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1
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Rehill AM, McCluskey S, Ledwith AE, Ryan TAJ, Ünlü B, Leon G, Charles-Messance H, Gilbert EH, Klavina P, Day EA, Coppinger J, O’Sullivan JM, McMahon C, O’Donnell JS, Curtis AM, O’Neill LAJ, Sheedy FJ, Preston RJS. Trained immunity causes myeloid cell hypercoagulability. SCIENCE ADVANCES 2025; 11:eads0105. [PMID: 40053582 PMCID: PMC11887800 DOI: 10.1126/sciadv.ads0105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 01/31/2025] [Indexed: 03/09/2025]
Abstract
The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell "trained immunity" describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation of macrophages trained previously with β-glucan or heme exhibited significantly enhanced procoagulant activity compared to macrophages stimulated with LPS alone, which was mediated by enhanced acid sphingomyelinase-mediated tissue factor decryption. Furthermore, splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Moreover, hematopoietic progenitor cells and bone marrow interstitial fluid from β-glucan-trained mice had enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent an opportunity for targeted intervention in immunothrombotic disease development.
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Affiliation(s)
- Aisling M. Rehill
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
| | - Seán McCluskey
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
| | - Anna E. Ledwith
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Tristram A. J. Ryan
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Betül Ünlü
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Gemma Leon
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
| | | | - Edmund H. Gilbert
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paula Klavina
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
| | - Emily A. Day
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Judith Coppinger
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Jamie M. O’Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Corrina McMahon
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
| | - James S. O’Donnell
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Annie M. Curtis
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Luke A. J. O’Neill
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Frederick J. Sheedy
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Roger J. S. Preston
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
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2
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Wang HN, Wang Y, Zhang SY, Bai L. Emerging roles of the acid sphingomyelinase/ceramide pathway in metabolic and cardiovascular diseases: Mechanistic insights and therapeutic implications. World J Cardiol 2025; 17:102308. [DOI: 10.4330/wjc.v17.i2.102308] [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: 10/14/2024] [Revised: 12/10/2024] [Accepted: 02/08/2025] [Indexed: 02/25/2025] Open
Abstract
Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases, posing a significant global public health challenge. Although the association between ceramides (Cers) and metabolic diseases is well-established, the role of the acid sphingomyelinase (ASMase)/Cer pathway in these diseases remains underexplored. This review synthesizes recent research on the biological functions, regulatory mechanisms, and targeted therapies related to the ASMase/Cer pathway in metabolic conditions, including obesity, diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. The effects of the ASMase/Cer pathway on metabolic disease-related indicators, such as glycolipid metabolism, insulin resistance, inflammation, and mitochondrial homeostasis are elucidated. Moreover, this article discusses the therapeutic strategies using ASMase/Cer inhibitors for inverse prevention and treatment of these metabolic diseases in light of the possible efficacy of blockade of the ASMase/Cer pathway in arresting the progression of metabolic diseases. These insights offered herein should provide insight into the contribution of the ASMase/Cer pathway to metabolic diseases and offer tools to develop therapeutic interventions for such pathologies and their severe complications.
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Affiliation(s)
- Hong-Ni Wang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ye Wang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Si-Yao Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Lan Bai
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
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Jiang L, Yuan C, Flaumenhaft R, Huang M. Recent advances in vascular thiol isomerases: insights into structures, functions in thrombosis and antithrombotic inhibitor development. Thromb J 2025; 23:16. [PMID: 39962537 PMCID: PMC11834194 DOI: 10.1186/s12959-025-00699-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/08/2025] [Indexed: 02/20/2025] Open
Abstract
Vascular thiol isomerases (VTIs) encompass proteins such as protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERp5), ERp46, ERp57, ERp72, thioredoxin-related transmembrane protein 1 (TMX1), and TMX4, and play pivotal functions in platelet aggregation and formation of thrombosis. Investigating vascular thiol isomerases, their substrates implicated in thrombosis, the underlying regulatory mechanisms, and the development of inhibitors targeting these enzymes represents a rapidly advancing frontier within vascular biology. In this review, we summarize the structural characteristics and functional attributes of VTIs, describe the associations between these enzymes and thrombosis, and outline the progress in developing inhibitors of VTIs for potential antithrombotic therapeutic applications.
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Affiliation(s)
- Longguang Jiang
- College of Chemistry, Fuzhou University, Fujian, 350108, China
- National and Local Joint Engineering Research Center On Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, 350116, China
| | - Cai Yuan
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, Fujian, China
- National and Local Joint Engineering Research Center On Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, 350116, China
| | - Robert Flaumenhaft
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA, 02215, USA.
| | - Mingdong Huang
- College of Chemistry, Fuzhou University, Fujian, 350108, China.
- National and Local Joint Engineering Research Center On Biopharmaceutical and Photodynamic Therapy Technologies, Fuzhou University, Fuzhou, 350116, China.
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Lee SH, Yang HW, Kang BS, Park MK, Kim DY, Song HK, Choi HC, Lee M, Choi BY, Son DS, Suh SW. Imipramine, an Acid Sphingomyelinase Inhibitor, Promotes Newborn Neuron Survival in the Hippocampus After Seizure. Cells 2025; 14:281. [PMID: 39996753 PMCID: PMC11853442 DOI: 10.3390/cells14040281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/11/2025] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
Epilepsy, a chronic neurological disorder, is triggered by various insults, including traumatic brain injury and stroke. Acid sphingomyelinase (ASMase), an enzyme that hydrolyzes sphingomyelin into ceramides, is implicated in oxidative stress, neuroinflammation, and neuronal apoptosis. Ceramides, which have pro-apoptotic properties, contribute to oxidative damage and lysosomal dysfunction, exacerbating neuronal injury. This study investigates the role of ASMase in epilepsy, hypothesizing that seizure activity upregulates ASMase, increasing ceramide levels, DNA damage, and neuronal apoptosis. We employed a pilocarpine-induced rat seizure model and examined the effects of imipramine, an ASMase inhibitor, administered intraperitoneally (10 mg/kg) for four weeks post-seizure induction. Histological and cognitive analyses showed that while imipramine did not prevent early neuronal death within the first week, it significantly reduced markers of neuronal apoptosis by four weeks. Imipramine also promoted hippocampal neurogenesis and preserved cognitive function, which is often impaired following seizures. These findings suggest that ASMase inhibition could mitigate neuronal apoptosis and improve cognitive recovery after seizures. Imipramine may serve as a promising therapeutic strategy for epilepsy-associated neuronal damage and cognitive deficits. Further studies should delineate the molecular mechanisms of ASMase inhibition and evaluate its long-term efficacy in addressing epilepsy-related neurodegeneration and functional impairments.
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Affiliation(s)
- Song Hee Lee
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.H.L.); (H.W.Y.); (B.S.K.); (M.K.P.); (D.Y.K.)
| | - Hyun Wook Yang
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.H.L.); (H.W.Y.); (B.S.K.); (M.K.P.); (D.Y.K.)
| | - Beom Seok Kang
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.H.L.); (H.W.Y.); (B.S.K.); (M.K.P.); (D.Y.K.)
| | - Min Kyu Park
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.H.L.); (H.W.Y.); (B.S.K.); (M.K.P.); (D.Y.K.)
| | - Dong Yeon Kim
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.H.L.); (H.W.Y.); (B.S.K.); (M.K.P.); (D.Y.K.)
| | - Hong Ki Song
- Department of Neurology, Kangdong Sacred Heart Hospital, Seoul 05355, Republic of Korea;
| | - Hui Chul Choi
- Department of Neurology, Hallym University Sacred Heart Hospital, Chuncheon 24253, Republic of Korea;
| | - Minwoo Lee
- Department of Neurology, Hallym University Sacred Heart Hospital, Anyang 14068, Republic of Korea;
| | - Bo Young Choi
- Department of Physical Education, Hallym University, Chuncheon 24253, Republic of Korea;
| | - Dae-Soon Son
- Division of Data Science, Data Science Convergence Research Center, Hallym University, Chuncheon 24253, Republic of Korea;
| | - Sang Won Suh
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.H.L.); (H.W.Y.); (B.S.K.); (M.K.P.); (D.Y.K.)
- Hallym Institute of Epilepsy Research, Chuncheon 24253, Republic of Korea
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Li L, Tan Q, Wu X, Mou X, Lin Z, Liu T, Huang W, Deng L, Jin T, Xia Q. Coagulopathy and acute pancreatitis: pathophysiology and clinical treatment. Front Immunol 2024; 15:1477160. [PMID: 39544925 PMCID: PMC11560453 DOI: 10.3389/fimmu.2024.1477160] [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: 08/07/2024] [Accepted: 10/10/2024] [Indexed: 11/17/2024] Open
Abstract
Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients' prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.
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Affiliation(s)
- Lan Li
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Qingyuan Tan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Xueying Wu
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaowen Mou
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Ziqi Lin
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Liu
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Huang
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- West China Biobank, West China Hospital, Sichuan University, Chengdu, China
| | - Lihui Deng
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Jin
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Qing Xia
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
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Hota S, Kumar M. ErpY-like Protein Interaction with Host Thrombin and Fibrinogen Intervenes the Plasma Coagulation through Extrinsic and Intrinsic Pathways. ACS Infect Dis 2024; 10:3256-3272. [PMID: 39231002 DOI: 10.1021/acsinfecdis.4c00266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/06/2024]
Abstract
The survival and proliferation of pathogenic Leptospira within a host are complex phenomena that require careful consideration. The ErpY-like lipoprotein, found on the outer membrane surface of Leptospira, plays a crucial role in enhancing the bacterium's pathogenicity. The rErpY-like protein, in its recombinant form, contributes significantly to spirochete virulence by interacting with various host factors, including host complement regulators. This interaction facilitates the bacterium's evasion of the host complement system, thereby augmenting its overall pathogenicity. The rErpY-like protein exhibits a robust binding affinity to soluble fibrinogen, a vital component of the host coagulation system. In this study, we demonstrate that the rErpY-like protein intervenes in the clotting process of the platelet-poor citrated plasma of bovines and humans in a concentration-dependent manner. It significantly reduces clot density, alters the viscoelastic properties of the clot, and diminishes the average clotting rate in plasma. Furthermore, the ErpY-like protein inhibits thrombin-catalyzed fibrin formation in a dose-dependent manner and exhibits saturable binding to thrombin, suggesting its significant role in leptospiral infection. These findings provide compelling evidence for the anticoagulant effect of the ErpY-like lipoprotein and its significant role in leptospiral infection.
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Affiliation(s)
- Saswat Hota
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Manish Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
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Riyaz S, Sun Y, Helmholz H, Medina TP, Medina OP, Wiese B, Will O, Albaraghtheh T, Mohamad FH, Hövener JB, Glüer CC, Römer RW. Inflammatory response toward a Mg-based metallic biomaterial implanted in a rat femur fracture model. Acta Biomater 2024; 185:41-54. [PMID: 38969080 DOI: 10.1016/j.actbio.2024.06.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/20/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024]
Abstract
The immune system plays an important role in fracture healing, by modulating the pro-inflammatory and anti-inflammatory responses occurring instantly upon injury. An imbalance in these responses can lead to adverse outcomes, such as non-union of fractures. Implants are used to support and stabilize complex fractures. Biodegradable metallic implants offer the potential to avoid a second surgery for implant removal, unlike non-degradable implants. However, considering our dynamic immune system it is important to conduct in-depth studies on the immune response to these implants in living systems. In this study, we investigated the immune response to Mg and Mg-10Gd in vivo in a rat femur fracture model with external fixation. In vivo imaging using liposomal formulations was used to monitor the fluorescence-related inflammation over time. We combine ex vivo methods with our in vivo study to evaluate and understand the systemic and local effects of the implants on the immune response. We observed no significant local or systemic effects in the Mg-10Gd implanted group compared to the SHAM and Mg implanted groups over time. Our findings suggest that Mg-10Gd is a more compatible implant material than Mg, with no adverse effects observed in the early phase of fracture healing during our 4-week study. STATEMENT OF SIGNIFICANCE: Degradable metallic implants in form of Mg and Mg-10Gd intramedullary pins were assessed in a rat femur fracture model, alongside a non-implanted SHAM group with special respect to the potential to induce an inflammatory response. This pre-clinical study combines innovative non-invasive in vivo imaging techniques associated with multimodal, ex vivo cellular and molecular analytics. The study contributes to the development and evaluation of degradable biometals and their clinical application potential. The study results indicate that Mg-10Gd did not exhibit any significant harmful effects compared to the SHAM and Mg groups.
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Affiliation(s)
- Sana Riyaz
- Helmholtz-Zentrum hereon GmbH, Institute of Metallic Biomaterials, Max-Planck-Straße 1, Geesthacht 21502, Germany.
| | - Yu Sun
- Helmholtz-Zentrum hereon GmbH, Institute of Metallic Biomaterials, Max-Planck-Straße 1, Geesthacht 21502, Germany
| | - Heike Helmholz
- Helmholtz-Zentrum hereon GmbH, Institute of Metallic Biomaterials, Max-Planck-Straße 1, Geesthacht 21502, Germany.
| | - Tuula Penate Medina
- Section Biomedical Imaging, Department of Radiology and Neuroradiology University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Am Botanischen Garten 14, 24118 Kiel, Germany; Institute for Experimental Cancer Research, Kiel University, 24105 Kiel, Germany
| | - Oula Penate Medina
- Section Biomedical Imaging, Department of Radiology and Neuroradiology University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Am Botanischen Garten 14, 24118 Kiel, Germany; Institute for Experimental Cancer Research, Kiel University, 24105 Kiel, Germany; Lonza Netherlands B.V., 6167 RB Geleen, the Netherlands
| | - Björn Wiese
- Helmholtz-Zentrum hereon GmbH, Institute of Metallic Biomaterials, Max-Planck-Straße 1, Geesthacht 21502, Germany
| | - Olga Will
- Section Biomedical Imaging, Department of Radiology and Neuroradiology University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Am Botanischen Garten 14, 24118 Kiel, Germany
| | - Tamadur Albaraghtheh
- Helmholtz-Zentrum hereon GmbH, Institute of Metallic Biomaterials, Max-Planck-Straße 1, Geesthacht 21502, Germany; Helmholtz-Zentrum hereon GmbH, Institute of Surface Science, Max-Planck-Straße 1, Geesthacht 21502, Germany
| | - Farhad Haj Mohamad
- Section Biomedical Imaging, Department of Radiology and Neuroradiology University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Am Botanischen Garten 14, 24118 Kiel, Germany
| | - Jan-Bernd Hövener
- Section Biomedical Imaging, Department of Radiology and Neuroradiology University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Am Botanischen Garten 14, 24118 Kiel, Germany
| | - Claus Christian Glüer
- Section Biomedical Imaging, Department of Radiology and Neuroradiology University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Am Botanischen Garten 14, 24118 Kiel, Germany
| | - Regine Willumeit Römer
- Helmholtz-Zentrum hereon GmbH, Institute of Metallic Biomaterials, Max-Planck-Straße 1, Geesthacht 21502, Germany
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Zhang RG, Zheng BW, Zhang J, Hao MY, Diao YH, Hu XJ, Liu YF, Liu XH, Zhu T, Zhao ZL, Rong HT. Spinal Lymphatic Dysfunction Aggravates the Recovery Process After Spinal Cord Injury. Neuroscience 2024; 549:84-91. [PMID: 38460904 DOI: 10.1016/j.neuroscience.2024.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 03/11/2024]
Abstract
We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway.
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Affiliation(s)
- Rui-Guang Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Bo-Wen Zheng
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Ming-Yu Hao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yu-Hang Diao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiao-Jun Hu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Ya-Fan Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xuan-Hui Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Tao Zhu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
| | - Zi-Long Zhao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
| | - Hong-Tao Rong
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
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Ji Y, Chen J, Pang L, Chen C, Ye J, Liu H, Chen H, Zhang S, Liu S, Liu B, Cheng C, Liu S, Zhong Y. The Acid Sphingomyelinase Inhibitor Amitriptyline Ameliorates TNF-α-Induced Endothelial Dysfunction. Cardiovasc Drugs Ther 2024; 38:43-56. [PMID: 36103099 PMCID: PMC10876840 DOI: 10.1007/s10557-022-07378-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE Inflammation associated endothelial cell (EC) dysfunction is key to atherosclerotic disease. Recent studies have demonstrated a protective role of amitriptyline in cardiomyocytes induced by hypoxia/reoxygenation. However, the mechanism by which amitriptyline regulates the inflammatory reaction in ECs remains unknown. Thus, the aim of this study was to investigate whether amitriptyline protects against inflammation in TNF-α-treated ECs. METHODS HUVECs were incubated with amitriptyline (2.5 μM) or TNF-α (20 ng/ml) for 24 h. EdU, tube formation, transwell, DHE fluorescence staining, and monocyte adhesion assays were performed to investigate endothelial function. Thoracic aortas were isolated from mice, and vascular tone was measured with a wire myograph system. The levels of ICAM-1, VCAM-1, MCP-1, phosphorylated MAPK and NF-κB were detected using western blotting. RESULTS Amitriptyline increased the phosphorylation of nitric oxide synthase (eNOS) and the release of NO. Amitriptyline significantly inhibited TNF-α-induced increases in ASMase activity and the release of ceramide and downregulated TNF-α-induced expression of proinflammatory proteins, including ICAM-1, VCAM-1, and MCP-1 in ECs, as well as the secretion of sICAM-1 and sVCAM-1. TNF-α treatment obviously increased monocyte adhesion and ROS production and impaired HUVEC proliferation, migration and tube formation, while amitriptyline rescued proliferation, migration, and tube formation and decreased monocyte adhesion and ROS production. Additionally, we demonstrated that amitriptyline suppressed TNF-α-induced MAPK phosphorylation as well as the activity of NF-κB in HUVECs. The results showed that the relaxation response of aortic rings to acetylcholine in the WT-TNF-α group was much lower than that in the WT group, and the sensitivity of aortic rings to acetylcholine in the WT-TNF-α group and WT-AMI-TNF-α group was significantly higher than that in the WT-TNF-α group. CONCLUSION These results suggest that amitriptyline reduces endothelial inflammation, consequently improving vascular endothelial function. Thus, the identification of amitriptyline as a potential strategy to improve endothelial function is important for preventing vascular diseases.
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Affiliation(s)
- Yang Ji
- Department of Emergency, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Jing Chen
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Lihua Pang
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Changnong Chen
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Jinhao Ye
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Hao Liu
- Department of Anesthesia, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Huanzhen Chen
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Songhui Zhang
- Department of Obstetrics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Shaojun Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Benrong Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Chuanfang Cheng
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Shiming Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China.
| | - Yun Zhong
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China.
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10
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Rehill AM, Leon G, McCluskey S, Schoen I, Hernandez-Santana Y, Annett S, Klavina P, Robson T, Curtis AM, Renné T, Hussey S, O'Donnell JS, Walsh PT, Preston RJS. Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability. J Thromb Haemost 2024; 22:394-409. [PMID: 37865288 DOI: 10.1016/j.jtha.2023.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 10/06/2023] [Accepted: 10/06/2023] [Indexed: 10/23/2023]
Abstract
BACKGROUND Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood. OBJECTIVES We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation. METHODS We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease. RESULTS Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity through reduced plasminogen activator inhibitor 1 activity. Macrophage polarization or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and activated protein C generation compared with macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice. CONCLUSION Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thromboinflammatory disease.
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Affiliation(s)
- Aisling M Rehill
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland. https://twitter.com/aislingrehill
| | - Gemma Leon
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland
| | - Sean McCluskey
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland
| | - Ingmar Schoen
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Yasmina Hernandez-Santana
- National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland; Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland
| | - Stephanie Annett
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Paula Klavina
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Tracy Robson
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Annie M Curtis
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Thomas Renné
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Seamus Hussey
- National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland; Department of Paediatrics, University College Dublin and Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - James S O'Donnell
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Patrick T Walsh
- National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland; Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland
| | - Roger J S Preston
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland.
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11
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Das K, Keshava S, Mukherjee T, Wang J, Magisetty J, Kolesnick R, Pendurthi UR, Rao LVM. Factor VIIa releases phosphatidylserine-enriched extracellular vesicles from endothelial cells by activating acid sphingomyelinase. J Thromb Haemost 2023; 21:3414-3431. [PMID: 37875382 PMCID: PMC11770839 DOI: 10.1016/j.jtha.2023.08.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 08/05/2023] [Accepted: 08/23/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND Our recent studies showed that activated factor (F) VII (FVIIa) releases extracellular vesicles (EVs) from the endothelium. FVIIa-released EVs were found to be enriched with phosphatidylserine (PS) and contribute to the hemostatic effect of FVIIa in thrombocytopenia and hemophilia. OBJECTIVE To investigate mechanisms by which FVIIa induces EV biogenesis and enriches EVs with PS. METHODS FVIIa activation of acid sphingomyelinase (aSMase) was evaluated by its translocation to the cell surface. The role of aSMase in the biogenesis of FVIIa-induced EVs and their enrichment with PS was investigated using specific siRNAs and inhibitors of aSMase and its downstream metabolites. Wild-type and aSMase-/- mice were injected with a control vehicle or FVIIa. EVs released into circulation were quantified by nanoparticle tracking analysis. EVs hemostatic potential was assessed in a murine thrombocytopenia model. RESULTS FVIIa activation of aSMase is responsible for both the externalization of PS and the release of EVs in endothelial cells. FVIIa-induced aSMase activation led to ceramide generation and de novo expression of transmembrane protein 16F. Inhibitors of ceramidases, sphingosine kinase, or sphingosine-1-phosphate receptor modulator blocked FVIIa-induced expression of transmembrane protein 16F and PS externalization without interfering with FVIIa release of EVs. In vivo, FVIIa release of EVs was markedly impaired in aSMase-/- mice compared with wild-type mice. Administration of a low dose of FVIIa, sufficient to induce EVs release, corrected bleeding associated with thrombocytopenia in wild-type mice but not in aSMase-/- mice. CONCLUSION Our study identifies a novel mechanism by which FVIIa induces PS externalization and releases PS-enriched EVs.
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Affiliation(s)
- Kaushik Das
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | - Tanmoy Mukherjee
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | - Jue Wang
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | - Jhansi Magisetty
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | | | - Usha R Pendurthi
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | - L Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, UT Tyler School of Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
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12
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Sachetto ATA, Mackman N. Monocyte Tissue Factor Expression: Lipopolysaccharide Induction and Roles in Pathological Activation of Coagulation. Thromb Haemost 2023; 123:1017-1033. [PMID: 37168007 PMCID: PMC10615589 DOI: 10.1055/a-2091-7006] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 05/08/2023] [Indexed: 05/13/2023]
Abstract
The coagulation system is a part of the mammalian host defense system. Pathogens and pathogen components, such as bacterial lipopolysaccharide (LPS), induce tissue factor (TF) expression in circulating monocytes that then activates the coagulation protease cascade. Formation of a clot limits dissemination of pathogens, enhances the recruitment of immune cells, and facilitates killing of pathogens. However, excessive activation of coagulation can lead to thrombosis. Here, we review studies on the mechanism of LPS induction of TF expression in monocytes and its contribution to thrombosis and disseminated intravascular coagulation. Binding of LPS to Toll-like receptor 4 on monocytes induces a transient expression of TF that involves activation of intracellular signaling pathways and binding of various transcription factors, such as c-rel/p65 and c-Fos/c-Jun, to the TF promoter. Inhibition of TF in endotoxemia and sepsis models reduces activation of coagulation and improves survival. Studies with endotoxemic mice showed that hematopoietic cells and myeloid cells play major roles in the activation of coagulation. Monocyte TF expression is also increased after surgery. Activated monocytes release TF-positive extracellular vesicles (EVs) and levels of circulating TF-positive EVs are increased in endotoxemic mice and in patients with sepsis. More recently, it was shown that inflammasomes contribute to the induction of TF expression and activation of coagulation in endotoxemic mice. Taken together, these studies indicate that monocyte TF plays a major role in activation of coagulation. Selective inhibition of monocyte TF expression may reduce pathologic activation of coagulation in sepsis and other diseases without affecting hemostasis.
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Affiliation(s)
- Ana T. A. Sachetto
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
| | - Nigel Mackman
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
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13
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Wu Z, Xiao Y, Wang Y. Portal vein thrombosis in liver cirrhosis: An updated overview. PORTAL HYPERTENSION & CIRRHOSIS 2023; 2:78-91. [DOI: 10.1002/poh2.46] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/11/2023] [Indexed: 01/03/2025]
Abstract
AbstractPortal vein thrombosis (PVT) is a frequent and severe complication in patients with cirrhosis; however, the pathophysiology of PVT needs to be better clarified. There are few significant predictive factors in clinical practice, and the impact of PVT on cirrhosis progression and its complications, such as gastrointestinal bleeding, hepatic encephalopathy, and hepatorenal syndrome, remains uncertain. In recent years, the understanding of the mechanisms of PVT has become more profound with the publication of related literature. Therefore, in this review, we aim to summarize the advanced progress in the epidemiology, hazards, risk factors, diagnosis and classification, and treatment of PVT to provide insight into clinical management.
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Affiliation(s)
- Zhinian Wu
- Department of Infectious Diseases The Third Affiliated Hospital of Hebei Medical University Shijiazhuang Hebei China
| | - Ying Xiao
- Department of Infectious Diseases The Third Affiliated Hospital of Hebei Medical University Shijiazhuang Hebei China
| | - Yadong Wang
- Department of Infectious Diseases The Third Affiliated Hospital of Hebei Medical University Shijiazhuang Hebei China
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14
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Maneta E, Aivalioti E, Tual-Chalot S, Emini Veseli B, Gatsiou A, Stamatelopoulos K, Stellos K. Endothelial dysfunction and immunothrombosis in sepsis. Front Immunol 2023; 14:1144229. [PMID: 37081895 PMCID: PMC10110956 DOI: 10.3389/fimmu.2023.1144229] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 03/13/2023] [Indexed: 04/07/2023] Open
Abstract
Sepsis is a life-threatening clinical syndrome characterized by multiorgan dysfunction caused by a dysregulated or over-reactive host response to infection. During sepsis, the coagulation cascade is triggered by activated cells of the innate immune system, such as neutrophils and monocytes, resulting in clot formation mainly in the microcirculation, a process known as immunothrombosis. Although this process aims to protect the host through inhibition of the pathogen’s dissemination and survival, endothelial dysfunction and microthrombotic complications can rapidly lead to multiple organ dysfunction. The development of treatments targeting endothelial innate immune responses and immunothrombosis could be of great significance for reducing morbidity and mortality in patients with sepsis. Medications modifying cell-specific immune responses or inhibiting platelet–endothelial interaction or platelet activation have been proposed. Herein, we discuss the underlying mechanisms of organ-specific endothelial dysfunction and immunothrombosis in sepsis and its complications, while highlighting the recent advances in the development of new therapeutic approaches aiming at improving the short- or long-term prognosis in sepsis.
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Affiliation(s)
- Eleni Maneta
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens Medical School, Athens, Greece
- *Correspondence: Eleni Maneta, ; Konstantinos Stellos, ;
| | - Evmorfia Aivalioti
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Simon Tual-Chalot
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Besa Emini Veseli
- Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Aikaterini Gatsiou
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Kimon Stamatelopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens Medical School, Athens, Greece
- Translational and Clinical Research Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Konstantinos Stellos
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
- Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany
- Department of Cardiology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
- *Correspondence: Eleni Maneta, ; Konstantinos Stellos, ;
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15
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Liu R, Duan T, Yu L, Tang Y, Liu S, Wang C, Fang WJ. Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis. Cardiovasc Diabetol 2023; 22:25. [PMID: 36732747 PMCID: PMC9896821 DOI: 10.1186/s12933-023-01747-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/18/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Increased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis. METHODS AND RESULTS We used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg-1 d-1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L-1) + palmitic acid (PA, 100 μmol L-1) or C16 ceramide (CER, 20 μmol L-1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated. CONCLUSIONS These results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.
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Affiliation(s)
- Ruijiao Liu
- grid.431010.7Department of Pharmacy, The Third Xiangya Hospital of Central South University, 138#Tong Zi PoRoad, Changsha, 410013 Hunan China
| | - Tengfei Duan
- grid.431010.7Department of Pharmacy, The Third Xiangya Hospital of Central South University, 138#Tong Zi PoRoad, Changsha, 410013 Hunan China
| | - Li Yu
- grid.452708.c0000 0004 1803 0208Department of Ultrasound Diagnosis, The Second Xiangya Hospital of Central South University, Changsha, 410013 Hunan China
| | - Yongzhong Tang
- grid.431010.7Department of Anesthesiology, The Third Xiangya Hospital of Central South University, Changsha, 410013 Hunan China
| | - Shikun Liu
- grid.431010.7Department of Pharmacy, The Third Xiangya Hospital of Central South University, 138#Tong Zi PoRoad, Changsha, 410013 Hunan China
| | - Chunjiang Wang
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, 138#Tong Zi PoRoad, Changsha, 410013, Hunan, China.
| | - Wei-Jin Fang
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, 138#Tong Zi PoRoad, Changsha, 410013, Hunan, China.
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16
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Wang J, Keshava S, Das K, Kolesnick R, Jiang XC, Pendurthi UR, Rao LVM. Alterations to Sphingomyelin Metabolism Affect Hemostasis and Thrombosis. Arterioscler Thromb Vasc Biol 2023; 43:64-78. [PMID: 36412194 PMCID: PMC9762718 DOI: 10.1161/atvbaha.122.318443] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Our recent studies suggest that sphingomyelin levels in the plasma membrane influence TF (tissue factor) procoagulant activity. The current study was performed to investigate how alterations to sphingomyelin metabolic pathway would affect TF procoagulant activity and thereby affect hemostatic and thrombotic processes. METHODS Macrophages and endothelial cells were transfected with specific siRNAs or infected with adenoviral vectors to alter sphingomyelin levels in the membrane. TF activity was measured in factor X activation assay. Saphenous vein incision-induced bleeding and the inferior vena cava ligation-induced flow restriction mouse models were used to evaluate hemostasis and thrombosis, respectively. RESULTS Overexpression of SMS (sphingomyelin synthase) 1 or SMS2 in human monocyte-derived macrophages suppresses ATP-stimulated TF procoagulant activity, whereas silencing SMS1 or SMS2 increases the basal cell surface TF activity to the same level as of ATP-decrypted TF activity. Consistent with the concept that sphingomyelin metabolism influences TF procoagulant activity, silencing of acid sphingomyelinase or neutral sphingomyelinase 2 or 3 attenuates ATP-induced enhanced TF procoagulant activity in macrophages and endothelial cells. Niemann-Pick disease fibroblasts with a higher concentration of sphingomyelin exhibited lower TF activity compared with wild-type fibroblasts. In vivo studies revealed that LPS+ATP-induced TF activity and thrombin generation were attenuated in ASMase-/- mice, while their levels were increased in SMS2-/- mice. Further studies revealed that acid sphingomyelinase deficiency leads to impaired hemostasis, whereas SMS2 deficiency increases thrombotic risk. CONCLUSIONS Overall, our data indicate that alterations in sphingomyelin metabolism would influence TF procoagulant activity and affect hemostatic and thrombotic processes.
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Affiliation(s)
- Jue Wang
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler (J.W., S.K., K.D., U.R.P., L.V.M.R.)
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler (J.W., S.K., K.D., U.R.P., L.V.M.R.)
| | - Kaushik Das
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler (J.W., S.K., K.D., U.R.P., L.V.M.R.)
| | | | | | - Usha R Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler (J.W., S.K., K.D., U.R.P., L.V.M.R.)
| | - L Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler (J.W., S.K., K.D., U.R.P., L.V.M.R.)
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Abstract
The need for a more precise test that replicates the in vivo hemostatic conditions is increasingly being recognized. Up to now, the thrombin generation assay (TGA) has become the most reliable approach to evaluate the status of coagulation activation. The clinical potential for the TGA is most promising in the prediction of venous thromboembolism recurrence. However, there is currently an urgent need for a standardized global test that can reliably detect, predict and monitor coagulation disorders in both clinical and experimental studies. We have recently modified the TGA to analyze not only tissue factor-driven coagulation, but the intrinsic coagulation pathway as well. In the present review, we discuss different TG tests, emphasizing the requirement for a better understanding of the evaluation of distinct coagulation pathways using this technique, as well as the standardization and clinical validation.
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18
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Tissue factor in cancer-associated thromboembolism: possible mechanisms and clinical applications. Br J Cancer 2022; 127:2099-2107. [PMID: 36097177 PMCID: PMC9467428 DOI: 10.1038/s41416-022-01968-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/29/2023] Open
Abstract
Venous and arterial thromboses, called as cancer-associated thromboembolism (CAT), are common complications in cancer patients that are associated with high mortality. The cell-surface glycoprotein tissue factor (TF) initiates the extrinsic blood coagulation cascade. TF is overexpressed in cancer cells and is a component of extracellular vesicles (EVs). Shedding of TF+EVs from cancer cells followed by association with coagulation factor VII (fVII) can trigger the blood coagulation cascade, followed by cancer-associated venous thromboembolism in some cancer types. Secretion of TF is controlled by multiple mechanisms of TF+EV biogenesis. The procoagulant function of TF is regulated via its conformational change. Thus, multiple steps participate in the elevation of plasma procoagulant activity. Whether cancer cell-derived TF is maximally active in the blood is unclear. Numerous mechanisms other than TF+EVs have been proposed as possible causes of CAT. In this review, we focused on a wide variety of regulatory and shedding mechanisms for TF, including the effect of SARS-CoV-2, to provide a broad overview for its role in CAT. Furthermore, we present the current technical issues in studying the relationship between CAT and TF.
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Immunothrombosis and the molecular control of tissue factor by pyroptosis: prospects for new anticoagulants. Biochem J 2022; 479:731-750. [PMID: 35344028 DOI: 10.1042/bcj20210522] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023]
Abstract
The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional 'waterfall' model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.
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20
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A simple and rapid method for extraction and measurement of circulating sphingolipids using LC-MS/MS: a targeted lipidomic analysis. Anal Bioanal Chem 2022; 414:2041-2054. [PMID: 35066602 DOI: 10.1007/s00216-021-03853-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/19/2021] [Accepted: 12/14/2021] [Indexed: 01/28/2023]
Abstract
Sphingolipids are a class of lipids with high structural diversity and biological pleiotropy. Mounting evidence supports a role for sphingolipids in regulating pathophysiology of cardiometabolic diseases, and they have been proposed as potential cardiometabolic biomarkers. Current methods for quantifying sphingolipids require laborious pretreatment and relatively large sample volumes, and cover limited species, hindering their application in epidemiological studies. Herein, we applied a time-, labor-, and sample-saving protocol simply using methanol for plasma sphingolipid extraction. It was compared with classical liquid-liquid extraction methods and showed significant advantages in terms of simplicity, sphingolipid coverage, and sample volume. By coupling the protocol with liquid chromatography using a wide-span mobile phase polarity parameter and tandem mass spectrometry operated in dynamic multiple reaction monitoring mode, 37 sphingolipids from 8 classes (sphingoid base, sphingoid base phosphate, ceramide-1-phosphate, lactosylceramide, hexosylceramide, sphingomyelin, ceramide, and dihydroceramide) were quantified within 16 min, using only 10 μL of human plasma. The current method showed good performance in terms of linearity (R2 > 0.99), intra- and interbatch accuracy (70-123%) and precision (RSD < 12%), matrix effect (91-121%), recovery (96-101%), analyte chemical stability (deviation < 19%), and carryover (< 16%). We successfully applied this method to quantify 33 detectable sphingolipids from 579 plasma samples of an epidemiological study within 10 days. The quantified sphingolipid concentrations were comparable with previous studies. Positive associations of ceramide C22:0/C24:0 and their precursors with homeostasis model assessment of insulin resistance suggested that the synthesis of the ceramides might be involved in insulin resistance. This novel method constitutes a simple and rapid approach to quantify circulating sphingolipids for epidemiological studies using targeted lipidomic analysis, which will help elucidate the sphingolipid-regulated pathways underlying cardiometabolic diseases.
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21
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Administration of an Acidic Sphingomyelinase (ASMase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death. Cells 2022; 11:cells11040667. [PMID: 35203316 PMCID: PMC8869983 DOI: 10.3390/cells11040667] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/31/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASMase activity can be influenced by cations, pH, redox, lipids, and other proteins in the cells, and there are many changes in these factors in hypoglycemia. Thus, we expect that ASMase is activated excessively after hypoglycemia. Ceramide is known to cause free radical production, excessive inflammation, calcium dysregulation, and lysosomal injury, resulting in apoptosis and the necrosis of neurons. Imipramine is mainly used in the treatment of depression and certain anxiety disorders, and it is particularly known as an ASMase inhibitor. We hypothesized that imipramine could decrease hippocampal neuronal death by reducing ceramide via the inhibition of ASMase after hypoglycemia. In the present study, we confirmed that the administration of imipramine significantly reduced hypoglycemia-induced neuronal death and improved cognitive function. Therefore, we suggest that imipramine may be a promising therapeutic tool for preventing hypoglycemia-induced neuronal death.
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22
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Jing H, Zuo N, Novakovic VA, Shi J. The Central Role of Extracellular Vesicles in the Mechanisms of Thrombosis in COVID-19 Patients With Cancer and Therapeutic Strategies. Front Cell Dev Biol 2022; 9:792335. [PMID: 35096822 PMCID: PMC8790316 DOI: 10.3389/fcell.2021.792335] [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: 10/10/2021] [Accepted: 12/16/2021] [Indexed: 12/19/2022] Open
Abstract
Cancer patients have increased SARS-CoV-2 susceptibility and are prone to developing severe COVID-19 infections. The incidence of venous thrombosis is approximately 20% in COVID-19 patients with cancer. It has been suggested that thrombus formation has been suggested to correlate with severe clinical manifestations, mortality, and sequelae. In this review, we primarily elaborate on the pathophysiological mechanisms of thrombosis in COVID-19 patients with cancer, emphasize the role of microparticles (MPs) and phosphatidylserine (PS) in coagulation, and propose an antithrombotic strategy. The coagulation mechanisms of COVID-19 and cancer synergistically amplify the coagulation cascade, and collectively promotes pulmonary microvascular occlusion. During systemic coagulation, the virus activates immune cells to release abundant proinflammatory cytokines, referred to as cytokine storm, resulting in the apoptosis of tumor and blood cells and subsequent MPs release. Additionally, we highlight that tumor cells contribute to MPs and coagulation by apoptosis owing to insufficient blood supply. A positive feedback loop of cytokines storm and MPs storm promotes microvascular coagulation storm, leading to microthrombi formation and inadequate blood perfusion. Microthrombi-damaged endothelial cells (ECs), tumor, and blood cells further aggravate the apoptosis of the cells and facilitate MPs storm. PS, especially on MPs, plays a pivotal role in the blood coagulation process, contributing to clot initiation, amplification, and propagation. Since coagulation is a common pathway of COVID-19 and cancer, and associated with mortality, patients would benefit from antithrombotic therapy. The above results lead us to assert that early stage antithrombotic therapy is optimal. This strategy is likely to maintain blood flow patency contributing to viral clearance, attenuating the formation of cytokines and MPs storm, maintaining oxygen saturation, and avoiding the progress of the disease.
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Affiliation(s)
- Haijiao Jing
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Nan Zuo
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Valerie A Novakovic
- Department of Research, VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States
| | - Jialan Shi
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China.,Department of Research, VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States.,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
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23
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The acid sphingomyelinase/ceramide system in COVID-19. Mol Psychiatry 2022; 27:307-314. [PMID: 34608263 PMCID: PMC8488928 DOI: 10.1038/s41380-021-01309-5] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 08/10/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023]
Abstract
Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.
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24
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Mackman N, Grover SP, Antoniak S. Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus. J Thromb Haemost 2021; 19:2652-2658. [PMID: 34418279 PMCID: PMC9770926 DOI: 10.1111/jth.15509] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TF-expressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis.
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Affiliation(s)
- Nigel Mackman
- Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Steven P Grover
- Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Silvio Antoniak
- Department of Pathology and Laboratory Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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25
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Vascular thiol isomerases: Structures, regulatory mechanisms, and inhibitor development. Drug Discov Today 2021; 27:626-635. [PMID: 34757205 DOI: 10.1016/j.drudis.2021.10.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 09/15/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022]
Abstract
Vascular thiol isomerases (VTIs), including PDI, ERp5, ERp57, ERp72, and thioredoxin-related transmembrane protein 1 (TMX1), have important roles in platelet aggregation and thrombosis. Research on VTIs, their substrates in thrombosis, their regulatory mechanisms, and inhibitor development is an emerging and rapidly evolving area in vascular biology. Here, we describe the structures and functions of VTIs, summarize the relationship between the vascular TIs and thrombosis, and focus on the development of VTI inhibitors for antithrombotic applications.
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Bonnet U, Claus B, Schaefer M, Kuhn J, Nyhuis P, Scherbaum N, Brüne M, Wakili V, Juckel G. Impact of Psychiatric and Related Somatic Medications on the Duration and Severity of COVID-19: A Retrospective Explorative Multi-center Study from the German Metropolitan Ruhr-area. PHARMACOPSYCHIATRY 2021; 55:30-39. [PMID: 34530483 DOI: 10.1055/a-1559-3904] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Several psychiatric and somatic medications are assumed to improve COVID-19-symptoms. These include antidepressants, antipsychotics, and anticonvulsants as well as anticoagulants, statins, and renin-angiotensin-aldosterone-system (RAAS)-inhibitors for somatic comorbid conditions. All these agents may reduce the hyperinflammatory response to SARS/CoV-2 or the related negative cardio-cerebrovascular outcomes. METHODS In a retrospective longitudinal, multi-center inpatient study, we sought to explore the influence of psychiatric medications on COVID-19, comprising the period from diagnosing SARS/CoV-2-infection via PCR (nasopharyngeal swab) up to the next 21 days. Ninety-six psychiatric inpatients (mean age [SD] 65.5 (20.1), 54% females) were included. The primary outcome was the COVID-19-duration. Secondary outcomes included symptom severity and the presence of residual symptoms. RESULTS COVID-19-related symptoms emerged in 60 (62.5%) patients, lasting 6.5 days on average. Six (6.3%) 56-95 years old patients died from or with COVID-19. COVID-19-duration and residual symptom-presence (n=22, 18%) were not significantly related to any substance. Respiratory and neuro-psychiatric symptom-load was significantly and negatively related to prescription of antidepressants and anticoagulants, respectively. Fatigue was negatively and positively related to RAAS-inhibitors and proton-pump-inhibitors, respectively. These significant relationships disappeared with p-value adjustment owed to multiple testing. The mean total psychiatric burden was not worsened across the study. DISCUSSION None of the tested medications was significantly associated with the COVID-19-duration and -severity up to the end of post-diagnosing week 3. However, there were a few biologically plausible and promising relationships with antidepressants, anticoagulants, and RAAS-inhibitors before p-value adjustment. These should encourage larger and prospective studies to re-evaluate the influence of somatic and psychiatric routine medications on COVID-19-related health outcomes.
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Affiliation(s)
- Udo Bonnet
- Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen, Essen, Germany.,LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - BenediktBernd Claus
- Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen, Essen, Germany.,PedScience, Datteln, Germany
| | - Martin Schaefer
- Department of Psychiatry, Psychotherapy, Psychoso-matics and Addiction Medicine, Evangelische Kliniken Essen-Mitte, Essen, Germany
| | - Jens Kuhn
- Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Johanniter Hospital Oberhausen, Oberhausen, Germany
| | | | - Norbert Scherbaum
- LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Martin Brüne
- Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany
| | - Velat Wakili
- Department of Psychiatry, Psychotherapy, Psychoso-matics and Addiction Medicine, Evangelische Kliniken Essen-Mitte, Essen, Germany
| | - Georg Juckel
- Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany
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27
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Das K, Keshava S, Ansari SA, Kondreddy V, Esmon CT, Griffin JH, Pendurthi UR, Rao LVM. Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect. Blood 2021; 137:3428-3442. [PMID: 33534910 PMCID: PMC8212509 DOI: 10.1182/blood.2020008417] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 01/11/2021] [Indexed: 12/14/2022] Open
Abstract
Recombinant factor FVIIa (rFVIIa) is used as a hemostatic agent to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients. Our recent studies showed that FVIIa binds endothelial cell protein C receptor (EPCR) and induces protease-activated receptor 1 (PAR1)-mediated biased signaling. The importance of FVIIa-EPCR-PAR1-mediated signaling in hemostasis is unknown. In the present study, we show that FVIIa induces the release of extracellular vesicles (EVs) from endothelial cells both in vitro and in vivo. Silencing of EPCR or PAR1 in endothelial cells blocked the FVIIa-induced generation of EVs. Consistent with these data, FVIIa treatment enhanced the release of EVs from murine brain endothelial cells isolated from wild-type (WT), EPCR-overexpressing, and PAR1-R46Q-mutant mice, but not EPCR-deficient or PAR1-R41Q-mutant mice. In vivo studies revealed that administration of FVIIa to WT, EPCR-overexpressing, and PAR1-R46Q-mutant mice, but not EPCR-deficient or PAR1-R41Q-mutant mice, increased the number of circulating EVs. EVs released in response to FVIIa treatment exhibit enhanced procoagulant activity. Infusion of FVIIa-generated EVs and not control EVs to platelet-depleted mice increased thrombin generation at the site of injury and reduced blood loss. Administration of FVIIa-generated EVs or generation of EVs endogenously by administering FVIIa augmented the hemostatic effect of FVIIa. Overall, our data reveal that FVIIa treatment, through FVIIa-EPCR-PAR1 signaling, releases EVs from the endothelium into the circulation, and these EVs contribute to the hemostatic effect of FVIIa.
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Affiliation(s)
- Kaushik Das
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX
| | - Shabbir A Ansari
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX
| | - Vijay Kondreddy
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX
| | - Charles T Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK; and
| | - John H Griffin
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA
| | - Usha R Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX
| | - L Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX
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28
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Novel mechanism regulating tissue factor activity. Blood 2021; 138:289-291. [PMID: 34323941 PMCID: PMC8320428 DOI: 10.1182/blood.2021012459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 05/25/2021] [Indexed: 11/30/2022] Open
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SARS-CoV-2 infection induces the activation of tissue factor-mediated coagulation by activation of acid sphingomyelinase. Blood 2021; 138:344-349. [PMID: 34075401 PMCID: PMC8172270 DOI: 10.1182/blood.2021010685] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/05/2021] [Indexed: 01/08/2023] Open
Abstract
SARS-CoV-2 infection is associated with the hypercoagulable state. Tissue factor (TF) is the primary cellular initiator of coagulation. Most of the TF expressed on cell surfaces remains cryptic. Sphingomyelin (SM) is responsible for maintaining TF in the encrypted state, and hydrolysis of SM by acid sphingomyelinase (ASMase) increases TF activity. ASMase was shown to play a role in virus infection biology. In the present study, we investigated the role of ASMase in SARS-CoV-2 infection-induced TF procoagulant activity. Infection of human monocyte-derived macrophages (MDMs) with SARs-CoV-2 spike protein pseudovirus (SARS-CoV-2-SP-PV) markedly increased TF procoagulant activity at the cell surface and released TF+ extracellular vesicles (EVs). The pseudovirus infection did not increase either TF protein expression or phosphatidylserine externalization. SARS-CoV-2-SP-PV infection induced the translocation of ASMase to the outer leaflet of the plasma membrane, which led to the hydrolysis of SM in the membrane. Pharmacological inhibitors or genetic silencing of ASMase attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Inhibition of SARS-CoV-2 receptor, angiotensin-converting enzyme-2, attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Overall, our data suggest that SARS-CoV-2 infection activates the coagulation by decrypting TF through activation of ASMase. Our data suggest that the FDA-approved functional inhibitors of ASMase may help treat hypercoagulability in COVID-19 patients.
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30
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Xiang H, Jin S, Tan F, Xu Y, Lu Y, Wu T. Physiological functions and therapeutic applications of neutral sphingomyelinase and acid sphingomyelinase. Biomed Pharmacother 2021; 139:111610. [PMID: 33957567 DOI: 10.1016/j.biopha.2021.111610] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/05/2021] [Accepted: 04/12/2021] [Indexed: 11/15/2022] Open
Abstract
Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.
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Affiliation(s)
- Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengjie Jin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fenglang Tan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifan Xu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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31
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Jiang J, Shi Y, Cao J, Lu Y, Sun G, Yang J. Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation. Lipids Health Dis 2021; 20:19. [PMID: 33612104 PMCID: PMC7897379 DOI: 10.1186/s12944-021-01446-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 02/08/2021] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND This study aimed to explore the effects of ceramide (Cer) on NLRP3 inflammasome activation and their underlying mechanisms. METHODS Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells and THP-1 macrophages was used as an in vitro model of inflammation. Western blotting and real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were measured by ELISA. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content. RESULTS Imipramine, a well-known inhibitor of ASM, significantly inhibited LPS/ATP-induced activity of ASM and the consequent accumulation of Cer. Additionally, imipramine suppressed the LPS/ATP-induced expression of thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β, and IL-18 at the protein and mRNA level. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced activation of TXNIP/NLRP3 inflammasome but did not affect LPS/ATP-induced ASM activation and Cer formation. TXNIP siRNA and verapamil inhibited C2-Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome. In addition, the pretreatment of cells with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked Cer-induced upregulation of nuclear factor-κB (NF-κB) activity, TXNIP expression, and NLRP3 inflammasome activation. Inhibition of NF-κB activation by SN50 prevented Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome but did not affect CD36 expression. CONCLUSION This study demonstrated that the ASM/Cer/TXNIP signaling pathway is involved in NLRP3 inflammasome activation. The results documented that the CD36-dependent NF-κB-TXNIP signaling pathway plays an essential role in the Cer-induced activation of NLRP3 inflammasomes in macrophages.
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Affiliation(s)
- Jianjun Jiang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Yining Shi
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China
| | - Jiyu Cao
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Youjin Lu
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China
| | - Gengyun Sun
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China.
| | - Jin Yang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China.
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Rosas M, Slatter DA, Obaji SG, Webber JP, Alvarez-Jarreta J, Thomas CP, Aldrovandi M, Tyrrell VJ, Jenkins PV, O’Donnell VB, Collins PW. The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles. PLoS One 2020; 15:e0240189. [PMID: 33031441 PMCID: PMC7544082 DOI: 10.1371/journal.pone.0240189] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023] Open
Abstract
Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6-9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane.
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Affiliation(s)
- Marcela Rosas
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - David A. Slatter
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Samya G. Obaji
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Jason P. Webber
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jorge Alvarez-Jarreta
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Christopher P. Thomas
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom
| | - Maceler Aldrovandi
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Victoria J. Tyrrell
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Peter V. Jenkins
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Valerie B. O’Donnell
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
| | - Peter W. Collins
- Institute of Infection and Immunity, and Systems Immunity Research Institute, School of Medicine Cardiff University, Cardiff, United Kingdom
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Vieira ML, Herwald H, Nascimento ALTO. The interplay between host haemostatic systems and Leptospira spp. infections. Crit Rev Microbiol 2020; 46:121-135. [PMID: 32141788 DOI: 10.1080/1040841x.2020.1735299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hemostasis is a defence mechanism that protects the integrity of the vascular system and is comprised of the coagulation cascade, fibrinolysis, platelet aggregation, and vascular endothelium. Besides the primary function in preserving the vascular integrity, the haemostatic system cooperates with immune and inflammatory processes to eliminate invading pathogens during microbial infections. Under pathological manifestations, hemostasis must therefore interact in a coordinated manner with inflammatory responses and immune reactions. Several pathogens can modulate these host-derived countermeasures by specifically targeting certain haemostatic components for their own benefit. Thus, the ability to modulate host defence systems has to be considered as an essential bacterial virulence mechanism. Complications that bacterial pathogens can induce are therefore often the consequence of evoked host responses. A comprehensive understanding of the molecular mechanisms triggered in infectious processes may help to develop prophylactic methods and novel therapies for the patients suffering from a particular infectious disease. This review aims to provide a critical updated compiling of recent studies on how the pathogenic Leptospira can interact with and manipulate the host haemostatic systems and the consequences for leptospirosis pathogenesis.
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Affiliation(s)
- Monica L Vieira
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Heiko Herwald
- Department of Clinical Sciences, Lund, Division of Infection Medicine, Lund University, Lund, Sweden
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