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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] [MESH Headings] [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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Wang JL, Li Z, Song ZX, Zhao S, Zhao LB, Shuang PZ, Liu FF, Li HZ, Wang XL, Liu P. The effect of spinal cord STING/ATG5-mediated autophagy activation on the development of diabetic neuropathic pain in rats. Biochem Biophys Res Commun 2025; 760:151686. [PMID: 40174367 DOI: 10.1016/j.bbrc.2025.151686] [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: 01/19/2025] [Revised: 03/21/2025] [Accepted: 03/22/2025] [Indexed: 04/04/2025]
Abstract
Diabetic neuropathic pain (DNP) is associated with concurrent spinal cord autophagy activation, mTOR pathway activation, and neuroinflammation. However, the mechanistic interplay between these processes remains unclear, as mTOR activation typically suppresses autophagy under physiological conditions. This study investigates the role of spinal STING/ATG5-mediated autophagy in DNP pathogenesis and its relationship with mTOR signaling and neuroinflammatory pathways. Utilizing a rat model of DNP, we observed significant increases in spinal autophagosome density, LC3-II/LC3-I ratio, and STING/ATG5 expression, accompanied by elevated p-mTOR/mTOR ratios, compared to healthy controls. Notably, Beclin-1 expression remained unchanged. Pharmacological inhibition of STING or ATG5 silencing via intrathecal administration attenuated mechanical allodynia and reduced LC3-II/LC3-I ratios, whereas STING activation exacerbated pain behaviors while further upregulating STING/ATG5 expression and LC3-II/LC3-I ratios, but paradoxically decreased p-mTOR/mTOR ratios. mTOR inhibition with rapamycin alleviated DNP symptoms and suppressed TNF-α/IL-1β-mediated neuroinflammation, yet failed to modulate LC3-II/LC3-I ratios despite increasing Beclin-1 expression. Crucially, STING/ATG5 pathway manipulation did not alter pro-inflammatory cytokine levels, while rapamycin's analgesic effects correlated with anti-inflammatory activity. These findings demonstrate that STING/ATG5-driven autophagy contributes to DNP progression through a mechanism independent of both canonical mTOR-dependent autophagy regulation and inflammatory cytokine modulation. Conversely, mTOR inhibition exerts therapeutic effects predominantly via anti-inflammatory pathways rather than autophagy regulation. This study identifies a novel non-canonical autophagy pathway in DNP pathophysiology and clarifies distinct mechanistic bases for STING/ATG5-versus mTOR-targeted interventions.
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Affiliation(s)
- Jia-Lu Wang
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Zhao Li
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Zhi-Xue Song
- HeBei Medical University, No. 361, Zhong Shan Road, Shi jia zhuang, 050000, China
| | - Shuang Zhao
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Long-Biao Zhao
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Peng-Zhan Shuang
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Fei-Fei Liu
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Hui-Zhou Li
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Xiu-Li Wang
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China
| | - Peng Liu
- Department of Anesthesiology, HeBei Medical University Third Hospital, No. 139 Zi qiang Road, Shijiazhuang, 050051, China.
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Chen J, Fei S, Chan LWC, Gan X, Shao B, Jiang H, Li S, Kuang P, Liu X, Yang S. Inflammatory signaling pathways in pancreatic β-cell: New insights into type 2 diabetes pathogenesis. Pharmacol Res 2025; 216:107776. [PMID: 40378943 DOI: 10.1016/j.phrs.2025.107776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/27/2025] [Accepted: 05/10/2025] [Indexed: 05/19/2025]
Abstract
Type 2 diabetes (T2D) is a complex metabolic disorder with a growing global prevalence, and there is a linking between inflammation in pancreatic β-cell and impaired glucose homeostasis which has emerged as a key player in the pathogenesis of T2D. Recent advances in research have provided new insights into various inflammatory signaling cascades in β-cell among which we focus on Toll-like Receptor 4 (TLR4), Nuclear Factor kappa B (NF-κB), Janus Kinase-Signal Transducer and Activator of Transcription (JAK/STAT), Platelet-Derived Growth Factor Receptor α (PDGFR-α), Stimulator of Interferon Genes (STING), and the death receptor TMEM219. TLR4 activation by pathogen- or damage-associated molecular patterns initiates NF-κB and mitogen-activated protein kinase (MAPK) cascades, promoting pro-inflammatory cytokine release and β-cell apoptosis. NF-κB acts as a central hub, integrating metabolic stress signals (e.g., glucolipotoxicity, ER stress) and amplifying inflammatory responses through crosstalk with JAK/STAT and STING pathways. Meanwhile, JAK/STAT signaling exhibits dual roles in β-cell survival and inflammation, influenced by cytokine milieu and feedback regulation. PDGFR-α, traditionally linked to β-cell proliferation, paradoxically contributes to pathological hyperplasia in obesity, while STING activation by cytosolic DNA triggers β-cell senescence and ferroptosis via IRF3/NF-κB. In this review, we synthesize recent advancements of these inflammatory signaling pathways in β-cells, and current therapeutic strategies targeting TLR4/NF-κB inhibitors, JAK/STAT modulators, STING antagonists, and the death receptor TMEM219 are discussed, alongside challenges in pathway specificity and clinical translation. Understanding these inflammatory signaling pathways and their interactions in pancreatic β-cell is essential for the development of novel therapeutic strategies to prevent or treat T2D.
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Affiliation(s)
- Jie Chen
- Department of Respiratory Medicine, Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China
| | - Shinuan Fei
- Pediatrics Department, Huangshi Maternal and Child Health Care Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435003, PR China
| | - Lawrence W C Chan
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, 99077, Hong Kong
| | - Xueting Gan
- Department of Pathology, Huangshi maternal and Child Health Care Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435003, PR China
| | - Bibo Shao
- Department of Intensive Care Unit, Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China
| | - Hong Jiang
- Department of Laboratory Medicine, Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China
| | - Sheng Li
- Department of Laboratory Medicine, Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China
| | - Peng Kuang
- Huangshi Maternal and Child Health Hospital Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China
| | - Xin Liu
- Department of Ultrasound Medicine Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China
| | - Sijun Yang
- Department of Laboratory Medicine, Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China.
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Wang S, Qin L, Liu F, Zhang Z. Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies. Cell Commun Signal 2025; 23:171. [PMID: 40197235 PMCID: PMC11977922 DOI: 10.1186/s12964-025-02169-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/23/2025] [Indexed: 04/10/2025] Open
Abstract
The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.
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Affiliation(s)
- Siwei Wang
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Qin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology), Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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Lan C, Li Y, Weng Z, Pan W, Lin W, Jiang Z, Yang L, Shen X. TLR4 mediates lipotoxic β-cell dysfunction by inhibiting the TMEM24/PI3K/AKT pathway. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 40170616 DOI: 10.3724/abbs.2025045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025] Open
Abstract
Immune imbalance is the core pathophysiological mechanism of the deterioration of β-cell function driven by lipid metabolism disorders. Toll-like receptor 4 (TLR4) inflammatory signaling is a key pathway that mediates lipotoxic injury in β-cells, but the underlying mechanism needs to be further elucidated. Transmembrane protein 24 (TMEM24) is a key transporter that regulates pulsatile insulin secretion, but its pathophysiology in lipotoxicity remains unclear. In this study, we investigate whether TLR4-mediated lipotoxicity is affected by the inhibition of TMEM24 expression. The PPI network shows that TLR4 is associated with both insulin secretion and ER stress proteins in islets from obese rats. Using in vitro lipotoxic β-cell models, we found that TMEM24 is the target signal of palmitic acid (PA)-induced insulin secretion impairment in islet β-cells, and TLR4 plays a mediating role in this process. Mechanistically, TLR4 mediates lipotoxicity by binding to TMEM24 and downregulating its protein expression to suppress PI3K/AKT signaling, leading to β-cell dysfunction. TLR4 knockout ameliorates islet function impairment through TMEM24/PI3K/AKT signaling in HFD-induced obese rats. Taken together, our results show that TLR4 mediates lipotoxicity in islet β-cells by inhibiting the TMEM24/PI3K/AKT pathway, and the mechanism of TLR4-mediated lipotoxicity is elucidated from the perspective of insulin vesicular secretion.
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Affiliation(s)
- Chao Lan
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yan Li
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Zhiyan Weng
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Wei Pan
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Wanxin Lin
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Zhen Jiang
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Liyong Yang
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Ximei Shen
- Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
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Guan C, Yang K, Ma C, Hao W, An J, Liu J, Jiang N, Fu S, Zhen D, Tang X. STING1 targets MYH9 to drive adipogenesis through the AKT/GSK3β/β-catenin pathway. Biochem Biophys Res Commun 2025; 749:151352. [PMID: 39847995 DOI: 10.1016/j.bbrc.2025.151352] [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: 12/10/2024] [Revised: 01/07/2025] [Accepted: 01/16/2025] [Indexed: 01/25/2025]
Abstract
Stimulator of interferon response cGAMP interactor 1 (STING1), as an innate immune adaptor protein that mediates DNA sensing, has attracted tremendous biomedical interest. However, several recent researches have revealed the key role of STING1 in regulating the metabolic pathway. Here, we investigated its role in adipocyte differentiation. Preadipocytes with lentivirus-mediated Sting1 knockdown or overexpression were constructed to examine the effect of STING1 on adipocyte differentiation in vitro. Proteomics was performed in adipocytes to explore the mechanisms by which STING1 exerts pro-adipogenesis effects. Coimmunoprecipitation (CoIP)/mass spectrometry (MS) assay were used to identify the interacting partners of STING1. Our results showed that STING1 was upregulated during adipogenic differentiation of 3T3-L1 and white adipose tissue-derived stromal vascular precursor cells (WAT-SVF), accompanied by upregulation of adipocyte marker genes, peroxisome proliferator-activated receptor gamma (Pparg) and CCAAT/enhancer-binding protein beta (Cebpβ). Knockdown or overexpression of Sting1 altered adipogenesis in adipocytes. Mechanistically, proteomics and CoIP/MS assay revealed that STING1 targets non-muscle myosin protein (MYH9) to block its expression, which enhances AKT/GSK3β signaling and mediates β-catenin accumulation, affecting adipogenesis-related genes in adipocytes. These findings suggest that STING1 targeting combined with MYH9 regulates adipocyte differentiation through the AKT/GSK3β/β-catenin pathway. This is a new potential target for the treatment of hypertrophic adipose tissue, or obesity.
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Affiliation(s)
- Conghui Guan
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Kuan Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Chengxu Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Wankun Hao
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Jinyang An
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Jinjin Liu
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Na Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Songbo Fu
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Donghu Zhen
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - Xulei Tang
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, China; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China.
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Gao D, Zhao B, Yu J, Li X, Yang D, Luo Y, Xia Y, Cai X, Guo Y. Deletion of stimulator of interferons genes aggravated cardiac dysfunction in physiological aged mice. Mech Ageing Dev 2024; 222:111978. [PMID: 39233064 DOI: 10.1016/j.mad.2024.111978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/15/2024] [Accepted: 08/31/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND Stimulator of interferons genes (STING) is crucial for innate immune response. It has been demonstrated that cGAS-STING pathway was the driver of aging-related inflammation. However, whether STING is involved in cardiac dysfunction during the physiological aging process remains unclear. METHODS Gene expression profiles were obtained from the Gene Expression Omnibus database, followed by weighted gene co-expression network analysis, gene ontology analysis and protein network interaction analysis to identify key pathway and genes associated with aging. The effects of STING on cardiac function, glucose homeostasis, inflammation, and autophagy in physiological aging were investigated with STING knockout mice. RESULTS Bioinformatics analysis revealed STING emerged as a hub gene of interest. Subsequent experiments demonstrated the activation of STING pathway in the heart of aged mice. Knockout of STING alleviated the inflammation in aged mice. However, Knockout of STING impaired glucose tolerance, inhibited autophagy, enhanced oxidative stress and aggravated cardiac dysfunction in aged mice. CONCLUSION Although reducing inflammation, long-term STING inhibition by genetic ablation exacerbated cardiac dysfunction in aged mice. Given the multifaceted nature of aging and the diverse cellular functions of STING beyond immune regulation, the negative effects of targeting STING as a strategy to mitigate aging phenotype should be fully considered.
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Affiliation(s)
- Diansa Gao
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Boying Zhao
- Division of Cardiothoracic Surgery, The Center Hospital of Chongqing University, Chongqing 400016, China
| | - Jiang Yu
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiaorong Li
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ding Yang
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yuan Luo
- Division of Cardiothoracic Surgery, The Center Hospital of Chongqing University, Chongqing 400016, China
| | - Yong Xia
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiongwei Cai
- Department of Gynecology, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing 400037, China.
| | - Yongzheng Guo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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Şancı E, Köksal Karayıldırım Ç, Dağdeviren M, Yiğittürk G, Buhur A, Erbaş O, Yavaşoğlu A, Karabay Yavaşoğlu NÜ. Oxidative stress and inflammatory markers in streptozotocin-induced acute and subacute toxicity response. Drug Chem Toxicol 2024; 47:933-948. [PMID: 38348650 DOI: 10.1080/01480545.2024.2315150] [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: 08/03/2023] [Accepted: 02/01/2024] [Indexed: 11/21/2024]
Abstract
Streptozotocin (STZ) is used as a diabetes-inducing agent in experimental animal studies. However, it is known that STZ-induced diabetic animals show significant increases in oxidative stress parameters and neurodegeneration besides their blood glucose level. In this study, the acute and subacute toxic effects of STZ on the liver, sciatic nerve, and brain tissues were investigated in vivo rat model. Sprague-Dawley rats were divided into two groups; while 50 mg/kg STZ was administered ip to the STZ group, only saline was administered to the control group. After STZ administration, three units (100 U/mL) of subcutaneous insulin glargine were applied daily to prevent the formation of diabetes. At 24 h, 1,2, and 4 weeks after applications, rats from each group were sacrificed and tissues were removed under anesthesia. At the end of the study, compared to the control, a significant decrease in SOD and GST activity and an increase in lipid peroxidation were detected in the liver and sciatic tissues of rats in the STZ-treated group in the first 24h. Considering the TUNEL, NFκB, and NOS2 expressions, it was noted that while the effects of STZ on the liver were observed in the acute stage (24h), it had subacute effects on the brain. When apoptosis-related gene expression (Bcl-2, Bax, CASP3, CASP8, CASP9, TNF-α) and immunohistochemistry were evaluated, the apoptotic effect of STZ was observed mostly in sciatic nerve tissues. Within the scope of the study, it was revealed that STZ did not only show selective toxicity to pancreatic β cells but also very toxic to other tissues and organs.
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Affiliation(s)
- Ebru Şancı
- Center for Drug Development and Pharmacokinetic Applications, Ege University, Bornova Izmir, Turkey
| | | | | | - Gürkan Yiğittürk
- Department of Histology and Embryology, Muğla Sıtkı Koçman University, Mugla, Turkey
| | - Aylin Buhur
- Department of Histology and Embryology, Ege University, Bornova Izmir, Turkey
| | - Oytun Erbaş
- Department of Physiology, Demiroğlu Bilim University, Istanbul, Turkey
| | - Altuğ Yavaşoğlu
- Department of Histology and Embryology, Ege University, Bornova Izmir, Turkey
| | - Nefise Ülkü Karabay Yavaşoğlu
- Center for Drug Development and Pharmacokinetic Applications, Ege University, Bornova Izmir, Turkey
- Department of Biology, Ege University, Bornova Izmir, Turkey
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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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Liu Y, Lou X. The Bidirectional Association Between Metabolic Syndrome and Long-COVID-19. Diabetes Metab Syndr Obes 2024; 17:3697-3710. [PMID: 39398386 PMCID: PMC11471063 DOI: 10.2147/dmso.s484733] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/22/2024] [Indexed: 10/15/2024] Open
Abstract
Background The rapid global spread of a new coronavirus disease known as COVID-19 has led to a significant increase in mortality rates, resulting in an unprecedented worldwide pandemic. Methods The impact of COVID-19, particularly its long-term effects, has also had a profound effect on the health and well-being of individuals.Metabolic syndrome increases the risk of heart and brain diseases, presenting a significant danger to human well-being. Purpose The prognosis of long COVID and the progression of metabolic syndrome interact with each other, but there is currently a lack of systematic reports.In this paper, the pathogenesis, related treatment and prognosis of long COVID and metabolic syndrome are systematically reviewed.
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Affiliation(s)
- Yanfen Liu
- Department of Endocrinology at Zhejiang University School of Medicine, Jinhua Hospital, Jinhua, People’s Republic of China
| | - Xueyong Lou
- Department of Endocrinology at Zhejiang University School of Medicine, Jinhua Hospital, Jinhua, People’s Republic of China
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11
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Wang L, Zhu Y, Zhang N, Xian Y, Tang Y, Ye J, Reza F, He G, Wen X, Jiang X. The multiple roles of interferon regulatory factor family in health and disease. Signal Transduct Target Ther 2024; 9:282. [PMID: 39384770 PMCID: PMC11486635 DOI: 10.1038/s41392-024-01980-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/12/2024] [Accepted: 09/10/2024] [Indexed: 10/11/2024] Open
Abstract
Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of various diseases, such as infectious diseases, autoimmune disorders, metabolic diseases, and cancers. In this context, IRFs display a dichotomous nature, functioning as both tumor suppressors and promoters, contingent upon the specific disease milieu. Post-translational modifications of IRFs, including phosphorylation and ubiquitination, play a crucial role in modulating their function, stability, and activation. As prospective biomarkers and therapeutic targets, IRFs present promising opportunities for disease intervention. Further research is needed to elucidate the precise mechanisms governing IRF regulation, potentially pioneering innovative therapeutic strategies, particularly in cancer treatment, where the equilibrium of IRF activities is of paramount importance.
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Affiliation(s)
- Lian Wang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanghui Zhu
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yali Xian
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yu Tang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Ye
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fekrazad Reza
- Radiation Sciences Research Center, Laser Research Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran
- International Network for Photo Medicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Gu He
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiang Wen
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Xian Jiang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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12
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Mohammadi S, Khorasani M. Implications of the cGAS-STING pathway in diabetes: Risk factors and therapeutic strategies. Int J Biol Macromol 2024; 278:134210. [PMID: 39069057 DOI: 10.1016/j.ijbiomac.2024.134210] [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: 05/12/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 07/30/2024]
Abstract
Diabetes mellitus is an increasingly prevalent metabolic disorder characterized by chronic hyperglycemia and impaired insulin action. Although the pathogenesis of diabetes is multifactorial, emerging evidence suggests that chronic low-grade inflammation plays a significant role in the development and progression of the disease. The cyclic GMP-AMP synthase (cGAS) and its downstream signaling pathway, the stimulator of interferon genes (STING), have recently gained attention in the field of diabetes research. This article aims to provide an overview of the role of cGAS-STING in diabetes, focusing on its involvement in the regulation of immune responses, inflammation, insulin resistance, and β-cell dysfunction. Understanding the contribution of cGAS-STING signaling in diabetes may lead to the development of targeted therapeutic strategies for this prevalent metabolic disorder. The results section presents key findings from multiple studies on the impact of STING in diabetes. It discusses the influence of STING on inflammation levels within a diabetic environment, its effect on insulin resistance, and its implications for the development and progression of diabetes. The cGAS-STING signaling pathway plays a crucial role in the development and progression of diabetes.
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Affiliation(s)
- Saeed Mohammadi
- Natural and Medical Sciences Research Center, University of Nizwa, 611, Oman
| | - Milad Khorasani
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran; Department of Biochemistry and Nutrition, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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13
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Ali HS, Al-Amodi HS, Hamady S, Roushdy MMS, Helmy Hasanin A, Ellithy G, Elmansy RA, Ahmed HHT, Ahmed EME, Elzoghby DMA, Kamel HFM, Hassan G, ELsawi HA, Farid LM, Abouelkhair MB, Habib EK, Elesawi M, Fikry H, Saleh LA, Matboli M. Rosavin improves insulin resistance and alleviates hepatic and kidney damage via modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals. RSC Med Chem 2024; 15:2098-2113. [PMID: 38911169 PMCID: PMC11187545 DOI: 10.1039/d4md00023d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/14/2024] [Indexed: 06/25/2024] Open
Abstract
Background: Inflammation-mediated insulin resistance in type 2 diabetes mellitus (T2DM) increases complications, necessitating investigation of its mechanism to find new safe therapies. This study investigated the effect of rosavin on the autophagy and the cGAS-STING pathway-related signatures (ZBP1, STING1, DDX58, LC3B, TNF-α) and on their epigenetic modifiers (miR-1976 and lncRNA AC074117.2) that were identified from in silico analysis in T2DM animals. Methods: A T2DM rat model was established by combining a high-fat diet (HFD) and streptozotocin (STZ). After four weeks from T2DM induction, HFD/STZ-induced T2DM rats were subdivided into an untreated group (T2DM group) and three treated groups which received 10, 20, or 30 mg per kg of R. rosea daily for 4 weeks. Results: The study found that rosavin can affect the cGAS-STING pathway-related RNA signatures by decreasing the expressions of ZBP1, STING1, DDX58, and miR-1976 while increasing the lncRNA AC074117.2 level in the liver, kidney, and adipose tissues. Rosavin prevented further weight loss, reduced serum insulin and glucose, improved insulin resistance and the lipid panel, and mitigated liver and kidney damage compared to the untreated T2DM group. The treatment also resulted in reduced inflammation levels and improved autophagy manifested by decreased immunostaining of TNF-α and increased immunostaining of LC3B in the liver and kidneys of the treated T2DM rats. Conclusion: Rosavin has shown potential in attenuating T2DM, inhibiting inflammation in the liver and kidneys, and improving metabolic disturbances in a T2DM animal model. The observed effect was linked to the activation of autophagy and suppression of the cGAS-STING pathway.
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Affiliation(s)
- Hebatallah S Ali
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University Cairo 11566 Egypt
| | - Hiba S Al-Amodi
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University Makkah 21955 Saudi Arabia
| | - Shaimaa Hamady
- Biochemistry Department, Faculty of Science, Ain Shams University Cairo Egypt
| | - Marian M S Roushdy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University Cairo 11566 Egypt
| | - Amany Helmy Hasanin
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University Cairo Egypt
| | - Ghada Ellithy
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University Cairo Egypt
| | - Rasha A Elmansy
- Anatomy Unit, Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University Buraydah Saudi Arabia
- Department of Anatomy and Cell Biology, Faculty of Medicine, Ain Shams University Egypt
| | - Hagir H T Ahmed
- Anatomy Unit, Department of Basic Medical Sciences, College of Medicine and Medical Sciences, AlNeelain University Sudan
| | - Enshrah M E Ahmed
- Pathology unit, Department of Basic Medical Sciences, College of Medicine and Medical Sciences, Gassim University Saudi Arabia
| | | | - Hala F M Kamel
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University Cairo 11566 Egypt
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University Makkah 21955 Saudi Arabia
| | - Ghida Hassan
- Physiology Department, Faculty of Medicine, Ain Shams University Egypt
| | - Hind A ELsawi
- Department of Internal Medicine, Badr University in Cairo Badr City Egypt
| | - Laila M Farid
- Pathology Department Faculty of Medicine, Ain Shams University Egypt
| | | | - Eman K Habib
- Department of Anatomy and Cell Biology, Faculty of Medicine, Ain Shams University Egypt
- Department of Anatomy and Cell Biology, Faculty of Medicine, Galala University Egypt
| | - Mohamed Elesawi
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University Cairo 11566 Egypt
| | - Heba Fikry
- Department of Histology, Faculty of Medicine, Ain Shams University Cairo Egypt
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University Cairo Egypt
| | - Marwa Matboli
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University Cairo 11566 Egypt
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14
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Yu L, Gao F, Li Y, Su D, Han L, Li Y, Zhang X, Feng Z. Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications. Biomed Pharmacother 2024; 175:116724. [PMID: 38761424 DOI: 10.1016/j.biopha.2024.116724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 05/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.
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Affiliation(s)
- Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Feifei Gao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Yaoxin Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Dan Su
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Liping Han
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yueming Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Xuehan Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China.
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15
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Gao J, Zou Y, Lv XY, Chen L, Hou XG. Novel insights into immune-related genes associated with type 2 diabetes mellitus-related cognitive impairment. World J Diabetes 2024; 15:735-757. [PMID: 38680704 PMCID: PMC11045412 DOI: 10.4239/wjd.v15.i4.735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/21/2024] [Accepted: 03/04/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND The cognitive impairment in type 2 diabetes mellitus (T2DM) is a multifaceted and advancing state that requires further exploration to fully comprehend. Neuroinflammation is considered to be one of the main mechanisms and the immune system has played a vital role in the progression of the disease. AIM To identify and validate the immune-related genes in the hippocampus associated with T2DM-related cognitive impairment. METHODS To identify differentially expressed genes (DEGs) between T2DM and controls, we used data from the Gene Expression Omnibus database GSE125387. To identify T2DM module genes, we used Weighted Gene Co-Expression Network Analysis. All the genes were subject to Gene Set Enrichment Analysis. Protein-protein interaction network construction and machine learning were utilized to identify three hub genes. Immune cell infiltration analysis was performed. The three hub genes were validated in GSE152539 via receiver operating characteristic curve analysis. Validation experiments including reverse transcription quantitative real-time PCR, Western blotting and immunohistochemistry were conducted both in vivo and in vitro. To identify potential drugs associated with hub genes, we used the Comparative Toxicogenomics Database (CTD). RESULTS A total of 576 DEGs were identified using GSE125387. By taking the intersection of DEGs, T2DM module genes, and immune-related genes, a total of 59 genes associated with the immune system were identified. Afterward, machine learning was utilized to identify three hub genes (H2-T24, Rac3, and Tfrc). The hub genes were associated with a variety of immune cells. The three hub genes were validated in GSE152539. Validation experiments were conducted at the mRNA and protein levels both in vivo and in vitro, consistent with the bioinformatics analysis. Additionally, 11 potential drugs associated with RAC3 and TFRC were identified based on the CTD. CONCLUSION Immune-related genes that differ in expression in the hippocampus are closely linked to microglia. We validated the expression of three hub genes both in vivo and in vitro, consistent with our bioinformatics results. We discovered 11 compounds associated with RAC3 and TFRC. These findings suggest that they are co-regulatory molecules of immunometabolism in diabetic cognitive impairment.
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Affiliation(s)
- Jing Gao
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xiao-Yu Lv
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xin-Guo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
- Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan 250012, Shandong Province, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan 250012, Shandong Province, China
- Department of Endocrinology, Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong Province, China
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16
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He X, Wedn A, Wang J, Gu Y, Liu H, Zhang J, Lin Z, Zhou R, Pang X, Cui Y. IUPHAR ECR review: The cGAS-STING pathway: Novel functions beyond innate immune and emerging therapeutic opportunities. Pharmacol Res 2024; 201:107063. [PMID: 38216006 DOI: 10.1016/j.phrs.2024.107063] [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: 12/07/2023] [Revised: 12/26/2023] [Accepted: 01/05/2024] [Indexed: 01/14/2024]
Abstract
Stimulator of interferon genes (STING) is a crucial innate immune sensor responsible for distinguishing pathogens and cytosolic DNA, mediating innate immune signaling pathways to defend the host. Recent studies have revealed additional regulatory functions of STING beyond its innate immune-related activities, including the regulation of cellular metabolism, DNA repair, cellular senescence, autophagy and various cell deaths. These findings highlight the broader implications of STING in cellular physiology beyond its role in innate immunity. Currently, approximately 10 STING agonists have entered the clinical stage. Unlike inhibitors, which have a maximum inhibition limit, agonists have the potential for infinite amplification. STING signaling is a complex process that requires precise regulation of STING to ensure balanced immune responses and prevent detrimental autoinflammation. Recent research on the structural mechanism of STING autoinhibition and its negative regulation by adaptor protein complex 1 (AP-1) provides valuable insights into its different effects under physiological and pathological conditions, offering a new perspective for developing immune regulatory drugs. Herein, we present a comprehensive overview of the regulatory functions and molecular mechanisms of STING beyond innate immune regulation, along with updated details of its structural mechanisms. We discuss the implications of these complex regulations in various diseases, emphasizing the importance and feasibility of targeting the immunity-dependent or immunity-independent functions of STING. Moreover, we highlight the current trend in drug development and key points for clinical research, basic research, and translational research related to STING.
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Affiliation(s)
- Xu He
- Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China; Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing 100034, China
| | - Abdalla Wedn
- School of Medicine, University of Pittsburgh, 5051 Centre Avenue, Pittsburgh, PA, USA
| | - Jian Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yanlun Gu
- Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Haidian District, Beijing 100191, China
| | - Hongjin Liu
- Department of General Surgery, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing 100034, China
| | - Juqi Zhang
- Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China; Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing 100034, China
| | - Zhiqiang Lin
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China
| | - Renpeng Zhou
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Anhui 230601, China; Department of Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven CT06519, USA.
| | - Xiaocong Pang
- Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China; Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing 100034, China.
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing 100191, China; Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing 100034, China.
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17
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Hong Z, Chen S, Sun J, Cheng D, Guo H, Mei J, Zhang X, Maimaiti M, Hao H, Cao P, Hu H, Wang C. STING signaling in islet macrophages impairs insulin secretion in obesity. SCIENCE CHINA. LIFE SCIENCES 2024; 67:345-359. [PMID: 37906411 DOI: 10.1007/s11427-022-2371-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/17/2023] [Indexed: 11/02/2023]
Abstract
The innate immune regulator stimulator of interferon genes (STING) mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines, which promotes the progression of various inflammatory and autoimmune diseases. Innate immune system plays a critical role in regulating obesity-induced islet dysfunction, whereas the potential effect of STING signaling is not fully understood. Here, we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet (HFD) feeding. Sting-/- alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of macrophages. Mechanically, palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in macrophages. Additionally, STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment of β cell insulin secretory granules. Pharmacologically inhibiting STING activation enhances insulin secretion to control hyperglycemia. Together, our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in diet--induced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.
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Affiliation(s)
- Ze Hong
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Saihua Chen
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Jing Sun
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Dan Cheng
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Hanli Guo
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Jiahao Mei
- School of Life Sciences, Westlake University, Hangzhou, 310012, China
| | - Xiang Zhang
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Munire Maimaiti
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Peng Cao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Haiyang Hu
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
| | - Chen Wang
- State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
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18
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Zou S, Wang B, Yi K, Su D, Chen Y, Li N, Geng Q. The critical roles of STING in mitochondrial homeostasis. Biochem Pharmacol 2024; 220:115938. [PMID: 38086488 DOI: 10.1016/j.bcp.2023.115938] [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: 08/29/2023] [Revised: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/20/2023]
Abstract
The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.
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Affiliation(s)
- Shishi Zou
- Department of Thoracic Surgery, Wuhan University Renmin Hospital, 430060, China
| | - Bo Wang
- Department of Thoracic Surgery, Wuhan University Renmin Hospital, 430060, China
| | - Ke Yi
- Department of Thoracic Surgery, Wuhan University Renmin Hospital, 430060, China
| | - Dandan Su
- Department of Neurology, Wuhan University Renmin Hospital, 430060, China
| | - Yukai Chen
- Department of Oncology, Wuhan University Renmin Hospital, 430060, China
| | - Ning Li
- Department of Thoracic Surgery, Wuhan University Renmin Hospital, 430060, China.
| | - Qing Geng
- Department of Thoracic Surgery, Wuhan University Renmin Hospital, 430060, China.
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19
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Liu W, Zhang Chen Z, Yang C, Fan Y, Qiao L, Xie S, Cao L. Update on the STING Signaling Pathway in Developing Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol 2024; 12:91-99. [PMID: 38250469 PMCID: PMC10794270 DOI: 10.14218/jcth.2023.00197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 08/11/2023] [Accepted: 08/29/2023] [Indexed: 01/23/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with limited treatment options. Inflammation caused by metabolic disturbances plays a significant role in NAFLD development. Stimulator of interferon gene (STING), a critical regulator of innate immunity, induces the production of interferons and other pro-inflammatory factors by recognizing cytoplasmic DNA to defend against pathogen infection. The STING-mediated signaling pathway appears to play a vital role in hepatic inflammation, metabolic disorders, and even carcinogenesis. Promisingly, pharmacological interventions targeting STING have shown improvements in the pathological state of NAFLD. Macrophages, dendritic cells, natural killer cells, and T cell pathways regulated by STING present potential novel druggable targets for NAFLD treatment. Further research and development in this area may offer new therapeutic options for managing NAFLD effectively.
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Affiliation(s)
- Wei Liu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhili Zhang Chen
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chenhui Yang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yaofu Fan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Liang Qiao
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shaofeng Xie
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Lin Cao
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China
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20
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Thomas P, Gallagher MT, Da Silva Xavier G. Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding. Front Endocrinol (Lausanne) 2023; 14:1275835. [PMID: 38144558 PMCID: PMC10739424 DOI: 10.3389/fendo.2023.1275835] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/13/2023] [Indexed: 12/26/2023] Open
Abstract
The propensity to develop type 2 diabetes (T2D) is known to have both environmental and hereditary components. In those with a genetic predisposition to T2D, it is widely believed that elevated concentrations of circulatory long-chain fatty acids (LC-FFA) significantly contribute towards the demise of insulin-producing pancreatic β-cells - the fundamental feature of the development of T2D. Over 25 years of research support that LC-FFA are deleterious to β-cells, through a process termed lipotoxicity. However, the work underpinning the theory of β-cell lipotoxicity is mostly based on rodent studies. Doubts have been raised as to whether lipotoxicity also occurs in humans. In this review, we examine the evidence, both in vivo and in vitro, for the pathogenic effects of LC-FFA on β-cell viability and function in humans, highlighting key species differences. In this way, we aim to uncover the role of lipotoxicity in the human pathogenesis of T2D and motivate the need for species-specific understanding.
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Affiliation(s)
- Patricia Thomas
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Meurig T. Gallagher
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Gabriela Da Silva Xavier
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
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21
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Khin PP, Lee JH, Jun HS. Pancreatic Beta-cell Dysfunction in Type 2 Diabetes. EUR J INFLAMM 2023. [DOI: 10.1177/1721727x231154152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.
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Affiliation(s)
- Phyu Phyu Khin
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155, Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
| | - Jong Han Lee
- Department of Marine Bio-industry, Hanseo University, Seosan, Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155, Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
- College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea
- Gachon Medical Research Institute, Gil Hospital, 21, Namdong-daero 774, beon-gil, Namdong-gu, Incheon, 21565, Republic of Korea
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22
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Wang Q, Li H, Lu H, Wang S, Li Y, Zhang Z, Han J, Yang Z, Yang Y, Hong Y. SAA1 exacerbates pancreatic β-cell dysfunction through activation of NF-κB signaling in high-fat diet-induced type 2 diabetes mice. Mol Cell Endocrinol 2023; 576:112043. [PMID: 37574124 DOI: 10.1016/j.mce.2023.112043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/08/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
Insufficient decompensated insulin secretion and insulin resistance caused by pancreatic β-cell dysfunction are the pathological bases of type 2 diabetes mellitus (T2DM). Glucolipotoxicity in pancreatic β-cells is an important factor leading to their dysfunction, closely related to inflammatory signals, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress (ERs). However, there may be other unproven regulatory mechanisms that govern pancreatic β-cell dysfunction. Therefore, further elucidation of the underlying mechanisms that lead to pancreatic β-cells dysfunction will provide a sufficient theoretical basis for the more effective prevention and treatment of T2DM. As a stress protein with pro-inflammatory properties, Serum Amyloid 1 (SAA1) promotes the progression of metabolic syndrome-related diseases by activating immune cells and damaging endothelial cells. In the development of T2DM, the activation of nuclear factor-kappa B (NF-κB) signaling aggravates pancreatic β-cells dysfunction under the stimulation of free fatty acids (FFAs), inflammatory factors, and chemokines. Moreover, the facilitating effect of SAA1 on the activation of the NF-κB signaling pathway has been demonstrated in other studies. In the present study, we demonstrated that SAA1 inhibits insulin secretion and promotes apoptotic molecular expression in pancreatic cells and islets and that NF-κB signaling inhibitors could reduce this effect of SAA1. SAA1 deficiency improved high-fat diet (HFD)-induced pancreatic β-cell dysfunction and decreased expression of NF-κB signaling molecules. Our findings suggested that HFD-induced SAA1 might exacerbate T2DM by enhancing pancreatic β-cell dysfunction; such a function of SAA1 might depend on NF-κB signaling activation.
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Affiliation(s)
- Qi Wang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Hong Li
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Henghao Lu
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Shumin Wang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yuxiu Li
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Zhenfen Zhang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Jing Han
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Zhe Yang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yanping Yang
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China
| | - Yan Hong
- Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China.
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23
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Luo L, An Y, Geng K, Wan S, Zhang F, Tan X, Jiang Z, Xu Y. High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis. Biochem Biophys Res Commun 2023; 668:82-89. [PMID: 37245293 DOI: 10.1016/j.bbrc.2023.05.081] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/17/2023] [Accepted: 05/21/2023] [Indexed: 05/30/2023]
Abstract
Chronic hyperglycemia-induced impairment of angiogenesis is important in diabetic foot ulcer (DFU). Additionally, the stimulator of interferon gene (STING), which is a key protein in innate immunity, mediates palmitic acid-induced lipotoxicity in metabolic diseases through oxidative stress-induced STING activation. However, the role of STING in DFU is unknown. In this study, we established a DFU mouse model with streptozotocin (STZ) injection and found that the expression of STING was significantly increased in the vascular endothelial cells of wound tissues from diabetic patients and in the STZ-induced diabetic mouse model. We further established high glucose (HG)-induced endothelial dysfunction with rat vascular endothelial cells and found that the expression of STING was also increased by high-glucose treatment. Moreover, the STING inhibitor, C176, promoted diabetic wound healing, whereas the STING activator, DMXAA, inhibited diabetic wound healing. Consistently, STING inhibition reversed the HG-induced reduction of CD31 and vascular endothelial growth factor (VEGF), inhibited apoptosis, and promoted migration of endothelial cells. Notably, DMXAA treatment alone was sufficient to induce endothelial cell dysfunction as a high-glucose treatment. Mechanistically, STING mediated HG-induced vascular endothelial cell dysfunction by activating the interferon regulatory factor 3/nuclear factor kappa B pathway. In conclusion, our study reveals an endothelial STING activation-mediated molecular mechanism in the pathogenesis of DFU and identifies STING as a novel potential therapeutic target for DFU.
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Affiliation(s)
- Lifang Luo
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China
| | - Ying An
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China
| | - Kang Geng
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China
| | - Shengrong Wan
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China
| | - Fanjie Zhang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China
| | - Xiaozhen Tan
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China
| | - Zongzhe Jiang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China; Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
| | - Yong Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China.
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24
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Xie R, Fan J, Wen J, Jin K, Zhan J, Yuan S, Tang Y, Nie X, Wen Z, Li H, Chen C, Wang DW. LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 32:689-703. [PMID: 37215148 PMCID: PMC10199406 DOI: 10.1016/j.omtn.2023.04.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/28/2023] [Indexed: 05/24/2023]
Abstract
Diabetes could directly induce cardiac injury, leading to cardiomyopathy. However, treatment strategies for diabetic cardiomyopathy remain limited. ZNF593-AS knockout and cardiomyocyte-specific transgenic mice were constructed. In addition, high-fat diet (HFD)-induced diabetic mouse model and db/db mice, another classic diabetic mouse model, were employed. ZNF593-AS was silenced using GapmeR, a modified antisense oligonucleotide, while overexpressed using a recombinant adeno-associated virus serotype 9-mediated gene delivery system. Transcriptome sequencing, RNA pull-down assays, and RNA immunoprecipitation assays were also performed to investigate the underlying mechanisms. ZNF593-AS expression was decreased in diabetic hearts. ZNF593-AS attenuated the palmitic acid-induced apoptosis of cardiomyocytes in vitro. In HFD-induced diabetic mice, ZNF593-AS deletion aggravated cardiac dysfunction and enhanced cardiac apoptosis and inflammation. In contrast, HFD-induced cardiac dysfunction was improved in ZNF593-AS transgenic mice. Consistently, ZNF593-AS exerted the same cardioprotective effects in db/db mice. Mechanistically, ZNF593-AS directly interacted with the functional domain of interferon regulatory factor 3 (IRF3), and suppressed fatty acid-induced phosphorylation and activation of IRF3, contributing to the amelioration of cardiac cell death and inflammation. In conclusion, our results identified the protective role of ZNF593-AS in diabetic cardiomyopathy, suggesting a novel potential therapeutic target.
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Affiliation(s)
- Rong Xie
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiahui Fan
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jianpei Wen
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kunying Jin
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiabing Zhan
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shuai Yuan
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuyan Tang
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiang Nie
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zheng Wen
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huaping Li
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chen Chen
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
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25
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Albadawy R, Hasanin AH, Agwa SHA, Hamady S, Mohamed RH, Gomaa E, Othman M, Yahia YA, Ghani AMA, Matboli M. Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model. Biol Res 2023; 56:11. [PMID: 36915161 PMCID: PMC10010022 DOI: 10.1186/s40659-023-00423-8] [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: 12/07/2022] [Accepted: 03/06/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty pancreatitis (NAFP) is one of the metabolic syndrome manifestations that need further studies to determine its molecular determinants and find effective medications. We aimed to investigate the potential effect of benzyl propylene glycoside on NAFP management via targeting the pancreatic cGAS-STING pathway-related genes (DDX58, NFκB1 & CHUK) and their upstream regulator miRNA (miR-1976) that were retrieved from bioinformatics analysis. METHODS The rats were fed either normal chow or a high-fat high-sucrose diet (HFHS), as a nutritional model for NAFP. After 8 weeks, the HFHS-fed rats were subdivided randomly into 4 groups; untreated HFHS group (NAFP model group) and three treated groups which received 3 doses of benzyl propylene glycoside (10, 20, and 30 mg/kg) daily for 4 weeks, parallel with HFHS feeding. RESULTS The molecular analysis revealed that benzyl propylene glycoside could modulate the expression of the pancreatic cGAS-STING pathway-related through the downregulation of the expression of DDX58, NFκB1, and CHUK mRNAs and upregulation of miR-1976 expression. Moreover, the applied treatment reversed insulin resistance, inflammation, and fibrosis observed in the untreated NAFP group, as evidenced by improved lipid panel, decreased body weight and the serum level of lipase and amylase, reduced protein levels of NFκB1 and caspase-3 with a significant reduction in area % of collagen fibers in the pancreatic sections of treated animals. CONCLUSION benzyl propylene glycoside showed a potential ability to attenuate NAFP development, inhibit pancreatic inflammation and fibrosis and reduce the pathological and metabolic disturbances monitored in the applied NAFP animal model. The detected effect was correlated with modulation of the expression of pancreatic (DDX58, NFκB1, and CHUK mRNAs and miR-1976) panel.
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Affiliation(s)
- Reda Albadawy
- Department of Gastroenterology, Hepatology & Infectious Disease, Faculty of Medicine, Benha University, Benha, 13518 Egypt
| | - Amany Helmy Hasanin
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sara H. A. Agwa
- Clinical Pathology and Molecular Genomics Unit, Medical Ain Shams Research Institute (MASRI), Faculty of Medicine, Ain Shams University, Cairo, 11382 Egypt
| | - Shaimaa Hamady
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, 11566 Egypt
| | - Reham Hussein Mohamed
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eman Gomaa
- Histology and Cell Biology Department, Faculty of Medicine, Ain Shams University, Giza, Egypt
| | - Mohamed Othman
- Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030 USA
| | - Yahia A. Yahia
- Chemistry Department, School of Science and Engineering, American University in Cairo, New Cairo, 11835 Egypt
- Biochemistry Department, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt
| | | | - Marwa Matboli
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, 11566 Egypt
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26
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Zhou X, Zhang H, Jiang Y, Wei L, Chen Y, Zhang J, Gao P, Zhu S, Fang C, Du Y, Su R, He M, Yu J, Wang S, Ding W, Feng L. The role of chemerin in the regulation of cGAS-STING pathway in gestational diabetes mellitus placenta. FASEB J 2023; 37:e22806. [PMID: 36786722 DOI: 10.1096/fj.202201611r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/09/2023] [Accepted: 01/24/2023] [Indexed: 02/15/2023]
Abstract
Recent studies already confirmed that placenta mitochondrial dysfunction is associated with the progression of gestational diabetes mellitus (GDM). Besides, a possible relationship between adipokine chemerin and disulfide-bond A oxidoreductase-like protein (DsbA-L) had been revealed, whereas the potential interaction remains unclear. In addition, very little is still known about the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and its mechanisms of action in the context of GDM. The present study aims to investigate the underlying mechanism of cGAS-STING pathway and its regulatory relationship with chemerin in GDM. A total of 50 participants, including 25 cases of GDM patients and 25 pregnant women with normal glucose tolerance, were enrolled, and their placenta tissues at term labor were collected. Besides, an insulin resistance cell model was established on the human trophoblastic cell line to explore the molecular mechanism of chemerin on cGAS-STING pathway. Results showed that there were mitochondrial pathological changes in GDM placenta, accompanied by the decreased expression of DsbA-L, increased level of chemerin, and the activation of cGAS-STING pathway. In the insulin resistant cell model, overexpression of chemerin upregulated protein expression of DsbA-L, and recombinant chemerin presented time-dependent inhibition on the cGAS-STING pathway, but this effect was not dependent on DsbA-L. In conclusion, elevated chemerin is probably a protective mechanism, which may be a potential therapeutic strategy for GDM.
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Affiliation(s)
- Xuan Zhou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiting Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Jiang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lijie Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuting Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingyi Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Gao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shenglan Zhu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenyun Fang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanyuan Du
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Su
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengzhou He
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Yu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaoshuai Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wencheng Ding
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Feng
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Guo Y, Li L, Yao Y, Li H. Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors. Metabolites 2022; 13:metabo13010051. [PMID: 36676976 PMCID: PMC9865674 DOI: 10.3390/metabo13010051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/07/2022] [Accepted: 11/23/2022] [Indexed: 12/31/2022] Open
Abstract
The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future.
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Affiliation(s)
- Yichuan Guo
- Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
| | - Lingqiao Li
- Zhejiang Starry Pharmaceutical Co., Ltd., Taizhou 317306, China
| | - Yuanfa Yao
- Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
- Correspondence: (Y.Y.); (H.L.)
| | - Hanbing Li
- Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
- Correspondence: (Y.Y.); (H.L.)
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28
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Audu CO, Melvin WJ, Joshi AD, Wolf SJ, Moon JY, Davis FM, Barrett EC, Mangum KD, Deng H, Xing X, Wasikowski R, Tsoi LC, Sharma SB, Bauer TM, Shadiow J, Corriere MA, Obi AT, Kunkel SL, Levi B, Moore BB, Gudjonsson JE, Smith AM, Gallagher KA. Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair. Cell Mol Immunol 2022; 19:1251-1262. [PMID: 36127466 PMCID: PMC9622909 DOI: 10.1038/s41423-022-00919-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 08/09/2022] [Indexed: 02/01/2023] Open
Abstract
Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.
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Affiliation(s)
- Christopher O Audu
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA
| | - William J Melvin
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
- Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Amrita D Joshi
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Sonya J Wolf
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Jadie Y Moon
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Frank M Davis
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Emily C Barrett
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
- Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kevin D Mangum
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Hongping Deng
- Department of Bioengineering, University of Illinois, Urbana-Champaign, Champaign, IL, USA
| | - Xianying Xing
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Rachel Wasikowski
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Lam C Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Sriganesh B Sharma
- Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Tyler M Bauer
- Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, MI, USA
| | - James Shadiow
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Matthew A Corriere
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Andrea T Obi
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Steven L Kunkel
- Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Benjamin Levi
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bethany B Moore
- Department of Surgery, Section of General Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Andrew M Smith
- Department of Bioengineering, University of Illinois, Urbana-Champaign, Champaign, IL, USA
| | - Katherine A Gallagher
- Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA.
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.
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29
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Nishimoto S, Sata M, Fukuda D. Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases. Front Cardiovasc Med 2022; 9:881181. [PMID: 36176986 PMCID: PMC9513035 DOI: 10.3389/fcvm.2022.881181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/15/2022] [Indexed: 11/14/2022] Open
Abstract
In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases.
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Affiliation(s)
- Sachiko Nishimoto
- Faculty of Clinical Nutrition and Dietetics, Konan Women’s University, Kobe, Japan
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Daiju Fukuda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Cardiovascular Medicine, Osaka Metropolitan University, Osaka, Japan
- *Correspondence: Daiju Fukuda, ,
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30
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Yang CL, Sun F, Wang FX, Rong SJ, Yue TT, Luo JH, Zhou Q, Wang CY, Liu SW. The interferon regulatory factors, a double-edged sword, in the pathogenesis of type 1 diabetes. Cell Immunol 2022; 379:104590. [PMID: 36030565 DOI: 10.1016/j.cellimm.2022.104590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/17/2022] [Accepted: 08/10/2022] [Indexed: 02/08/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease resulted from the unrestrained inflammatory attack towards the insulin-producing islet β cells. Although the exact etiology underlying T1D remains elusive, viral infections, especially those specific strains of enterovirus, are acknowledged as a critical environmental cue involved in the early phase of disease initiation. Viral infections could either directly impede β cell function, or elicit pathological autoinflammatory reactions for β cell killing. Autoimmune responses are bolstered by a massive body of virus-derived exogenous pathogen-associated molecular patterns (PAMPs) and the presence of β cell-derived damage-associated molecular patterns (DAMPs). In particular, the nucleic acid components and the downstream nucleic acid sensing pathways serve as the major effector mechanism. The endogenous retroviral RNA, mitochondrial DNA (mtDNA) and genomic fragments generated by stressed or dying β cells induce host responses reminiscent of viral infection, a phenomenon termed as viral mimicry during the early stage of T1D development. Given that the interferon regulatory factors (IRFs) are considered as hub transcription factors to modulate immune responses relevant to viral infection, we thus sought to summarize the critical role of IRFs in T1D pathogenesis. We discuss with focus for the impact of IRFs on the sensitivity of β cells to cytokine stimulation, the vulnerability of β cells to viral infection/mimicry, and the intensity of immune response. Together, targeting certain IRF members, alone or together with other therapeutics, could be a promising strategy against T1D.
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Affiliation(s)
- Chun-Liang Yang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Fei Sun
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Fa-Xi Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Shan-Jie Rong
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Tian-Tian Yue
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China; Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Hui Luo
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Qing Zhou
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Cong-Yi Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.
| | - Shi-Wei Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, the Third Hospital of Shanxi Medical University, Taiyuan, China.
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31
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Lv C, Sun Y, Zhang ZY, Aboelela Z, Qiu X, Meng ZX. β-cell dynamics in type 2 diabetes and in dietary and exercise interventions. J Mol Cell Biol 2022; 14:6656373. [PMID: 35929791 PMCID: PMC9710517 DOI: 10.1093/jmcb/mjac046] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/07/2022] [Accepted: 08/03/2022] [Indexed: 01/14/2023] Open
Abstract
Pancreatic β-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes (T2D). Recent clinical and experimental studies have suggested that the functional capacity of β-cells, particularly in the first phase of insulin secretion, is a primary contributor to the progression of T2D and its associated complications. Pancreatic β-cells undergo dynamic compensation and decompensation processes during the development of T2D, in which metabolic stresses such as endoplasmic reticulum stress, oxidative stress, and inflammatory signals are key regulators of β-cell dynamics. Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D, especially in the early stages. Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague, accumulating evidence has implicated the improvement of β-cell functional capacity. In this review, we summarize recent advances in the understanding of the dynamic adaptations of β-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions on β-cell dysfunction in T2D. This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D, and more importantly, it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.
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Affiliation(s)
- Chengan Lv
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yuchen Sun
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China,Zhejiang University–University of Edinburgh Institute (ZJE), Zhejiang University, Haining 314400, China
| | - Zhe Yu Zhang
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zeyad Aboelela
- Department of Pathology and Pathophysiology and Metabolic Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China,Bachelors of Surgery, Bachelors of Medicine (MBBS), Zhejiang University School of Medicine, Hangzhou 310003, China
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32
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Dai Y, Ma X, Zhang J, Yu S, Zhu Y, Wang J. hsa_circ_0115355 promotes pancreatic β-cell function in patients with type 2 diabetes through the miR-145/SIRT1 axis. J Clin Lab Anal 2022; 36:e24583. [PMID: 35778952 PMCID: PMC9396171 DOI: 10.1002/jcla.24583] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is a complex metabolic disease closely related to obesity, a growing global health problem. T2DM is characterized by decreased islet beta‐cell mass and impaired insulin release from these cells, and this dysfunction is exacerbated by hyperglycemia (glucolipotoxicity). Circular RNAs (circRNAs) are abnormally expressed and play a regulatory role in T2DM. Objective This study aimed to evaluate the function and molecular mechanism of hsa_circ_0115355 in the progression of T2DM. Methods The regulatory effect of hsa_circ_0115355 on INS‐1 cell function was assessed under glucolipotoxicity by MTT, flow cytometry analysis, and insulin secretion assay. Dual‐luciferase experiments revealed a direct interaction of hsa_circ_0115355 with miR‐145 and miR‐145 with SIRT1. Furthermore, the regulatory role of the hsa_circ_0115355/miR‐145/SIRT1 axis was verified by examining the function of INS‐1. Results In this study, hsa_circ_0115355 was significantly underexpressed in both patients with T2DM and INS‐1 cell lines. This study thus showed that hsa_circ_0115355 inhibits the occurrence and development of T2DM by regulating the expression of SIRT1 by adsorbing miR‐145. Conclusion The underexpression hsa_circ_0115355 is also a potential novel diagnostic marker and therapeutic target for T2DM.
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Affiliation(s)
- Ying Dai
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Xudan Ma
- Ningbo University School of Medicine, Ningbo, China
| | | | - Shuting Yu
- Ningbo University School of Medicine, Ningbo, China
| | - Yuchao Zhu
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China.,Ningbo University School of Medicine, Ningbo, China
| | - Jianhua Wang
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China.,Ningbo University School of Medicine, Ningbo, China
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Ishaq A, Tchkonia T, Kirkland JL, Siervo M, Saretzki G. Palmitate induces DNA damage and senescence in human adipocytes in vitro that can be alleviated by oleic acid but not inorganic nitrate. Exp Gerontol 2022; 163:111798. [PMID: 35390489 PMCID: PMC9214712 DOI: 10.1016/j.exger.2022.111798] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022]
Abstract
Hypertrophy in white adipose tissue (WAT) can result in sustained systemic inflammation, hyperlipidaemia, insulin resistance, and onset of senescence in adipocytes. Inflammation and hypertrophy can be induced in vitro using palmitic acid (PA). WAT adipocytes have innately low β-oxidation capacity, while inorganic nitrate can promote a beiging phenotype, with promotion of β-oxidation when cells are exposed to nitrate during differentiation. We hypothesized that treatment of human adipocytes with PA in vitro can induce senescence, which might be attenuated by nitrate treatment through stimulation of β-oxidation to remove accumulated lipids. Differentiated subcutaneous and omental adipocytes were treated with PA and nitrate and senescence markers were analyzed. PA induced DNA damage and increased p16INK4a levels in both human subcutaneous and omental adipocytes in vitro. However, lipid accumulation and lipid droplet size increased after PA treatment only in subcutaneous adipocytes. Thus, hypertrophy and senescence seem not to be causally associated. Contrary to our expectations, subsequent treatment of PA-induced adipocytes with nitrate did not attenuate PA-induced lipid accumulation or senescence. Instead, we found a significantly beneficial effect of oleic acid (OA) on human subcutaneous adipocytes when applied together with PA, which reduced the DNA damage caused by PA treatment.
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Affiliation(s)
- Abbas Ishaq
- Biosciences Institute, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Tamara Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, United States of America
| | - James L Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, United States of America
| | - Mario Siervo
- Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK; School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Gabriele Saretzki
- Biosciences Institute, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
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34
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Liu H, Zhou W, Guo L, Zhang H, Guan L, Yan X, Zhai Y, Qiao Y, Wang Z, Zhao J, Lyu K, Li P, Wang H, Peng L. Quercetin protects against palmitate-induced pancreatic β-cell apoptosis by restoring lysosomal function and autophagic flux. J Nutr Biochem 2022; 107:109060. [DOI: 10.1016/j.jnutbio.2022.109060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 04/08/2022] [Accepted: 04/20/2022] [Indexed: 11/26/2022]
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35
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Hu H, Zhao R, He Q, Cui C, Song J, Guo X, Zang N, Yang M, Zou Y, Yang J, Li J, Wang L, Xia L, Wang L, He F, Hou X, Yan F, Chen L. cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic β-cells induced by metabolic stress. FASEB J 2022; 36:e22266. [PMID: 35357035 DOI: 10.1096/fj.202101988r] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/21/2022] [Accepted: 03/08/2022] [Indexed: 12/17/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by impaired pancreatic β cell function and insulin resistance. Recent studies have shown that the accumulation of senescent β cells under metabolic stress conditions leads to the progression of T2DM, while senolysis can improve the prognosis. However, the specific mechanism of β cell senescence is still unclear. In this study, we found that the increased load of senescence pancreatic β cells in both older mice and obese mice induced by high-fat diet (HFD) (DIO mice) was accompanied by activation of the Cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway and using cGAS or STING small interfering RNA or STING inhibitor C176 to downregulate this pathway reduced the senescence-associated secretion profile (SASP) and senescence of Min6 cells treated with palmitic acid or hydrogen peroxide. C176 intervention in DIO mice also significantly reduced the inflammation and senescence of the islets, thereby protecting the function of pancreatic β cell and glucose metabolism. Our study further revealed that mitochondrial DNA (mtDNA) leakage under metabolic stress conditions was critical for the activation of the cGAS-STING pathway, which can be reversed by the mtDNA depleting agent ethidium bromide. Consistently, mtDNA leakage was more severe in older mice and was accelerated by a chronic HFD. In conclusion, we demonstrate that cytoplasmic mtDNA activates the cGAS-STING pathway to mediate SASP during the accelerated senescence of pancreatic β-cells induced by metabolic stress, and this process can be downregulated by the STING inhibitor C176.
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Affiliation(s)
- Huiqing Hu
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ruxing Zhao
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Qin He
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jinquan Li
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Longqing Xia
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Falian He
- Nuolai Biomedical Technology Co., Ltd., Taian, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China.,Nuolai Biomedical Technology Co., Ltd., Taian, China
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36
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Li H, Hu L, Wang L, Wang Y, Shao M, Chen Y, Wu W, Wang L. Iron Activates cGAS-STING Signaling and Promotes Hepatic Inflammation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:2211-2220. [PMID: 35133148 DOI: 10.1021/acs.jafc.1c06681] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Iron deposition and chronic inflammation are associated with chronic liver diseases, such as alcoholic liver disease, nonalcoholic fatty liver disease, and chronic hepatitis B and C. However, the relationship between iron deposition and chronic inflammation in these diseases is still unclear. In the current study, we aimed to investigate the effect of iron on chronic inflammation in HepG2 cells and mice liver. We demonstrated that iron treatment enhanced the expression of cGAS, STING, and their downstream targets, including TBK1, IRF-3, and NF-κB in HepG2 cells and mice liver. We also found that treatment of HepG2 cells and mice with ferric ammonium citrate increased the expression of inflammatory cytokines, such as IFN-β. Finally, we found that genes involved in iron metabolism and the STING signaling pathway were up-regulated in liver cancer tissues, and the survival time of patients with high expression of these genes in tumor tissues was significantly shortened. These results suggest that iron overload may promote the progress of the chronic liver disease by activating cGAS-STING-mediated chronic inflammation, which provides a new idea for the development of drugs for the treatment of the chronic liver disease.
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Affiliation(s)
- Hailang Li
- Department of Pharmacy, Xiamen Medical College, Xiamen 361023, China
| | - Ling Hu
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Liwen Wang
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Yixuan Wang
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Meiqi Shao
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Yupei Chen
- Department of Pharmacy, Xiamen Medical College, Xiamen 361023, China
| | - Wenlin Wu
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
- Fujian Province Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou Normal University, Quanzhou 362000, China
| | - Lei Wang
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
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37
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Xiaohong L, Zhenting Z, Yunjie Y, Wei C, Xiangjin X, Kun X, Xin L, Lu L, Jun L, Pin C. Activation of the STING-IRF3 pathway involved in psoriasis with diabetes mellitus. J Cell Mol Med 2022; 26:2139-2151. [PMID: 35174638 PMCID: PMC8995451 DOI: 10.1111/jcmm.17236] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/30/2022] [Accepted: 02/02/2022] [Indexed: 12/22/2022] Open
Abstract
Psoriasis and type 2 diabetes mellitus (T2DM) share similar inflammatory pathways in their pathogenesis. The stimulator of interferon genes (STING)‐interferon regulatory factor 3 (IRF3) pathway has recently been shown to play an important role in immune and metabolic diseases. In this study, we investigated the activation of the STING‐IRF3 pathway in human immortalized keratinocytes (HaCaT) cells treated with palmitic acid (PA) and imiquimod (IMQ). Additionally, we detected the STING‐IRF3 pathway in diabetic mice with imiquimod (IMQ)‐induced psoriasis and assessed the potential of STING inhibitor C‐176. Furthermore, skin samples from patients with psoriasis and diabetes were collected for immunohistochemical analysis. The results indicated that the STING‐IRF3 pathway was activated in HaCaT cells. Moreover, the STING pathway was also found to be induced in the skin tissue of diabetic mice with psoriasis; the inflammatory responses were ameliorated by treatment with C‐176. In the skin tissue samples of patients with psoriasis and diabetes, immunohistochemistry showed that the expression levels of STING and phosphorylated IRF3 were also significantly increased. Thus, we conclude that the STING‐IRF3 pathway is involved in the inflammatory response in the manifestation of psoriasis with T2DM. Inhibition of the activation of the STING pathway can ameliorate the development of psoriasis in diabetes and could be targeted for the development of therapeutic agents for these conditions.
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Affiliation(s)
- Li Xiaohong
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Zhang Zhenting
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yu Yunjie
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Cai Wei
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Xu Xiangjin
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China.,Department of Endocrinology, 900th Hospital of the Joint Logistics Team, Fuzhou, China
| | - Xie Kun
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Lin Xin
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Lin Lu
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Lu Jun
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Laboratory of Basic Medicine, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Chen Pin
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China.,Department of Endocrinology, 900th Hospital of the Joint Logistics Team, Fuzhou, China
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38
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A distinct role of STING in regulating glucose homeostasis through insulin sensitivity and insulin secretion. Proc Natl Acad Sci U S A 2022; 119:2101848119. [PMID: 35145023 PMCID: PMC8851542 DOI: 10.1073/pnas.2101848119] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2021] [Indexed: 12/20/2022] Open
Abstract
The role of STING in maintaining glucose homeostasis remains unknown. Herein, using global and β-cell–specific STING knockout mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through β-cells and peripheral tissues. Specially, while global STING knockout beneficially alleviated insulin resistance and glucose intolerance induced by high-fat diet, it surprisingly impaired islet glucose-stimulated insulin secretion (GSIS). Further analyses revealed that STING deficiency down-regulated expression of β-cell key transcription factor Pax6, impairing Pax6 nuclear localization and binding activity to the promoters of its target genes, including Glut2 and Abcc8, causing impaired GSIS. These data highlight pathophysiological significance of fine-tuned STING signaling in β-cells and insulin target tissues for maintaining glucose homeostasis. Insulin resistance and β-cell dysfunction are two main molecular bases yet to be further elucidated for type 2 diabetes (T2D). Accumulating evidence indicates that stimulator of interferon genes (STING) plays an important role in regulating insulin sensitivity. However, its function in β-cells remains unknown. Herein, using global STING knockout (STING−/−) and β-cell–specific STING knockout (STING-βKO) mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through peripheral tissues and β-cells. Specially, although STING−/− beneficially alleviated insulin resistance and glucose intolerance induced by high-fat diet, it surprisingly impaired islet glucose-stimulated insulin secretion (GSIS). Importantly, STING is decreased in islets of db/db mice and patients with T2D, suggesting a possible role of STING in β-cell dysfunction. Indeed, STING-βKO caused glucose intolerance due to impaired GSIS, indicating that STING is required for normal β-cell function. Islet transcriptome analysis showed that STING deficiency decreased expression of β-cell function–related genes, including Glut2, Kcnj11, and Abcc8, contributing to impaired GSIS. Mechanistically, the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and cleavage under targets and tagmentation (CUT&Tag) analyses suggested that Pax6 was the transcription factor that might be associated with defective GSIS in STING-βKO mice. Indeed, Pax6 messenger RNA and protein levels were down-regulated and its nuclear localization was lost in STING-βKO β-cells. Together, these data revealed a function of STING in the regulation of insulin secretion and established pathophysiological significance of fine-tuned STING within β-cells and insulin target tissues for maintaining glucose homeostasis.
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Römer A, Rawat D, Linn T, Petry SF. Preparation of fatty acid solutions exerts significant impact on experimental outcomes in cell culture models of lipotoxicity. Biol Methods Protoc 2022; 7:bpab023. [PMID: 35036572 PMCID: PMC8754478 DOI: 10.1093/biomethods/bpab023] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/25/2021] [Accepted: 11/30/2021] [Indexed: 11/14/2022] Open
Abstract
Free fatty acids are essentially involved in the pathogenesis of chronic diseases such as diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular disease. They promote mitochondrial dysfunction, oxidative stress, respiratory chain uncoupling, and endoplasmic reticulum stress and modulate stress-sensitive pathways. These detrimental biological effects summarized as lipotoxicity mainly depend on fatty acid carbon chain length, degree of unsaturation, concentration, and treatment time. Preparation of fatty acid solutions involves dissolving and complexing. Solvent toxicity and concentration, amount of bovine serum albumin (BSA), and ratio of albumin to fatty acids can vary significantly between equal concentrations, mediating considerable harmful effects and/or interference with certain assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Herein, we studied the impact of commonly used solvents ethanol and dimethyl sulfoxide and varying concentrations of BSA directly and in solution with oleic acid on MTT to formazan conversion, adenosine triphosphate level, and insulin content and secretion of murine β-cell line MIN6 employing different treatment duration. Our data show that experimental outcomes and assay readouts can be significantly affected by mere preparation of fatty acid solutions and should thus be carefully considered and described in detail to ensure comparability and distinct evaluation of data.
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Affiliation(s)
- Axel Römer
- Clinical Research Unit, Center of Internal Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Divya Rawat
- Clinical Research Unit, Center of Internal Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Thomas Linn
- Clinical Research Unit, Center of Internal Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
| | - Sebastian F Petry
- Clinical Research Unit, Center of Internal Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany
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40
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Cao L, Xu E, Zheng R, Zhangchen Z, Zhong R, Huang F, Ye J, Sun H, Fan Y, Xie S, Chen Y, Xu Y, Cao J, Cao W, Liu C. Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages. Chin Med 2022; 17:7. [PMID: 34983596 PMCID: PMC8728979 DOI: 10.1186/s13020-021-00559-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/18/2021] [Indexed: 11/25/2022] Open
Abstract
Background Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and high fat diet (HFD) induced NAFLD mice model. The STING signaling-mediated inflammation has been shown to play a critical role in metabolic disorders. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation remains unclear. This study was to determine the role of STING-mediated inflammation in the HFD-induced hepatic-lipid deposition treated with LGZG. Methods The anti-inflammatory and anti-steatotic effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immuno-chemistry. Mice bone-marrow-derived macrophages (BMDMs) and primary liver macrophages were treated with STING-specific agonist (DMXAA), LGZG and its critical components respectively. The treated culture supernatant of BMDMs and primary liver macrophages from each group was co-cultured with palmitic acid-treated mouse primary hepatocytes or mouse liver cell line AML-12 respectively to detect whether the activation of STING-mediated pathway is involved in the anti-steatotic effect of LGZG. The hepatocyte lipid deposition in vivo and in vitro were detected by oil red staining. Mitochondrial DNA release of mouse liver extracts were detected by real time PCR. The expression of proteins and inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA. Results LGZG significantly ameliorated HFD induced hepatic steatosis, oxidative stress, hepatic mitochondrial damage and mitochondrial DNA release, which was correlated with reduction of the expression level of STING as well as the infiltration of STING-positive macrophages in the livers of HFD fed mice. The critical components of LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in liver macrophages induced by DMXAA, LPS, thereby reducing the release of IFNβ and TNFα. Co-incubating the culture supernatant of LGZG treated liver macrophages and PA-stimulated hepatocytes significantly inhibited the PA-induced lipid deposition. Conclusion This study demonstrates that LGZG can ameliorate HFD-induced hepatic-lipid deposition through inhibiting STING-TBK1-NF-κB pathway in liver macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.
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Affiliation(s)
- Lin Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China. .,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.
| | - Erjin Xu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Rendong Zheng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Zhili Zhangchen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Rongling Zhong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Fei Huang
- Suzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, No. 18 Yangsu Road, Gusu District, Suzhou, 215002, China
| | - Juan Ye
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Hongping Sun
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Yaofu Fan
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Shaofeng Xie
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Yu Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Yijiao Xu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China
| | - Jing Cao
- Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Qinhuai District, Nanjing, 210029, China
| | - Wen Cao
- The Affiliated Jiangning Hospital of Nanjing Medical University, No. 169, Dongshan street, Hushan Road, Jiangning District, Nanjing, 211100, China.
| | - Chao Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China. .,Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, China.
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You S, Zheng J, Chen Y, Huang H. Research progress on the mechanism of beta-cell apoptosis in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2022; 13:976465. [PMID: 36060972 PMCID: PMC9434279 DOI: 10.3389/fendo.2022.976465] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Type 2 diabetes mellitus(T2DM) is regarded as one of the most severe chronic metabolic diseases worldwide, which poses a great threat to human safety and health. The main feature of T2DM is the deterioration of pancreatic beta-cell function. More and more studies have shown that the decline of pancreatic beta-cell function in T2DM can be attributable to beta-cell apoptosis, but the exact mechanisms of beta-cell apoptosis in T2DM are not yet fully clarified. Therefore, in this review, we will focus on the current status and progress of research on the mechanism of pancreatic beta-cell apoptosis in T2DM, to provide new ideas for T2DM treatment strategies.
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Affiliation(s)
- SuFang You
- The Second Clinical Medical College of Fujian Medical University, Quanzhou, China
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - JingYi Zheng
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - YuPing Chen
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - HuiBin Huang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- *Correspondence: HuiBin Huang,
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The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B 2022; 12:50-75. [PMID: 35127372 PMCID: PMC8799861 DOI: 10.1016/j.apsb.2021.05.011] [Citation(s) in RCA: 175] [Impact Index Per Article: 58.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/05/2021] [Accepted: 04/15/2021] [Indexed: 12/12/2022] Open
Abstract
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.
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Key Words
- AA, amino acids
- AAD, aortic aneurysm and dissection
- AKT, protein kinase B
- AMPK, AMP-activated protein kinase
- ATP, adenosine triphosphate
- Ang II, angiotensin II
- CBD, C-binding domain
- CDG, c-di-GMP
- CDNs, cyclic dinucleotides
- CTD, C-terminal domain
- CTT, C-terminal tail
- CVDs, cardiovascular diseases
- Cardiovascular diseases
- Cys, cysteine
- DAMPs, danger-associated molecular patterns
- Damage-associated molecular patterns
- DsbA-L, disulfide-bond A oxidoreductase-like protein
- ER stress
- ER, endoplasmic reticulum
- GTP, guanosine triphosphate
- HAQ, R71H-G230A-R293Q
- HFD, high-fat diet
- ICAM-1, intracellular adhesion molecule 1
- IFN, interferon
- IFN-I, type 1 interferon
- IFNAR, interferon receptors
- IFNIC, interferon-inducible cells
- IKK, IκB kinase
- IL, interleukin
- IRF3, interferon regulatory factor 3
- ISGs, IRF-3-dependent interferon-stimulated genes
- Inflammation
- LBD, ligand-binding pocket
- LPS, lipopolysaccharides
- MI, myocardial infarction
- MLKL, mixed lineage kinase domain-like protein
- MST1, mammalian Ste20-like kinases 1
- Metabolic diseases
- Mitochondria
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-kappa B
- NLRP3, NOD-, LRR- and pyrin domain-containing protein 3
- NO2-FA, nitro-fatty acids
- NTase, nucleotidyltransferase
- PDE3B/4, phosphodiesterase-3B/4
- PKA, protein kinase A
- PPI, protein–protein interface
- Poly: I.C, polyinosinic-polycytidylic acid
- ROS, reactive oxygen species
- SAVI, STING-associated vasculopathy with onset in infancy
- SNPs, single nucleotide polymorphisms
- STIM1, stromal interaction molecule 1
- STING
- STING, stimulator of interferon genes
- Ser, serine
- TAK1, transforming growth factor β-activated kinase 1
- TBK1, TANK-binding kinase 1
- TFAM, mitochondrial transcription factor A
- TLR, Toll-like receptors
- TM, transmembrane
- TNFα, tumor necrosis factor-alpha
- TRAF6, tumor necrosis factor receptor-associated factor 6
- TREX1, three prime repair exonuclease 1
- YAP1, Yes-associated protein 1
- cGAMP, 2′,3′-cyclic GMP–AMP
- cGAS
- cGAS, cyclic GMP–AMP synthase
- dsDNA, double-stranded DNA
- hSTING, human stimulator of interferon genes
- mTOR, mammalian target of rapamycin
- mtDNA, mitochondrial DNA
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Mohseni G, Li J, Ariston Gabriel AN, Du L, Wang YS, Wang C. The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer. Front Immunol 2021; 12:781032. [PMID: 34858438 PMCID: PMC8630697 DOI: 10.3389/fimmu.2021.781032] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/25/2021] [Indexed: 12/23/2022] Open
Abstract
The activation of stimulator of interferon genes (STING) signalling pathway has been suggested to promote the immune responses against malignancy. STING is activated in response to the detection of cytosolic DNA and can induce type I interferons and link innate immunity with the adaptive immune system. Due to accretive evidence demonstrating that the STING pathway regulates the immune cells of the tumor microenvironment (TME), STING as a cancer biotherapy has attracted considerable attention. Pancreatic cancer, with a highly immunosuppressive TME, remains fatal cancer. STING has been applied to the treatment of pancreatic cancer through distinct strategies. This review reveals the role of STING signalling on pancreatic tumors and other diseases related to the pancreas. We then discuss new advances of STING in either monotherapy or combination methods for pancreatic cancer immunotherapy.
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Affiliation(s)
- Ghazal Mohseni
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Abakundana Nsenga Ariston Gabriel
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun-Shan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Xu J, Wang P, Li Z, Li Z, Han D, Wen M, Zhao Q, Zhang L, Ma Y, Liu W, Jiang M, Zhang X, Cao X. IRF3-binding lncRNA-ISIR strengthens interferon production in viral infection and autoinflammation. Cell Rep 2021; 37:109926. [PMID: 34731629 DOI: 10.1016/j.celrep.2021.109926] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/26/2021] [Accepted: 10/12/2021] [Indexed: 11/17/2022] Open
Abstract
Interferon regulatory factor 3 (IRF3) is an essential transductor for initiation of many immune responses. Here, we show that lncRNA-ISIR directly binds IRF3 to promote its phosphorylation, dimerization, and nuclear translocation, along with enhanced target gene productions. In vivo lncRNA-ISIR deficiency results in reduced IFN production, uncontrolled viral replication, and increased mortality. The human homolog, AK131315, also binds IRF3 and promotes its activation. More important, AK131315 expression is positively correlated with type I interferon (IFN-I) level and severity in patients with lupus. Mechanistically, in resting cells, IRF3 is bound to suppressor protein Flightless-1 (Fli-1), which keeps its inactive state. Upon infection, IFN-I-induced lncRNA-ISIR binds IRF3 at DNA-binding domain in cytoplasm and removes Fli-1's association from IRF3, consequently facilitating IRF3 activation. Our results demonstrate that IFN-I-inducible lncRNA-ISIR feedback strengthens IRF3 activation by removing suppressive Fli-1 in immune responses, revealing a method of lncRNA-mediated modulation of transcription factor (TF) activation.
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Affiliation(s)
- Junfang Xu
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Pin Wang
- National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China.
| | - Zemeng Li
- National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
| | - Zhiqing Li
- National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
| | - Dan Han
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
| | - Mingyue Wen
- National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
| | - Qihang Zhao
- National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
| | - Lianfeng Zhang
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Yuanwu Ma
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Wei Liu
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Minghong Jiang
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xuetao Cao
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing 100021, China.
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45
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Kgatle MM, Lawal IO, Mashabela G, Boshomane TMG, Koatale PC, Mahasha PW, Ndlovu H, Vorster M, Rodrigues HG, Zeevaart JR, Gordon S, Moura-Alves P, Sathekge MM. COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks. Front Immunol 2021; 12:752380. [PMID: 34691068 PMCID: PMC8531724 DOI: 10.3389/fimmu.2021.752380] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/21/2021] [Indexed: 12/19/2022] Open
Abstract
The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression.
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Affiliation(s)
- Mankgopo Magdeline Kgatle
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
| | - Ismaheel Opeyemi Lawal
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, Steve Biko Academic Hospital, Pretoria, South Africa
| | - Gabriel Mashabela
- SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DSI/NRF Centre of Excellence for Biomedical TB Research, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Tebatso Moshoeu Gillian Boshomane
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, Steve Biko Academic Hospital, Pretoria, South Africa
- Nuclear and Oncology Division, AXIM Medical (Pty), Midrand
| | - Palesa Caroline Koatale
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
| | - Phetole Walter Mahasha
- Precision Medicine and SAMRC Genomic Centre, Grants, Innovation, and Product Development (GIPD) Unit, South African Medical Research Council, Pretoria, South Africa
| | - Honest Ndlovu
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
| | - Mariza Vorster
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
| | - Hosana Gomes Rodrigues
- Laboratory of Nutrients and Tissue Repair, School of Applied Sciences, University of Campinas, Campinas, Brazil
| | - Jan Rijn Zeevaart
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South Africa
- South African Nuclear Energy Corporation, Radiochemistry and NuMeRI PreClinical Imaging Facility, Mahikeng, South Africa
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Siamon Gordon
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - Pedro Moura-Alves
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Mike Machaba Sathekge
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South Africa
- Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
- SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DSI/NRF Centre of Excellence for Biomedical TB Research, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Fukuda D, Pham PT, Sata M. Emerging Roles of the Innate Immune System Regulated by DNA Sensors in the Development of Vascular and Metabolic Diseases. J Atheroscler Thromb 2021; 29:297-307. [PMID: 34248111 PMCID: PMC8894111 DOI: 10.5551/jat.rv17059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)—one of the most studied DNA sensors—recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.
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Affiliation(s)
- Daiju Fukuda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Phuong Tran Pham
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
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Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies. Int J Mol Sci 2021; 22:ijms22105303. [PMID: 34069914 PMCID: PMC8157542 DOI: 10.3390/ijms22105303] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/22/2022] Open
Abstract
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.
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Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review. Antioxidants (Basel) 2021; 10:antiox10020293. [PMID: 33672062 PMCID: PMC7919463 DOI: 10.3390/antiox10020293] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/06/2021] [Accepted: 02/11/2021] [Indexed: 02/08/2023] Open
Abstract
Lipotoxicity is a major contributor to type 2 diabetes mainly promoting mitochondrial dysfunction. Lipotoxic stress is mediated by elevated levels of free fatty acids through various mechanisms and pathways. Impaired peroxisome proliferator-activated receptor (PPAR) signaling, enhanced oxidative stress levels, and uncoupling of the respiratory chain result in ATP deficiency, while β-cell viability can be severely impaired by lipotoxic modulation of PI3K/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways. However, fatty acids are physiologically required for an unimpaired β-cell function. Thus, preparation, concentration, and treatment duration determine whether the outcome is beneficial or detrimental when fatty acids are employed in experimental setups. Further, ageing is a crucial contributor to β-cell decay. Cellular senescence is connected to loss of function in β-cells and can further be promoted by lipotoxicity. The potential benefit of nutrients has been broadly investigated, and particularly polyphenols were shown to be protective against both lipotoxicity and cellular senescence, maintaining the physiology of β-cells. Positive effects on blood glucose regulation, mitigation of oxidative stress by radical scavenging properties or regulation of antioxidative enzymes, and modulation of apoptotic factors were reported. This review summarizes the significance of lipotoxicity and cellular senescence for mitochondrial dysfunction in the pancreatic β-cell and outlines potential beneficial effects of plant-based nutrients by the example of polyphenols.
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Smith JA. STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation? Front Immunol 2021; 11:611347. [PMID: 33552072 PMCID: PMC7858662 DOI: 10.3389/fimmu.2020.611347] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022] Open
Abstract
The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.
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Affiliation(s)
- Judith A Smith
- Department of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
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50
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Developmental Programming and Glucolipotoxicity: Insights on Beta Cell Inflammation and Diabetes. Metabolites 2020; 10:metabo10110444. [PMID: 33158303 PMCID: PMC7694373 DOI: 10.3390/metabo10110444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/23/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Stimuli or insults during critical developmental transitions induce alterations in progeny anatomy, physiology, and metabolism that may be transient, sometimes reversible, but often durable, which defines programming. Glucolipotoxicity is the combined, synergistic, deleterious effect of simultaneously elevated glucose (chronic hyperglycemia) and saturated fatty acids (derived from high-fat diet overconsumption and subsequent metabolism) that are harmful to organs, micro-organs, and cells. Glucolipotoxicity induces beta cell death, dysfunction, and failure through endoplasmic reticulum and oxidative stress and inflammation. In beta cells, the misfolding of pro/insulin proteins beyond the cellular threshold triggers the unfolded protein response and endoplasmic reticulum stress. Consequentially there is incomplete and inadequate pro/insulin biosynthesis and impaired insulin secretion. Cellular stress triggers cellular inflammation, where immune cells migrate to, infiltrate, and amplify in beta cells, leading to beta cell inflammation. Endoplasmic reticulum stress reciprocally induces beta cell inflammation, whereas beta cell inflammation can self-activate and further exacerbate its inflammation. These metabolic sequelae reflect the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes.
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