
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
- Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Cardio-Pulmonary Institute (CPI), Justus-Liebig-University, Giessen, Germany.
| | - Sarah A Ware
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Claudia J Lagranha
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Brett A Kaufman
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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3
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Wang J, Guo Y, Hu J, Peng J. STING Activation in Various Cell Types in Metabolic Dysfunction-Associated Steatotic Liver Disease. Liver Int 2025; 45:e70063. [PMID: 40116753 DOI: 10.1111/liv.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/07/2025] [Accepted: 02/28/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND During the hepatic histological progression in metabolic dysfunction-associated steatotic liver disease (MASLD), the immunological mechanisms play a the pivotal role, especially when progressing to metabolic dysfunction-associated steatohepatitis (MASH). The discovery of the stimulator of interferon genes (STING) marked a significant advancement in understanding the immune system. METHODS We searched literature on STING involved in MASLD in PubMed to summarise the role of intrahepatic or extrahepatic STING signal pathways and the potential agonists or inhibitors of STING in MASLD. RESULTS Besides inflammation and type I interferon response induced by STING activation in the intrahepatic or extrahepatic immune cells, STING activation in hepatocytes leads to protein aggregates and lipid deposition. STING activation in hepatic macrophages inhibits autophagy in hepatocytes and promotes hepatic stellate cells (HSCs) activation. STING activation in HSCs promotes HSC activation and exacerbates liver sinusoidal endothelial cells (LSECs) impairment. However, it was also reported that STING activation in hepatic macrophages promotes lipophagy in hepatocytes and STING activation in HSCs leads to HSC senescence. STING activation in LSEC, inhibits angiogenesis. For extrahepatic tissue, STING signalling participates in the regulation of the intestinal permeability, intestinal microecology and insulin action in adipocytes, which were all involved in the pathogenesis of MASLD. CONCLUSION There're plenty of STING ligands in MASLD. How STING activation affects the intercellular conversation in MASLD deserves thorough investigation.
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Affiliation(s)
- JingJing Wang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Guo
- Department of Nephropathy, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Hu
- Department of Nephropathy, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinghua Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
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Wang Q, Hao W, Guo C, Cao H, Wang B, Li X, Yu R, Xu L, Li J. The regenerative wound healing effects and molecular mechanism of Isaria cicadae Miquel rice fermentation extract. Appl Microbiol Biotechnol 2025; 109:40. [PMID: 39928145 PMCID: PMC11811436 DOI: 10.1007/s00253-025-13412-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/16/2024] [Accepted: 01/15/2025] [Indexed: 02/11/2025]
Abstract
Human skin wounds primarily heal through reparative wound healing without pilosebaceous units or other appendages, rather than regenerative wound healing. Hair follicle (HF) regeneration is a significant challenge for skin wound healing. The effects and underlying mechanisms of Isaria cicadae Miquel rice fermentation extract (IMFRE) remain unclear, although it has anti-inflammatory, antioxidant, and reparative effects on oxidative damage in keratinocytes. We assessed the regenerative wound healing ability of IMFRE and its related molecular mechanisms through experimental validation and network pharmacology analysis. Our findings suggest that IMFRE could be an important potential solution for regenerative wound healing of skin hair follicle by utilizing the Hippo pathway regulatory mechanism. KEY POINTS: • IMFRE was found to significantly enhance the wound healing rate of mouse skin. • CK15 and CD34 were significantly increased by high-dose IMFRE intervention. • IMFRE could inhibit EGFR, GPCR, and Integrin expression.
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Affiliation(s)
- Qin Wang
- Wuxi Institute of Inspection, Testing and Certification, Wuxi, Jiangsu, China
| | - Wenwen Hao
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Guo
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Hui Cao
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Beiqi Wang
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xingyang Li
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ruilian Yu
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Li Xu
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jing Li
- Wuxi Institute of Inspection, Testing and Certification, Wuxi, Jiangsu, China
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Kn S, Shetty SS, Shetty P. Lipid-laden uterus: Investigating uterine fibroids and lipid association. Pathol Res Pract 2025; 266:155772. [PMID: 39709872 DOI: 10.1016/j.prp.2024.155772] [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: 10/19/2024] [Revised: 12/06/2024] [Accepted: 12/11/2024] [Indexed: 12/24/2024]
Abstract
Uterine Fibroids (UF) are the most common (about 70 % cases) benign gynecological smooth muscle tumors of the uterus in women of reproductive age, characterized by abnormal cholesterol, lipoproteins, and triglyceride levels, and are a major public health concern. Despite its high prevalence, this condition remains complex and poorly understood. These tumors are hormone-dependent and hormones and lipid levels are inversely related. This review delves into the existing literature and critically evaluates studies that explore the potential relationship between lipids in the pathogenesis of uterine fibroids. This review concludes by critically appraising the research gaps in the involvement of lipids and signaling pathways in the pathogenesis of uterine fibroids and future directions for investigating this intriguing biological connection. By elucidating the potential link between uterine fibroids and lipids, this review paves the way for an improved understanding of fibroid pathogenesis, personalized risk assessment, and novel lipid-lowering therapeutic strategies.
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Affiliation(s)
- Sandeepa Kn
- Nitte (Deemed To Be University), KS Hegde Medical Academy (KSHEMA), Central Research Laboratory, Cellomics, Lipidomics and Molecular Genetics Division, India
| | - Shilpa S Shetty
- Nitte (Deemed To Be University), KS Hegde Medical Academy (KSHEMA), Central Research Laboratory, Cellomics, Lipidomics and Molecular Genetics Division, India.
| | - Prasannakumar Shetty
- Nitte (Deemed To Be University), KS Hegde Medical Academy (KSHEMA), Department of obstetrics and gynecology, India; Nitte (Deemed To Be University), KS Hegde Medical Academy (KSHEMA), KSHEMA IVF Fertility & Reproductive Medicine Centre India, India
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Zhao Z, Wu W, Zhang Q, Xing T, Bai Y, Li S, Zhang D, Che H, Guo X. Mechanism and therapeutic potential of hippo signaling pathway in type 2 diabetes and its complications. Biomed Pharmacother 2025; 183:117817. [PMID: 39842269 DOI: 10.1016/j.biopha.2025.117817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/22/2024] [Accepted: 01/09/2025] [Indexed: 01/24/2025] Open
Abstract
Loss of pancreatic islet cell mass and function is one of the most important factors in the development of type 2 diabetes mellitus, and hyperglycemia-induced lesions in other organs are also associated with apoptosis or hyperproliferation of the corresponding tissue cells. The Hippo signaling pathway is a key signal in the regulation of cell growth, proliferation and apoptosis, which has been shown to play an important role in the regulation of diabetes mellitus and its complications. Excessive activation of the Hippo signaling pathway under high glucose conditions triggered apoptosis and decreased insulin secretion in pancreatic islet cells, while dysregulation of the Hippo signaling pathway in the cells of other organ tissues led to proliferation or apoptosis and promoted tissue fibrosis, which aggravated the progression of diabetes mellitus and its complications. This article reviews the mechanisms of Hippo signaling, its individual and reciprocal regulation in diabetic pancreatic pathology, and its emerging role in the pathophysiology of diabetic complications. Potential therapeutics for diabetes mellitus that have been shown to target the Hippo signaling pathway are also summarized to provide information for the clinical management of type 2 diabetes mellitus.
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Affiliation(s)
- Ziqi Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Weijie Wu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Qianyi Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Tiancheng Xing
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yiling Bai
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Shuoqi Li
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Dandan Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Huilian Che
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
| | - Xiaohui Guo
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
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Chen Q, Wang Y, Wang J, Ouyang X, Zhong J, Huang Y, Huang Z, Zheng B, Peng L, Tang X, Li S. Lipotoxicity Induces Cardiomyocyte Ferroptosis via Activating the STING Pathway. Antioxid Redox Signal 2025; 42:184-198. [PMID: 39001814 DOI: 10.1089/ars.2023.0510] [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] [Indexed: 07/15/2024]
Abstract
Objective: Lipotoxicity is a well-established contributor to cardiomyocyte death and heart damage, with ferroptosis being identified as a crucial death mode in cardiomyocyte disease. This study aims to explore the potential role and mechanism of ferroptosis in lipotoxicity-induced myocardial injury. Methods: Eight-week high-fat diet (HFD) Sprague-Dawley rat and H9c2 cardiomyocytes treated with palmitic acid (PA) were established for an in vivo and in vitro lipotoxic model. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were used to inhibit ferroptosis. Myocardial-specific stimulator of interferon genes (STING) knockdown rat (Stingmyo-KD) with HFD was further introduced. Rat cardiac structure and function, cell viability, the level of lipid peroxidation, malondialdehyde (MDA), glutathione (GSH), mitochondrial function, ferroptosis-related proteins, and STING pathway-related proteins in H9c2 cells/myocardium were detected. Results: HFD rats with a ferroptosis inhibitor showed improved cardiac structure and function, reduced lipid peroxidation, and restored GSH, which was further confirmed in H9c2 cell. The time-dependent activation of the STING pathway following PA stimulation was observed. Knockdown of the expression of STING could reduce PA-induced cell death, lipid peroxidation, and MDA levels while restoring the GSH. In addition, both HFD Stingmyo-KD rats and HFD rats with systematic inhibition by the STING inhibitor exhibited mitigating lipotoxicity-induced myocardial ferroptosis and reducing myocardial injury. Innovation and Conclusion: These findings suggest that lipotoxicity can induce ferroptosis in cardiomyocytes through the activation of the STING pathway, providing new targets and strategies for the treatment of lipotoxicity cardiomyopathy. Antioxid. Redox Signal. 42, 184-198.
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Affiliation(s)
- Qian Chen
- Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yina Wang
- VIP medical service center, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiafu Wang
- Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaolan Ouyang
- Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junlin Zhong
- Department of Ultrasonography, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yao Huang
- Zhongshan School of Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhuoshan Huang
- Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Benrong Zheng
- VIP medical service center, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Long Peng
- Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xixiang Tang
- VIP medical service center, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Suhua Li
- Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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8
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Patil R, Wang H, Kazaleh M, Ailawadi G, Salmon M. Dysregulation of Mitochondrial Homeostasis in Cardiovascular Diseases. Pharmaceuticals (Basel) 2025; 18:112. [PMID: 39861173 PMCID: PMC11768260 DOI: 10.3390/ph18010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Mitochondria dysfunction plays a central role in the development of vascular diseases as oxidative stress promotes alterations in mitochondrial morphology and function that contribute to disease progression. Redox imbalances can affect normal cellular processes including mitochondrial biogenesis, electrochemical equilibrium, and the regulation of mitochondrial DNA. In this review, we will discuss these imbalances and, in particular, the potential role of mitochondrial fusion, fission, biogenesis, and mitophagy in the context of vascular diseases and how the dysregulation of normal function might contribute to disease progression. We will also discuss potential implications of targeting mitochondrial regulation as therapeutic targets to treat vascular disease formation.
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Affiliation(s)
- Ricky Patil
- Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (H.W.); (M.K.); (G.A.); (M.S.)
| | - Hui Wang
- Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (H.W.); (M.K.); (G.A.); (M.S.)
| | - Matthew Kazaleh
- Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (H.W.); (M.K.); (G.A.); (M.S.)
| | - Gorav Ailawadi
- Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (H.W.); (M.K.); (G.A.); (M.S.)
- Frankel Cardiovascular Center, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Morgan Salmon
- Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (H.W.); (M.K.); (G.A.); (M.S.)
- Frankel Cardiovascular Center, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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9
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Hu C, Francisco J, Del Re DP, Sadoshima J. Decoding the Impact of the Hippo Pathway on Different Cell Types in Heart Failure. Circ J 2024; 89:6-15. [PMID: 38644191 DOI: 10.1253/circj.cj-24-0171] [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] [Indexed: 04/23/2024]
Abstract
The evolutionarily conserved Hippo pathway plays a pivotal role in governing a variety of biological processes. Heart failure (HF) is a major global health problem with a significant risk of mortality. This review provides a contemporary understanding of the Hippo pathway in regulating different cell types during HF. Through a systematic analysis of each component's regulatory mechanisms within the Hippo pathway, we elucidate their specific effects on cardiomyocytes, fibroblasts, endothelial cells, and macrophages in response to various cardiac injuries. Insights gleaned from both in vitro and in vivo studies highlight the therapeutic promise of targeting the Hippo pathway to address cardiovascular diseases, particularly HF.
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Affiliation(s)
- Chengchen Hu
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School
| | - Jamie Francisco
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School
| | - Dominic P Del Re
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School
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10
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Khoi CS, Lin TY, Chiang CK. Targeting Insulin Resistance, Reactive Oxygen Species, Inflammation, Programmed Cell Death, ER Stress, and Mitochondrial Dysfunction for the Therapeutic Prevention of Free Fatty Acid-Induced Vascular Endothelial Lipotoxicity. Antioxidants (Basel) 2024; 13:1486. [PMID: 39765815 PMCID: PMC11673094 DOI: 10.3390/antiox13121486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/11/2025] Open
Abstract
Excessive intake of free fatty acids (FFAs), especially saturated fatty acids, can lead to atherosclerosis and increase the incidence of cardiovascular diseases. FFAs also contribute to obesity, hyperlipidemia, and nonalcoholic fatty liver disease. Palmitic acid (PA) is human plasma's most abundant saturated fatty acid. It is often used to study the toxicity caused by free fatty acids in different organs, including vascular lipotoxicity. Fatty acid overload induces endothelial dysfunction through various molecular mechanisms. Endothelial dysfunction alters vascular homeostasis by reducing vasodilation and increasing proinflammatory and prothrombotic states. It is also linked to atherosclerosis, which leads to coronary artery disease, peripheral artery disease, and stroke. In this review, we summarize the latest studies, revealing the molecular mechanism of free fatty acid-induced vascular dysfunction, targeting insulin resistance, reactive oxygen species, inflammation, programmed cell death, ER stress, and mitochondrial dysfunction. Meanwhile, this review provides new strategies and perspectives for preventing and reducing the impact of cardiovascular diseases on human health through the relevant targeting molecular mechanism.
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Affiliation(s)
- Chong-Sun Khoi
- Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 220216, Taiwan;
- Graduate School of Biotechnology and Bioengineering, College of Engineering, Yuan Ze University, Taoyuan City 320315, Taiwan
| | - Tzu-Yu Lin
- Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 220216, Taiwan;
- Department of Mechanical Engineering, College of Engineering, Yuan Ze University, Taoyuan City 320315, Taiwan
| | - Chih-Kang Chiang
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei City 10617, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei City 10617, Taiwan
- Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei City 100229, Taiwan
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11
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Zhang X, Wu W, Li Y, Peng Z. Exploring the role and therapeutic potential of lipid metabolism in acute kidney injury. Ren Fail 2024; 46:2403652. [PMID: 39319697 PMCID: PMC11425701 DOI: 10.1080/0886022x.2024.2403652] [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: 07/04/2024] [Revised: 09/06/2024] [Accepted: 09/06/2024] [Indexed: 09/26/2024] Open
Abstract
Acute kidney injury (AKI) is a prevalent condition, yet no specific treatment is available. Extensive research has revealed the pivotal role of lipid-related alterations in AKI. Lipid metabolism plays an essential role in the sustenance of the kidneys. In addition to their energy-supplying function, lipids contribute to the formation of renal biomembranes and the establishment of the renal microenvironment. Moreover, lipids or their metabolites actively participate in signal transduction, which governs various vital biological processes, such as proliferation, differentiation, apoptosis, autophagy, and epithelial-mesenchymal transition. While previous studies have focused predominantly on abnormalities in lipid metabolism in chronic kidney disease, this review focuses on lipid metabolism anomalies in AKI. We explore the significance of lipid metabolism products as potential biomarkers for the early diagnosis and classification of AKI. Additionally, this review assesses current preclinical investigations on the modulation of lipid metabolism in the progression of AKI. Finally, on the basis of existing research, this review proposes future directions, highlights challenges, and presents novel targets and innovative ideas for the treatment of and intervention in AKI.
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Affiliation(s)
- Xiaoyu Zhang
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
| | - Wen Wu
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
- Department of Critical Care Medicine, Yichang Central People's Hospital, Yichang, China
| | - Yiming Li
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
| | - Zhiyong Peng
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
- Department of Critical Care Medicine, Center of Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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12
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Yang H, Sun P, Zhou S, Tang Y, Li S, Li W, Yu X, Liu H, Wu Y. Chlamydia psittaci infection induces IFN-I and IL-1β through the cGAS-STING-IRF3/NLRP3 pathway via mitochondrial oxidative stress in human macrophages. Vet Microbiol 2024; 299:110292. [PMID: 39581075 DOI: 10.1016/j.vetmic.2024.110292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/05/2024] [Accepted: 10/26/2024] [Indexed: 11/26/2024]
Abstract
Chlamydia psittaci (C. psittaci) is a multi-host pathogen that elicits robust innate immune responses in macrophages. Chlamydiae target host mitochondria to manipulate the cellular fate and metabolic functions. However, the effect of C. psittaci on the host mitochondria remains obscure. This study investigated how C. psittaci, post-infection in human macrophages, induces mitochondrial oxidative stress and damage to activate the cGAS-STING-IRF3/NLRP3 pathway for IFN-I and IL-1β production. Results demonstrate that C. psittaci increased mitochondrial ROS (mtROS) production. This induced the release of oxidized mitochondrial DNA (mtDNA) into the cytoplasm of macrophages. It also augmented IFN-I and IL-1β production dependent on the cGAS-STING pathway. Macrophages pre-treated with mtROS inhibitor mito-TEMPO displayed reduced oxidized mtDNA. This consequently lowered IFN-I and IL-1β production via the cGAS-STING pathway induced by C. psittaci. Additionally, we found that mtROS production may inhibit C. psittaci proliferation through the synergistic action of IFN-I and IL-1β. In conclusion, our study reveals that C. psittaci induces mtROS production leading to mtDNA release. This activates the cGAS-STING-IRF3/NLRP3 pathway to increase IFN-I and IL-1β production. This study elucidates a novel mechanism of bacterial pathogen activation in the cGAS-STING pathway. This reveals the molecular mechanisms underlying the immune response to C. psittaci infection and proposes potential targets for the treatment of C. psittaci related diseases.
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Affiliation(s)
- Hongyu Yang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Peiyuan Sun
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Shi Zhou
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Yuanyuan Tang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Sijia Li
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Weiwei Li
- Department of Clinical Laboratory, The Second People's Hospital of Foshan, China
| | - Xiang Yu
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Hanying Liu
- Health Management Medicine Center, the Third Xiangya Hospital, Central South University, Changsha, China.
| | - Yimou Wu
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.
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13
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Fan MW, Tian JL, Chen T, Zhang C, Liu XR, Zhao ZJ, Zhang SH, Chen Y. Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications. World J Diabetes 2024; 15:2041-2057. [PMID: 39493568 PMCID: PMC11525733 DOI: 10.4239/wjd.v15.i10.2041] [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: 05/18/2024] [Revised: 08/14/2024] [Accepted: 08/26/2024] [Indexed: 09/26/2024] Open
Abstract
Diabetes mellitus (DM) is one of the major causes of mortality worldwide, with inflammation being an important factor in its onset and development. This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway in mediating inflammatory responses. Furthermore, it comprehensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM, diabetic gastroenteropathy, diabetic cardiomyopathy, non-alcoholic fatty liver disease, and other complications. Additionally, the role of cGAS-STING in autonomic dysfunction and intestinal dysregulation, which can lead to digestive complications, has been discussed. Altogether, this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.
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Affiliation(s)
- Ming-Wei Fan
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Jin-Lan Tian
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Tan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Can Zhang
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Xin-Ru Liu
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Zi-Jian Zhao
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Shu-Hui Zhang
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Yan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
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14
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Preeti K, Sood A, Fernandes V, Khan I, Khatri DK, Singh SB. Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment. Mol Neurobiol 2024; 61:6217-6244. [PMID: 38285288 DOI: 10.1007/s12035-024-03933-y] [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: 09/08/2023] [Accepted: 01/05/2024] [Indexed: 01/30/2024]
Abstract
Type-1 IFN (interferon)-associated innate immune response is increasingly getting attention in neurodegenerative and metabolic diseases like type 2 diabetes (T2DM). However, its significance in T2DM/lipotoxicity-induced neuroglia changes and cognitive impairment is missing. The present study aims to evaluate the involvement of cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon gene), IRF3 (interferon regulatory factor-3), TBK (TANK binding kinase)-mediated Type-1 IFN response in the diabetic brain, and lipotoxicity (palmitate-bovine serum albumin conjugate/PA-BSA)-induced changes in cells (neuro2a and BV2). T2DM was induced in C57/BL6 mice by feeding on a high-fat diet (HFD, 60% Kcal) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) in the 12th week. Plasma biochemical parameter analysis, neurobehavioral assessment, protein expression, and quantitative polymerase chain reaction study were carried out to decipher the hypothesis. T2DM-associated metabolic and lipotoxic stress led to mitochondrial impairment causing leakage of mtDNA to the cytoplasm further commencing cGAS activation and its downstream signaling. The diseased hippocampus and cortex showed decreased expression of synaptophysin (p < 0.01) and PSD-95 (p < 0.01, p < 0.05) with increased expression of cGAS (p < 0.001), p-STING (p < 0.001), p-STAT1 (signal transducer and activator of transcription) (p < 0.01), and IFN-β (p < 0.001) compared to normal control. The IFN-β/p-STAT1-mediated microglia activation was executed employing a conditioned media approach. C-176, a selective STING inhibitor, alleviated cGAS/p-STING/IFN-β expression and proinflammatory microglia/M1-associated markers (CD16 expression, CXCL10, TNF-α, IL-1β mRNA fold change) in the diabetic brain. The present study suggests Type-1IFN response may result in neuroglia dyshomeostasis affecting normal brain function. Alleviating STING signaling has the potential to protect T2DM-associated central ailment.
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Affiliation(s)
- Kumari Preeti
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Anika Sood
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Valencia Fernandes
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Islauddin Khan
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Dharmendra Kumar Khatri
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
- Department of Pharmacology, Shobhaben Pratapbai Patel School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Mumbai, 400056, India.
| | - Shashi Bala Singh
- Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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15
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Boone C, Lewis SC. Bridging lipid metabolism and mitochondrial genome maintenance. J Biol Chem 2024; 300:107498. [PMID: 38944117 PMCID: PMC11326895 DOI: 10.1016/j.jbc.2024.107498] [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: 12/19/2023] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/01/2024] Open
Abstract
Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.
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Affiliation(s)
- Casadora Boone
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA
| | - Samantha C Lewis
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA; Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.
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16
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Yu F, Zong B, Ji L, Sun P, Jia D, Wang R. Free Fatty Acids and Free Fatty Acid Receptors: Role in Regulating Arterial Function. Int J Mol Sci 2024; 25:7853. [PMID: 39063095 PMCID: PMC11277118 DOI: 10.3390/ijms25147853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/13/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
The metabolic network's primary sources of free fatty acids (FFAs) are long- and medium-chain fatty acids of triglyceride origin and short-chain fatty acids produced by intestinal microorganisms through dietary fibre fermentation. Recent studies have demonstrated that FFAs not only serve as an energy source for the body's metabolism but also participate in regulating arterial function. Excess FFAs have been shown to lead to endothelial dysfunction, vascular hypertrophy, and vessel wall stiffness, which are important triggers of arterial hypertension and atherosclerosis. Nevertheless, free fatty acid receptors (FFARs) are involved in the regulation of arterial functions, including the proliferation, differentiation, migration, apoptosis, inflammation, and angiogenesis of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). They actively regulate hypertension, endothelial dysfunction, and atherosclerosis. The objective of this review is to examine the roles and heterogeneity of FFAs and FFARs in the regulation of arterial function, with a view to identifying the points of intersection between their actions and providing new insights into the prevention and treatment of diseases associated with arterial dysfunction, as well as the development of targeted drugs.
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Affiliation(s)
- Fengzhi Yu
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (F.Y.); (L.J.)
| | - Boyi Zong
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China; (B.Z.); (P.S.)
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
| | - Lili Ji
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (F.Y.); (L.J.)
| | - Peng Sun
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China; (B.Z.); (P.S.)
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
| | - Dandan Jia
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (F.Y.); (L.J.)
| | - Ru Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (F.Y.); (L.J.)
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17
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Sun K, Lu F, Hou L, Zhang X, Pan C, Liu H, Zheng Z, Guo Z, Ruan Z, Hou Y, Zhang J, Guo F, Zhu W. IRF1 regulation of ZBP1 links mitochondrial DNA and chondrocyte damage in osteoarthritis. Cell Commun Signal 2024; 22:366. [PMID: 39026271 PMCID: PMC11256489 DOI: 10.1186/s12964-024-01744-1] [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: 11/20/2023] [Accepted: 07/10/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Z-DNA binding protein 1 (ZBP1) is a nucleic acid sensor that is involved in multiple inflammatory diseases, but whether and how it contributes to osteoarthritis (OA) are unclear. METHODS Cartilage tissues were harvested from patients with OA and a murine model of OA to evaluate ZBP1 expression. Subsequently, the functional role and mechanism of ZBP1 were examined in primary chondrocytes, and the role of ZBP1 in OA was explored in mouse models. RESULTS We showed the upregulation of ZBP1 in articular cartilage originating from OA patients and mice with OA after destabilization of the medial meniscus (DMM) surgery. Specifically, knockdown of ZBP1 alleviated chondrocyte damage and protected mice from DMM-induced OA. Mechanistically, tumor necrosis factor alpha induced ZBP1 overexpression in an interferon regulatory factor 1 (IRF1)-dependent manner and elicited the activation of ZBP1 via mitochondrial DNA (mtDNA) release and ZBP1 binding. The upregulated and activated ZBP1 could interact with receptor-interacting protein kinase 1 and activate the transforming growth factor-beta-activated kinase 1-NF-κB signaling pathway, which led to chondrocyte inflammation and extracellular matrix degradation. Moreover, inhibition of the mtDNA-IRF1-ZBP1 axis with Cyclosporine A, a blocker of mtDNA release, could delay the progression of DMM-induced OA. CONCLUSIONS Our data revealed the pathological role of the mtDNA-IRF1-ZBP1 axis in OA chondrocytes, suggesting that inhibition of this axis could be a viable therapeutic approach for OA.
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Affiliation(s)
- Kai Sun
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Fan Lu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Liangcai Hou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xiong Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Chunran Pan
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Haigang Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Zehang Zheng
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Zhou Guo
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Zhaoxuan Ruan
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Yanjun Hou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Jinming Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Fengjing Guo
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Wentao Zhu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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18
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Hu X, Yuan X, Zhang G, Song H, Ji P, Guo Y, Liu Z, Tian Y, Shen R, Wang D. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis. Life Sci 2024; 344:122452. [PMID: 38462226 DOI: 10.1016/j.lfs.2024.122452] [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: 11/23/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 03/12/2024]
Abstract
The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
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Affiliation(s)
- Xiaohui Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Guokun Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Haoyun Song
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Zihua Liu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu Province 73000, China
| | - Yixiao Tian
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province 730000, China.
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19
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Biswal P, Sahu MR, Ahmad MH, Mondal AC. The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease. Mitochondrion 2024; 76:101885. [PMID: 38643865 DOI: 10.1016/j.mito.2024.101885] [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: 01/30/2024] [Revised: 04/10/2024] [Accepted: 04/18/2024] [Indexed: 04/23/2024]
Abstract
Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.
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Affiliation(s)
- Priyanka Biswal
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Manas Ranjan Sahu
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Mir Hilal Ahmad
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Amal Chandra Mondal
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
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20
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Zhang BC, Laursen MF, Hu L, Hazrati H, Narita R, Jensen LS, Hansen AS, Huang J, Zhang Y, Ding X, Muyesier M, Nilsson E, Banasik A, Zeiler C, Mogensen TH, Etzerodt A, Agger R, Johannsen M, Kofod-Olsen E, Paludan SR, Jakobsen MR. Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. Nat Commun 2024; 15:2760. [PMID: 38553448 PMCID: PMC10980718 DOI: 10.1038/s41467-024-47046-5] [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: 05/24/2023] [Accepted: 03/18/2024] [Indexed: 04/02/2024] Open
Abstract
The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STING-dependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy.
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Affiliation(s)
- Bao-Cun Zhang
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark.
| | - Marlene F Laursen
- Department of Health Science and Technology, Aalborg University, DK-9220, Aalborg, Denmark
| | - Lili Hu
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Hossein Hazrati
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
- Department of Forensic Medicine, Aarhus University, DK-8200, Aarhus N, Denmark
| | - Ryo Narita
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Lea S Jensen
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Aida S Hansen
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Jinrong Huang
- Department of Biology, University of Copenhagen, DK-2100, Copenhagen Ø, Denmark
| | - Yan Zhang
- Department of Engineering, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Xiangning Ding
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | | | - Emil Nilsson
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Agnieszka Banasik
- Department of Health Science and Technology, Aalborg University, DK-9220, Aalborg, Denmark
| | - Christina Zeiler
- Department of Health Science and Technology, Aalborg University, DK-9220, Aalborg, Denmark
| | - Trine H Mogensen
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
- Department of Infectious Diseases, Aarhus University Hospital, DK-8200, Aarhus N, Denmark
| | - Anders Etzerodt
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Ralf Agger
- Department of Health Science and Technology, Aalborg University, DK-9220, Aalborg, Denmark
| | - Mogens Johannsen
- Department of Forensic Medicine, Aarhus University, DK-8200, Aarhus N, Denmark
| | - Emil Kofod-Olsen
- Department of Health Science and Technology, Aalborg University, DK-9220, Aalborg, Denmark
| | - Søren R Paludan
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark.
| | - Martin R Jakobsen
- Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark.
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21
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Li Z, Zhang Y, Zhao B, Xue Q, Wang C, Wan S, Wang J, Chen X, Qi X. Non-cytopathic bovine viral diarrhea virus (BVDV) inhibits innate immune responses via induction of mitophagy. Vet Res 2024; 55:27. [PMID: 38443986 PMCID: PMC10916263 DOI: 10.1186/s13567-024-01284-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/29/2024] [Indexed: 03/07/2024] Open
Abstract
Bovine viral diarrhea virus (BVDV) belongs to the genus Pestivirus within the family Flaviviridae. Mitophagy plays important roles in virus-host interactions. Here, we provide evidence that non-cytopathic (NCP) BVDV shifts the balance of mitochondrial dynamics toward fission and induces mitophagy to inhibit innate immune responses. Mechanistically, NCP BVDV triggers the translocation of dynamin-related protein (Drp1) to mitochondria and stimulates its phosphorylation at Ser616, leading to mitochondrial fission. In parallel, NCP BVDV-induced complete mitophagy via Parkin-dependent pathway contributes to eliminating damaged mitochondria to inhibit MAVS- and mtDNA-cGAS-mediated innate immunity responses, mtROS-mediated inflammatory responses and apoptosis initiation. Importantly, we demonstrate that the LIR motif of ERNS is essential for mitophagy induction. In conclusion, this study is the first to show that NCP BVDV-induced mitophagy plays a central role in promoting cell survival and inhibiting innate immune responses in vitro.
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Affiliation(s)
- Zhijun Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs, Xi'an, China
| | - Ying Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs, Xi'an, China
| | - Bao Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
- Shaanxi Animal Disease Control Center, Xi'an, China
| | - Qinghong Xue
- China Institute of Veterinary Drug Control, Beijing, China
| | - Chunjiang Wang
- Hebei Veyong Pharmaceutical Co., Ltd, Shijiazhuang, China
| | - Siyu Wan
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs, Xi'an, China
| | - Jingyu Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs, Xi'an, China
| | - Xiwen Chen
- Animal Disease Prevention and Control & Healthy Breeding Engineering Technology Research Center, Mianyang Normal University, Mianyang, Sichuan, China.
| | - Xuefeng Qi
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
- Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs, Xi'an, China.
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22
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Zhao Z, Li B, Chen Q, Xiang X, Xu X, Han S, Lai W, Li Y, Xu W, Mai K, Ai Q. Dietary palm oil enhances Sterol regulatory element-binding protein 2-mediated cholesterol biosynthesis through inducing endoplasmic reticulum stress in muscle of large yellow croaker ( Larimichthys crocea). Br J Nutr 2024; 131:553-566. [PMID: 37699661 DOI: 10.1017/s0007114523001344] [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] [Indexed: 09/14/2023]
Abstract
Sterol regulatory element-binding protein 2 (SREBP2) is considered to be a major regulator to control cholesterol homoeostasis in mammals. However, the role of SREBP2 in teleost remains poorly understand. Here, we explored the molecular characterisation of SREBP2 and identified SREBP2 as a key modulator for 3-hydroxy-3-methylglutaryl-coenzyme A reductase and 7-dehydrocholesterol reductase, which were rate-limiting enzymes of cholesterol biosynthesis. Moreover, dietary palm oil in vivo or palmitic acid (PA) treatment in vitro elevated cholesterol content through triggering SREBP2-mediated cholesterol biosynthesis in large yellow croaker. Furthermore, our results also found that PA-induced activation of SREBP2 was dependent on the stimulating of endoplasmic reticulum stress (ERS) in croaker myocytes and inhibition of ERS by 4-Phenylbutyric acid alleviated PA-induced SREBP2 activation and cholesterol biosynthesis. In summary, our findings reveal a novel insight for understanding the role of SREBP2 in the regulation of cholesterol metabolism in fish and may deepen the link between dietary fatty acid and cholesterol biosynthesis.
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Affiliation(s)
- Zengqi Zhao
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Baolin Li
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Qiang Chen
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Xiaojun Xiang
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Xiang Xu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Shangzhe Han
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Wencong Lai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Yueru Li
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Wei Xu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, Shandong266237, People's Republic of China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Ocean University of China, 5 Yushan Road, Qingdao, Shandong266003, People's Republic of China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, Shandong266237, People's Republic of China
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23
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He W, Tang M, Gu R, Wu X, Mu X, Nie X. The Role of p53 in Regulating Chronic Inflammation and PANoptosis in Diabetic Wounds. Aging Dis 2024; 16:AD.2024.0212. [PMID: 38377027 PMCID: PMC11745441 DOI: 10.14336/ad.2024.0212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 02/12/2024] [Indexed: 02/22/2024] Open
Abstract
Diabetic wounds represent a formidable challenge in the clinical management of diabetes mellitus, markedly diminishing the patient's quality of life. These wounds arise from a multifaceted etiology, with the pathophysiological underpinnings remaining elusive and complex. Diabetes precipitates neuropathies and vasculopathies in the lower extremities, culminating in infections, ulcerations, and extensive tissue damage. The hallmarks of non-healing diabetic wounds include senescence, persistent inflammation, heightened apoptosis, and attenuated cellular proliferation. The TP53 gene, a pivotal tumor suppressor frequently silenced in human malignancies, orchestrates cellular proliferation, senescence, DNA repair, and apoptosis. While p53 is integral in cell cycle regulation, its role in initial tissue repair appears to be deleterious. In typical cutaneous wounds, p53 levels transiently dip, swiftly reverting to baseline. Yet in diabetic wounds, protracted p53 activation impedes healing via two distinct pathways: i) activating the p53-p21-Retinoblastoma (RB) axis, which halts the cell cycle, and ii) upregulating the cGAS-STING and nuclear factor-kappaB (NF-κB) cascades, instigating ferroptosis and pyroptosis. Furthermore, p53 intersects with various metabolic pathways, including glycolysis, gluconeogenesis, oxidative phosphorylation, and autophagy. In diabetic wounds, p53 may drive metabolic reprogramming, thus potentially derailing macrophage polarization. This review synthesizes case studies investigating the therapeutic modulation of p53 in diabetic wounds care. In summation, p53 modulates chronic inflammation and cellular aging within diabetic cutaneous wounds and is implicated in a novel cell death modality, encompassing ferroptosis and pyroptosis, which hinders the reparative process.
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Affiliation(s)
- Wenjie He
- College of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
- Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China.
| | - Ming Tang
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis 38105, USA.
| | - Rifang Gu
- School Medical Office, Zunyi Medical University, Zunyi 563006, China.
| | - Xingqian Wu
- College of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
- Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China.
| | - Xinrui Mu
- College of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
- Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China.
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi 563006, China.
- Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China.
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24
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Uppala R, Sarkar MK, Young KZ, Ma F, Vemulapalli P, Wasikowski R, Plazyo O, Swindell WR, Maverakis E, Gharaee-Kermani M, Billi AC, Tsoi LC, Kahlenberg JM, Gudjonsson JE. HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling. iScience 2024; 27:108986. [PMID: 38327798 PMCID: PMC10847730 DOI: 10.1016/j.isci.2024.108986] [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: 09/21/2023] [Revised: 11/10/2023] [Accepted: 01/17/2024] [Indexed: 02/09/2024] Open
Abstract
Interferon (IFN) activity exhibits a gender bias in human skin, skewed toward females. We show that HERC6, an IFN-induced E3 ubiquitin ligase, is induced in human keratinocytes through the epidermal type I IFN; IFN-κ. HERC6 knockdown in human keratinocytes results in enhanced induction of interferon-stimulated genes (ISGs) upon treatment with a double-stranded (ds) DNA STING activator cGAMP but not in response to the RNA-sensing TLR3 agonist. Keratinocytes lacking HERC6 exhibit sustained STING-TBK1 signaling following cGAMP stimulation through modulation of LATS2 and TBK1 activity, unmasking more robust ISG responses in female keratinocytes. This enhanced female-biased immune response with loss of HERC6 depends on VGLL3, a regulator of type I IFN signature. These data identify HERC6 as a previously unrecognized negative regulator of ISG expression specific to dsDNA sensing and establish it as a regulator of female-biased immune responses through modulation of STING signaling.
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Affiliation(s)
- Ranjitha Uppala
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mrinal K. Sarkar
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kelly Z. Young
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Feiyang Ma
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Rachael Wasikowski
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Olesya Plazyo
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - William R. Swindell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Emanual Maverakis
- Department of Dermatology, University of California, Davis, Davis, CA 95616, USA
| | - Mehrnaz Gharaee-Kermani
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Allison C. Billi
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lam C. Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - J. Michelle Kahlenberg
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA
| | - Johann E. Gudjonsson
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA
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25
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Ding W, Chen J, Zhao L, Wu S, Chen X, Chen H. Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases. Front Cell Dev Biol 2024; 12:1287447. [PMID: 38425502 PMCID: PMC10902119 DOI: 10.3389/fcell.2024.1287447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/23/2024] [Indexed: 03/02/2024] Open
Abstract
Mitochondrial dysfunction is one of the hallmarks of cardiovascular aging. The leakage of mitochondrial DNA (mtDNA) is increased in senescent cells, which are resistant to programmed cell death such as apoptosis. Due to its similarity to prokaryotic DNA, mtDNA could be recognized by cellular DNA sensors and trigger innate immune responses, resulting in chronic inflammatory conditions during aging. The mechanisms include cGAS-STING signaling, TLR-9 and inflammasomes activation. Mitochondrial quality controls such as mitophagy could prevent mitochondria from triggering harmful inflammatory responses, but when this homeostasis is out of balance, mtDNA-induced inflammation could become pathogenic and contribute to age-related cardiovascular diseases. Here, we summarize recent studies on mechanisms by which mtDNA promotes inflammation and aging-related cardiovascular diseases, and discuss the potential value of mtDNA in early screening and as therapeutic targets.
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Affiliation(s)
- Wanyue Ding
- Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Jingyu Chen
- Department of Chinese Medicine Internal Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lei Zhao
- Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Shuang Wu
- Southern Medical University Affiliated Qiqihar Hospital, The First Hospital of Qiqihar, Qiqihaer, Heilongjiang, China
| | - Xiaomei Chen
- Integrated Traditional Chinese and Western Medicine Syndrome Laboratory, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Hong Chen
- Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
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26
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He W, Mu X, Wu X, Liu Y, Deng J, Liu Y, Han F, Nie X. The cGAS-STING pathway: a therapeutic target in diabetes and its complications. BURNS & TRAUMA 2024; 12:tkad050. [PMID: 38312740 PMCID: PMC10838060 DOI: 10.1093/burnst/tkad050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/22/2023] [Accepted: 10/09/2023] [Indexed: 02/06/2024]
Abstract
Diabetic wound healing (DWH) represents a major complication of diabetes where inflammation is a key impediment to proper healing. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage. However, the contribution of cGAS-STING activation to impaired healing in DWH remains understudied. In this review, we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH. We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing. Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models. We highlight key knowledge gaps regarding cGAS-STING in DWH, including its relationships with endoplasmic reticulum stress and metal-ion signaling. Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH. This review synthesizes current understanding of how cGAS-STING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.
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Affiliation(s)
- Wenjie He
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Xingrui Mu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Xingqian Wu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Ye Liu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Junyu Deng
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Yiqiu Liu
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
| | - Felicity Han
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Xuqiang Nie
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- College of Pharmacy, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, No. 6 Xuefu West Road, Xinpu New District, Zunyi 563006, China
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27
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Park HJ, Jeong JH, Choi YH, Park SH. Hexane Fraction of Adenophora triphylla var. japonica Root Extract Inhibits Angiogenesis and Endothelial Cell-Induced Erlotinib Resistance in Lung Cancer Cells. Molecules 2024; 29:597. [PMID: 38338342 PMCID: PMC10856037 DOI: 10.3390/molecules29030597] [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: 12/29/2023] [Revised: 01/20/2024] [Accepted: 01/24/2024] [Indexed: 02/12/2024] Open
Abstract
The aim of this study was to investigate the anti-angiogenic effects of the hexane fraction of Adenophora triphylla var. japonica root extract (HAT) and its influence on the development of erlotinib resistance in human lung cancer cells. HAT significantly reduced the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). The phosphorylation levels of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream molecules were decreased via HAT, indicating its anti-angiogenic potential in endothelial cells (ECs). A docking analysis demonstrated that β-sitosterol and lupeol, representative components of HAT, exhibit a high affinity for binding to VEGFR2. In addition, conditioned media from HAT-pretreated H1299 human lung cancer cells attenuated cancer-cell-induced chemotaxis of HUVECs, which was attributed to the decreased expression of angiogenic and chemotactic factors in H1299 cells. Interestingly, co-culture of erlotinib-sensitive PC9 human lung cancer cells with HUVECs induced erlotinib resistance in PC9 cells. However, co-culture with HAT-pretreated HUVECs partially restored the sensitivity of PC9 cells to erlotinib. HAT inhibited the development of erlotinib resistance by attenuating hepatocyte growth factor (HGF) production by ECs. Taken together, our results demonstrate that HAT exerts its anticancer effects by regulating the crosstalk between ECs and lung cancer cells.
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Affiliation(s)
- Hyun-Ji Park
- Department of Pathology, College of Korean Medicine, Dong-eui University, Busan 47227, Republic of Korea; (H.-J.P.); (J.-H.J.)
| | - Jae-Hoon Jeong
- Department of Pathology, College of Korean Medicine, Dong-eui University, Busan 47227, Republic of Korea; (H.-J.P.); (J.-H.J.)
| | - Yung-Hyun Choi
- Department of Biochemistry, College of Korean Medicine, Dong-eui University, Busan 47227, Republic of Korea;
| | - Shin-Hyung Park
- Department of Pathology, College of Korean Medicine, Dong-eui University, Busan 47227, Republic of Korea; (H.-J.P.); (J.-H.J.)
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28
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Gong J, Gao X, Ge S, Li H, Wang R, Zhao L. The Role of cGAS-STING Signalling in Metabolic Diseases: from Signalling Networks to Targeted Intervention. Int J Biol Sci 2024; 20:152-174. [PMID: 38164186 PMCID: PMC10750282 DOI: 10.7150/ijbs.84890] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 10/17/2023] [Indexed: 01/03/2024] Open
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) is a crucial innate defence mechanism against viral infection in the innate immune system, as it principally induces the production of type I interferons. Immune responses and metabolic control are inextricably linked, and chronic low-grade inflammation promotes the development of metabolic diseases. The cGAS-STING pathway activated by double-stranded DNA (dsDNA), cyclic dinucleotides (CDNs), endoplasmic reticulum stress (ER stress), mitochondrial stress, and energy imbalance in metabolic cells and immune cells triggers proinflammatory responses and metabolic disorders. Abnormal overactivation of the pathway is closely associated with metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), insulin resistance and cardiovascular diseases (CVDs). The interaction of cGAS-STING with other pathways, such as the nuclear factor-kappa B (NF-κB), Jun N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), autophagy, pyroptosis and insulin signalling pathways, is considered an important mechanism by which cGAS-STING regulates inflammation and metabolism. This review focuses on the link between immune responses related to the cGAS-STING pathway and metabolic diseases and cGAS-STING interaction with other pathways for mediating signal input and affecting output. Moreover, potential inhibitors of the cGAS-STING pathway and therapeutic prospects against metabolic diseases are discussed. This review provides a comprehensive perspective on the involvement of STING in immune-related metabolic diseases.
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Affiliation(s)
- Jiahui Gong
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Xilong Gao
- Key Laboratory of Functional Dairy, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Shaoyang Ge
- Hebei Engineering Research Center of Animal Product, Sanhe 065200, China
| | - Hongliang Li
- Inner Mongolia Mengniu Dairy (Group) Co., Ltd., Hohhot 011517, China
| | - Ran Wang
- Key Laboratory of Functional Dairy, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
- Research Center for Probiotics, China Agricultural University, Sanhe 065200, China
| | - Liang Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
- Key Laboratory of Functional Dairy, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
- Food Laboratory of Zhongyuan, Luohe 462300, China
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29
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An Y, Geng K, Wang HY, Wan SR, Ma XM, Long Y, Xu Y, Jiang ZZ. Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes. Cell Commun Signal 2023; 21:365. [PMID: 38129863 PMCID: PMC10734150 DOI: 10.1186/s12964-023-01393-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: 05/20/2023] [Accepted: 11/11/2023] [Indexed: 12/23/2023] Open
Abstract
Hyperglycaemia-induced endothelial dysfunction is a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy. STING, which is a newly discovered regulator of innate immunity, has also been reported to play an important role in various metabolic diseases. However, the role of STING in diabetes-induced endothelial cell dysfunction is unknown. In this study, we established a diabetic macroangiopathy mouse model by streptozotocin (STZ) injection combined with high-fat diet (HFD) feeding and a glucotoxicity cell model in high glucose (HG)-treated rat aortic endothelial cells (RAECs). We found that STING expression was specifically increased in the endothelial cells of diabetic arteries, as well as in HG-treated RAECs. Moreover, genetic deletion of STING significantly ameliorated diabetes-induced endothelial cell dysfunction and apoptosis in vivo. Likewise, STING inhibition by C-176 reversed HG-induced migration dysfunction and apoptosis in RAECs, whereas STING activation by DMXAA resulted in migration dysfunction and apoptosis. Mechanistically, hyperglycaemia-induced oxidative stress promoted endothelial mitochondrial dysfunction and mtDNA release, which subsequently activated the cGAS-STING system and the cGAS-STING-dependent IRF3/NF-kB pathway, ultimately resulting in inflammation and apoptosis. In conclusion, our study identified a novel role of STING in diabetes-induced aortic endothelial cell injury and suggested that STING inhibition was a potential new therapeutic strategy for the treatment of diabetic macroangiopathy. Video Abstract.
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Affiliation(s)
- Ying An
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China
| | - Kang Geng
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China
- Department of Plastic and Burn Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000
| | - Hong-Ya Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China
| | - Sheng-Rong Wan
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China
| | - Xiu-Mei Ma
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
| | - Yang Long
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000.
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China.
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China.
| | - Zong-Zhe Jiang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000.
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China.
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, Sichuan, China.
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China, 646000.
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30
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Zhou Z, Ou-yang C, Chen Q, Ren Z, Guo X, Lei M, Liu C, Yang X. Trafficking and effect of released DNA on cGAS-STING signaling pathway and cardiovascular disease. Front Immunol 2023; 14:1287130. [PMID: 38152400 PMCID: PMC10751357 DOI: 10.3389/fimmu.2023.1287130] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 12/01/2023] [Indexed: 12/29/2023] Open
Abstract
Evidence from clinical research and animal studies indicates that inflammation is an important factor in the occurrence and development of cardiovascular disease (CVD). Emerging evidence shows that nucleic acids serve as crucial pathogen-associated molecular patterns (PAMPs) or non-infectious damage-associated molecular patterns (DAMPs), are released and then recognized by pattern recognition receptors (PRRs), which activates immunological signaling pathways for host defense. Mechanistically, the released nucleic acids activate cyclic GMP-AMP synthase (cGAS) and its downstream receptor stimulator of interferon genes (STING) to promote type I interferons (IFNs) production, which play an important regulatory function during the initiation of an innate immune response to various diseases, including CVD. This pathway represents an essential defense regulatory mechanism in an organism's innate immune system. In this review, we outline the overall profile of cGAS-STING signaling, summarize the latest findings on nucleic acid release and trafficking, and discuss their potential role in CVD. This review also sheds light on potential directions for future investigations on CVD.
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Affiliation(s)
- Zimo Zhou
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Army Medical University, Chongqing, China
| | - Changhan Ou-yang
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Zhanhong Ren
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Xiying Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Xiaosong Yang
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
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Luo X, Liu M, Wang S, Chen Y, Bao X, Lv Y, Zhang S, Xu B, Weng X, Bai X, Zeng M, Zhao C, Li J, Jia H, Yu B. Combining metabolomics and OCT to reveal plasma metabolic profiling and biomarkers of plaque erosion and plaque rupture in STEMI patients. Int J Cardiol 2023; 390:131223. [PMID: 37517782 DOI: 10.1016/j.ijcard.2023.131223] [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: 10/20/2022] [Revised: 01/15/2023] [Accepted: 02/26/2023] [Indexed: 08/01/2023]
Abstract
OBJECTIVE Plaque erosion (PE) and plaque rupture (PR) are the main subtypes of ST-segment elevation myocardial infarction (STEMI), the differences of metabolic patterns between PE and PR remain largely unknown. METHODS 132 STEMI patients were divided into training set (PR, n = 36; PE, n = 36) and test set (PR, n = 30; PE, n = 30), the plasma from patients were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry. RESULTS We identified 56 and 28 differences in training and test set, respectively. Among these metabolites, it was found that docosahexaenoic acid (DHA), salicylic acid and proline were recognized in both tests. Receiver Operating Characteristic (ROC) analysis showed that the area under curve of docosahexaenoic acid (DHA) was 0.81 and 0.75 in training and test samples, respectively; proline was 0.67 and 0.74 in training and test samples, respectively; salicylic acid was 0.70 and 0.73 in training and test samples, respectively. CONCLUSIONS DHA, salicylic acid, and proline could be used as non-invasive biomarkers to differentiate PE and PR.
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Affiliation(s)
- Xing Luo
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Minghao Liu
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Shengfang Wang
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Yuwu Chen
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Xiaoyi Bao
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Ying Lv
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Shan Zhang
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Biyi Xu
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Xiuzhu Weng
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Xiaoxuan Bai
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Ming Zeng
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Chen Zhao
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Ji Li
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
| | - Haibo Jia
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China.
| | - Bo Yu
- Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China.
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Myint M, Oppedisano F, De Giorgi V, Kim BM, Marincola FM, Alter HJ, Nesci S. Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions. J Transl Med 2023; 21:757. [PMID: 37884933 PMCID: PMC10605416 DOI: 10.1186/s12967-023-04627-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 10/14/2023] [Indexed: 10/28/2023] Open
Abstract
Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.
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Affiliation(s)
| | - Francesca Oppedisano
- Department of Health Sciences, Institute of Research for Food Safety and Health, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Valeria De Giorgi
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | | | | | - Harvey J Alter
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | - Salvatore Nesci
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Italy.
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Ma X, Xin D, She R, Liu D, Ge J, Mei Z. Novel insight into cGAS-STING pathway in ischemic stroke: from pre- to post-disease. Front Immunol 2023; 14:1275408. [PMID: 37915571 PMCID: PMC10616885 DOI: 10.3389/fimmu.2023.1275408] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023] Open
Abstract
Ischemic stroke, a primary cause of disability and the second leading cause of mortality, has emerged as an urgent public health issue. Growing evidence suggests that the Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) pathway, a component of innate immunity, is closely associated with microglia activation, neuroinflammation, and regulated cell death in ischemic stroke. However, the mechanisms underlying this pathway remain inadequately understood. This article comprehensively reviews the existing literature on the cGAS-STING pathway and its multifaceted relationship with ischemic stroke. Initially, it examines how various risk factors and pre-disease mechanisms such as metabolic dysfunction and senescence (e.g., hypertension, hyperglycemia, hyperlipidemia) affect the cGAS-STING pathway in relation to ischemic stroke. Subsequently, we explore in depth the potential pathophysiological relationship between this pathway and oxidative stress, endoplasmic reticulum stress, neuroinflammation as well as regulated cell death including ferroptosis and PANoptosis following cerebral ischemia injury. Finally, it suggests that intervention targeting the cGAS-STING pathway may serve as promising therapeutic strategies for addressing neuroinflammation associated with ischemic stroke. Taken together, this review concludes that targeting the microglia cGAS-STING pathway may shed light on the exploration of new therapeutic strategies against ischemic stroke.
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Affiliation(s)
- Xiaoqi Ma
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Dan Xin
- Institute of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ruining She
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Danhong Liu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jinwen Ge
- Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Zhigang Mei
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
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Chakraborty A, Li Y, Zhang C, Li Y, Rebello KR, Li S, Xu S, Vasquez HG, Zhang L, Luo W, Wang G, Chen K, Coselli JS, LeMaire SA, Shen YH. Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections. Circulation 2023; 148:959-977. [PMID: 37555319 PMCID: PMC10529114 DOI: 10.1161/circulationaha.123.063332] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 07/17/2023] [Indexed: 08/10/2023]
Abstract
BACKGROUND Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified. METHODS We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis. RESULTS Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix-producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting-/- mice, the aortic stress-induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues. CONCLUSIONS Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.
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Affiliation(s)
- Abhijit Chakraborty
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Yanming Li
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Chen Zhang
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Yang Li
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Kimberly R Rebello
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Shengyu Li
- Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, TX (S.L., G.W.)
| | - Samantha Xu
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
| | - Hernan G Vasquez
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Lin Zhang
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Wei Luo
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Guangyu Wang
- Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, TX (S.L., G.W.)
| | - Kaifu Chen
- Department of Pediatrics, Harvard Medical School, Boston, MA (K.C.)
| | - Joseph S Coselli
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Cardiovascular Research Institute (J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Scott A LeMaire
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Cardiovascular Research Institute (J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Department of Cardiovascular Surgery, The Texas Heart Institute, Houston (A.C., Y.L., C.Z., K.R.R., Y.L., W.L., H.G.V., L.Z., J.S.C., S.A.L.)
| | - Ying H Shen
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (A.C., Y.L., C.Z., K.R.R., Y.L., S.X., W.L., H.G.V., L.Z., J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
- Cardiovascular Research Institute (J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX
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Chen X, Liu Z, Huang L, Li Z, Dai X. Targeting the mechanism of IRF3 in sepsis-associated acute kidney injury via the Hippo pathway. Int Immunopharmacol 2023; 122:110625. [PMID: 37441808 DOI: 10.1016/j.intimp.2023.110625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/22/2023] [Accepted: 07/06/2023] [Indexed: 07/15/2023]
Abstract
Sepsis-induced inflammatory damage and adaptive repair are critical in the pathophysiological mechanisms of acute kidney injury (AKI). Here, we investigated the role of interferon regulatory factor three (IRF3) and subsequent activation of the Hippo pathway in inflammatory damage and repair using an in vitro cell model of LPS-induced AKI. LPS caused the phosphorylation and activation of IRF3 in the early stages of sepsis, and activated IRF3 enhanced the production of type I interferon (IFN), resulting in an excessive inflammatory response. Furthermore, LPS generated considerably more inflammatory injury than intended cell death, and IRF3 activation triggered the Hippo pathway, causing a reduction in YAP, which eventually impaired proliferation and repair in surviving renal tubular epithelial cells and exacerbated the development of AKI. In conclusion, IRF3 promoted the development of sepsis-associated AKI (SAKI) by modulating the Hippo pathway.
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Affiliation(s)
- Xiaomei Chen
- Institute of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affliated Hospital of Xiangnan University, Hunan 423000, People's Republic of China
| | - Ze Liu
- School of Nursing, Xiangnan University, Hunan 423000, People's Republic of China
| | - Lingkun Huang
- Department of Anaesthesiology, The First People's Hospital of Chenzhou, The First Affliated Hospital of Xiangnan University, Hunan 423000, People's Republic of China
| | - Zhenhua Li
- Institute of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affliated Hospital of Xiangnan University, Hunan 423000, People's Republic of China.
| | - Xingui Dai
- Institute of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affliated Hospital of Xiangnan University, Hunan 423000, People's Republic of China.
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Xiong Y, Leng Y, Tian H, Deng X, Li W, Li W, Xia Z. Decreased MFN2 activates the cGAS-STING pathway in diabetic myocardial ischaemia-reperfusion by triggering the release of mitochondrial DNA. Cell Commun Signal 2023; 21:192. [PMID: 37537600 PMCID: PMC10398939 DOI: 10.1186/s12964-023-01216-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND The cause of aggravation of diabetic myocardial damage is yet to be elucidated; damage to mitochondrial function has been a longstanding focus of research. During diabetic myocardial ischaemia-reperfusion (MI/R), it remains unclear whether reduced mitochondrial fusion exacerbates myocardial injury by generating free damaged mitochondrial DNA (mitoDNA) and activating the cGAS-STING pathway. METHODS In this study, a mouse model of diabetes was established (by feeding mice a high-fat diet (HFD) plus a low dose of streptozotocin (STZ)), a MI/R model was established by cardiac ischaemia for 2 h and reperfusion for 30 min, and a cellular model of glycolipid toxicity induced by high glucose (HG) and palmitic acid (PA) was established in H9C2 cells. RESULTS We observed that altered mitochondrial dynamics during diabetic MI/R led to increased mitoDNA in the cytosol, activation of the cGAS-STING pathway, and phosphorylation of the downstream targets TBK1 and IRF3. In the cellular model we found that cytosolic mitoDNA was the result of reduced mitochondrial fusion induced by HG and PA, which also resulted in cGAS-STING signalling and activation of downstream targets. Moreover, inhibition of STING by H-151 significantly ameliorated myocardial injury induced by MFN2 knockdown in both the cell and mouse models. The use of a fat-soluble antioxidant CoQ10 improved cardiac function in the mouse models. CONCLUSIONS Our study elucidated the critical role of cGAS-STING activation, triggered by increased cytosolic mitoDNA due to decreased mitochondrial fusion, in the pathogenesis of diabetic MI/R injury. This provides preclinical insights for the treatment of diabetic MI/R injury. Video Abstract.
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Affiliation(s)
- Yonghong Xiong
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan Leng
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hao Tian
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xinqi Deng
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wenyuan Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Zhongyuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
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Abstract
According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.
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Affiliation(s)
- Laura E Newman
- Salk Institute for Biological Studies, La Jolla, California, USA;
| | - Gerald S Shadel
- Salk Institute for Biological Studies, La Jolla, California, USA;
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38
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Yu H, Wang H, Liu J, Huang T, Man Y, Xiang L. The effect of ROS-YAP crosstalk on osteoimmune response orchestrating osteogenesis. Cell Cycle 2023; 22:1391-1405. [PMID: 37161399 PMCID: PMC10228400 DOI: 10.1080/15384101.2023.2211830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 02/25/2023] [Accepted: 03/14/2023] [Indexed: 05/11/2023] Open
Abstract
Bone defect repair is a common medical concern. In spite of various existing treatments, its management still requires improvement. Here we show that YAP, a downstream signaling of Hippo pathway, might interplay with redox oxygen species (ROS) and modulate osteoimmunology, which refers to the interaction between immune and skeletal system during bone defect repair. We modulated the ROS level of RAW264.7 cells and found YAP level was reversely regulated. Meanwhile, we detected the feedback of YAP on oxidation level. The results demonstrated that the antioxidant enzyme expression was in proportion to the YAP level of RAW264.7 cells. Additionally, indirect coculture system was applied and it indicated that RAW264.7 cells under oxidative stress could impede proliferation and migration ability of MC3T3-E1 pre-osteoblasts. Consistently, in vivo experiment verified high oxidant level slowed down mice osteogenesis during bone defect repair, while antioxidant and upregulation of YAP accelerated this process. Additionally, we established a mouse model with YAP conditional knockout in macrophages. The results identified that deficiency of YAP in macrophages negatively affected bone defect repair in vivo. In summary, our study indicated that ROS and YAP could jointly modulate osteogenesis via their effect on osteoimmunology.ABBREVIATIONS: GPX4, glutathione peroxidase 4; NAC, N-Acetyl-L-cysteine; qRT-PCR, real-time quantitative PCR; ROS, reactive oxygen species; Tb.N, trabecular number; Tb.Sp, trabecular separation.
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Affiliation(s)
- Hui Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Mucosa and Periodontitis, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Haochen Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiayi Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Tianyu Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Man
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Xiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Wei X, Huang G, Liu J, Ge J, Zhang W, Mei Z. An update on the role of Hippo signaling pathway in ischemia-associated central nervous system diseases. Biomed Pharmacother 2023; 162:114619. [PMID: 37004330 DOI: 10.1016/j.biopha.2023.114619] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
The most frequent reason of morbidity and mortality in the world, cerebral ischemia sets off a chain of molecular and cellular pathologies that associated with some central nervous system (CNS) disorders mainly including ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy and other CNS diseases. In recent times, despite significant advancements in the treatment of the pathological processes underlying various neurological illnesses, effective therapeutic approaches that are specifically targeted to minimizing the damage of such diseases remain absent. Hippo signaling pathway, characterized by enzyme linked reactions between MSTI/2, LAST1/2, and YAP or TAZ proteins, controls cell division, survival, and differentiation, as well as being engaged in a variety of biological activities, such as the development and transformation of the nervous system. Recently, accumulating studies demonstrated that Hippo pathway takes part in the processes of ischemic stroke, AD, PD, etc., including but not limited to oxidative stress, inflammatory response, blood-brain barrier damage, mitochondrial disorders, and neural cells death. Thus, it's crucial to understand the molecular basis of the Hippo signaling pathway for determining potential new therapeutic targets against ischemia-associated CNS diseases. Here, we discuss latest advances in the deciphering of the Hippo signaling pathway and highlight the therapeutic potential of targeting the pathway in treating ischemia-associated CNS diseases.
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Elzinga SE, Koubek EJ, Hayes JM, Carter A, Mendelson FE, Webber-Davis I, Lentz SI, Feldman EL. Modeling the innate inflammatory cGAS/STING pathway: sexually dimorphic effects on microglia and cognition in obesity and prediabetes. Front Cell Neurosci 2023; 17:1167688. [PMID: 37206668 PMCID: PMC10188944 DOI: 10.3389/fncel.2023.1167688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 04/06/2023] [Indexed: 05/21/2023] Open
Abstract
Introduction The prevalence of obesity, prediabetes, and diabetes continues to grow worldwide. These metabolic dysfunctions predispose individuals to neurodegenerative diseases and cognitive impairment, including dementias such as Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The innate inflammatory cGAS/STING pathway plays a pivotal role in metabolic dysfunction and is an emerging target of interest in multiple neurodegenerative diseases, including AD/ADRD. Therefore, our goal was to establish a murine model to specifically target the cGAS/STING pathway to study obesity- and prediabetes-induced cognitive impairment. Methods We performed two pilot studies in cGAS knockout (cGAS-/-) male and female mice designed to characterize basic metabolic and inflammatory phenotypes and examine the impact of high-fat diet (HFD) on metabolic, inflammatory, and cognitive parameters. Results cGAS-/- mice displayed normal metabolic profiles and retained the ability to respond to inflammatory stimuli, as indicated by an increase in plasma inflammatory cytokine production in response to lipopolysaccharide injection. HFD feeding caused expected increases in body weight and decreases in glucose tolerance, although onset was accelerated in females versus males. While HFD did not increase plasma or hippocampal inflammatory cytokine production, it did alter microglial morphology to a state indicative of activation, particularly in female cGAS-/- mice. However, HFD negatively impacted cognitive outcomes in male, but not female animals. Discussion Collectively, these results suggest that cGAS-/- mice display sexually dimorphic responses to HFD, possibly based on differences in microglial morphology and cognition.
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Affiliation(s)
- Sarah E. Elzinga
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - Emily J. Koubek
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - John M. Hayes
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - A. Carter
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - Faye E. Mendelson
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - Ian Webber-Davis
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - Stephen I. Lentz
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
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Yin Y, Tan M, Han L, Zhang L, Zhang Y, Zhang J, Pan W, Bai J, Jiang T, Li H. The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy. Acta Pharm Sin B 2023; 13:1956-1975. [PMID: 37250161 PMCID: PMC10213817 DOI: 10.1016/j.apsb.2023.01.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/09/2022] [Accepted: 11/18/2022] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.
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Affiliation(s)
- Yunfei Yin
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Mingyue Tan
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Lianhua Han
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Lei Zhang
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yue Zhang
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jun Zhang
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wanqian Pan
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Jiaxiang Bai
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Department of Orthopedics, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Tingbo Jiang
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Hongxia Li
- Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
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Zheng L, Duan SL. Molecular regulation mechanism of intestinal stem cells in mucosal injury and repair in ulcerative colitis. World J Gastroenterol 2023; 29:2380-2396. [PMID: 37179583 PMCID: PMC10167905 DOI: 10.3748/wjg.v29.i16.2380] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 01/26/2023] [Accepted: 04/07/2023] [Indexed: 04/24/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease with complex causes. The main pathological changes were intestinal mucosal injury. Leucine-rich repeat-containing G protein coupled receptor 5 (LGR5)-labeled small intestine stem cells (ISCs) were located at the bottom of the small intestine recess and inlaid among Paneth cells. LGR5+ small ISCs are active proliferative adult stem cells, and their self-renewal, proliferation and differentiation disorders are closely related to the occurrence of intestinal inflammatory diseases. The Notch signaling pathway and Wnt/β-catenin signaling pathway are important regulators of LGR5-positive ISCs and together maintain the function of LGR5-positive ISCs. More importantly, the surviving stem cells after intestinal mucosal injury accelerate division, restore the number of stem cells, multiply and differentiate into mature intestinal epithelial cells, and repair the damaged intestinal mucosa. Therefore, in-depth study of multiple pathways and transplantation of LGR5-positive ISCs may become a new target for the treatment of UC.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 730000, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 730000, Shaanxi Province, China
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Luo J, Lu C, Chen Y, Wu X, Zhu C, Cui W, Yu S, Li N, Pan Y, Zhao W, Yang Q, Yang X. Nuclear translocation of cGAS orchestrates VEGF-A-mediated angiogenesis. Cell Rep 2023; 42:112328. [PMID: 37027305 DOI: 10.1016/j.celrep.2023.112328] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 12/20/2022] [Accepted: 03/17/2023] [Indexed: 04/08/2023] Open
Abstract
Cyclic GMP-AMP synthase (cGAS) senses cytosolic incoming DNA and consequently activates stimulator of interferon response cGAMP interactor 1 (STING) to mount immune response. Here, we show nuclear cGAS could regulate VEGF-A-mediated angiogenesis in an immune-independent manner. We found VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway. Moreover, nuclear cGAS subsequently regulates miR-212-5p-ARPC3 cascade to modulate VEGF-A-mediated angiogenesis through affecting cytoskeletal dynamics and VEGFR2 trafficking from trans-Golgi network (TGN) to plasma membrane via a regulatory feedback loop. In contrast, cGAS deficiency remarkably impairs VEGF-A-mediated angiogenesis in vivo and in vitro. Furthermore, we found strong association between the expression of nuclear cGAS and VEGF-A, and the malignancy and prognosis in malignant glioma, suggesting that nuclear cGAS might play important roles in human pathology. Collectively, our findings illustrated the function of cGAS in angiogenesis other than immune surveillance, which might be a potential therapeutic target for pathological angiogenesis-related diseases.
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Affiliation(s)
- Juanjuan Luo
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Chunjiao Lu
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yang Chen
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Xuewei Wu
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Chenchen Zhu
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Wei Cui
- College of Life Science and Biopharmaceutical of Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Shicang Yu
- Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ningning Li
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Yihang Pan
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Weijiang Zhao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Qingkai Yang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Xiaojun Yang
- Shantou University Medical College, Shantou, Guangdong 515041, China.
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Zhang C, Li Y, Chakraborty A, Li Y, Rebello KR, Ren P, Luo W, Zhang L, Lu HS, Cassis LA, Coselli JS, Daugherty A, LeMaire SA, Shen YH. Aortic Stress Activates an Adaptive Program in Thoracic Aortic Smooth Muscle Cells That Maintains Aortic Strength and Protects Against Aneurysm and Dissection in Mice. Arterioscler Thromb Vasc Biol 2023; 43:234-252. [PMID: 36579645 PMCID: PMC9877188 DOI: 10.1161/atvbaha.122.318135] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 12/08/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD). METHODS We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific Yap deletion. RESULTS In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-β (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg, Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (eg, Lox) and increased their transcript abundance. SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased AAD incidence. CONCLUSIONS Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.
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Affiliation(s)
- Chen Zhang
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Yanming Li
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Abhijit Chakraborty
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Yang Li
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Kimberly R Rebello
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Pingping Ren
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Wei Luo
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Lin Zhang
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
| | - Hong S Lu
- Saha Cardiovascular Research Center (H.S.L., A.D.), University of Kentucky, Lexington
- Department of Physiology (H.S.L., A.D.), University of Kentucky, Lexington
| | - Lisa A Cassis
- Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington
| | - Joseph S Coselli
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (J.S.C., S.A.L., Y.S.)
| | - Alan Daugherty
- Saha Cardiovascular Research Center (H.S.L., A.D.), University of Kentucky, Lexington
- Department of Physiology (H.S.L., A.D.), University of Kentucky, Lexington
| | - Scott A LeMaire
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Texas Heart Institute, Houston (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L.)
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (J.S.C., S.A.L., Y.S.)
| | - Ying H Shen
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (C.Z., Y.L., A.C., Y.L., K.R.R., P.R., W.L., L.Z., J.S.C., S.A.L., Y.H.S.)
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (J.S.C., S.A.L., Y.S.)
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Chen Z, Sun X, Li X, Liu N. Oleoylethanolamide alleviates hyperlipidaemia-mediated vascular calcification via attenuating mitochondrial DNA stress triggered autophagy-dependent ferroptosis by activating PPARα. Biochem Pharmacol 2023; 208:115379. [PMID: 36525991 DOI: 10.1016/j.bcp.2022.115379] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/04/2022] [Accepted: 12/07/2022] [Indexed: 12/15/2022]
Abstract
Vascular calcification, a prevalent pathological alteration in metabolic syndromes, is tightly related with cardiometabolic risk events. Ferroptosis, a newly iron-dependent programmed cell death, induced by palmitic acid (PA), the major saturated free fatty acid in hyperlipidemia, is a vital mechanism of vascular calcification. Recent studies reported that ferroptosis is a distinctive type of cell death dependent on autophagy, with the lipotoxicity of PA on cell viability being closely linked with autophagy. Oleoylethanolamide (OEA), an endogenous bioactive mediator of lipid homeostasis, exerts vascular protection against intimal calcification, atherosclerosis; however, its beneficial effect on vascular smooth muscle cell (VSMC)-associated medial calcification has not been investigated. Our aim was to characterize the effect of OEA on vascular calcification and ferroptosis of VSMCs under hyperlipidaemia/PA exposure. In vivo, vascular calcification model was induced in rats by high-fat diet and vitamin D3 plus nicotine; in vitro, VSMCs ferroptosis was induced by PA or plus β-glycerophosphate mimicking vascular calcification. The calcium deposition in hyperlipidaemia-mediated rat thoracic aortas, the PA-induced ferroptosis and subsequent calcium deposition in VSMCs, were suppressed by OEA treatment. Additionally, CGAS-STING1-induced ferritinophagy, the main molecular mechanism of PA-triggered ferroptosis of VSMCs, was activated by mitochondrial DNA damage; however, early administration of OEA alleviated these phenomena. Intriguingly, overexpression of peroxisome proliferator activated receptor alpha (PPARα) contributed to a decrease in PA-induced ferroptosis, whereas PPARɑ knockdown inhibited the OEA-mediated anti-ferroptotic effects. Collectively, our study demonstrated that OEA serves as a prospective candidate for the prevention and treatment of vascular calcification in metabolic abnormality syndromes.
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Affiliation(s)
- Zhengdong Chen
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, PR China
| | - Xuejiao Sun
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, PR China
| | - Xiaoxue Li
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, PR China
| | - Naifeng Liu
- Department of Cardiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, PR China.
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Gao Z, Gao Z, Zhang H, Hou S, Zhou Y, Liu X. Targeting STING: From antiviral immunity to treat osteoporosis. Front Immunol 2023; 13:1095577. [PMID: 36741390 PMCID: PMC9891206 DOI: 10.3389/fimmu.2022.1095577] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/30/2022] [Indexed: 01/19/2023] Open
Abstract
The cGAS-STING signaling pathway can trigger innate immune responses by detecting dsDNA from outside or within the host. In addition, the cGAS-STING signaling pathway has emerged as a critical mediator of the inflammatory response and a new target for inflammatory diseases. STING activation leads to dimerization and translocation to the endoplasmic reticulum Golgi intermediate compartment or Golgi apparatus catalyzed by TBK1, triggers the production of IRF3 and NF-κB and translocates to the nucleus to induce a subsequent interferon response and pro-inflammatory factor production. Osteoporosis is a degenerative bone metabolic disease accompanied by chronic sterile inflammation. Activating the STING/IFN-β signaling pathway can reduce bone resorption by inhibiting osteoclast differentiation. Conversely, activation of STING/NF-κB leads to the formation of osteoporosis by increasing bone resorption and decreasing bone formation. In addition, activation of STING inhibits the generation of type H vessels with the capacity to osteogenesis, thereby inhibiting bone formation. Here, we outline the mechanism of action of STING and its downstream in osteoporosis and discuss the role of targeting STING in the treatment of osteoporosis, thus providing new ideas for the treatment of osteoporosis.
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Affiliation(s)
- Zhonghua Gao
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhongguo Gao
- Department of Medical Laboratory Technology, School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei, China
| | - Hao Zhang
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shoubo Hou
- Department of General Practice, General Hospital of Central Theater Command, Wuhan, Hubei, China
| | - Yunhua Zhou
- Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Yunhua Zhou, ; Xiangjie Liu,
| | - Xiangjie Liu
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Yunhua Zhou, ; Xiangjie Liu,
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Yang S, Wang S, Chen L, Wang Z, Chen J, Ni Q, Guo X, Zhang L, Xue G. Neutrophil Extracellular Traps Delay Diabetic Wound Healing by Inducing Endothelial-to-Mesenchymal Transition via the Hippo pathway. Int J Biol Sci 2023; 19:347-361. [PMID: 36594092 PMCID: PMC9760440 DOI: 10.7150/ijbs.78046] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 11/05/2022] [Indexed: 12/23/2022] Open
Abstract
Diabetic foot ulcers (DFUs) are among the most frequent complications of diabetes with significant morbidity and mortality. Diabetes can trigger neutrophils to undergo histone citrullination by protein arginine deiminase 4 (encoded by Padi4 in mice) and release neutrophil extracellular traps (NETs). The specific mechanism of NETs-mediated wound healing impairment in diabetes remains unknown. In this study, we show neutrophils are more susceptible to NETosis in diabetic wound environments. Via in vitro experiments and in vivo models of wound healing using wide-type and Padi4 -/- mice, we demonstrate NETs can induce the activation of PAK2 via the membrane receptor TLR-9. Then PAK2 phosphorylates the intracellular protein Merlin/NF2 to inhibit the Hippo-YAP pathway. YAP binds to transcription factor SMAD2 and translocates from the cytoplasm into the nucleus to promote endothelial-to-mesenchymal transition (EndMT), which ultimately impedes angiogenesis and delays wound healing. Suppression of the Merlin/YAP/SMAD2 pathway can attenuate NET-induced EndMT. Inhibition of NETosis accelerates wound healing by reducing EndMT and promoting angiogenesis. Cumulatively, these data suggest NETosis delays diabetic wound healing by inducing EndMT via the Hippo-YAP pathway. Increased understanding of the molecular mechanism that regulates NETosis and EndMT will be of considerable value for providing cellular targets amenable to therapeutic intervention for DFUs.
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Affiliation(s)
- Shuofei Yang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China,✉ Corresponding authors: Shuofei Yang, , Telephone No. +86 13764227372; Lan Zhang, , Telephone No. +86 13764227372; Guanhua Xue, , Telephone No. +86 13310166810
| | - ShuangShuang Wang
- Songyuan Central Hospital, Songyuan Children's Hospital, Songyuan, China
| | - Liang Chen
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China
| | - Zheyu Wang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China
| | - Jiaquan Chen
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China
| | - Qihong Ni
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China
| | - Xiangjiang Guo
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China
| | - Lan Zhang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China,✉ Corresponding authors: Shuofei Yang, , Telephone No. +86 13764227372; Lan Zhang, , Telephone No. +86 13764227372; Guanhua Xue, , Telephone No. +86 13310166810
| | - Guanhua Xue
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China,✉ Corresponding authors: Shuofei Yang, , Telephone No. +86 13764227372; Lan Zhang, , Telephone No. +86 13764227372; Guanhua Xue, , Telephone No. +86 13310166810
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48
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Ariel A. JMJD3 regulates diabetic wound repair in a STINGy fashion. Cell Mol Immunol 2023; 20:110-111. [PMID: 36323930 PMCID: PMC9794684 DOI: 10.1038/s41423-022-00937-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 10/11/2022] [Indexed: 12/29/2022] Open
Affiliation(s)
- Amiram Ariel
- Departments of Biology and Human Biology, University of Haifa, Haifa, Israel.
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49
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Exploring Myocardial Ischemia-Reperfusion Injury Mechanism of Cinnamon by Network Pharmacology, Molecular Docking, and Experiment Validation. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2023; 2023:1066057. [PMID: 36873789 PMCID: PMC9981296 DOI: 10.1155/2023/1066057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/13/2023] [Accepted: 02/01/2023] [Indexed: 02/25/2023]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is a common complication of acute myocardial infarction that seriously endangers human health. Cinnamon, a traditional Chinese medicine, has been used to counteract MIRI as it has been shown to possess anti-inflammatory and antioxidant properties. To investigate the mechanisms of action of cinnamon in the treatment of MIRI, a deep learning-based network pharmacology method was established to predict potential active compounds and targets. The results of the network pharmacology showed that oleic acid, palmitic acid, beta-sitosterol, eugenol, taxifolin, and cinnamaldehyde were the main active compounds, and phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK), interleukin (IL)-7, and hypoxia-inducible factor 1 (HIF-1) are promising signaling pathways. Further molecular docking tests revealed that these active compounds and targets exhibited good binding abilities. Finally, experimental validation using a zebrafish model demonstrated that taxifolin, the active compound of cinnamon, has a potential protective effect against MIRI.
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50
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Wu X, He W, Mu X, Liu Y, Deng J, Liu Y, Nie X. Macrophage polarization in diabetic wound healing. BURNS & TRAUMA 2022; 10:tkac051. [PMID: 36601058 PMCID: PMC9797953 DOI: 10.1093/burnst/tkac051] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/22/2022] [Indexed: 12/31/2022]
Abstract
Impaired wound healing is one of the severe complications of diabetes. Macrophages have been shown to play a vital role in wound healing. In different wound environments, macrophages are classified into two phenotypes: classically activated macrophages and alternatively activated macrophages. Dysregulation of macrophage phenotypes leads to severely impaired wound healing in diabetes. Particularly, uncontrolled inflammation and abnormal macrophage phenotype are important reasons hindering the closure of diabetic wounds. This article reviews the functions of macrophages at various stages of wound healing, the relationship between macrophage phenotypic dysregulation and diabetic wound healing and the mechanism of macrophage polarization in diabetic wound healing. New therapeutic drugs targeting phagocyte polarization to promote the healing of diabetic wounds might provide a new strategy for treating chronic diabetic wound healing.
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Affiliation(s)
- Xingqian Wu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Wenjie He
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Xingrui Mu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Ye Liu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Junyu Deng
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Yiqiu Liu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- Cancer and Ageing Research Program, School of Biomedical Sciences, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane 4102, Australia
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