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SUZUKI K. Thrombomodulin: A key regulator of intravascular blood coagulation, fibrinolysis, and inflammation, and a treatment for disseminated intravascular coagulation. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2025; 101:75-97. [PMID: 39694492 PMCID: PMC11893221 DOI: 10.2183/pjab.101.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024]
Abstract
Thrombomodulin (TM) is an important regulator of intravascular blood coagulation, fibrinolysis, and inflammation. TM inhibits the procoagulant and proinflammatory activities of thrombin and promotes the thrombin-induced activation of protein C (PC) bound to the endothelial PC receptor (EPCR). Activated PC (APC) inactivates coagulation factors Va and VIIIa, thereby inhibiting blood clotting. APC bound to EPCR exerts anti-inflammatory and cytoprotective effects on vascular endothelial cells. TM promotes the activation of thrombin-activatable fibrinolysis inhibitor, and also protects cells in blood vessels from inflammation caused by pathogen-associated and damaged cell-associated molecules. Excessive anticoagulant, fibrinolytic, anti-inflammatory, and tissue regenerative effects in the TM-PC pathway are controlled by PC inhibitor. A recombinant TM drug (TM), a soluble form of natural TM developed from the cloned human TM gene, has been evaluated for efficacy in many clinical trials and approved as a treatment for disseminated intravascular coagulation (DIC) caused by diseases such as sepsis, solid tumors, hematopoietic tumors, and trauma. It is currently widely used to treat DIC in Japan.
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Affiliation(s)
- Koji SUZUKI
- Professor, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
- Vice President for Research, Suzuka University of Medical Science, Suzuka, Mie, Japan
- Professor Emeritus, Mie University, Tsu, Mie, Japan
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Zhu HJ, Dong HY, Qian CR, Ma QQ, Li RS, Fu M, He Y, Lu P. Intact N-glycopeptide analysis of human platelets reveals a Glycostructure important for platelet function. Glycobiology 2025; 35:cwae088. [PMID: 39846809 DOI: 10.1093/glycob/cwae088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/11/2024] [Accepted: 10/30/2024] [Indexed: 01/24/2025] Open
Abstract
Glycosylation is an important posttranslational modification in platelets, and the glycosylation pattern is critical for platelet function. To date, the exploration of the roles of various glycoforms in specific platelet functions is largely lacking. In this study, a global analysis of intact N-glycopeptides in human platelets was performed to map all the glycopeptides, glycosites and glycans of platelets. The glycopeptides were enriched by the ZIC- hydrophilic interaction chromatography method and then analyzed by Liquid Chromatography-Tandem Mass Spectrometry analysis. A total of 1,425 intact glycopeptides belonging to 190 N-glycoproteins from human platelets were identified. Moreover, 358 glycans modified 328 glycosites from those glycoproteins. Functional analysis revealed that these glycoproteins are involved mainly in processes and pathways related to platelet adhesion. Among the proteins in these adhesion-related annotations, von Willebrand factor, thrombospondin 1and glycoprotein V were found to contain a possible Lewis y structure, and this finding was further verified by immunoprecipitation assays. As a blood group-related antigen, Lewis y was previously reported to exist in human platelets, but its function remains unclear. Since the glycosylation of von Willebrand factor, thrombospondin 1 and glycoprotein V is involved in platelet-collagen adhesion, the importance of Lewis y on platelet function was evaluated by adhesion assays, which demonstrated that the blockade of Lewis y on platelets decreased the adhesion of platelets to collagen I under both static and flow conditions.
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Affiliation(s)
- Hui-Jun Zhu
- Institute of Blood Transfusion, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
| | - Hang-Yan Dong
- PhoemeCare Biotech Co., Ltd, 10 Tianxiu Road, Beijing 100091, China
| | - Cheng-Rui Qian
- Institute of Blood Transfusion, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
| | - Qin-Qin Ma
- Institute of Blood Transfusion, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
| | - Rui-Shu Li
- Institute of Blood Transfusion, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
| | - Min Fu
- Institute of Blood Transfusion, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
| | - Ye He
- Donor Service Department, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
| | - Ping Lu
- Institute of Blood Transfusion, Shanghai Blood Center, 1191 Hongqiao Road, Shanghai 200051, China
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Xiao X, Wang J, Ma J, Peng X, Wu S, Chen X, Lu H, Tan C, Fang L, Xiao S. Interferon lambda 4 is a gut antimicrobial protein. Proc Natl Acad Sci U S A 2024; 121:e2409684121. [PMID: 39436662 PMCID: PMC11536128 DOI: 10.1073/pnas.2409684121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/11/2024] [Indexed: 10/23/2024] Open
Abstract
To withstand complex microbial challenges, the mammalian gut largely depends on the secretion of diverse antimicrobial proteins. Type III interferons (IFNλs) are ordinarily considered inducible antiviral cytokines involved in intestinal immunity. Unlike other IFNλs, we found that newly identified IFNλ4 is an intestinal antibacterial protein. Large amounts of natural IFNλ4 are present in the secretory layer of the intestinal tracts of healthy piglets, which suggests that IFNλ4 is in direct physiological contact with microbial pathogens. We also identified two biochemical functions of mammalian IFNλ4, the induction of bacterial agglutination and direct microbial killing, which are not functions of the other IFNλs. Further mechanistic investigations revealed that after binding to the carbohydrate fraction of lipopolysaccharide, mammalian IFNλ4 self-assembles into bacteria-surrounding nanoparticles that agglutinate bacteria, and that its unique cationic amphiphilic molecular structure facilitates the destruction of bacterial membranes. Our data reveal features of IFNλ4 distinct from those of previously reported IFNλs and suggest that noncanonical IFNλ4 is deeply involved in intestinal immunity, beyond simply cytokine signaling.
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Affiliation(s)
- Xun Xiao
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Jinting Wang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Jun Ma
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Xuan Peng
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Shengqiang Wu
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Xiaolei Chen
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Hao Lu
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Chen Tan
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Liurong Fang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Shaobo Xiao
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
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Hong YK, Cheng TL, Hsu CK, Lee FT, Chang BI, Wang KC, Chang LY, Wu HL, Lai CH. Regulation of matrix reloading by tumor endothelial marker 1 protects against abdominal aortic aneurysm. Int J Biol Sci 2024; 20:3691-3709. [PMID: 39113704 PMCID: PMC11302889 DOI: 10.7150/ijbs.93526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 06/23/2024] [Indexed: 08/10/2024] Open
Abstract
Tumor endothelial marker 1 (TEM1), an activated mesenchymal cell marker, is implicated in tissue remodeling and repair. Herein, we investigated the role and therapeutic implications of TEM1 in abdominal aortic aneurysm (AAA), a potentially life-threatening aortic disease characterized by vascular inflammation and matrix turnover. Characterization of human AAA revealed increased TEM1 expression derived mainly from medial vascular smooth muscle cells (VSMCs) and adventitial fibroblasts. Bioinformatics analysis demonstrated the association between TEM1-expressing VSMCs and fibroblasts and collagen gene expression. Consistently, collagen content and TEM1 expressed by VSMCs and fibroblasts were increased during CaCl2-induced AAA formation in mice. TEM1 silencing in VSMCs and fibroblasts inhibited transforming growth factor-β1-induced phenotypic change, SMAD2 phosphorylation, and COL1A1 gene expression. Also, Tem1 deficiency reduced collagen synthesis and exacerbated CaCl2-induced AAA formation in mice without disturbing elastin destruction and inflammatory responses. In contrast, rTEM1 promoted phenotypic change and COL1A1 gene expression through SMAD2 phosphorylation in VSMCs and fibroblasts. Treatment with rTEM1 enhanced collagen synthesis, attenuated elastin fragmentation, and inhibited CaCl2-induced and angiotensin II-infused AAA formation. In summary, TEM1 in resident stromal cells regulates collagen synthesis to counteract aortic wall failure during AAA formation. Matrix integrity restored by rTEM1 treatment may hold therapeutic potential against AAA.
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Affiliation(s)
- Yi-Kai Hong
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Lin Cheng
- Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Orthopedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- College of Professional Studies, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Fang-Tzu Lee
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Bi-Ing Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Kuan-Chieh Wang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Lan-Yun Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chao-Han Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Giri H, Biswas I, Rezaie AR. Thrombomodulin: a multifunctional receptor modulating the endothelial quiescence. J Thromb Haemost 2024; 22:905-914. [PMID: 38266676 PMCID: PMC10960680 DOI: 10.1016/j.jtha.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/01/2024] [Accepted: 01/05/2024] [Indexed: 01/26/2024]
Abstract
Thrombomodulin (TM) is a type 1 receptor best known for its function as an anticoagulant cofactor for thrombin activation of protein C on the surface of vascular endothelial cells. In addition to its anticoagulant cofactor function, TM also regulates fibrinolysis, complement, and inflammatory pathways. TM is a multidomain receptor protein with a lectin-like domain at its N-terminus that has been shown to exhibit direct anti-inflammatory functions. This domain is followed by 6 epidermal growth factor-like domains that support the interaction of TM with thrombin. The interaction inhibits the procoagulant function of thrombin and enables the protease to regulate the anticoagulant and fibrinolytic pathways by activating protein C and thrombin-activatable fibrinolysis inhibitor. TM has a Thr/Ser-rich region immediately above the membrane surface that harbors chondroitin sulfate glycosaminoglycans, and this region is followed by a single-spanning transmembrane and a C-terminal cytoplasmic domain. The structure and physiological function of the extracellular domains of TM have been extensively studied, and numerous excellent review articles have been published. However, the physiological function of the cytoplasmic domain of TM has remained poorly understood. Recent data from our laboratory suggest that intracellular signaling by the cytoplasmic domain of TM plays key roles in maintaining quiescence by modulating phosphatase and tensin homolog signaling in endothelial cells. This article briefly reviews the structure and function of extracellular domains of TM and focuses on the mechanism and possible physiological importance of the cytoplasmic domain of TM in modulating phosphatase and tensin homolog signaling in endothelial cells.
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Affiliation(s)
- Hemant Giri
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Indranil Biswas
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Alireza R Rezaie
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
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Benedet PO, Safikhan NS, Pereira MJ, Lum BM, Botezelli JD, Kuo CH, Wu HL, Craddock BP, Miller WT, Eriksson JW, Yue JTY, Conway EM. CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation. EBioMedicine 2024; 99:104906. [PMID: 38061240 PMCID: PMC10750038 DOI: 10.1016/j.ebiom.2023.104906] [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: 07/15/2023] [Revised: 11/24/2023] [Accepted: 11/25/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. METHODS Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. FINDINGS Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. INTERPRETATION Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. FUNDING Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.
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Affiliation(s)
- Patricia O Benedet
- Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Nooshin S Safikhan
- Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Maria J Pereira
- Department of Medical Sciences, Clinical Diabetology & Metabolism, Uppsala University, Sweden
| | - Bryan M Lum
- Department of Physiology, Alberta Diabetes Institute and Group on Molecular and Cell Biology of Lipids, University of Alberta, Canada
| | - José Diego Botezelli
- Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Barbara P Craddock
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA
| | - W Todd Miller
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA; Veterans Affairs Medical Center, Northport, NY, USA
| | - Jan W Eriksson
- Department of Medical Sciences, Clinical Diabetology & Metabolism, Uppsala University, Sweden
| | - Jessica T Y Yue
- Department of Physiology, Alberta Diabetes Institute and Group on Molecular and Cell Biology of Lipids, University of Alberta, Canada
| | - Edward M Conway
- Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
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Cao B, Jin J, Tang Z, Luo Q, An J, Pang W. Exploring Mechanisms of Houshiheisan in Treating Ischemic Stroke with Network Pharmacology and Independent Cascade Model. Comb Chem High Throughput Screen 2024; 27:959-968. [PMID: 37565556 DOI: 10.2174/1386207326666230810094557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 06/03/2023] [Accepted: 06/21/2023] [Indexed: 08/12/2023]
Abstract
BACKGROUND Houshiheisan (HSHS) has been effective in the treatment of ischemic stroke (IS) for centuries. However, its mechanisms are still underexplored. OBJECTIVE The objective of this study is to identify the active ingredients and mechanisms of HSHS in treating IS. METHODS We searched the main active compounds in HSHS and their potential targets, and key targets related to IS. Based on the common targets of HSHS and IS, we further expanded genes by KEGG database to obtain target genes and related genes, as well as gene interactions in the form of A→B, and then constructed a directed network including traditional Chinese medicines (TCMs), active compounds and genes. Finally, based on enrichment analysis, independent cascade (IC) model, and molecular docking, we explored the mechanisms of HSHS in treating IS. RESULTS A directed network with 6,348 nodes and 64,996 edges was constructed. The enrichment analysis suggested that the AGE pathway, glucose metabolic pathway, lipid metabolic pathway, and inflammation pathway played critical roles in the treatment of IS by HSHS. Furthermore, the gene ontologies (GOs) of three monarch drugs in HSHS mainly involved cellular response to chemical stress, blood coagulation, hemostasis, positive regulation of MAPK cascade, and regulation of inflammatory response. Several candidate drug molecules were identified by molecular docking. CONCLUSION This study advocated potential drug development with targets in the AGE signaling pathway, with emphasis on neuroprotective, anti-inflammatory, and anti-apoptotic functions. The molecular docking simulation indicated that the ligand-target combination selection method based on the IC model was effective and reliable.
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Affiliation(s)
- Bo Cao
- Department of Health Informatics and Management, School of Health Humanities, Peking University, Beijing, 100191, China
| | - Jiao Jin
- School of Statistics, Beijing Normal University, Beijing, 100875, China
| | - Zhiyu Tang
- Department of Health Informatics and Management, School of Health Humanities, Peking University, Beijing, 100191, China
| | - Qiong Luo
- School of Nursing, Peking University, Beijing, 100191, China
| | - Jinbing An
- Department of Health Informatics and Management, School of Health Humanities, Peking University, Beijing, 100191, China
| | - Wei Pang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
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Guo X, Shen P, Shao R, Hong T, Liu W, Shen Y, Su F, Wang Q, He B. Efferocytosis-inspired nanodrug treats sepsis by alleviating inflammation and secondary immunosuppression. Biomed Mater 2023; 18:055020. [PMID: 37567216 DOI: 10.1088/1748-605x/acef9a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 08/10/2023] [Indexed: 08/13/2023]
Abstract
Uncontrolled inflammation storm induced by sepsis may lead to severe organ dysfunction and secondary immunosuppression, which is one of the main reasons for high mortality and prolonged hospitalization of septic patients. However, there is a lack of effective treatments for it at present. Here, we report an efferocytosis-inspired nanodrug (BCN@M) to treat sepsis and secondary immunosuppression via regulating the macrophage function. Bioactive molecular curcumin was loaded with bovine serum albumin and then coated with the damaged erythrocyte membrane derived from septic mice. It was found that the septic erythrocytes promoted the efferocytosis signal and BCN@M uptake efficiency by macrophages. The well-constructed BCN@M nanodrug reduced the hyperinflammation in sepsis and restored the bacterial clearance ability of macrophage in the secondary immunosuppression state. This study highlights BCN@M as an efferocytosis-inspired nanodrug to alleviate hyperinflammation and secondary immunosuppression of sepsis.
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Affiliation(s)
- Xiaoyu Guo
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Centre for Cardiopulmonary Translational Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Department of Anesthesiology, Huadong Hospital affiliated to Fudan University, Shanghai, People's Republic of China
| | - Peiming Shen
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Rongjiao Shao
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Centre for Cardiopulmonary Translational Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Ting Hong
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Department of Anesthesiology, Huadong Hospital affiliated to Fudan University, Shanghai, People's Republic of China
| | - Weizhuo Liu
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Centre for Cardiopulmonary Translational Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yi Shen
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Centre for Cardiopulmonary Translational Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Fan Su
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Centre for Cardiopulmonary Translational Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Qinlan Wang
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Bin He
- Department of Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Huang SE, Kuo CH, Shiao SY, Shen CR, Lee FT, Chang BI, Hsu JH, Wu HL, Yeh JL, Lai CH. Soluble CD93 lectin-like domain sequesters HMGB1 to ameliorate inflammatory diseases. Theranostics 2023; 13:4059-4078. [PMID: 37554277 PMCID: PMC10405849 DOI: 10.7150/thno.84935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/06/2023] [Indexed: 08/10/2023] Open
Abstract
Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (sCD93) upon inflammatory stimuli. sCD93 effectively enhances apoptotic cell clearance and has been proposed as an inflammatory disease biomarker. The function of sCD93 involved directly in inflammation remains to be determined. Herein, we attempted to examine the hypothesis that sCD93 might sequester proinflammatory high-mobility group box 1 protein (HMGB1), exerting anti-inflammatory properties. Methods: Different forms of soluble recombinant human CD93 (rCD93) were prepared by a mammalian protein expression system. rCD93-HMGB1 interaction was assessed using co-immunoprecipitation and solid-phase binding assays. Effects of soluble rCD93 were evaluated in HMGB1-induced macrophage and vascular smooth muscle cells (VSMC) activation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, CaCl2-induced and angiotensin II-infused abdominal aortic aneurysm (AAA) formation and ovariectomized-induced osteoporosis in mice. Results: Protein binding studies revealed that soluble rCD93, via the lectin-like domain (D1), can bind to HMGB1 and intercept HMGB1-receptor interaction. Soluble rCD93 containing D1 inhibited HMGB1-induced proinflammatory cytokine production and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation in macrophages and VSMCs, thereby attenuating CaCl2-induced and angiotensin II-infused AAA models. During osteoclastogenesis, RANKL stimulated HMGB1 secretion that promoted RANKL-induced osteoclastogenesis in return. Soluble rCD93 containing D1 impeded RANKL-induced osteoclastogenic marker gene expression and intracellular MAPK/NF-κB signaling, thereby mitigating ovariectomized-induced osteoporosis. Conclusion: These findings demonstrate the therapeutic potential of soluble recombinant CD93 containing D1 in inflammatory diseases. Our study highlights a novel anti-inflammatory mechanism, i.e., sequestration of HMGB1, through which sCD93 prevents HMGB1-receptor interaction on effector cells and alleviates inflammation.
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Affiliation(s)
- Shang-En Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Si-Yu Shiao
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Rui Shen
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Fang-Tzu Lee
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bi-Ing Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Jong-Hau Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hua-Lin Wu
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Jwu-Lai Yeh
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chao-Han Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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10
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Nakatake R, Okuyama T, Kotsuka M, Ishizaki M, Kitade H, Yoshizawa K, Tolba RH, Nishizawa M, Sekimoto M. COMBINATION THERAPY WITH A SENSE OLIGONUCLEOTIDE TO INDUCIBLE NITRIC OXIDE SYNTHASE MRNA AND HUMAN SOLUBLE THROMBOMODULIN IMPROVES SURVIVAL OF SEPSIS MODEL RATS AFTER PARTIAL HEPATECTOMY. Shock 2023; 60:84-91. [PMID: 37141168 DOI: 10.1097/shk.0000000000002135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
ABSTRACT Sepsis after a major hepatectomy is a critical problem. In septic shock, the inflammatory mediator, nitric oxide (NO), is overproduced in hepatocytes and macrophages. The natural antisense (AS) transcripts, non-coding RNAs, are transcribed from a gene that encodes inducible nitric oxide synthase (iNOS). iNOS AS transcripts interact with and stabilize iNOS mRNAs. A single-stranded "sense oligonucleotide" (designated as SO1) corresponding to the iNOS mRNA sequence inhibits mRNA-AS transcript interactions and reduces iNOS mRNA levels in rat hepatocytes. In contrast, recombinant human soluble thrombomodulin (rTM) treats disseminated intravascular coagulopathy by suppressing coagulation, inflammation, and apoptosis. In this study, the combination therapy of SO1 and a low dose of rTM was evaluated for hepatoprotection in a rat septic shock model after partial hepatectomy. Rats underwent 70% hepatectomy, followed by intravenous (i.v.) injection of lipopolysaccharide (LPS) after 48 h. SO1 was injected (i.v.) simultaneously with LPS, whereas rTM was injected (i.v.) 1 h before LPS injection. Similarly to our previous report, SO1 increased survival after LPS injection. When rTM, which has different mechanisms of action, was combined with SO1, it did not interfere with the effect of SO1 and showed a significant increase in survival compared with LPS alone treatment. In serum, the combined treatment decreased NO levels. In the liver, the combined treatment inhibited iNOS mRNA and protein expression. A decreased iNOS AS transcript expression by the combined treatment was also observed. The combined treatment decreased mRNA expression of the inflammatory and pro-apoptotic genes while increasing that of the anti-apoptotic gene. Furthermore, the combined treatment reduced the number of myeloperoxidase-positive cells. These results suggested that the combination of SO1 and rTM has therapeutic potential for sepsis.
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Affiliation(s)
| | - Tetsuya Okuyama
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Masaya Kotsuka
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | | | - Hiroaki Kitade
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Katsuhiko Yoshizawa
- Laboratory of Environmental Sciences, Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women's University, Nishinomiya, Japan
| | - Rene H Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany
| | - Mikio Nishizawa
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan
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11
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Kang L, Yang AL, Lai CH, Chen TJ, Lin SY, Wang YH, Wang CZ, Conway EM, Wu HL, Ho ML, Chang JK, Chen CH, Cheng TL. Chondrocyte Thrombomodulin Protects against Osteoarthritis. Int J Mol Sci 2023; 24:ijms24119522. [PMID: 37298473 DOI: 10.3390/ijms24119522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/24/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Osteoarthritis (OA) is a prevalent form of arthritis that affects over 32.5 million adults worldwide, causing significant cartilage damage and disability. Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TMLeD/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1β (IL-1β)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TMLeD/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders.
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Grants
- 110-2314-B-037-022- Ministry of Science and Technology, Executive Yuan, Taiwan
- 111-2314-B-037-055- Ministry of Science and Technology, Executive Yuan, Taiwan
- 110-2314-B-006 -037 -MY3 Ministry of Science and Technology, Executive Yuan, Taiwan
- 110-2314-B-037 -029 -MY3 Ministry of Science and Technology, Executive Yuan, Taiwan
- 111-2314-B-037-106 Ministry of Science and Technology, Executive Yuan, Taiwan
- KMTTH- 111-R002 Kaohsiung Municipal Ta-Tung Hospital
- KMTTH-DK(A)112001 Kaohsiung Municipal Ta-Tung Hospital
- KMU-TC112A02 Kaohsiung Medical University
- KMUH-DK(A)110003 Kaohsiung Medical University
- KMU-DK(B) 110002 Kaohsiung Medical University
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Affiliation(s)
- Lin Kang
- Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan
| | - Ai-Lun Yang
- Institute of Sports Sciences, University of Taipei, Taipei 11153, Taiwan
| | - Chao-Han Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Tsan-Ju Chen
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Sung-Yen Lin
- Department of Orthopaedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yan-Hsiung Wang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chau-Zen Wang
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- College of Professional Studies, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Edward M Conway
- Centre for Blood Research, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Mei-Ling Ho
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- College of Professional Studies, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 800, Taiwan
| | - Je-Ken Chang
- Department of Orthopaedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 800, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Chung-Hwan Chen
- Department of Orthopaedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Tsung-Lin Cheng
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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12
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Kato H, Hagihara M, Asai N, Umemura T, Hirai J, Mori N, Yamagishi Y, Iwamoto T, Mikamo H. Efficacy and safety of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation - A meta-analysis. Thromb Res 2023; 226:165-172. [PMID: 37182388 DOI: 10.1016/j.thromres.2023.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/30/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND Recombinant human soluble thrombomodulin (rhTM) is used to treat sepsis-induced disseminated intravascular coagulation (DIC). However, no consistent clinical guidelines exist regarding the administration of rhTM in patients with sepsis-induced DIC. Therefore, we conducted this meta-analysis to evaluate the efficacy and safety of rhTM therapy in patients with sepsis-induced DIC. METHODS EMBASE, PubMed, Scopus, Ichushi, and CINAHL databases were used to search for relevant articles that met the inclusion criteria of patients with sepsis-induced DIC treated with and without rhTM through November 2022. Mortality, DIC resolution, and incidence of bleeding complications were evaluated. DIC resolution was defined as the recovery from DIC after the start of DIC treatment. RESULTS Of the 1697 citations identified for screening, 17 studies involving 2296 patients were included. Administering rhTM significantly reduced mortality (odds ratio (OR) 0.54, 95 % confidence interval (CI) 0.42-0.71) and improved DIC resolution (OR 2.88, 95 % CI 1.83-4.52). There were no significant differences in the incidence of bleeding complications between the rhTM and control groups (OR 0.92, 95 % CI 0.66-1.28). CONCLUSIONS Our meta-analysis revealed that rhTM could reduce mortality and improve DIC resolution without increasing the risk of bleeding in patients with sepsis-induced DIC. Our findings suggest that rhTM is a relatively effective and safe anticoagulant for the treatment of sepsis-induced DIC. SUMMARY Recombinant human soluble thrombomodulin reduced mortality without increasing the bleeding risk in the treatment of sepsis-induced disseminated intravascular coagulation.
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Affiliation(s)
- Hideo Kato
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan; Department of Pharmacy, Mie University Hospital, Mie, Japan; Department of Clinical Pharmaceutics, Division of Clinical Medical Science, Mie University Graduate School of Medicine, Mie, Japan
| | - Mao Hagihara
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan; Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University Hospital, Aichi, Japan
| | - Nobuhiro Asai
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan
| | - Takumi Umemura
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan
| | - Jun Hirai
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan
| | - Nobuaki Mori
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan
| | - Yuka Yamagishi
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan
| | - Takuya Iwamoto
- Department of Pharmacy, Mie University Hospital, Mie, Japan; Department of Clinical Pharmaceutics, Division of Clinical Medical Science, Mie University Graduate School of Medicine, Mie, Japan
| | - Hiroshige Mikamo
- Department of Clinical Infectious Diseases, Aichi Medical University, Aichi, Japan.
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13
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Ono S, Hatayama N, Miyamoto K, Naito M, Ishimoto T, Ito Y. Intimal growth on the luminal surface of arteriovenous grafts in rats. Clin Exp Nephrol 2023; 27:402-410. [PMID: 36773176 DOI: 10.1007/s10157-023-02320-6] [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: 06/27/2022] [Accepted: 01/17/2023] [Indexed: 02/12/2023]
Abstract
BACKGROUND Endothelial cells are known to grow on the luminal surface of arteriovenous grafts (AVGs) used in hemodialysis. Although endothelial cells are important for preventing infection, a detailed growth of endothelial cells in AVGs is unknown. This study sought to create a simpler animal model of AVGs and to investigate how endothelial cells form on the luminal surface. METHODS Polyethylene grafts were placed between the cervical artery and vein of Wistar rats. The grafts were removed at 6 h, 24 h, 3 days, or 7 days after placement. The luminal surface was observed under optical and polarizing microscopy and stained with endothelial cell markers (LEL, CD31), the progenitor cell marker CD34, and the macrophage marker ED-1. RESULTS Microscopy demonstrated many diffuse vascular endothelial cells on the luminal surface of AVGs after placement. While there was no difference in the number of LEL-positive cells between the arterial side (AS) and venous side (VS) at 6 h or 7 days, there were significantly more of these cells on the VS at both 24 h and 3 days (p < 0.05). Analysis at 24 h showed some CD31-positive cells and few CD34-positive cells. CONCLUSIONS This was the first study to use a simple rat model of AVG placement. Endothelial cell formation was initially more active on the VS than on the AS, but these cells subsequently increased in number across the luminal surface. Future clinical studies might contribute clinically by confirming whether AS versus VS puncture results in different infection rates.
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Affiliation(s)
- Sumihisa Ono
- Department of Nephrology, Central Japan International Medical Center, 1-1, Kenkounomachi, Minokamoshi, Gifu, Japan.,Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1, Yazakokarimata, Nagakute, Aichi, Japan
| | - Naoyuki Hatayama
- Department of Anatomy, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, Japan.
| | - Kanyu Miyamoto
- Department of Nephrology, Central Japan International Medical Center, 1-1, Kenkounomachi, Minokamoshi, Gifu, Japan
| | - Munekazu Naito
- Department of Anatomy, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, Japan
| | - Takuji Ishimoto
- Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1, Yazakokarimata, Nagakute, Aichi, Japan
| | - Yasuhiko Ito
- Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1, Yazakokarimata, Nagakute, Aichi, Japan.
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14
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Kono H, Hosomura N, Amemiya H, Kawaida H, Furuya S, Shoda K, Akaike H, Kawaguchi Y, Ichikawa D. Recombinant Human Thrombomodulin Reduces Mortality and Acute Lung Injury Caused by Septic Peritonitis in Rats. Immunohorizons 2023; 7:159-167. [PMID: 36706425 PMCID: PMC10563402 DOI: 10.4049/immunohorizons.2200094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/29/2023] Open
Abstract
This study aimed to investigate the therapeutic effects of recombinant human thrombomodulin (rhTM) on acute lung injury (ALI) caused by sepsis in rats. Rats that underwent cecal ligation and puncture (CLP) were treated with or without rhTM, and then mortality was analyzed. In another set of experiments, ALI was assessed. Furthermore, microthrombosis in the lungs was investigated by immunohistochemistry. Moreover, plasma inflammatory and anti-inflammatory cytokines, such as TNF-α, high-mobility group box chromosomal protein 1 (HMGB-1), and IL-10, were evaluated by ELISA. Production of TNF-α and HMGB-1 by isolated tissue macrophages (Mφs) was assessed in vitro. Mortality after CLP was significantly improved by rhTM treatment. In addition, rhTM treatment improved the wet/dry weight ratio of the lungs, the pulmonary microvascular permeability, and the lung injury scores in animals that underwent CLP. Microthrombosis was detected in the lungs after CLP. These pathophysiological changes were blunted by rhTM treatment. Increased plasma TNF-α and HMGB-1 levels were blunted by rhTM treatment; however, the anti-inflammatory cytokine IL-10 was significantly greater in the rhTM(+) group than in the rhTM(-) group. Increased TNF-α and HMGB-1 production by the tissue Mφs stimulated with LPS were significantly blunted by rhTM treatment in vitro, but the production of IL-10 by the tissue Mφs was not changed in the cells incubated with rhTM. Overall, rhTM improved the mortality caused by septic peritonitis. The possible mechanisms are most likely anti-inflammatory and anticoagulant effects, which lead to the prevention of ALI.
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Affiliation(s)
- Hiroshi Kono
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Naohiro Hosomura
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hidetake Amemiya
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hiromichi Kawaida
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinji Furuya
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Katsutoshi Shoda
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hidenori Akaike
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yoshihiko Kawaguchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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15
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Yokoyama H, Tateishi K, Baba Y, Kobayashi A, Hashimoto M, Fukuda S, Yamao H, Maruyama T, Nakata M, Matsushita M. Thrombin cleaves recombinant soluble thrombomodulin into a lectin-like domain fragment and a fragment with protein C-activating cofactor activity. Biosci Trends 2022; 16:444-446. [PMID: 36450579 DOI: 10.5582/bst.2022.01472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Thrombomodulin (TM) is a transmembrane protein that plays an important role in regulating the coagulation system by acting as a cofactor for thrombin in protein C activation. Additionally, TM is involved in inflammation. Previous studies have shown that soluble fragments of TM of varying sizes, which are derived from membrane-bound TM, are present in plasma and urine. Soluble fragments of TM are speculated to exhibit biological activity. Among these, a lectin-like domain fragment (TMD1) is of particular importance. Recombinant TMD1 has previously been shown to attenuate lipopolysaccharide-induced inflammation. Here, we report that thrombin cleaves recombinant soluble TM, which is used for the treatment of disseminated intravascular coagulation associated with sepsis, into TMD1 and a fragment comprising the C-terminal portion of TM (TMD23), the latter of which retains the cofactor activity for activating protein C. Our findings suggest that thrombin not only activates protein C on membrane-bound TM but may also cleave TM to generate TMD1.
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Affiliation(s)
- Hirota Yokoyama
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Koichiro Tateishi
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Yurie Baba
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Akina Kobayashi
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Manami Hashimoto
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Shion Fukuda
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Hinano Yamao
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Taiga Maruyama
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Munehiro Nakata
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | - Misao Matsushita
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
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16
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Voelker MT, Hechaichi N, Ndongson-Dongmo B, Lemm J, Heller R, Bauer R, Conway EM, Theilmeier G, Stehr SN. Role of the lectin-like domain of thrombomodulin in septic cardiomyopathy. Life Sci 2022; 306:120830. [PMID: 35872006 DOI: 10.1016/j.lfs.2022.120830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/10/2022] [Accepted: 07/18/2022] [Indexed: 11/25/2022]
Abstract
AIMS Septic cardiomyopathy is a severe complication of sepsis and septic shock. This study aimed to evaluate the role of thrombomodulin and its lectin-like domain (LLD-TM) in the development of septic cardiomyopathy and the link between LLD-TM, HMGB-1, and toll-like receptors 2/4 (TLR 2/4) to intracellular mechanisms resulting in reduced cardiac function. MATERIALS AND METHODS Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TMLeD/LeD), and severity of disease and cardiac function was compared. Cell cultures of cardiomyocytes were prepared from hearts harvested from wildtype and TMLeD/LeD mice. Cultures of neonatal cardiomyocytes were transfected with complete human thrombomodulin or human thrombomodulin deficient of LLD-TM and when TLR-2 and/or TLR-4 were blocked. All cultures were challenged with inflammatory stimuli. KEY FINDINGS Lack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM. SIGNIFICANCE Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy.
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Affiliation(s)
- Maria Theresa Voelker
- Department of Anaesthesiology and Critical Care Medicine, University Hospital Leipzig, Germany.
| | - Nadine Hechaichi
- Center for Sepsis Control and Care, University Hospital Jena, Germany
| | - Bernadin Ndongson-Dongmo
- Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Jana Lemm
- Center for Sepsis Control and Care, University Hospital Jena, Germany
| | - Regine Heller
- Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Reinhardt Bauer
- Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Edward M Conway
- UBC Centre for Blood Research, Faculty of Medicine, Division of Haematology, Life Sciences Institute, Vancouver, British Columbia, Canada
| | - Gregor Theilmeier
- Division of Perioperative Inflammation and Infection, Faculty of Medicine and Health Sciences, Oldenburg, Germany
| | - Sebastian N Stehr
- Department of Anaesthesiology and Critical Care Medicine, University Hospital Leipzig, Germany; Center for Sepsis Control and Care, University Hospital Jena, Germany
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17
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Boron M, Hauzer-Martin T, Keil J, Sun XL. Circulating Thrombomodulin: Release Mechanisms, Measurements, and Levels in Diseases and Medical Procedures. TH OPEN 2022; 6:e194-e212. [PMID: 36046203 PMCID: PMC9273331 DOI: 10.1055/a-1801-2055] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/11/2022] [Indexed: 12/02/2022] Open
Abstract
Thrombomodulin (TM) is a type-I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (<10 ng/mL) in the blood but is elevated in several pathological conditions associated with endothelial dysfunction such as cardiovascular, inflammatory, infection, and metabolic diseases. Therefore, sTM level has been examined for monitoring disease development, such as disseminated intravascular coagulation (DIC), sepsis and multiple organ dysfunction syndrome in patients with novel coronavirus disease 2019 (COVID-19) recently. In addition, microvesicles (MVs) that contain membrane TM (MV-TM) have been found to be released from activated cells which also contribute to levels of circulating TM in certain diseases. Several release mechanisms of sTM and MV-TM have been reported, including enzymatic, chemical, and TM mutation mechanisms. Measurements of sTM and MV-TM have been developed and explored as biomarkers in many diseases. In this review, we summarize all these advances in three categories as follows: (1) release mechanisms of circulating TM, (2) methods for measuring circulating TM in biological samples, and (3) correlation of circulating TM with diseases. Altogether, it provides a whole picture of recent advances on circulating TM in health and disease.
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Affiliation(s)
- Mallorie Boron
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
| | - Tiffany Hauzer-Martin
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
| | - Joseph Keil
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
| | - Xue-Long Sun
- Department of Chemistry and Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, Ohio, United States
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Yu M, Chang S, Xu J, Zhang H, Jiang Y. Genome-wide identification of endosialin family of C-type lectins in common carp (Cyprinus carpio) and their response following Aeromonas hydrophila infection. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 129:104338. [PMID: 34995551 DOI: 10.1016/j.dci.2021.104338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 06/14/2023]
Abstract
The endosialin family is the group XIV of C-type lectin, regulating several processes involved in innate immunity and inflammation. Endosialin family genes have been extensively studied in human and mammals, however, rarely reported in teleost. In the present study, a set of 8 endosialin family genes was identified across the entire common carp genome. Functional domain and motif prediction and phylogenetic analysis supported their annotation and orthologies. Through examining gene copy number across several vertebrates, endosialin family genes were found have undergone gene duplication. Most of the endosialin family genes were ubiquitously expressed during common carp early developmental stages, and presented tissue-specific expression patterns in various healthy tissues, with relatively high expression in intestine, liver, gill, spleen and kidney, indicating their likely essential roles in maintaining homeostasis and host immune response. After Aeromonas hydrophila infection, gene thbd-1, thbd-2 and cd93-2 were significantly up-regulated at one or more timepoints in spleen and kidney, while gene cd248a-1, cd248a-2, cd248b-1, cd248b-2, and cd93-1 were significantly down-regulated. Taken together, all these results suggested that endosialin family genes were involved in host immune response to A. hydrophila infection in common carp, and provided fundamental genomic resources for better understanding the critical roles of endosialin family on the primary innate immune processes in teleost.
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Affiliation(s)
- Minghui Yu
- College of Fisheries and Life, Shanghai Ocean University, Shanghai, China; Key Laboratory of Aquatic Genomics, Ministry of Agriculture and Rural Affairs, CAFS Key Laboratory of Aquatic Genomics, Chinese Academy of Fishery Sciences, Beijing, China
| | - Songhuan Chang
- College of Fisheries and Life, Shanghai Ocean University, Shanghai, China; Key Laboratory of Aquatic Genomics, Ministry of Agriculture and Rural Affairs, CAFS Key Laboratory of Aquatic Genomics, Chinese Academy of Fishery Sciences, Beijing, China
| | - Jian Xu
- Key Laboratory of Aquatic Genomics, Ministry of Agriculture and Rural Affairs, CAFS Key Laboratory of Aquatic Genomics, Chinese Academy of Fishery Sciences, Beijing, China
| | - Hanyuan Zhang
- Key Laboratory of Aquatic Genomics, Ministry of Agriculture and Rural Affairs, CAFS Key Laboratory of Aquatic Genomics, Chinese Academy of Fishery Sciences, Beijing, China
| | - Yanliang Jiang
- Key Laboratory of Aquatic Genomics, Ministry of Agriculture and Rural Affairs, CAFS Key Laboratory of Aquatic Genomics, Chinese Academy of Fishery Sciences, Beijing, China.
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19
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Tsai MS, Wang LC, Wu HL, Tzeng SF, Conway EM, Hsu SM, Chen SH. Absence of the lectin-like domain of thrombomodulin reduces HSV-1 lethality of mice with increased microglia responses. J Neuroinflammation 2022; 19:66. [PMID: 35277184 PMCID: PMC8915510 DOI: 10.1186/s12974-022-02426-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 02/28/2022] [Indexed: 01/12/2023] Open
Abstract
Background Herpes simplex virus 1 (HSV-1) can induce fatal encephalitis. Cellular factors regulate the host immunity to affect the severity of HSV-1 encephalitis. Recent reports focus on the significance of thrombomodulin (TM), especially the domain 1, lectin-like domain (TM-LeD), which modulates the immune responses to bacterial infections and toxins and various diseases in murine models. Few studies have investigated the importance of TM-LeD in viral infections, which are also regulated by the host immunity. Methods In vivo studies comparing wild-type and TM-LeD knockout mice were performed to determine the role of TM-LeD on HSV-1 lethality. In vitro studies using brain microglia cultured from mice or a human microglia cell line to investigate whether and how TM-LeD affects microglia to reduce HSV-1 replication in brain neurons cultured from mice or in a human neuronal cell line. Results Absence of TM-LeD decreased the mortality, tissue viral loads, and brain neuron apoptosis of HSV-1-infected mice with increases in the number, proliferation, and phagocytic activity of brain microglia. Moreover, TM-LeD deficiency enhanced the phagocytic activity of brain microglia cultured from mice or of a human microglia cell line. Co-culture of mouse primary brain microglia and neurons or human microglia and neuronal cell lines revealed that TM-LeD deficiency augmented the capacity of microglia to reduce HSV-1 replication in neurons. Conclusions Overall, TM-LeD suppresses microglia responses to enhance HSV-1 infection. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02426-w.
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20
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Mitaka C, Kawagoe I, Satoh D, Hayashida M. Effect of Recombinant Human Soluble Thrombomodulin on Coagulation-Related Variables in Patients With Sepsis-Induced Disseminated Intravascular Coagulation: A Retrospective Observational Study. Clin Appl Thromb Hemost 2021; 27:10760296211050356. [PMID: 34859680 PMCID: PMC8646186 DOI: 10.1177/10760296211050356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
To evaluate associations among coagulation-related variables, resolution of disseminated intravascular coagulation (DIC) and mortality, we retrospectively investigated 123 patients with sepsis-induced DIC treated with recombinant human soluble thrombomodulin (rTM). Changes in coagulation-related variables before and after treatment with rTM were examined. Further, associations between coagulation-related variables and DIC resolution were evaluated. The platelet count, prothrombin international normalized ratio (PT-INR), and fibrin/fibrinogen degradation products (FDP) significantly (p < .001) improved after rTM administration in survivors (n = 98), but not in nonsurvivors (n = 25). However, the DIC score significantly (p < .001) reduced in survivors and in nonsurvivors. Among coagulation-related variables examined before rTM, only PT-INR was significantly (p = .0395) lower in survivors than in nonsurvivors, and PT-INR before rTM was significantly (p = .0029) lower in patients attaining than not attaining DIC resolution (n = 87 and 36, respectively). The 28-day mortality was significantly lower in patients attaining than not attaining DIC resolution (11.5% vs 41.7%, p = .0001). In conclusion, the initiation of rTM administration before marked PT-INR elevation may be important to induce DIC resolution and thus to decrease mortality in patients with sepsis-induced DIC. Conversely, the treatment with rTM in patients with marked PT-INR elevation may be not so effective in achieving such goals.
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21
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Huang YH, Kuo CH, Peng IC, Chang YS, Tseng SH, Conway EM, Wu HL. Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway. Cell Mol Life Sci 2021; 78:7681-7692. [PMID: 34705054 PMCID: PMC11072095 DOI: 10.1007/s00018-021-03950-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/12/2021] [Accepted: 09/21/2021] [Indexed: 12/24/2022]
Abstract
Pathological angiogenesis (PA) contributes to various ocular diseases, including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, which are major causes of blindness over the world. Current treatments focus on anti-vascular endothelial growth factor (VEGF) therapy, but persistent avascular retina, recurrent intravitreal neovascularization, and general adverse effects are reported. We have previously found that recombinant thrombomodulin domain 1 (rTMD1) can suppress vascular inflammation. However, the function of rTMD1 in VEGF-induced PA remains unknown. In this study, we found that rTMD1 inhibited VEGF-induced angiogenesis in vitro. In an oxygen induced retinopathy (OIR) animal model, rTMD1 treatment significantly decreased retinal neovascularization but spared normal physiological vessel growth. Furthermore, loss of TMD1 significantly promoted PA in OIR. Meanwhile, hypoxia-inducible factor-1α, the transcription factor that upregulates VEGF, was suppressed after rTMD1 treatment. The levels of interleukin-6, and intercellular adhesion molecule-1 were also significantly suppressed. In conclusion, our results indicate that rTMD1 not only has dual effects to suppress PA and inflammation in OIR, but also can be a potential HIF-1α inhibitor for clinical use. These data bring forth the possibility of rTMD1 as a novel therapeutic agent for PA.
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MESH Headings
- Animals
- Apoptosis
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Female
- Gene Expression Regulation
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Retinal Neovascularization/genetics
- Retinal Neovascularization/metabolism
- Retinal Neovascularization/pathology
- Retinal Neovascularization/prevention & control
- Thrombomodulin/genetics
- Thrombomodulin/metabolism
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Mice
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Affiliation(s)
- Yi-Hsun Huang
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
| | - Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - I-Chen Peng
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Sheng Chang
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Sung-Huei Tseng
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Edward M Conway
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
| | - Hua-Lin Wu
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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22
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Zhang YY, Ning BT. Signaling pathways and intervention therapies in sepsis. Signal Transduct Target Ther 2021; 6:407. [PMID: 34824200 PMCID: PMC8613465 DOI: 10.1038/s41392-021-00816-9] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/19/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection. Over decades, advanced understanding of host-microorganism interaction has gradually unmasked the genuine nature of sepsis, guiding toward new definition and novel therapeutic approaches. Diverse clinical manifestations and outcomes among infectious patients have suggested the heterogeneity of immunopathology, while systemic inflammatory responses and deteriorating organ function observed in critically ill patients imply the extensively hyperactivated cascades by the host defense system. From focusing on microorganism pathogenicity, research interests have turned toward the molecular basis of host responses. Though progress has been made regarding recognition and management of clinical sepsis, incidence and mortality rate remain high. Furthermore, clinical trials of therapeutics have failed to obtain promising results. As far as we know, there was no systematic review addressing sepsis-related molecular signaling pathways and intervention therapy in literature. Increasing studies have succeeded to confirm novel functions of involved signaling pathways and comment on efficacy of intervention therapies amid sepsis. However, few of these studies attempt to elucidate the underlining mechanism in progression of sepsis, while other failed to integrate preliminary findings and describe in a broader view. This review focuses on the important signaling pathways, potential molecular mechanism, and pathway-associated therapy in sepsis. Host-derived molecules interacting with activated cells possess pivotal role for sepsis pathogenesis by dynamic regulation of signaling pathways. Cross-talk and functions of these molecules are also discussed in detail. Lastly, potential novel therapeutic strategies precisely targeting on signaling pathways and molecules are mentioned.
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Affiliation(s)
- Yun-Yu Zhang
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Bo-Tao Ning
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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23
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Watanabe E, Akamatsu T, Ohmori M, Kato M, Takeuchi N, Ishiwada N, Nishimura R, Hishiki H, Fujimura L, Ito C, Hatano M. Recombinant thrombomodulin attenuates hyper-inflammation and glycocalyx damage in a murine model of Streptococcus pneumoniae-induced sepsis. Cytokine 2021; 149:155723. [PMID: 34662822 DOI: 10.1016/j.cyto.2021.155723] [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: 08/15/2021] [Accepted: 09/20/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE The anticoagulant agent recombinant thrombomodulin (rTM) activates protein C to prevent excessive coagulation and also possibly regulates hyper-inflammation via neutralization of high-mobility-group B1 (HMG-B1). The glycocalyx layer in endothelial cells also plays a pivotal role in preventing septic shock-associated hyperpermeability. The present study examined the effect of rTM in a murine model of Streptococcus pneumoniae-induced sepsis. METHODS Male C57BL/6N mice were injected intratracheally via midline cervical incision with 2 × 107 CFU of S. pneumoniae (capsular subtype 19A). Control mice were sham-treated identically but injected with saline. rTM (10 mg/kg) was injected intraperitoneally 3 h after septic insult. Blood concentrations of soluble inflammatory mediators (interleukin [IL]-1β, IL-6, IL-10, and tumor necrosis factor [TNF]-α) were determined using a microarray immunoassay. Serum concentrations of HMG-B1 and syndecan-1, as a parameter of glycocalyx damage, were determined by enzyme-linked immunosorbent assay. The glycocalyx was also evaluated with electron microscopy. The lungs were removed, and digested to cells, which were then stained with a mixture of fluorophore-conjugated antibodies. Anti-mouse primary antibodies included PE-Cy7-conjugated anti-CD31, AlexaFluor 700-conjugated anti-CD45, PerCP-Cy5.5-conjugated anti-CD326, APC-conjugated anti-TNF-α, PE-conjugated anti-IL-6, and PE-conjugated anti-IL-10. A total of 1 × 106 cells per sample were analyzed, and 2 × 105 events were recorded by flow cytometry, and parameters were compared with/without rTM treatment. RESULTS The blood concentration of TNF-α was significantly reduced 24 h after intratracheal injection in S. pneumoniae-challenged mice treated with rTM (P = 0.016). Levels of IL-10 in the lung endothelium of rTM-treated S. pneumoniae-challenged mice increased significantly 12 h after intratracheal injection (P = 0.03). Intriguingly, serum HMGB-1 and syndecan-1 levels decreased significantly (P = 0.010 and 0.015, respectively) in rTM-treated mice 24 h after intratracheal injection of S. pneumoniae. Electron microscopy indicated that rTM treatment preserved the morphology of the glycocalyx layer in septic mice. CONCLUSIONS These data suggest that rTM modulates local inflammation in the lung endothelium, thus diminishing systemic inflammation, i.e., hypercytokinemia. Furthermore, rTM treatment reduced serum syndecan-1 levels, thus preventing glycocalyx damage. The use of rTM to treat sepsis caused by bacterial pneumonia could therefore help prevent both excessive inflammation and glycocalyx injury in the lung endothelium.
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Affiliation(s)
- Eizo Watanabe
- Department of General Medical Science, Chiba University Graduate School of Medicine, Japan; Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Japan.
| | | | | | - Mayu Kato
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Japan
| | - Noriko Takeuchi
- Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, Japan
| | - Naruhiko Ishiwada
- Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, Japan
| | - Rintaro Nishimura
- Departments of Respirology, Graduate School of Medicine, Chiba University, Japan
| | - Haruka Hishiki
- Departments of Pediatrics, Graduate School of Medicine, Chiba University, Japan
| | | | - Chizuru Ito
- Department of Functional Anatomy, Reproductive Biology and Medicine, Graduate School of Medicine, Chiba University, Japan
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24
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Cheng TL, Lin YS, Hong YK, Ma CY, Tsai HW, Shi GY, Wu HL, Lai CH. Role of tumor endothelial marker 1 (Endosialin/CD248) lectin-like domain in lipopolysaccharide-induced macrophage activation and sepsis in mice. Transl Res 2021; 232:150-162. [PMID: 33737161 DOI: 10.1016/j.trsl.2021.03.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 11/16/2022]
Abstract
Deleterious hyper-inflammation resulting from macrophage activation may aggravate sepsis and lead to lethality. Tumor endothelial marker 1 (TEM1), a type I transmembrane glycoprotein containing six functional domains, has been implicated in cancer and chronic sterile inflammatory disorders. However, the role of TEM1 in acute sepsis remains to be determined. Herein we explored the functional significance of the TEM1 lectin-like domain (TEM1D1) in monocyte/macrophage activation and sepsis using TEM1D1-deleted (TEM1LeD/LeD) transgenic mice and recombinant TEM1D1 (rTEM1D1) protein. Under stimulation with lipopolysaccharides (LPS) or several other toll-like receptor agonists, TEM1LeD/LeD macrophages produced lower levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than wild-type TEM1wt/wt macrophages. Compared with TEM1wt/wt macrophages, LPS-macrophage binding and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation were suppressed in TEM1LeD/LeD macrophages. In vivo, TEM1D1 deletion improved survival in LPS-challenged mice with reduction of circulating TNF-α and IL-6 and alleviation of lung injury and pulmonary leukocyte accumulation. In contrast, rTEM1D1 could bind to LPS and markedly suppress LPS-macrophage binding, MAPK/NF-κB signaling in macrophages and proinflammatory cytokine production. Treatment with rTEM1D1 improved survival and attenuated circulating TNF-α and IL-6, lung injury and pulmonary accumulation of leukocytes in LPS-challenged mice. These findings demonstrated differential roles for the TEM1 lectin-like domain in macrophages and soluble TEM1 lectin-like domain in sepsis. TEM1 in macrophages mediates LPS-induced inflammation via its lectin-like domain, whereas rTEM1D1 interferes with LPS-induced macrophage activation and sepsis.
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Affiliation(s)
- Tsung-Lin Cheng
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Orthopedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Syuan Lin
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Kai Hong
- Department of Dermatology, National Cheng Kung University hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yuan Ma
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Guey-Yueh Shi
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chao-Han Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
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25
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Elevated plasma levels of syndecan-1 and soluble thrombomodulin predict adverse outcomes in thrombotic thrombocytopenic purpura. Blood Adv 2021; 4:5378-5388. [PMID: 33141886 DOI: 10.1182/bloodadvances.2020003065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023] Open
Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13 activity. Despite recent advances in early diagnosis and novel therapeutics, the mortality rate of acute iTTP remains as high as 10% to 20%. Moreover, a reliable clinical and laboratory parameter that predicts disease severity and outcomes is lacking. We show in the present study that plasma levels of syndecan-1 (Sdc-1) and soluble thrombomodulin (sTM) on admission were dramatically increased in patients with acute iTTP and remained substantially elevated in a subset of patients compared with healthy controls. The elevated admission plasma levels of Sdc-1 and sTM were associated with abnormal Glasgow coma scale scores, low estimated glomerular filtration rates, the need for intensive care, and in-hospital mortality rates. Moreover, a further simultaneous increase in plasma Sdc-1 and sTM levels at the time of clinical response/remission (eg, when normalization of platelet counts and substantial reduction of serum lactate dehydrogenase activity were achieved) was highly predictive of iTTP recurrence. These results demonstrate that endothelial injury, resulting from disseminated microvascular thromboses, is severe and persistent in patients with acute iTTP. Plasma levels of Sdc-1 and sTM on admission and in remission are predictive of in-hospital mortality and recurrence of acute iTTP, respectively. Thus, an incorporation of such novel plasma biomarkers into the risk assessment in acute iTTP may help implement a more vigorous and intensive therapeutic strategy for these patients.
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26
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Kato Y, Nishida O, Kuriyama N, Nakamura T, Kawaji T, Onouchi T, Hasegawa D, Shimomura Y. Effects of Thrombomodulin in Reducing Lethality and Suppressing Neutrophil Extracellular Trap Formation in the Lungs and Liver in a Lipopolysaccharide-Induced Murine Septic Shock Model. Int J Mol Sci 2021; 22:4933. [PMID: 34066510 PMCID: PMC8124404 DOI: 10.3390/ijms22094933] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/19/2022] Open
Abstract
Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1β. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis.
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Affiliation(s)
- Yu Kato
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
| | - Osamu Nishida
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
| | - Naohide Kuriyama
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
| | - Tomoyuki Nakamura
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
| | - Takahiro Kawaji
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
| | - Takanori Onouchi
- Center for Joint Research Facilities Support, Research Promotion and Support Headquarters, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan;
| | - Daisuke Hasegawa
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
| | - Yasuyo Shimomura
- Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan; (Y.K.); (O.N.); (N.K.); (T.N.); (T.K.); (D.H.)
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Liu N, Liu C, Yang Y, Ma G, Wei G, Liu S, Kong L, Du G. Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation. Pharmacol Res 2021; 169:105650. [PMID: 33964468 DOI: 10.1016/j.phrs.2021.105650] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/02/2021] [Accepted: 04/29/2021] [Indexed: 02/08/2023]
Abstract
Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT.
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Affiliation(s)
- Nannan Liu
- College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Chengdi Liu
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Yujiao Yang
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China
| | - Guodong Ma
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Guangyi Wei
- College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Shan Liu
- College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Linglei Kong
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
| | - Guanhua Du
- College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, 280 Waihuan East Road, Panyu District, Guangdong 510006, PR China; Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
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28
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Kawasoe J, Uchida Y, Miyauchi T, Kadono K, Hirao H, Saga K, Watanabe T, Ueda S, Terajima H, Uemoto S. The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice. Am J Transplant 2021; 21:540-551. [PMID: 32805077 PMCID: PMC7891328 DOI: 10.1111/ajt.16269] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/13/2020] [Accepted: 08/03/2020] [Indexed: 01/25/2023]
Abstract
Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.
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Affiliation(s)
- Junya Kawasoe
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Yoichiro Uchida
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Tomoyuki Miyauchi
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Kentaro Kadono
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hirofumi Hirao
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kenichi Saga
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Takeshi Watanabe
- Division of Immunology, Institute for Frontier Life and Medical SciencesKyoto UniversityKyotoJapan
| | - Shugo Ueda
- Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Hiroaki Terajima
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan,Department of Gastroenterological Surgery and OncologyThe Tazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Shinji Uemoto
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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Chang LY, Lai CH, Kuo CH, Chang BI, Wu HL, Cheng TL. Recombinant thrombomodulin lectin-like domain attenuates porphyromonas gingivalis lipopolysaccharide-induced osteoclastogenesis and periodontal bone resorption. J Periodontol 2021; 92:1622-1634. [PMID: 33438207 DOI: 10.1002/jper.20-0732] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/18/2020] [Accepted: 01/07/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Evidence demonstrates that the thrombomodulin (TM) lectin domain (TMD1) exerts anti-inflammatory functions. Lipopolysaccharides derived from Porphyromonas gingivalis (Pg-LPS) are considered a major pathogenic factor for chronic periodontitis, promoting inflammation, osteoclastogenesis and alveolar bone resorption. Herein, we aimed to evaluate the potential therapeutic effect of recombinant TMD1 (rTMD1) in suppression of Pg-LPS-induced osteoclastogenesis and periodontal bone loss. METHODS In vitro, the effects of Pg-LPS, tumor necrosis factor (TNF)-α and rTMD1 on osteoclast differentiation were investigated using receptor activator of nuclear factor-κB ligand (RANKL)-stimulated RAW 264.7 macrophages. In vivo, the effects of rTMD1 treatment were evaluated in a model of experimental periodontitis induced by direct injection of Pg-LPS into the vestibular gingiva. RESULTS Administration of Pg-LPS to RANKL-stimulated RAW 264.7 macrophages resulted in upregulation of CD86 and osteoclast marker (eg, Dc-stamp and Trap) gene expression and increase of pro-inflammatory cytokine production (e.g., TNF-α) during osteoclast differentiation, and rTMD1 can attenuate these effects. Also, rTMD1 inhibited Pg-LPS-enhanced in vitro bone resorption in a dose-dependent manner. Moreover, TNF-α promoted phosphorylation of p38 and ERK during osteoclast differentiation, and the signal activation can be inhibited by rTMD1. Finally, treatment with rTMD1 hindered Pg-LPS-induced alveolar bone loss in experimental periodontitis in mice. CONCLUSION Our study demonstrated that rTMD1 attenuates Pg-LPS-enhanced M1 macrophage polarization, osteoclastogenesis and periodontal bone resorption and thus holds therapeutic promise for periodontitis.
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Affiliation(s)
- Lan-Yun Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chao-Han Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Cheng-Hsiang Kuo
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bi-Ing Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Lin Cheng
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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30
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Abstract
Dendritic cells are a specialized subset of hematopoietic cells essential for mounting immunity against tumors and infectious disease as well as inducing tolerance for maintenance of homeostasis. DCs are equipped with number of immunoregulatory or stimulatory molecules that interact with other leukocytes to modulate their functions. Recent advances in DC biology identified a specific role for the conventional dendritic cell type 1 (cDC1) in eliciting cytotoxic CD8+ T cells essential for clearance of tumors and infected cells. The critical role of this subset in eliciting immune responses or inducing tolerance has largely been defined in mice whereas the biology of human cDC1 is poorly characterized owing to their extremely low frequency in tissues. A detailed characterization of the functions of many immunoregulatory and stimulatory molecules expressed by human cDC1 is critical for understanding their biology to exploit this subset for designing novel therapeutic modalities against cancer, infectious disease and autoimmune disorders.
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Affiliation(s)
- Sreekumar Balan
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Kristen J Radford
- Cancer Immunotherapies Laboratory, Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Nina Bhardwaj
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, United States; Extramural member Parker Institute of Cancer Immunotherapy, CA, United States.
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31
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Ito T, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Hirayama A, Honda G, Saito H. Effects of thrombomodulin alfa on hemostatic parameters in disseminated intravascular coagulation: Post hoc analysis of a phase 3 randomized controlled trial. Res Pract Thromb Haemost 2020; 4:1141-1149. [PMID: 33134780 PMCID: PMC7590306 DOI: 10.1002/rth2.12419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 06/15/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The efficacy and safety of thrombomodulin alfa (TM-α), a cofactor protein promoting thrombin-mediated protein C activation, have been examined in a phase 3 randomized, double-blinded, parallel-group trial in Japan. We have previously reported that TM-α is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC). OBJECTIVE To investigate the basis for the efficacy of TM-α in the phase 3 clinical trial in Japan through post hoc analysis of coagulation and fibrinolysis parameters. PATIENTS/METHODS The 227 patients of the full analysis set population described in the original phase 3 trial in Japan were included in this analysis. Changes in parameters between before and after TM-α or heparin administration in each of the two patient groups, with underlying diseases of either hematologic malignancy or infection, were studied separately and results were compared between TM-α and heparin treatment groups in a post hoc manner. RESULTS TM-α administration did not prolong activated partial thromboplastin time but significantly decreased thrombin-antithrombin complex levels compared with heparin treatment. TM-α administration reduced consumption of endogenous anticoagulants such as antithrombin and protein C by DIC, compared with the heparin group. DIC scores were decreased in both TM-α and heparin groups during the 6-day treatment. CONCLUSION TM-α can alleviate intravascular coagulation and consumption of anticoagulants without extending coagulation times. This may be associated with the relatively low risk of bleeding during TM-α treatment.
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Affiliation(s)
- Takashi Ito
- Department of Systems Biology in ThromboregulationKagoshima University Graduates School of Medical and Dental SciencesKagoshimaJapan
| | - Ikuro Maruyama
- Department of Systems Biology in ThromboregulationKagoshima University Graduates School of Medical and Dental SciencesKagoshimaJapan
| | - Shuji Shimazaki
- Department of Emergency Medical SystemDisaster and EMS Rescue InstituteKokushikan UniversityTokyoJapan
| | | | | | | | | | - Hidehiko Saito
- National Hospital Organization Nagoya Medical CenterAichiJapan
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32
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Watanabe-Kusunoki K, Nakazawa D, Ishizu A, Atsumi T. Thrombomodulin as a Physiological Modulator of Intravascular Injury. Front Immunol 2020; 11:575890. [PMID: 33042158 PMCID: PMC7525002 DOI: 10.3389/fimmu.2020.575890] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/19/2020] [Indexed: 12/17/2022] Open
Abstract
Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelial- and blood cell-derived damage-associated molecular patterns (DAMPs), and DAMP-mediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.
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Affiliation(s)
- Kanako Watanabe-Kusunoki
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Daigo Nakazawa
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akihiro Ishizu
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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33
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Chen CH, Lai CH, Hong YK, Lu JM, Lin SY, Lee TC, Chang LY, Ho ML, Conway EM, Wu HL, Cheng TL. Thrombomodulin Functional Domains Support Osteoblast Differentiation and Bone Healing in Diabetes in Mice. J Bone Miner Res 2020; 35:1812-1823. [PMID: 32329910 DOI: 10.1002/jbmr.4036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/07/2020] [Accepted: 04/18/2020] [Indexed: 11/05/2022]
Abstract
Thrombomodulin (TM) is a transmembrane glycoprotein that contains five functional domains. Soluble TM (sTM), comprising extracellular domains TMD1 (lectin-like), TMD2 (epidermal growth factor [EGF]-like repeat containing), and TMD3 (serine-threonine rich), can be shed from cells by the intramembrane protease rhomboid-like-2 (RHBDL2). TM is expressed by osteoblasts, yet its role there has not been determined. Herein we aimed to investigate the properties of TM and its domains in osteoblast function and bone repair following injury in diabetes. In response to a scratch injury of cultured osteoblast-like MG63 cells, expression of TM and RHBDL2 was enhanced, with increased release of sTM. Conditioned media from the injured cells promoted osteoblast migration, an effect that was lacking with conditioned media from MG63 cells in which TM was silenced by shRNA. Exogenous recombinant TMD1 had no effect on osteoblast activities or on bone repair in vivo. However, TM domains 2 and 3 (TMD2/3), induced MG63 cell migration, proliferation and mineralization in vitro, and when locally administered in mice, improved in vivo healing of injured calvarium. This beneficial effect of TMD2/3, mediated via fibroblast growth factor receptor (FGFR)/ERK signaling pathways, was also observed in vitro under high glucose conditions where endogenous TM expression was reduced, and in vivo in diabetic mice following tibia fracture or calvarium injury, where the osteoblastic response and healing were otherwise dampened. Taken together, osteoblast TM participates in bone healing, and recombinant TMD2/3 holds promise as a novel therapy for diabetic bone defect healing. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Chung-Hwan Chen
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chao-Han Lai
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Kai Hong
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jui-Ming Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sung-Yen Lin
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tien-Ching Lee
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lan-Yun Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Mei-Ling Ho
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Edward M Conway
- Centre for Blood Research, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Lin Cheng
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Ram C, Jha AK, Ghosh A, Gairola S, Syed AM, Murty US, Naidu VGM, Sahu BD. Targeting NLRP3 inflammasome as a promising approach for treatment of diabetic nephropathy: Preclinical evidences with therapeutic approaches. Eur J Pharmacol 2020; 885:173503. [PMID: 32858047 DOI: 10.1016/j.ejphar.2020.173503] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/19/2020] [Accepted: 08/23/2020] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus is an increasingly prevalent disease around the globe. The epidemic of diabetes mellitus and its complications pretenses the foremost health threat globally. Diabetic nephropathy is the notable complication in diabetes, leading to end-stage renal disease (ESRD) and premature death. Abundant experimental evidence indicates that oxidative stress and inflammation are the important mediators in diabetic kidney diseases and interlinked with various signal transduction molecular mechanisms. Inflammasomes are the critical components of innate immunity and are recognized as a critical mediator of inflammation and autoimmune disorders. NOD-like receptor protein 3 (NLRP3) inflammasome is the well-characterized protein and it exhibits the sterile inflammation through the regulation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 production in tissues. In recent years, the role of NLRP3 inflammasome in the pathophysiology of diabetic kidney diseases in both clinical and experimental studies has generated great interest. In the current review, we focused on and discussed the role of NLRP3 inflammasome in diabetic nephropathy. A literature review was performed using online databases namely, PubMed, Scopus, Google Scholar and Web of science to explore the possible pharmacological interventions that blunt the NLRP3 inflammasome-caspase-1-IL-1β/IL-18 axis and shown to have a beneficial effect in diabetic kidney diseases. This review describes the inhibition of NLRP3 inflammasome activation as a promising therapeutic target for drug discovery in future.
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Affiliation(s)
- Chetan Ram
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Ankush Kumar Jha
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Aparajita Ghosh
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Shobhit Gairola
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Abu Mohammad Syed
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Upadhyayula Suryanarayana Murty
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - V G M Naidu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Bidya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India.
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35
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Shiono A, Sasaki H, Sekine R, Abe Y, Matsumura Y, Inagaki T, Tanaka T, Kodama T, Aburatani H, Sakai J, Takagi H. PPARα activation directly upregulates thrombomodulin in the diabetic retina. Sci Rep 2020; 10:10837. [PMID: 32616724 PMCID: PMC7331602 DOI: 10.1038/s41598-020-67579-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 06/08/2020] [Indexed: 12/19/2022] Open
Abstract
Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.
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Affiliation(s)
- Akira Shiono
- Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan
| | - Hiroki Sasaki
- Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan
| | - Reio Sekine
- Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan
| | - Yohei Abe
- Division of Metabolic Medicine, The University of Tokyo, RCAST, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan
| | - Yoshihiro Matsumura
- Division of Metabolic Medicine, The University of Tokyo, RCAST, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan
| | - Takeshi Inagaki
- Laboratory of Epigenetics and Metabolism, IMCR, Gunma University, 3-39-15 Showa-cho, Maebashi, Gunma, Japan
| | - Toshiya Tanaka
- Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan
| | - Tatsuhiko Kodama
- Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan
| | - Juro Sakai
- Division of Metabolic Medicine, The University of Tokyo, RCAST, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.,Molecular Physiology and Metabolism Division, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba, Sendai, Miyagi, Japan
| | - Hitoshi Takagi
- Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan.
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36
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Yamato M, Asahina Y, Koizumi S, Shigeki T, Yajima A, Kimura Y, Iwatani H. Lactate predicts the 28-day survival rate in patients with septic shock treated with the combination of PMX-DHP and rTM. Ther Apher Dial 2020; 24:492-498. [PMID: 32524733 DOI: 10.1111/1744-9987.13544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We have previously reported that combination therapy with polymyxin-B direct hemoperfusion (PMX-DHP) and recombinant thrombomodulin (rTM) is effective in patients with septic shock accompanied by disseminated intravascular coagulation (DIC). Two previous studies reporting the favorable effect of early initiation of PMX-DHP for septic shock did not focus on the combination therapy of PMX-DHP and rTM. This retrospective study included 47 consecutive patients who underwent the combination therapy of PMX-DHP and rTM for septic shock with DIC from August 2011 to August 2016. Main exposure was early or late initiation of PMX-DHP. PMX-DHP initiated within 12 hours after catecholamine administration was designated as early group (N = 25) and later than 12 hours as late group (N = 22). Main outcome was 28-day survival rate. The patient characteristics were age median 73 (IQR 68-78) years, 26 men (55%), APACHE II score 32.7 ± 7.7 and lactate 26.0 (18.0-41.0) mg/dL. The 28-day survival rate after PMX-DHP initiation was 76.6% and was not significantly different in the two groups. In the early group, APACHE II score was lower (P = .02), and lactate was higher (P = .005) than in the late group. Lactate was the only predictor of 28-day mortality [odds ratio (95%CI) per 1 mg/dL, 1.08 (1.03-1.19); P = .037] in multivariate logistic regression analysis adjusted with age, sex, APACHE II score, lactate and timing of PMX-DHP initiation. Late PMX-DHP initiation did not lead to statistically worse 28-day survival rate in this combination therapy. The combination therapy of PMX-DHP and rTM may improve the therapeutic effect of PMX-DHP and modify the effect of early PMX-DHP on the prognosis. Lactate may be an appropriate indicator rather than time after catecholamine administration if we discuss when to start PMX-DHP in this combination therapy.
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Affiliation(s)
- Masafumi Yamato
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yuta Asahina
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Shintaro Koizumi
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Takatomo Shigeki
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Ayako Yajima
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yoshiki Kimura
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Hirotsugu Iwatani
- Department of Nephrology, National Hospital Organization Osaka National Hospital, Osaka, Japan
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Pan B, Gao J, Chen W, Liu C, Shang L, Xu M, Fu C, Zhu S, Niu M, Xu K. Selective inhibition of interleukin-1 receptor-associated kinase 1 ameliorates lipopolysaccharide-induced sepsis in mice. Int Immunopharmacol 2020; 85:106597. [PMID: 32422509 DOI: 10.1016/j.intimp.2020.106597] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/29/2020] [Accepted: 05/10/2020] [Indexed: 12/26/2022]
Abstract
Interleukin-1 receptor-associated kinases (IRAKs), particularly IRAK1 and IRAK4, are important in transducing signal from Toll-like receptor 4. We interrogated if a selective inhibition of IRAK1 could alleviate lipopolysaccharide (LPS)-induced sepsis. In this study, we tested the impact of a novel selective IRAK1 inhibitor Jh-X-119-01 on LPS-induced sepsis in mice. Survival at day 5 was 13.3% in control group where septic mice were treated by vehicle, while the values were 37.5% (p = 0.046, vs. control) and 56.3% (p = 0.003, vs. control) for 5 mg/kg and 10 mg/kg Jh-X-119-01-treated mice. Jh-X-119-01 alleviated lung injury and reduced production of TNFα and IFNγ in peritoneal macrophages. Jh-X-119-01 decreased phosphorylation of NF-κB and mRNA levels of IL-6 and TNFα in LPS-treated macrophages in vitro. Jh-X-119-01 selectively inhibited IRAK1 phosphorylation comparing with a non-selective IRAK1/4 inhibitor which simultaneously inhibited phosphorylation of IRAK1 and IRAK4. Both Jh-X-119-01 and IRAK1/4 inhibitor increased survival of septic mice, but Jh-X-119-01-treated mice had higher blood CD11b+ cell counts than IRAK1/4 inhibitor-treated ones [24 h: (1.18 ± 0.26) × 106/ml vs. (0.79 ± 0.20) × 106/ml, p = 0.001; 48 h: (1.00 ± 0.30) × 106/ml vs. (0.67 ± 0.23) × 106/ml, p = 0.042]. IRAK1/4 inhibitor induced more apoptosis of macrophages than Jh-X-119-01 did in vitro. IRAK1/4 inhibitor decreased protein levels of anti-apoptotic BCL-2 and MCL-1 in RAW 264.7 and THP-1 cells, an effect not seen in Jh-X-119-01-treated cells. In conclusion, Jh-X-119-01 selectively inhibited activation of IRAK1 and protected mice from LPS-induced sepsis. Jh-X-119-01 showed less toxicity on macrophages comparing with a non-selective IRAK1/4 inhibitor.
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Affiliation(s)
- Bin Pan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China
| | - Jun Gao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Wei Chen
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China
| | - Cong Liu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Longmei Shang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
| | - Mengdi Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China
| | - Chunling Fu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China
| | - Shengyun Zhu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China
| | - Mingshan Niu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
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Thrombomodulin induces anti-inflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo. J Pharmacol Sci 2020; 143:17-22. [PMID: 32122774 DOI: 10.1016/j.jphs.2020.01.001] [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] [Received: 06/09/2019] [Revised: 10/08/2019] [Accepted: 10/17/2019] [Indexed: 12/30/2022] Open
Abstract
Thrombomodulin (TM) is an integral membrane protein expressed on the surface of vascular endothelial cells that suppresses blood coagulation. Recent studies have shown that TM exhibits anti-inflammatory effects by inhibiting leukocyte recruitment. However, the actual modes of action of TM in vivo remain unclear. Here, we describe the pharmacological effects of recombinant human soluble TM (TM alfa) on leukocyte dynamics in living mice using intravital imaging techniques. Under control conditions, neutrophils exhibited three distinct types of adhesion behavior in vessels: 1) "non-adhesion", in which cells flowed without vessel adhesion; 2) "rolling adhesion", in which cells transiently interacted with the endothelium; and 3) "tight binding", in which cells bound strongly to the endothelial cells. Compared to control conditions, local lipopolysaccharide stimulation resulted in an increased frequency of rolling adhesion that was not homogeneously distributed on vessel walls but occurred at specific endothelial sites. Under inflammatory conditions, TM alfa, particularly the D1 domain which is a lectin-like region of TM, significantly decreased the frequency of rolling adhesion, but did not influence the number of tight bindings. This was the first study to demonstrate that TM alfa exerts anti-inflammatory effects by inhibiting rolling adhesion of neutrophils to vascular endothelial cells in living mice.
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Watanabe-Kusunoki K, Nakazawa D, Kusunoki Y, Kudo T, Hattanda F, Nishio S, Masuda S, Tomaru U, Kondo T, Atsumi T, Ishizu A. Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection. J Autoimmun 2019; 108:102390. [PMID: 31883830 DOI: 10.1016/j.jaut.2019.102390] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/10/2019] [Accepted: 12/13/2019] [Indexed: 12/13/2022]
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing vasculitis with the presence of pathogenic ANCA. ANCA can potentially cause neutrophil activation and induce neutrophil extracellular traps (NETs), resulting in endothelial damage as well as activation of autoreactive B cells and alternative complement pathway. Recombinant thrombomodulin (rTM) protects the endothelium from vascular injury during disseminated intravascular coagulation, thus we hypothesized that rTM ameliorates necrotizing vasculitis in AAV. In this study, rTM was administered in an experimental AAV rat model. Treatment of experimental AAV rats with rTM improved pulmonary hemorrhage and glomerulonephritis, with a suppression of ANCA production and NETs formation. In addition, in vitro experiments showed that rTM bound to neutrophils via Mac-1 (macrophage-1 antigen) and inhibited ANCA-induced NETs formation accompanied by a suppression of histone citrullination, leading to a protection of the endothelium from NETs toxicity. Additionally, rTM affected lymphocytes leading to the inhibition of pro-inflammatory cytokine/chemokin in PBMC during the antibody production process, which might indirectly be involved in the reduction of pathogenic ANCA. Our data revealed that the rTM could ameliorate autoimmune vasculitis through a combination of different biological mechanisms.
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Affiliation(s)
- Kanako Watanabe-Kusunoki
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Daigo Nakazawa
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Yoshihiro Kusunoki
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takashi Kudo
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Fumihiko Hattanda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Saori Nishio
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Sakiko Masuda
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Utano Tomaru
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takeshi Kondo
- Department of Hematology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akihiro Ishizu
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
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Imaura M, Tsumori M, Nagase S, Omura K, Takahashi H, Hatoyama-Tanaka S, Katagiri F, Takayanagi R, Kanno H, Yamada Y. Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation. Shock 2019; 54:50-55. [DOI: 10.1097/shk.0000000000001477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Lee GH, Chang CL, Chiu WT, Hsiao TH, Chen PY, Wang KC, Kuo CH, Chen BH, Shi GY, Wu HL, Fu TF. A thrombomodulin-like gene is crucial to the collective migration of epibolic blastomeres during germ layer formation and organogenesis in zebrafish. J Biomed Sci 2019; 26:60. [PMID: 31451113 PMCID: PMC6709559 DOI: 10.1186/s12929-019-0549-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/25/2019] [Indexed: 12/02/2022] Open
Abstract
Background Thrombomodulin (TM), an integral membrane protein, has long been known for its anticoagulant activity. Recent studies showed that TM displays multifaceted activities, including the involvement in cell adhesion and collective cell migration in vitro. However, whether TM contributes similarly to these biological processes in vivo remains elusive. Methods We adapted zebrafish, a prominent animal model for studying molecular/cellular activity, embryonic development, diseases mechanism and drug discovery, to examine how TM functions in modulating cell migration during germ layer formation, a normal and crucial physiological process involving massive cell movement in the very early stages of life. In addition, an in vivo assay was developed to examine the anti-hemostatic activity of TM in zebrafish larva. Results We found that zebrafish TM-b, a zebrafish TM-like protein, was expressed mainly in vasculatures and displayed anti-hemostatic activity. Knocking-down TM-b led to malformation of multiple organs, including vessels, heart, blood cells and neural tissues. Delayed epiboly and incoherent movement of yolk syncytial layer were also observed in early TM-b morphants. Whole mount immunostaining revealed the co-localization of TM-b with both actin and microtubules in epibolic blastomeres. Single-cell tracking revealed impeded migration of blastomeres during epiboly in TM-b-deficient embryos. Conclusion Our results showed that TM-b is crucial to the collective migration of blastomeres during germ layer formation. The structural and functional compatibility and conservation between zebrafish TM-b and mammalian TM support the properness of using zebrafish as an in vivo platform for studying the biological significance and medical use of TM. Electronic supplementary material The online version of this article (10.1186/s12929-019-0549-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Gang-Hui Lee
- The Institute of Basic Medical Science College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Lin Chang
- Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan.,Cardiovascular Research Center College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Tai Chiu
- Department of Biomedical Engineering College of Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Tsun-Hsien Hsiao
- The Institute of Basic Medical Science College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Yuan Chen
- The Institute of Basic Medical Science College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuan-Chieh Wang
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University College of Medicine, Tainan, Taiwan.,Department of Food Safety/ Hygiene and Risk Management College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pharmacy College of Pharmacy and Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Cheng-Hsiang Kuo
- Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Bing-Hung Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.,The Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Guey-Yueh Shi
- The Institute of Basic Medical Science College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan.,Cardiovascular Research Center College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hua-Lin Wu
- The Institute of Basic Medical Science College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan. .,Cardiovascular Research Center College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Tzu-Fun Fu
- The Institute of Basic Medical Science College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University College of Medicine, Tainan, Taiwan.
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42
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Ito T, Thachil J, Asakura H, Levy JH, Iba T. Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2019; 23:280. [PMID: 31416465 PMCID: PMC6694689 DOI: 10.1186/s13054-019-2552-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 07/23/2019] [Indexed: 12/11/2022]
Abstract
Thrombomodulin plays a vital role in maintaining intravascular patency due to its anticoagulant, antiinflammatory, and cytoprotective properties. However, under pathological conditions such as sepsis and systemic inflammation, endothelial thrombomodulin expression is downregulated and its function impaired. As a result, administering thrombomodulin represents a potential therapeutic modality. Recently, the effect of recombinant thrombomodulin administration in sepsis-induced coagulopathy was evaluated in a randomized controlled study (SCARLET). A 2.6% 28-day absolute mortality reduction (26.8% vs. 29.4%) was reported in 800 patients studied that was not statistically significant; however, a post hoc analysis revealed a 5.4% absolute mortality reduction among the patients who fulfilled the entry criterion at baseline. The risk of bleeding did not increase compared to placebo control. Favorable effects of thrombomodulin administration have been reported not only in sepsis-induced coagulopathy but also in disseminated intravascular coagulations with various backgrounds. Interestingly, beneficial effects of recombinant thrombomodulin in respiratory, renal, and cardiovascular diseases might depend on its anti-inflammatory mechanisms. In this review, we summarize the accumulated knowledge of endogenous as well as recombinant thrombomodulin from basic to clinical aspects and suggest future directions for this novel therapeutic agent.
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Affiliation(s)
- Takashi Ito
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
| | - Jecko Thachil
- Department of Haematology, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Hidesaku Asakura
- Third Department of Internal Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Jerrold H Levy
- Department of Anesthesiology, Critical Care and Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Toshiaki Iba
- Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Khan KA, McMurray JL, Mohammed F, Bicknell R. C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation. FEBS J 2019; 286:3299-3332. [PMID: 31287944 PMCID: PMC6852297 DOI: 10.1111/febs.14985] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 05/21/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023]
Abstract
The C‐type lectin domain (CTLD) group 14 family of transmembrane glycoproteins consist of thrombomodulin, CD93, CLEC14A and CD248 (endosialin or tumour endothelial marker‐1). These cell surface proteins exhibit similar ectodomain architecture and yet mediate a diverse range of cellular functions, including but not restricted to angiogenesis, inflammation and cell adhesion. Thrombomodulin, CD93 and CLEC14A can be expressed by endothelial cells, whereas CD248 is expressed by vasculature associated pericytes, activated fibroblasts and tumour cells among other cell types. In this article, we review the current literature of these family members including their expression profiles, interacting partners, as well as established and speculated functions. We focus primarily on their roles in the vasculature and inflammation as well as their contributions to tumour immunology. The CTLD group 14 family shares several characteristic features including their ability to be proteolytically cleaved and engagement of some shared extracellular matrix ligands. Each family member has strong links to tumour development and in particular CD93, CLEC14A and CD248 have been proposed as attractive candidate targets for cancer therapy.
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Affiliation(s)
- Kabir A Khan
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Canada
| | - Jack L McMurray
- Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Fiyaz Mohammed
- Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Roy Bicknell
- Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, UK
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van Leeuwen-Kerkhoff N, Westers TM, Poddighe PJ, de Gruijl TD, Kordasti S, van de Loosdrecht AA. Thrombomodulin-expressing monocytes are associated with low-risk features in myelodysplastic syndromes and dampen excessive immune activation. Haematologica 2019; 105:961-971. [PMID: 31273091 PMCID: PMC7109736 DOI: 10.3324/haematol.2019.219303] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/02/2019] [Indexed: 12/13/2022] Open
Abstract
The bone marrow of patients with low-risk myelodysplastic syndromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response generally contributes to antitumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an important aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and destabilizing inflammation in lower-risk disease. In this study we investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of MDS patients in different risk groups. Patient-derived classical monocytes showed high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombomodulin. The presence of thrombomodulin on monocytes from MDS patients correlated with lower-risk disease groups and better overall and leukemia-free survival. Using multidimensional mass cytometry, in an in-vitro setting, we showed that thrombomodulin-positive monocytes could polarize naïve T cells toward cell clusters which are closer to T helper type 2 and T regulatory cell phenotypes and less likely to contribute to effective immune surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low-risk MDS and may represent a new mechanism in the protection against disproportionate immune activation.
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Affiliation(s)
| | - Theresia M Westers
- Department of Hematology, Amsterdam UMC, Cancer Center Amsterdam, the Netherlands
| | - Pino J Poddighe
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam, the Netherlands
| | - Tanja D de Gruijl
- Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, the Netherlands
| | - Shahram Kordasti
- Comprehensive Cancer Center, King's College London and Guy's Hospital, London, UK
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Thrombomodulin Regulation of Mitogen-Activated Protein Kinases. Int J Mol Sci 2019; 20:ijms20081851. [PMID: 30991642 PMCID: PMC6514922 DOI: 10.3390/ijms20081851] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 04/08/2019] [Accepted: 04/13/2019] [Indexed: 12/12/2022] Open
Abstract
The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs.
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46
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Jayathilake C, Maini PK, Hopf HW, Sean McElwain DL, Byrne HM, Flegg MB, Flegg JA. A mathematical model of the use of supplemental oxygen to combat surgical site infection. J Theor Biol 2019; 466:11-23. [PMID: 30659823 DOI: 10.1016/j.jtbi.2019.01.021] [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: 06/04/2018] [Revised: 12/13/2018] [Accepted: 01/11/2019] [Indexed: 11/26/2022]
Abstract
Infections are a common complication of any surgery, often requiring a recovery period in hospital. Supplemental oxygen therapy administered during and immediately after surgery is thought to enhance the immune response to bacterial contamination. However, aerobic bacteria thrive in oxygen-rich environments, and so it is unclear whether oxygen has a net positive effect on recovery. Here, we develop a mathematical model of post-surgery infection to investigate the efficacy of supplemental oxygen therapy on surgical-site infections. A 4-species, coupled, set of non-linear partial differential equations that describes the space-time dependence of neutrophils, bacteria, chemoattractant and oxygen is developed and analysed to determine its underlying properties. Through numerical solutions, we quantify the efficacy of different supplemental oxygen regimes on the treatment of surgical site infections in wounds of different initial bacterial load. A sensitivity analysis is performed to investigate the robustness of the predictions to changes in the model parameters. The numerical results are in good agreement with analyses of the associated well-mixed model. Our model findings provide insight into how the nature of the contaminant and its initial density influence bacterial infection dynamics in the surgical wound.
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Affiliation(s)
| | - Philip K Maini
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom.
| | | | - D L Sean McElwain
- School of Mathematical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
| | - Helen M Byrne
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom.
| | - Mark B Flegg
- School of Mathematical Sciences, Monash University, Australia.
| | - Jennifer A Flegg
- School of Mathematics and Statistics, University of Melbourne, Australia.
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Duffy binding-like 1α adhesin from Plasmodium falciparum recognizes ABH histo-blood group saccharide in a type specific manner. Carbohydr Polym 2019; 207:266-275. [PMID: 30600009 DOI: 10.1016/j.carbpol.2018.11.082] [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: 06/21/2018] [Revised: 10/30/2018] [Accepted: 11/25/2018] [Indexed: 11/20/2022]
Abstract
The ability of erythrocytes, infected by Plasmodium falciparum, to adhere to endothelial cells (cytoadherence) and to capture uninfected erythrocyte (rosetting) is the leading cause of death by severe malaria. Evidences link the binding of the adhesin Duffy Binding Like1-α (DBL1α) domain to the ABH histo-blood antigens with formation of rosettes. Inspired by this very close relationship between the disease susceptibility and individual blood type, here we investigate the structural requirements involved in the interaction of DBL1α with A, B and H histo-blood determinants and their subtypes. Our results evidence the high preference of DBL1α to A epitopes, in comparison to B and H epitopes. DBL1α interacts with ABH epitopes in subtype specific manner, presenting a remarkable affinity for type 2 structures, Fucα1-2Galβ1-4GlcNAcβ1, particularly the A2 epitope. The contacts made by DBL1α binding pocket and the ABH histo-blood groups were mapped by theoretical methods and supported by NMR experiments.
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Kawamoto E, Nago N, Okamoto T, Gaowa A, Masui-Ito A, Sakakura Y, Akama Y, Soe ZY, Prajuabjinda O, Darkwah S, Appiah MG, Myint PK, Obeng G, Park EJ, Imai H, Shimaoka M. Anti-adhesive effects of human soluble thrombomodulin and its domains. Biochem Biophys Res Commun 2019; 511:312-317. [PMID: 30777333 DOI: 10.1016/j.bbrc.2019.02.041] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 02/08/2019] [Indexed: 11/29/2022]
Abstract
We reported previously that leukocyte β2 integrins (LFA-1 and Mac-1) bind to the serine/threonine-rich domain of thrombomodulin (TM) expressed on vascular endothelial cells (VECs). Recombinant human soluble TM (rhsTM, TMD123) has been approved as a therapeutic drug for septic disseminated intravascular coagulation. However, the roles of TMD123 on the adhesion of leukocyte integrins to VECs remain unclear. In the current study, we have revealed that an integrin-dependent binding between human peripheral blood mononuclear cells (PBMCs) and VECs was inhibited by TMD123. Next, using mutant proteins composed of isolated TM extracellular domains, we examined the structural characteristics responsible for the anti-adhesion properties of TMD123. Namely, we investigated whether the effects of the binding of TM and leukocytes was inhibited by the administration of TMD123. In fact, we confirmed that TMD123, TMD1, and TMD3 inhibited the binding of PBMCs to the immobilized recombinant proteins TMD123 and TMD3. These results indicate that TMD123 inhibited the adhesion of leukocytes to endothelial cells via β2 integrins and endothelial TM. Moreover, since TMD1 might bind to leukocytes via other adhesion receptors than integrins, TMD1 and TMD3 appear to inhibit leukocyte binding to TM on VECs via different mechanisms. In summary, TMD123 (rhsTM), TMD1 or TMD3 is a promising treatment option for sepsis that attenuates integrin-dependent binding of leukocytes to VECs, and may inhibit the undesirable adhesion and migration of leukocytes to VECs in sepsis.
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Affiliation(s)
- Eiji Kawamoto
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan; Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan.
| | - Nodoka Nago
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan; Department of Clinical Nutrition, Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishioka, Suzuka-city, Mie, 510-0293, Japan
| | - Takayuki Okamoto
- Department of Pharmacology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo-city, Shimane, 693-8501, Japan
| | - Arong Gaowa
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Asami Masui-Ito
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan; Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Yosuke Sakakura
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Yuichi Akama
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan; Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Zay Yar Soe
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Onmanee Prajuabjinda
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Samuel Darkwah
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Michael G Appiah
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Phyoe Kyawe Myint
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Gideon Obeng
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Eun Jeong Park
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Hiroshi Imai
- Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan
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Festoff BW, Citron BA. Thrombin and the Coag-Inflammatory Nexus in Neurotrauma, ALS, and Other Neurodegenerative Disorders. Front Neurol 2019; 10:59. [PMID: 30804878 PMCID: PMC6371052 DOI: 10.3389/fneur.2019.00059] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/17/2019] [Indexed: 12/15/2022] Open
Abstract
This review details our current understanding of thrombin signaling in neurodegeneration, with a focus on amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) as well as future directions to be pursued. The key factors are multifunctional and involved in regulatory pathways, namely innate immune and the coagulation cascade activation, that are essential for normal nervous system function and health. These two major host defense systems have a long history in evolution and include elements and regulators of the coagulation pathway that have significant impacts on both the peripheral and central nervous system in health and disease. The clotting cascade responds to a variety of insults to the CNS including injury and infection. The blood brain barrier is affected by these responses and its compromise also contributes to these detrimental effects. Important molecules in signaling that contribute to or protect against neurodegeneration include thrombin, thrombomodulin (TM), protease activated receptor 1 (PAR1), damage associated molecular patterns (DAMPs), such as high mobility group box protein 1 (HMGB1) and those released from mitochondria (mtDAMPs). Each of these molecules are entangled in choices dependent upon specific signaling pathways in play. For example, the particular cleavage of PAR1 by thrombin vs. activated protein C (APC) will have downstream effects through coupled factors to result in toxicity or neuroprotection. Furthermore, numerous interactions influence these choices such as the interplay between HMGB1, thrombin, and TM. Our hope is that improved understanding of the ways that components of the coagulation cascade affect innate immune inflammatory responses and influence the course of neurodegeneration, especially after injury, will lead to effective therapeutic approaches for ALS, traumatic brain injury, and other neurodegenerative disorders.
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Affiliation(s)
- Barry W Festoff
- pHLOGISTIX LLC, Fairway, KS, United States.,Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Bruce A Citron
- Laboratory of Molecular Biology Research & Development, VA New Jersey Health Care System, East Orange, NJ, United States.,Department of Pharmacology, Physiology & Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, United States
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Ookura M, Hosono N, Tasaki T, Oiwa K, Fujita K, Ito K, Lee S, Matsuda Y, Morita M, Tai K, Negoro E, Kishi S, Iwasaki H, Ueda T, Yamauchi T. Successful treatment of disseminated intravascular coagulation by recombinant human soluble thrombomodulin in patients with acute myeloid leukemia. Medicine (Baltimore) 2018; 97:e12981. [PMID: 30383650 PMCID: PMC6221668 DOI: 10.1097/md.0000000000012981] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Disseminated intravascular coagulation (DIC) is a life-threatening condition that frequently occurs in patients with hematologic malignancies. Currently, recombinant human soluble thrombomodulin (rTM) is a therapeutic DIC drug that is manufactured and sold in Japan only. We evaluated the efficacy of rTM compared to that of gabexate mesilate (GM), which was previously used routinely for treating DIC in Japan, in patients with acute myeloid leukemia (AML). This retrospective study enrolled 43 AML patients, including 17 with acute promyelocytic leukemia (APL), that was complicated with DIC. DIC resolution rates in non-APL AML and rTM-treated APL patients were 68.4% and 81.8%, respectively. In non-APL AML patients, the duration of rTM administration was significantly shorter than that of GM (7 vs 11 days), suggesting that rTM could improve DIC earlier than GM, although rTM was used in patients with more severe DIC. Moreover, treatment with rTM significantly improved DIC score, fibrinogen, fibrin/fibrinogen degradation product (FDP), and prothrombin time (PT) ratio. Conversely, treatment with GM only improved the DIC score and FDP. In APL patients, the duration of rTM administration was also significantly shorter than that of GM. No severe side effects associated with the progression of bleeding were observed during rTM administration. These findings suggest that rTM is safe, and its anti-DIC effects are more prompt than GM for treating AML patients with DIC.
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Affiliation(s)
- Miyuki Ookura
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Naoko Hosono
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Toshiki Tasaki
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Kana Oiwa
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Kei Fujita
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Kazuhiro Ito
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Shin Lee
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Yasufumi Matsuda
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Mihoko Morita
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Katsunori Tai
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Eiju Negoro
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
| | - Shinji Kishi
- Department of Health and Nutrition, Jin-ai University
| | | | | | - Takahiro Yamauchi
- Department of Hematology and Oncology, Faculty of Medical Science, University of Fukui
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