|
1
|
Pfeiffer S, Swoboda I. The allergenic potential of enolases: physiological and pathophysiological insights. Curr Opin Allergy Clin Immunol 2025; 25:212-219. [PMID: 40131768 PMCID: PMC12052056 DOI: 10.1097/aci.0000000000001068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
PURPOSE OF REVIEW This review gives an overview on the current knowledge of the physiological and pathophysiological features of enolases and how these features might contribute to the enzymes' allergenic properties. It summarizes the most recent literature on allergenic enolases and raises questions that need to be answered in the future to gain a better understanding of the role of enolases in allergic diseases. RECENT FINDINGS The recent identification of two novel allergenic enolases, from London plane tree and whiff, further supports the uniqueness of this allergen family: the occurrence of enolases in the three major kingdoms of life and the capability to induce allergic symptoms via inhalation, ingestion, and skin contact. SUMMARY The importance and uniqueness of enolases as allergenic molecules is widely accepted. However, studies linking the biochemical and physiological features of enolases with their potential to induce allergies are still needed. This would contribute to a better understanding about the role of enolases in the induction of allergic diseases, to improve specificity and sensitivity of allergy diagnosis and to further enable the development of patient-tailored prophylactic and therapeutic approaches.
Collapse
Affiliation(s)
- Sandra Pfeiffer
- The Molecular Biotechnology Section, Department Applied Life Sciences, FH Campus Wien, University of Applied Sciences, Vienna, Austria
| | | |
Collapse
|
|
2
|
Li ZX, Wang YF, Chiang LT, Hsu LJ, Wang SM, Wang JR, Wu HL, Chen SH, Chang CF. Plasminogen deficiency reduces disease severity and immune responses in enterovirus A71-infected mice. Microbiol Spectr 2025:e0331124. [PMID: 40377310 DOI: 10.1128/spectrum.03311-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 04/04/2025] [Indexed: 05/18/2025] Open
Abstract
Enterovirus A71 (EV-A71) is a causative agent of hand, foot, and mouth diseases. EV-A71 infections may result in severe neurological complications in children. Although several receptors or attachment molecules for EV-A71 have been identified, EV-A71 can still infect host cells even after blocking these receptors with antibodies. We have previously identified plasminogen (PLG), a circulating zymogen of plasmin, as a cell membrane-associated EV-A71-interacting glycoprotein. We confirmed that anti-PLG antibodies could reduce the binding of EV-A71 to RD cells as anti-SCARB2 and anti-nucleolin. Knockdown of PLG reduced EV-A71 binding to RD cells, and preincubation of PLG with EV-A71 increased virus binding. Enzyme-linked immunosorbent assay and surface plasmon resonance assays demonstrated the direct binding of PLG to EV-A71. We further evaluated the biological characteristics of EV-A71-infected PLG knockout (heterozygous) and wild-type mice. We found that the clinical scores and mortality of WT mice were higher than those of PLG-knockout mice after EV-A71 infection. The viral loads in the spinal cord of PLG knockout mice were lower than those in WT mice 6 days post-infection. EV-A71-associated cytokines such as IL-1β, IL-6, MCP-1, IL-10, and IFN-γ were investigated. Serum IL-10 and MCP-1 expression were significantly higher in EV-71-infected WT mice than in PLG knockout mice, and MCP-1 may be one of the critical chemokines that induce intense inflammation and chemoattracts leukocytes. Our findings reveal a possible role for PLG in EV-A71 infection/pathogenesis and shed light on developing novel therapeutic approaches and drugs to prevent EV-A71 infection.IMPORTANCEUnderstanding the pathogenesis of enterovirus A71 (EV-A71) for developing novel drugs or therapeutic approaches has always been a significant issue. In this study, we demonstrated the interactions between plasminogen (PLG) and EV-A71, characterized the biological effects of EV-A71-infected PLG knockout mice, and evaluated their immune response. We found that EV-A71 caused more severe tissue damage than PLG knockout mice in skeletal muscle, spinal cord, and brain stem. Higher virus protein was observed in these tissues of WT mice. The reduced clinical scores, mortality, and cytokine expression suggested PLG may be involved in EV-A71 infection-induced cytokine storm. The findings and animal model in the current study provide the new drug target for anti-EV-A71 drug discovery.
Collapse
Affiliation(s)
- Zheng-Xun Li
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Ya-Fang Wang
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan City, Taiwan
| | - Li-Ting Chiang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Li-Jin Hsu
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Shih-Min Wang
- Department of Pediatric, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Jen-Ren Wang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Hua-Lin Wu
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Shun-Hua Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Chuan-Fa Chang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- University Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan City, Taiwan
| |
Collapse
|
|
3
|
Hucklesby JJW, Angel CE, Graham ES, Dunbar PR, Birch NP, Loef EJ. Plasmin reduces human T cell arrest on endothelial-like cells by cleaving bound CCL21 from the cell surface. Exp Cell Res 2025; 446:114480. [PMID: 40010560 DOI: 10.1016/j.yexcr.2025.114480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 02/16/2025] [Accepted: 02/22/2025] [Indexed: 02/28/2025]
Abstract
CCL21 is a key homeostatic chemokine best known for its role in lymphocyte homing and compartmentalization in the lymph node. CCL21 also plays a role in trans-endothelial migration and is known to be bound to the surface of endothelial cells in high endothelial venules and inflamed tissues. The effects of CCL21 are highly dependent on its form; full-length CCL21 can bind to the surface of endothelial cells and induce lymphocyte arrest and transendothelial migration, whereas truncated CCL21 cannot. Earlier literature indicates that plasmin can cleave CCL21 from the surface of immune cells, although the mechanism regulating this process on endothelial cells has not been studied. This study demonstrates that the human endothelial-like cell lines ECV304 (LS12) and HMEC-1 can bind the plasmin precursor plasminogen to their cell surface. Furthermore, ECV304 (LS12) cells could endogenously activate plasminogen, yielding plasmin that subsequently released cell surface CCL21. In contrast, cell-surface CCL21 was only released from HMEC-1 after exogenous tPA activated the surface-bound plasminogen. Finally, it was shown that plasmin reduced T cell adhesion to endothelial-like cells with cell surface CCL21 under shear stress conditions. Collectively, for the first time, these data demonstrate that plasmin can cleave endothelial cell surface CCL21, reducing T cell adhesion to endothelial cells under shear stress. Interestingly, this study also indicates that endothelial cells' differential expression of plasminogen activators may regulate plasmin availability and influence T-cell arrest.
Collapse
Affiliation(s)
- James Jack Willis Hucklesby
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Department of Molecular Medicine and Pathology, The University of Auckland, New Zealand
| | - Catherine Elizabeth Angel
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Euan Scott Graham
- Department of Molecular Medicine and Pathology, The University of Auckland, New Zealand; Centre for Brain Research and Brain Research New Zealand, Rangahau Roro Aotearoa, University of Auckland, Auckland, New Zealand
| | - Peter Rod Dunbar
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Nigel Peter Birch
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Centre for Brain Research and Brain Research New Zealand, Rangahau Roro Aotearoa, University of Auckland, Auckland, New Zealand
| | - Evert Jan Loef
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
| |
Collapse
|
|
4
|
Ponticelli C. Membranous Nephropathy. J Clin Med 2025; 14:761. [PMID: 39941432 PMCID: PMC11818350 DOI: 10.3390/jcm14030761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/19/2024] [Accepted: 12/24/2024] [Indexed: 02/16/2025] Open
Abstract
Membranous nephropathy is a glomerular disease that may be caused by exogenous risk factors in genetically predisposed individuals (primary MN) or may be associated with other autoimmune diseases, drug exposure, or cytotoxic agents (secondary MN). Primary membranous nephropathy (PMN) is an autoimmune disease in which antigens-mainly the phospholipase A2 receptor-are located in the podocytes and are targeted by circulating antibodies, leading to in situ formation of immune complexes that activate the complement system. Clinically, the disease is characterized by nephrotic syndrome (NS) and associated complications. The outcome of PMN can vary, but untreated patients with NS may progress to end-stage kidney disease (ESKD) in 35-40% of cases within 10 years. Treatment primarily aims to prevent NS complications and progression to ESKD. The most commonly used immunosuppressive drugs are rituximab, corticosteroids, cyclophosphamide, and calcineurin inhibitors. Most patients may experience an improvement of proteinuria, which can sometimes be followed by NS relapse. Fewer than 50% of patients with PMN achieve complete and stable remission. In addition to immunosuppressive therapy, antiproteinuric, anti-lipemic, and anticoagulant medicaments are often required.
Collapse
|
|
5
|
Okura GC, Bharadwaj AG, Waisman DM. Calreticulin-From the Endoplasmic Reticulum to the Plasma Membrane-Adventures of a Wandering Protein. Cancers (Basel) 2025; 17:288. [PMID: 39858072 PMCID: PMC11764459 DOI: 10.3390/cancers17020288] [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: 11/18/2024] [Revised: 01/11/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Calreticulin (CRT) is a 46 kDa highly conserved protein initially identified as calregulin, a prominent Ca2+-binding protein of the endoplasmic reticulum (ER). Subsequent studies have established that CRT functions in the ER's protein folding response and Ca2+ homeostatic mechanisms. An ER retention signal on the carboxyl terminus of CRT suggested that CRT was restricted to the ER. However, the identification of CRT in the nucleus and cytosol has established that CRT is a multi-compartmental, multifunctional protein. CRT also plays an important role in cancer progression. Most recently, CRT was identified on the cell surface and shown to be a potent 'eat-me' signal that plays a key role in the uptake of apoptotic and viable cancer cells by phagocytes. Elevated CRT exposure on the outer leaflet of cancer cells has been linked with anticancer immunity and superior therapeutic outcomes in patients with non-small cell lung carcinoma, colorectal carcinoma, acute myeloid leukemia, ovarian cancer, and high-grade serous carcinomas. Mutations in the CRT gene have been identified in a subset of patients with myeloproliferative neoplasms. The most recent studies from our laboratory have revealed a new and significant function for extracellular CRT as a plasminogen receptor. This discovery has profound implications for our understanding of the role of CRT in myeloproliferative neoplasms, specifically, essential thrombocythemia.
Collapse
Affiliation(s)
- Gillian C. Okura
- Department of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; (G.C.O.); (A.G.B.)
| | - Alamelu G. Bharadwaj
- Department of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; (G.C.O.); (A.G.B.)
| | - David M. Waisman
- Department of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; (G.C.O.); (A.G.B.)
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS B3H 1X5, Canada
| |
Collapse
|
|
6
|
Ngo TKN, Wu HL, Kuo CH, Tu TY. Studying the role of thrombomodulin-plasminogen interaction in spatial and interfacial invasion of melanoma metastatic progression. Int J Biol Macromol 2025; 284:138053. [PMID: 39592039 DOI: 10.1016/j.ijbiomac.2024.138053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/11/2024] [Accepted: 11/23/2024] [Indexed: 11/28/2024]
Abstract
Thrombomodulin (TM), a transmembrane glycoprotein, has emerged as a key factor in the metastatic spread of various cancers, including malignant melanoma. Despite its recognized significance, the underlying mechanisms of TM's involvement in enhancing metastasis remain incompletely understood. This study addresses this knowledge gap by utilizing spatial and interfacial invasion models in vitro to investigate the effect of the interaction between TM and plasminogen (Plg) on melanoma invasion. While it is well established that Plg induces a chain reaction in the plasmin system, leading to the activation of metalloproteases that promote tumor cell invasion and metastasis, this study is the first to demonstrate that TM binding to Plg can enhance these activations in spatial and interfacial invasion models in vitro. These results highlight the potential of TM as a crucial target for the development of drugs aimed at significantly inhibiting melanoma metastasis and improving patient survival.
Collapse
Affiliation(s)
- Thi Kim Ngan Ngo
- Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 70101, Taiwan
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University
| | - Cheng-Hsiang Kuo
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Ting-Yuan Tu
- Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 70101, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 70101, Taiwan; Medical Device Innovation Center, National Cheng Kung University, Tainan 70101, Taiwan.
| |
Collapse
|
|
7
|
Wang X, Wang M, Lin Q, He L, Zhang B, Chen X, Chen G, Du H, Lang C, Peng X, Dai Y. Osteoblast-Derived ECM1 Promotes Anti-Androgen Resistance in Bone Metastatic Prostate Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407662. [PMID: 39563492 PMCID: PMC11727142 DOI: 10.1002/advs.202407662] [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: 07/07/2024] [Revised: 10/14/2024] [Indexed: 11/21/2024]
Abstract
Acquired resistance to hormonal therapy, particularly enzalutamide (ENZ), remains a significant obstacle in the treatment of advanced bone metastatic prostate cancer. Here, it is demonstrated that under ENZ treatment, osteoblasts in the bone microenvironment secrete increased levels of extracellular matrix protein 1 (ECM1), which affects surrounding prostate cancer cells, promoting tumor cell proliferation and anti-androgen resistance. Mechanistically, ECM1 interacts with the enolase 1 (ENO1) receptor on the prostate cancer cell membrane, leading to its phosphorylation at the Y189 site. This event further recruits adapter proteins including growth factor receptor-bound protein 2 (GRB2) and son of sevenless homolog 1 (SOS1), which activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway to induce anti-androgen resistance. Furthermore, inhibiting ECM1 or utilizing the ENO1-targeting inhibitor phosphonoacetohydroxamate (PhAH) significantly restores tumor cell sensitivity to ENZ. Taken together, a potential mechanism is identified through which osteoblast-derived ECM1 drives resistance in bone metastatic prostate cancer under ENZ treatment. Additionally, the findings indicate that ECM1 and ENO1 may serve as potential targets for developing therapies for bone metastatic castration-resistant prostate cancer.
Collapse
Affiliation(s)
- Xinwen Wang
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| | - Min Wang
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
- Department of PathologyGuangzhou First People's HospitalGuangzhou510080China
| | - Qijun Lin
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| | - Lixin He
- Department of Experimental ResearchState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Baolin Zhang
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| | - Xin Chen
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| | - Guanhong Chen
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| | - Hong Du
- Department of PathologyGuangzhou First People's HospitalGuangzhou510080China
| | - Chuandong Lang
- Department of OrthopedicsThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230001China
| | - Xinsheng Peng
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| | - Yuhu Dai
- Department of Orthopedic Surgerythe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhou510080China
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou510080China
| |
Collapse
|
|
8
|
Hou N, Zhou H, Li J, Xiong X, Deng H, Xiong S. Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm. Immun Inflamm Dis 2024; 12:e1268. [PMID: 39530309 PMCID: PMC11555488 DOI: 10.1002/iid3.1268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/03/2024] [Accepted: 04/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA. AIMS This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA. METHODS We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes. RESULTS The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA. CONCLUSION Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages.
Collapse
Affiliation(s)
- Ningxin Hou
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hongmin Zhou
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jun Li
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoxing Xiong
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hongping Deng
- Department of Vascular SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Sizheng Xiong
- Department of Vascular SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| |
Collapse
|
|
9
|
Kusakabe Y, Matsumoto K, Tsuyuki T, Hayashi Y, Watanabe H. Baicalin target protein, Annexin A2, is a target of new antitumor drugs. Sci Rep 2024; 14:21814. [PMID: 39294172 PMCID: PMC11410801 DOI: 10.1038/s41598-024-68528-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 07/24/2024] [Indexed: 09/20/2024] Open
Abstract
Baicalin is a flavonoid extracted from Scutellaria baicalensis Georgi. As it has significant antitumor and apoptosis-inducing effects, baicalin may be useful as a lead compound in new antitumor drug development. However, as the pharmacological actions of baicalin have yet to be elucidated, we isolated its target protein, which was successfully identified as Annexin A2. Annexin A2 forms a heterotetramer with S100A10 protein, which plays an important role in the plasminogen activator system. The heterotetramer bound to tissue plasminogen activator (tPA) activates the conversion of plasminogen to plasmin and promotes the expression of STAT-3 and NF-κB, which are target genes involved in the development of cancer. Moreover, NF-κB and STAT-3 induce the expression of cell inhibitors of apoptotic proteins and inhibit apoptosis. To examine whether these antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2, we prepared Annexin A2 knockdown HepG2 cells. We compared mRNA expression by RT-qPCR and apoptosis by caspase-3 activity assays in Annexin A2 knockdown HepG2 cells. The results showed that the antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2. The results of this study suggest that agents capable of inhibiting Annexin A2 may be useful candidates for the development of novel antitumor agents.
Collapse
Affiliation(s)
| | | | | | | | - Hideaki Watanabe
- Department of Dermatology, Showa University Northern Yokohama Hospital, Chigasakichuo, Tsuduki-ku, Yokohama City, Kanagawa, Japan.
| |
Collapse
|
|
10
|
Liu D, Li R, Wang Y, Li D, Li L. Identification and validation of genes associated with prognosis of cisplatin-resistant ovarian cancer. BMC Cancer 2024; 24:508. [PMID: 39103807 DOI: 10.1186/s12885-024-12264-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/15/2024] [Indexed: 08/07/2024] Open
Abstract
PURPOSE To investigate the role of prognostic genes related to cisplatin resistance in ovarian cancer during disease progression. METHOD The gene expression profile of the NCI-60 cell line was acquired through comprehensive analysis of the GEO database accession GSE116439. We performed a thorough analysis of gene expression differences in samples from seven individuals exposed to cisplatin concentrations of 0 nM compared to seven samples exposed to 15000 nM over a 24-h period. Key genes were initially identified through LASSO regression, followed by their enrichment through differential gene function analysis (GO) and pathway enrichment analysis (KEGG). Subsequently, a prognostic risk model was established for these key genes. The prognostic model's performance was assessed through K-M survival curves and ROC curves. To examine the variance in immune cell infiltration between the high and low-risk groups, CIBERSORTx analysis was employed. Finally, validation of prognostic gene expression in cisplatin-resistant ovarian cancer was carried out using clinical samples, employing RT-qPCR and Western Blot techniques. RESULTS A total of 132 differential genes were found between cisplatin resistance and control group, and 8 key prognostic genes were selected by analysis, namely VPS13B, PLGRKT, CDKAL1, TBC1D22A, TAP1, PPP3CA, CUX1 and PPP1R15A. The efficacy of the risk assessment model derived from prognostic biomarkers, as indicated by favorable performance on both Kaplan-Meier survival curves and ROC curves. Significant variations in the abundance of Macrophages M1, T cells CD4 memory resting, T cells follicular helper, and T cells gamma delta were observed between the high and low-risk groups. To further validate our findings, RT-qPCR and Western Blot analyses were employed, confirming differential expression of the identified eight key genes between the two groups. CONCLUSION VPS13B, TBC1D22A, PPP3CA, CUX1 and PPP1R15A were identified as poor prognostic genes of cisplatin resistance in ovarian cancer, while PLGRKT, CDKAL1 and TAP1 were identified as good prognostic genes. This offers a novel perspective for future advancements in ovarian cancer treatment, suggesting potential avenues for the development of new therapeutic targets.
Collapse
Affiliation(s)
- Dajiang Liu
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, China.
| | - Ruiyun Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yidan Wang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Dan Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Leilei Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| |
Collapse
|
|
11
|
Sabljic N, Thachil J, Pantic N, Mitrovic M. Hemorrhage in acute promyelocytic leukemia-fibrinolysis in focus. Res Pract Thromb Haemost 2024; 8:102499. [PMID: 39130779 PMCID: PMC11314889 DOI: 10.1016/j.rpth.2024.102499] [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] [Received: 11/16/2023] [Revised: 05/23/2024] [Accepted: 06/13/2024] [Indexed: 08/13/2024] Open
Abstract
Coagulopathy continues to be a major challenge in the management of patients with acute promyelocytic leukemia (APL). Novel differentiating agents have led to improved survival in these patients, but perturbations in coagulation continue to have an impact on their prognosis. The most worrisome of coagulation disturbances is bleeding, which is not an uncommon cause of early death in APL. Despite this, there are no consistent predictors of this high risk of fatal hemorrhage in APL. In this context, the fibrinolytic system has been identified as a crucial role player in APL coagulopathy. However, the current guidelines for the management of APL give little regard to tests that measure the fibrinolytic system while giving more importance to close monitoring of conventional coagulation tests and platelet counts to identify the coagulopathy. More recently, viscoelastic tests have come to usefulness in determining global hemostasis and have been widely used for "diagnosing" hyperfibrinolysis in selected clinical settings. In this review, we attempt to describe risk assessment models for diagnosing APL coagulopathy, describe the possible application of viscoelastic tests in this setting, and persuade clinicians to reconsider the use of antifibrinolytics to improve survival of APL patients.
Collapse
Affiliation(s)
- Nikica Sabljic
- Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Jecko Thachil
- Department of Hematology, Manchester Royal Infirmary, Manchester, United Kingdom
| | - Nikola Pantic
- Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Mirjana Mitrovic
- Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
|
12
|
de Matos Silva S, Echeverri CR, Mendes-Giannini MJS, Fusco-Almeida AM, Gonzalez A. Common virulence factors between Histoplasma and Paracoccidioides: Recognition of Hsp60 and Enolase by CR3 and plasmin receptors in host cells. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100246. [PMID: 39022313 PMCID: PMC11253281 DOI: 10.1016/j.crmicr.2024.100246] [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: 07/20/2024] Open
Abstract
Over the last two decades, the incidence of Invasive Fungal Infections (IFIs) globally has risen, posing a considerable challenge despite available antifungal therapies. Addressing this, the World Health Organization (WHO) prioritized research on specific fungi, notably Histoplasma spp. and Paracoccidioides spp. These dimorphic fungi have a mycelial life cycle in soil and a yeast phase associated with tissues of mammalian hosts. Inhalation of conidia and mycelial fragments initiates the infection, crucially transforming into the yeast form within the host, influenced by factors like temperature, host immunity, and hormonal status. Survival and multiplication within alveolar macrophages are crucial for disease progression, where innate immune responses play a pivotal role in overcoming physical barriers. The transition to pathogenic yeast, triggered by increased temperature, involves yeast phase-specific gene expression, closely linked to infection establishment and pathogenicity. Cell adhesion mechanisms during host-pathogen interactions are intricately linked to fungal virulence, which is critical for tissue colonization and disease development. Yeast replication within macrophages leads to their rupture, aiding pathogen dissemination. Immune cells, especially macrophages, dendritic cells, and neutrophils, are key players during infection control, with macrophages crucial for defense, tissue integrity, and pathogen elimination. Recognition of common virulence molecules such as heat- shock protein-60 (Hsp60) and enolase by pattern recognition receptors (PRRs), mainly via the complement receptor 3 (CR3) and plasmin receptor pathways, respectively, could be pivotal in host-pathogen interactions for Histoplasma spp. and Paracoccidioides spp., influencing adhesion, phagocytosis, and inflammatory regulation. This review provides a comprehensive overview of the dynamic of these two IFIs between host and pathogen. Further research into these fungi's virulence factors promises insights into pathogenic mechanisms, potentially guiding the development of effective treatment strategies.
Collapse
Affiliation(s)
- Samanta de Matos Silva
- Laboratory of Mycology, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
- Nucleous of Proteomics, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
- Basic and Applied Microbiology Group (MICROBA), School of Microbiology, Universidad de Antioquia (UdeA), Medellín, Colombia
| | - Carolina Rodriguez Echeverri
- Laboratory of Mycology, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
- Nucleous of Proteomics, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
- Basic and Applied Microbiology Group (MICROBA), School of Microbiology, Universidad de Antioquia (UdeA), Medellín, Colombia
| | - Maria José Soares Mendes-Giannini
- Laboratory of Mycology, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
- Nucleous of Proteomics, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
| | - Ana Marisa Fusco-Almeida
- Laboratory of Mycology, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
- Nucleous of Proteomics, Department of Clinical Analysis, School of Pharmaceutical Science, Paulista State University (UNESP), Araraquara, Brazil
| | - Angel Gonzalez
- Basic and Applied Microbiology Group (MICROBA), School of Microbiology, Universidad de Antioquia (UdeA), Medellín, Colombia
| |
Collapse
|
|
13
|
Kanno Y. The Roles of Fibrinolytic Factors in Bone Destruction Caused by Inflammation. Cells 2024; 13:516. [PMID: 38534360 PMCID: PMC10968824 DOI: 10.3390/cells13060516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 03/28/2024] Open
Abstract
Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis frequently result in bone destruction. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-17 are known to influence bone loss by promoting the differentiation and activation of osteoclasts. Fibrinolytic factors, such as plasminogen (Plg), plasmin, urokinase-type plasminogen activator (uPA), its receptor (uPAR), tissue-type plasminogen activator (tPA), α2-antiplasmin (α2AP), and plasminogen activator inhibitor-1 (PAI-1) are expressed in osteoclasts and osteoblasts and are considered essential in maintaining bone homeostasis by regulating the functions of both osteoclasts and osteoblasts. Additionally, fibrinolytic factors are associated with the regulation of inflammation and the immune system. This review explores the roles of fibrinolytic factors in bone destruction caused by inflammation.
Collapse
Affiliation(s)
- Yosuke Kanno
- Department of Molecular Pathology, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, 97-1 Kodo Kyotanabe, Kyoto 610-0395, Japan
| |
Collapse
|
|
14
|
Kristjansen KA, Engel Krag A, Schmidt H, Hölmich LR, Bønnelykke-Behrndtz ML. Perioperative treatment with tranexamic acid in melanoma (PRIME): protocol for a Danish multicentre randomised controlled trial investigating the prognostic and treatment-related impact of the plasminogen-plasmin pathway. BMJ Open 2024; 14:e077012. [PMID: 38309757 PMCID: PMC10840044 DOI: 10.1136/bmjopen-2023-077012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 01/18/2024] [Indexed: 02/05/2024] Open
Abstract
INTRODUCTION Inflammation is a hallmark of cancer and is involved in tumour growth and dissemination. However, the hallmarks of cancer are also the hallmarks of wound healing, and modulating the wound inflammatory response and immune contexture in relation to cancer surgery may represent effective targets of therapies.Repurposing anti-inflammatory drugs in a cancer setting has gained increasing interest in recent years. Interestingly, the known and thoroughly tested antifibrinolytic drug tranexamic acid reduces the risk of bleeding, but it is also suggested to play important roles in anti-inflammatory pathways, improving wound healing and affecting anti-carcinogenic mechanisms.As a novel approach, we will conduct a randomised controlled trial using perioperative treatment with tranexamic acid, aiming to prevent early relapses by >10% for patients with melanoma. METHODS AND ANALYSIS Design: investigator-initiated parallel, two-arm, randomised, blinded, Danish multicentre superiority trial. PATIENTS ≥T2 b melanoma and eligible for sentinel lymph node biopsy (n=1204).Project drug: tranexamic acid or placebo. TREATMENT before surgery (intravenous 15 mg/kg) and daily (peroral 1000 mg x 3) through postoperative day 4. PRIMARY OUTCOME relapse within 2 years after surgery.Primary analysis: risk difference between the treatment arms (χ2 test). SECONDARY OUTCOMES postoperative complications, adverse events and survival.Inclusion period: summer 2023 to summer 2026. ETHICS AND DISSEMINATION The trial will be initiated during the summer of 2023 and is approved by the National Committee on Health Research Ethics, the Danish Medicine Agency, and registered under the Data Protection Act. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Patients included in the study will adhere to normal Danish treatment protocols and standards of care, and we expect only mild and temporary side effects. Positive and negative results will be published in peer-reviewed journals, with authorships adhering to the Vancouver rules. TRIAL REGISTRATION NUMBER NCT05899465; ClinicalTrials.gov Identifier.
Collapse
Affiliation(s)
- Karoline Assifuah Kristjansen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Plastic and Breast Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - Andreas Engel Krag
- Department of Plastic and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik Schmidt
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Lisbet Rosenkrantz Hölmich
- Department of Plastic Surgery, Herlev Hospital, Herlev, Denmark
- Department of Clinical Medicine, Copenhagen University Hospital, Kobenhavn, Denmark
| | | |
Collapse
|
|
15
|
Bharadwaj AG, Okura GC, Woods JW, Allen EA, Miller VA, Kempster E, Hancock MA, Gujar S, Slibinskas R, Waisman DM. Identification and characterization of calreticulin as a novel plasminogen receptor. J Biol Chem 2024; 300:105465. [PMID: 37979915 PMCID: PMC10770727 DOI: 10.1016/j.jbc.2023.105465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/22/2023] [Accepted: 11/06/2023] [Indexed: 11/20/2023] Open
Abstract
Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular functions, including roles in calcium homeostasis and protein folding. Recently, several extracellular functions have been identified for CRT, including roles in cancer cell invasion and phagocytosis of apoptotic and cancer cells by macrophages. In the current report, we uncover a novel function for extracellular CRT and report that CRT functions as a plasminogen-binding receptor that regulates the conversion of plasminogen to plasmin. We show that human recombinant or bovine tissue-derived CRT dramatically stimulated the conversion of plasminogen to plasmin by tissue plasminogen activator or urokinase-type plasminogen activator. Surface plasmon resonance analysis revealed that CRT-bound plasminogen (KD = 1.8 μM) with moderate affinity. Plasminogen binding and activation by CRT were inhibited by ε-aminocaproic acid, suggesting that an internal lysine residue of CRT interacts with plasminogen. We subsequently show that clinically relevant CRT variants (lacking four or eight lysines in carboxyl-terminal region) exhibited decreased plasminogen activation. Furthermore, CRT-deficient fibroblasts generated 90% less plasmin and CRT-depleted MDA MB 231 cells also demonstrated a significant reduction in plasmin generation. Moreover, treatment of fibroblasts with mitoxantrone dramatically stimulated plasmin generation by WT but not CRT-deficient fibroblasts. Our results suggest that CRT is an important cellular plasminogen regulatory protein. Given that CRT can empower cells with plasmin proteolytic activity, this discovery may provide new mechanistic insight into the established role of CRT in cancer.
Collapse
Affiliation(s)
- Alamelu G Bharadwaj
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Gillian C Okura
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - John W Woods
- Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Erica A Allen
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Victoria A Miller
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Emma Kempster
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Mark A Hancock
- McGill SPR-MS Facility, McGill University, Montréal, Québec, Canada
| | - Shashi Gujar
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Rimantas Slibinskas
- Life Sciences Center, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania
| | - David M Waisman
- Departments of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
| |
Collapse
|
|
16
|
Lam T, Medcalf RL, Cloud GC, Myles PS, Keragala CB. Tranexamic acid for haemostasis and beyond: does dose matter? Thromb J 2023; 21:94. [PMID: 37700271 PMCID: PMC10496216 DOI: 10.1186/s12959-023-00540-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023] Open
Abstract
Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue that competes for the lysine binding sites in plasminogen and tissue-type plasminogen activator impairing its interaction with the exposed lysine residues on the fibrin surface. The presence of TXA therefore, impairs the plasminogen and tPA engagement and subsequent plasmin generation on the fibrin surface, protecting fibrin clot from proteolytic degradation. However, critical lysine binding sites for plasmin(ogen) also exist on other proteins and on various cell-surface receptors allowing plasmin to exert potent effects on other targets that are unrelated to classical fibrinolysis, notably in relation to immunity and inflammation. Indeed, TXA was reported to significantly reduce post-surgical infection rates in patients after cardiac surgery unrelated to its haemostatic effects. This has provided an impetus to consider TXA in other indications beyond inhibition of fibrinolysis. While there is extensive literature on the optimal dosage of TXA to reduce bleeding rates and transfusion needs, it remains to be determined if these dosages also apply to blocking the non-canonical effects of plasmin.
Collapse
Affiliation(s)
- Tammy Lam
- Australian Centre for Blood Diseases, Monash AMREP Building, Monash University, Level 1 Walkway, Via The Alfred Centre, 99 Commercial Rd, Melbourne, 3004, Australia
| | - Robert L Medcalf
- Australian Centre for Blood Diseases, Monash AMREP Building, Monash University, Level 1 Walkway, Via The Alfred Centre, 99 Commercial Rd, Melbourne, 3004, Australia
| | - Geoffrey C Cloud
- Department of Clinical Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Paul S Myles
- Department of Anaesthesiology and Perioperative Medicine, Alfred Hospital, Melbourne VIC, Australia
- Department of Anaesthesiology and Perioperative Medicine, Monash University, Melbourne VIC, Australia
| | - Charithani B Keragala
- Australian Centre for Blood Diseases, Monash AMREP Building, Monash University, Level 1 Walkway, Via The Alfred Centre, 99 Commercial Rd, Melbourne, 3004, Australia.
| |
Collapse
|
|
17
|
Xie Q, Xing H, Wen X, Liu B, Wei Y, Yu Y, Xie X, Song D, Shao G, Xiong Q, Feng Z. Identification of the multiple roles of enolase as an plasminogen receptor and adhesin in Mycoplasma hyopneumoniae. Microb Pathog 2023; 174:105934. [PMID: 36481292 DOI: 10.1016/j.micpath.2022.105934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/07/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
Mycoplasma hyopneumoniae is the etiological agent underlying porcine enzootic pneumonia, a chronic respiratory disease worldwide. The recruitment of plasminogen to the surface and subsequently promotion of plasmin conversion by the surface-located receptor, have been reported to assist the adhesion and invasion of Mycoplasmas. The surface localization and plasminogen-binding ability of M. hyopneumoniae enolase were previously confirmed; however, the biological functions were not be determined, especially the role as a plasminogen receptor. Here, using ELISA and SPR analyses, we confirmed the stable binding of M. hyopneumoniae enolase to plasminogen in a dose-dependent manner. The facilitation of the activation of plasminogen in the presence of tPA and direct activation of plasminogen at low efficiency without tPA addition by M. hyopneumoniae enolase were also determined using a plasmin-specific chromogenic substrate. Notably, the C-terminal and N-terminal regions located in M. hyopneumoniae enolase play an important role in plasminogen binding and activation. Additionally, we demonstrate that M. hyopneumoniae enolase can competitively inhibit the adherence of M. hyopneumoniae to PK15 cells. These results provide insight into the role of enolase in M. hyopneumoniae infection, a mechanism that manipulates the proteolytic system of the host.
Collapse
Affiliation(s)
- Qingyun Xie
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Huixuan Xing
- Institute of Animal Science, Tibet Agricultural and Animal Husbandry College, Linzhi, 860000, China
| | - Xiaoyun Wen
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, China
| | - Beibei Liu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Yanna Wei
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Yanfei Yu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Xing Xie
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Daesub Song
- College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Guoqing Shao
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Qiyan Xiong
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China.
| | - Zhixin Feng
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China.
| |
Collapse
|
|
18
|
Prudovsky I, Kacer D, Zucco VV, Palmeri M, Falank C, Kramer R, Carter D, Rappold J. Tranexamic acid: Beyond antifibrinolysis. Transfusion 2022; 62 Suppl 1:S301-S312. [PMID: 35834488 DOI: 10.1111/trf.16976] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 11/30/2022]
Abstract
Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis.
Collapse
Affiliation(s)
- Igor Prudovsky
- Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, USA
| | - Doreen Kacer
- Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, USA
| | - Victoria Vieira Zucco
- Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, USA
| | - Monica Palmeri
- Maine Medical Center Cardiovascular Institute, Maine Medical Center, Portland, Maine, USA
| | - Carolyne Falank
- Department of Trauma, Maine Medical Center, Maine Medical Center, Portland, Maine, USA
| | - Robert Kramer
- Maine Medical Center Cardiovascular Institute, Maine Medical Center, Portland, Maine, USA
| | - Damien Carter
- Department of Trauma, Maine Medical Center, Maine Medical Center, Portland, Maine, USA
| | - Joseph Rappold
- Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, USA.,Department of Trauma, Maine Medical Center, Maine Medical Center, Portland, Maine, USA
| |
Collapse
|
|
19
|
Tranexamic Acid and Its Potential Anti-Inflammatory Effect: A Systematic Review. Semin Thromb Hemost 2022; 48:568-595. [PMID: 35636449 DOI: 10.1055/s-0042-1742741] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Tranexamic acid (TXA) is an antifibrinolytic drug primarily used for reducing blood loss in patients with major bleedings. Animal and cell studies have shown that TXA might modulate the inflammatory response by either enhancing or inhibiting cytokine levels. Furthermore, recent human studies have found altered inflammatory biomarkers in patients receiving TXA when compared with patients who did not receive TXA. In this systematic review we investigated the effect of TXA on inflammatory biomarkers in different patient groups. A systematic literature search was conducted on the databases PubMed and Embase to identify all original articles that investigated inflammatory biomarkers in patients receiving TXA and compared them to a relevant control group. The review was performed according to the PRISMA guidelines, and the literature search was performed on November 29, 2021. Thirty-three studies were included, among which 14 studies compared patients receiving TXA with patients getting no medication, another 14 studies investigated different dosing regimens of TXA, and finally five studies examined the administration form of TXA. The present review suggests that TXA has an anti-inflammatory effect in patients undergoing orthopaedic surgery illustrated by decreased levels of C-reactive protein and interleukin-6 in patients receiving TXA compared with patients receiving no or lower doses of TXA. However, the anti-inflammatory effect was not found in patients undergoing cardiac surgery, pediatric craniosynostosis patients, or in rheumatoid arthritis patients. The inflammatory response was not affected by administration form of TXA (oral, intravenous, or topical). In conclusion, an anti-inflammatory effect of TXA was consistently found among orthopaedic patients only.
Collapse
|
|
20
|
Miles LA, Krajewski S, Baik N, Parmer RJ, Mueller BM. Plg-RKT Expression in Human Breast Cancer Tissues. Biomolecules 2022; 12:biom12040503. [PMID: 35454092 PMCID: PMC9028288 DOI: 10.3390/biom12040503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/12/2022] Open
Abstract
The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface. Plg-RKT is a structurally unique plasminogen receptor because it is an integral membrane protein that is synthesized with and binds plasminogen via a C-terminal lysine exposed on the cell surface. Here, we have investigated the expression of Plg-RKT in human breast tumors and human breast cancer cell lines. Breast cancer progression tissue microarrays were probed with anti-Plg-RKT mAB and we found that Plg-RKT is widely expressed in human breast tumors, that its expression is increased in tumors that have spread to draining lymph nodes and distant organs, and that Plg-RKT expression is most pronounced in hormone receptor (HR)-positive tumors. Plg-RKT was detected by Western blotting in human breast cancer cell lines. By flow cytometry, Plg-RKT cell surface expression was highest on the most aggressive tumor cell line. Future studies are warranted to address the functions of Plg-RKT in breast cancer.
Collapse
Affiliation(s)
- Lindsey A. Miles
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA; (L.A.M.); (N.B.)
| | | | - Nagyung Baik
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA; (L.A.M.); (N.B.)
| | - Robert J. Parmer
- Department of Medicine, Veterans Administration San Diego Healthcare System, University of California San Diego, San Diego, CA 92161, USA;
| | - Barbara M. Mueller
- San Diego Biomedical Research Institute, San Diego, CA 92121, USA
- Correspondence:
| |
Collapse
|
|
21
|
Chen R, Zhao L, Gan R, Feng Z, Cui C, Xie X, Hao F, Zhang Z, Wang L, Ran T, Wang W, Zhang S, Li Y, Zhang W, Pang M, Xiong Q, Shao G. Evidence for the Rapid and Divergent Evolution of Mycoplasmas: Structural and Phylogenetic Analysis of Enolases. Front Mol Biosci 2022; 8:811106. [PMID: 35145997 PMCID: PMC8822174 DOI: 10.3389/fmolb.2021.811106] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 12/29/2021] [Indexed: 12/21/2022] Open
Abstract
Mycoplasmas are a group of prokaryotes without cell walls that have evolved through several rounds of degenerative evolution. With a low cell DNA G + C content and definitively long genetic lineages, mycoplasmas are thought to be in a state of rapid evolution. However, little associated evidence has been provided. Enolase is a key enzyme in glycolysis that is widely found in all species from the three domains, and it is evolutionarily conserved. In our previous studies, enolase acted as a virulence factor and participated in cell-surface adhesion in Mycoplasma hyopneumoniae. Furthermore, unique loop regions were first found in the crystal structure of Mhp Eno. Here, enolase structures from Mycoplasma pneumoniae and Mycoplasma bovis were determined. An extra helix 7 is specific and conservatively found in almost all mycoplasma enolases, as confirmed by crystal structures and sequence alignment. Particular motifs for helix 7, which is composed of F-K/G-K-L/F-K-X-A-I, have been proposed and could be regarded as molecular markers. To our surprise, the genetic distances between any two mycoplasma enolases were obviously longer than those between the two corresponding species themselves, indicating divergent evolution of mycoplasma enolases, whereas no horizontal gene transfer was detected in mycoplasma enolase genens. Furthermore, different evolutionary patterns were adopted by different loop regions of mycoplasma enolase. Enolases from different Mycoplasma species also showed different affinities for PLG and fibronectin. Our results indicate the rapid and divergent evolution of mycoplasma enolase and mycoplasmas. This study will also aid understanding the independent evolution of Mycoplasma species after separation from their common ancestor.
Collapse
Affiliation(s)
- Rong Chen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Lin Zhao
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Rong Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Zhixin Feng
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Chenxi Cui
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xing Xie
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Fei Hao
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Zhenzhen Zhang
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Li Wang
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Tingting Ran
- Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, China
| | - Weiwu Wang
- Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, China
| | - Shuijun Zhang
- College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Yufeng Li
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Wei Zhang
- Key Lab of Animal Bacteriology of Ministry of Agriculture, OIE Reference Lab for Swine Streptococcosis, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
- *Correspondence: Wei Zhang, ; Maoda Pang, ; Qiyan Xiong,
| | - Maoda Pang
- State Key Laboratory Cultivation Base of MOST, Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- *Correspondence: Wei Zhang, ; Maoda Pang, ; Qiyan Xiong,
| | - Qiyan Xiong
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- *Correspondence: Wei Zhang, ; Maoda Pang, ; Qiyan Xiong,
| | - Guoqing Shao
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| |
Collapse
|
|
22
|
Altered protein profile of plasma extracellular vesicles in oral squamous cell carcinoma development. J Proteomics 2022; 251:104422. [PMID: 34775099 DOI: 10.1016/j.jprot.2021.104422] [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: 06/08/2021] [Revised: 09/16/2021] [Accepted: 11/01/2021] [Indexed: 11/20/2022]
Abstract
Extracellular vesicles (EVs) are involved in a wide range of pathological processes and recognized as potential and novel biomarkers for oral squamous cell carcinoma (OSCC). Here, we describe the plasma EV proteome of rats with 4-nitroquinoline-1-oxide (4NQO)-induced OSCC or moderate dysplasia (MD), which can progress to OSCC, by tandem mass tag (TMT)-labeled mass spectrometry. The proteomic profiles suggest the differential expression of various proteins in MD and OSCC, some well-recognized pathological changes (e.g., translation, ATP metabolism, and mesenchymal transition), and some novel pathological changes (e.g., podosome, focal adhesion, and S100 binding). We re-examined the presence of traditional exosomal markers and the reported novel pan-EV markers. In summary, these results suggest potential EV biomarkers and underlying pathological changes in early OSCC as well as the presence of oral-derived EVs in plasma and the need for pan-EV markers. SIGNIFICANCE: This research suggests potential EV biomarkers and underlying pathological changes in early OSCC as well as the presence of oral-derived EVs in plasma and the need for pan-EV markers.
Collapse
|
|
23
|
Sharma S, Watanabe T, Nishimoto T, Takihara T, Mlakar L, Nguyen XX, Sanderson M, Su Y, Chambers RA, Feghali-Bostwick C. E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects. JCI Insight 2021; 6:144935. [PMID: 34935642 PMCID: PMC8783693 DOI: 10.1172/jci.insight.144935] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/10/2021] [Indexed: 12/28/2022] Open
Abstract
Fibroproliferative disorders such as systemic sclerosis (SSc) have no effective therapies and result in significant morbidity and mortality. We recently demonstrated that the C-terminal domain of endostatin, known as E4, prevented and reversed both dermal and pulmonary fibrosis. Our goal was to identify the mechanism by which E4 abrogates fibrosis and its cell surface binding partner(s). Our findings show that E4 activated the urokinase pathway and increased the urokinase plasminogen activator (uPA) to type 1 plasminogen activator inhibitor (PAI-1) ratio. In addition, E4 substantially increased MMP-1 and MMP-3 expression and activity. In vivo, E4 reversed bleomycin induction of PAI-1 and increased uPA activity. In patients with SSc, the uPA/PAI-1 ratio was decreased in both lung tissues and pulmonary fibroblasts compared with normal donors. Proteins bound to biotinylated-E4 were identified as enolase-1 (ENO) and uPA receptor (uPAR). The antifibrotic effects of E4 required uPAR. Further, ENO mediated the fibrotic effects of TGF-β1 and exerted TGF-β1–independent fibrotic effects. Our findings suggest that the antifibrotic effect of E4 is mediated, in part, by regulation of the urokinase pathway and induction of MMP-1 and MMP-3 levels and activity in a uPAR-dependent manner, thus promoting extracellular matrix degradation. Further, our findings identify a moonlighting function for the glycolytic enzyme ENO in fibrosis.
Collapse
Affiliation(s)
- Shailza Sharma
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Tomoya Watanabe
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Tetsuya Nishimoto
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Takahisa Takihara
- Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Logan Mlakar
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Xinh-Xinh Nguyen
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Matthew Sanderson
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yunyun Su
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Roger A Chambers
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Carol Feghali-Bostwick
- Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| |
Collapse
|
|
24
|
Bharadwaj AG, Kempster E, Waisman DM. The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor. Biomolecules 2021; 11:biom11121772. [PMID: 34944416 PMCID: PMC8698604 DOI: 10.3390/biom11121772] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/13/2022] Open
Abstract
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis.
Collapse
Affiliation(s)
- Alamelu G. Bharadwaj
- Departments of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; (A.G.B.); (E.K.)
- Departments of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS B3H 1X5, Canada
| | - Emma Kempster
- Departments of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; (A.G.B.); (E.K.)
| | - David M. Waisman
- Departments of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; (A.G.B.); (E.K.)
- Departments of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS B3H 1X5, Canada
- Correspondence: ; Tel.: +1-(902)-494-1803; Fax: +1-(902)-494-1355
| |
Collapse
|
|
25
|
Qiao G, Wu A, Chen X, Tian Y, Lin X. Enolase 1, a Moonlighting Protein, as a Potential Target for Cancer Treatment. Int J Biol Sci 2021; 17:3981-3992. [PMID: 34671213 PMCID: PMC8495383 DOI: 10.7150/ijbs.63556] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022] Open
Abstract
Enolase 1 (ENO1) is a moonlighting protein, function as a glycolysis enzyme, a plasminogen receptor and a DNA binding protein. ENO1 play an important role in the process of cancer development. The transcription, translation, post-translational modifying activities and the immunoregulatory role of ENO1 at the cancer development is receiving increasing attention. Some function model studies have shown that ENO1 is a potential target for cancer treatment. In this review, we provide a comprehensive overview of the characterization, function, related transduction cascades of ENO1 and its roles in the pathophysiology of cancers, which is a consequence of ENO1 signaling dysregulation. And the development of novels anticancer agents that targets ENO1 may provide a more attractive option for the treatment of cancers. The data of sarcoma and functional cancer models indicates that ENO1 may become a new potential target for anticancer therapy.
Collapse
Affiliation(s)
- Gan Qiao
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China (Q.G, ).,School of Pharmacy, Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, China
| | - Anguo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Drugability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.,Education Ministry Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou, 646000, China
| | - Xiaoliang Chen
- Schools of Medicine; Shanxi Datong University, Datong, Shanxi, 037009, China
| | - Ye Tian
- The Eighth Affiliated Hospital Sun Yat-sen University,Shenzhen, Guangdong, China
| | - Xiukun Lin
- College of Life Sci., Shandong University of Technology, Zibo, Shandong, China
| |
Collapse
|
|
26
|
Juneja GK, Castelo M, Yeh CH, Cerroni SE, Hansen BE, Chessum JE, Abraham J, Cani E, Dwivedi DJ, Fraser DD, Slessarev M, Martin C, McGilvray S, Gross PL, Liaw PC, Weitz JI, Kim PY. Biomarkers of coagulation, endothelial function, and fibrinolysis in critically ill patients with COVID-19: A single-center prospective longitudinal study. J Thromb Haemost 2021; 19:1546-1557. [PMID: 33826233 PMCID: PMC8250276 DOI: 10.1111/jth.15327] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/26/2021] [Accepted: 03/30/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in coronavirus disease 2019 (COVID-19). We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential. METHODS We performed a single-center prospective study of 14 adult COVID-19(+) intensive care unit patients who were age- and sex-matched to 14 COVID-19(-) intensive care unit patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Baseline values for 10 biomarkers of interest were compared between the three groups, and visualized using Fisher's linear discriminant function. Linear repeated-measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts. RESULTS Elevated D-dimer was the strongest contributor in distinguishing COVID-19 status; however, D-dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor-1 (PAI-1), and plasminogen as biomarkers associated with death. Longitudinal multivariate k-means clustering on these biomarkers alone identified two clusters of COVID-19(+) patients: low (30%) and high (100%) mortality groups. Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI-1 levels, and lower plasminogen levels. CONCLUSIONS Longitudinal trajectories of clot lysis time, sTM, PAI-1, and plasminogen may have predictive ability for mortality in COVID-19.
Collapse
Affiliation(s)
- Ganeem K Juneja
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medical Sciences, McMaster University, Hamilton, ON, Canada
| | - Matthew Castelo
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Calvin H Yeh
- Department of Medicine, Division of Emergency Medicine, University of Toronto, Toronto, ON, Canada
| | - Samantha E Cerroni
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Bettina E Hansen
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - James E Chessum
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medical Sciences, McMaster University, Hamilton, ON, Canada
| | - Joel Abraham
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medical Sciences, McMaster University, Hamilton, ON, Canada
| | - Erblin Cani
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medical Sciences, McMaster University, Hamilton, ON, Canada
| | - Dhruva J Dwivedi
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Douglas D Fraser
- Lawson Health Research Institute, London, ON, Canada
- Pediatrics, Western University, London, ON, Canada
- Clinical Neurological Sciences, Western University, London, ON, Canada
- Physiology & Pharmacology, Western University, London, ON, Canada
| | - Marat Slessarev
- Lawson Health Research Institute, London, ON, Canada
- Medicine, Western University, London, ON, Canada
| | - Claudio Martin
- Lawson Health Research Institute, London, ON, Canada
- Medicine, Western University, London, ON, Canada
| | - Scott McGilvray
- Department of Medicine, Division of Emergency Medicine, University of Toronto, Toronto, ON, Canada
| | - Peter L Gross
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Patricia C Liaw
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Jeffrey I Weitz
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Paul Y Kim
- Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| |
Collapse
|
|
27
|
The plasminogen protein is associated with high myopia as revealed by the iTRAQ-based proteomic analysis of the aqueous humor. Sci Rep 2021; 11:8789. [PMID: 33888814 PMCID: PMC8062568 DOI: 10.1038/s41598-021-88220-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/09/2021] [Indexed: 11/09/2022] Open
Abstract
To explore the pathogenesis of high myopia (HM) using quantitative proteomics. The aqueous humor of patients with simple nuclear cataract and nuclear cataract complicated with HM (hereinafter referred to as "C" and "HM" groups, respectively) were collected. The isobaric tags for relative and absolute quantitation (iTRAQ)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach was employed to explore differentially expressed proteins (DEPs). Bioinformatics was used to interpret the proteomic results. Furthermore, the plasminogen (PLG) protein was confirmed by enzyme-linked immunosorbent assay (ELISA) as the candidate biomarker for HM through a receiver operating characteristic curve analysis. The study showed 32 upregulated and 26 downregulated proteins. The gene ontology analysis demonstrated that 58 DEPs corresponded to 325 biological processes, 33 cell components, and 45 molecular functional annotations. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the upregulated DEPs were highly enriched in the coagulation and complement cascades, consistent with the gene set enrichment analysis. Our data suggested that some DEPs might be hallmarks of the development of HM. ELISA confirmed that the PLG expression levels were significantly upregulated in HM. This was a new study investigating alterations in protein levels and affected pathways in HM using iTRAQ-based quantitative proteomics. Our study provided a comprehensive dataset on overall protein changes and shed light on its potential molecular mechanism in human HM.
Collapse
|
|
28
|
Miller JJ, Bohnsack RN, Olson LJ, Ishihara M, Aoki K, Tiemeyer M, Dahms NM. Tissue plasminogen activator is a ligand of cation-independent mannose 6-phosphate receptor and consists of glycoforms that contain mannose 6-phosphate. Sci Rep 2021; 11:8213. [PMID: 33859256 PMCID: PMC8050316 DOI: 10.1038/s41598-021-87579-z] [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: 01/18/2021] [Accepted: 03/30/2021] [Indexed: 01/18/2023] Open
Abstract
Plasmin is the key enzyme in fibrinolysis. Upon interaction with plasminogen activators, the zymogen plasminogen is converted to active plasmin. Some studies indicate plasminogen activation is regulated by cation-independent mannose 6-phosphate receptor (CI-MPR), a protein that facilitates lysosomal enzyme trafficking and insulin-like growth factor 2 downregulation. Plasminogen regulation may be accomplished by CI-MPR binding to plasminogen or urokinase plasminogen activator receptor. We asked whether other members of the plasminogen activation system, such as tissue plasminogen activator (tPA), also interact with CI-MPR. Because tPA is a glycoprotein with three N-linked glycosylation sites, we hypothesized that tPA contains mannose 6-phosphate (M6P) and binds CI-MPR in a M6P-dependent manner. Using surface plasmon resonance, we found that two sources of tPA bound the extracellular region of human and bovine CI-MPR with low-mid nanomolar affinities. Binding was partially inhibited with phosphatase treatment or M6P. Subsequent studies revealed that the five N-terminal domains of CI-MPR were sufficient for tPA binding, and this interaction was also partially mediated by M6P. The three glycosylation sites of tPA were analyzed by mass spectrometry, and glycoforms containing M6P and M6P-N-acetylglucosamine were identified at position N448 of tPA. In summary, we found that tPA contains M6P and is a CI-MPR ligand.
Collapse
Affiliation(s)
- James J Miller
- Department of Biochemistry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Richard N Bohnsack
- Department of Biochemistry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Linda J Olson
- Department of Biochemistry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Mayumi Ishihara
- Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Rd, Athens, GA, 30602, USA
| | - Kazuhiro Aoki
- Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Rd, Athens, GA, 30602, USA
| | - Michael Tiemeyer
- Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Rd, Athens, GA, 30602, USA.
| | - Nancy M Dahms
- Department of Biochemistry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd, Milwaukee, WI, 53226, USA.
| |
Collapse
|
|
29
|
Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy. Cancers (Basel) 2021; 13:cancers13081838. [PMID: 33921488 PMCID: PMC8070608 DOI: 10.3390/cancers13081838] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 03/19/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary In this review, we present a detailed discussion of how the plasminogen-activation system is utilized by tumor cells in their unrelenting attack on the tissues surrounding them. Plasmin is an enzyme which is responsible for digesting several proteins that hold the tissues surrounding solid tumors together. In this process tumor cells utilize the activity of plasmin to digest tissue barriers in order to leave the tumour site and spread to other parts of the body. We specifically focus on the role of plasminogen receptor—p11 which is an important regulatory protein that facilitates the conversion of plasminogen to plasmin and by this means promotes the attack by the tumour cells on their surrounding tissues. Abstract The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.
Collapse
|
|
30
|
Napolitano F, Montuori N. The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis. J Clin Med 2021; 10:518. [PMID: 33535668 PMCID: PMC7867209 DOI: 10.3390/jcm10030518] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/28/2021] [Indexed: 12/21/2022] Open
Abstract
The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. The plasminogen activation (PA) system includes urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), and two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In addition to the regulation of fibrinolysis, the PA system plays an important role in other biological processes, which include degradation of extracellular matrix such as embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and immune response. Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. Different forms of angioedema are linked to uncontrolled activation of coagulation and fibrinolysis systems. Moreover, plasmin itself can induce a potentiation of bradykinin production with consequent swelling episodes. The number of studies investigating the PA system involvement in angioedema has grown in recent years, highlighting its relevance in etiopathogenesis. In this review, we present the components and diverse functions of the PA system in physiology and its importance in angioedema pathogenesis.
Collapse
Affiliation(s)
| | - Nunzia Montuori
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80135 Naples, Italy;
| |
Collapse
|
|
31
|
Rizo G, Barrera AD, Jimenez LE, García EV, García DC, Roldán-Olarte M. Exogenous activation and inhibition of plasminogen/plasmin activity during in vitro maturation of bovine cumulus-oocyte complexes: A biological and spectroscopic approach. Mol Reprod Dev 2020; 88:67-79. [PMID: 33244844 DOI: 10.1002/mrd.23441] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 11/15/2020] [Indexed: 12/17/2022]
Abstract
This study deals with the effect of plasminogen/plasmin on the in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs). Exogenous plasminogen activator streptokinase (SK) added to the IVM medium revealed similar values of cumulus expansion and oocyte nuclear maturation compared to controls (standard IVM medium). However, a decrease in both determinations was observed in COCs matured with the supplementation of ɛ-aminocaproic acid (ɛ-ACA), a specific plasmin inhibitor. After in vitro fertilization, no differences were observed in either cleavage or blastocyst rates between SK and control groups; however, ε-ACA treatment caused a decrease in both developmental rates. Zona pellucida (ZP) digestion time decreased in the SK group while it increased in the ε-ACA group. Raman microspectroscopy revealed an increase in the intensity of the band corresponding to the glycerol group of sialic acid in the ZP of oocytes matured with SK, whereas ZP spectra of oocytes treated with ɛ-ACA presented similarities with immature oocytes. The results indicate that although treatment with SK did not alter oocyte developmental competence, it induced modifications in the ZP of oocytes that could modify the folding of glycoproteins. Plasmin inhibition impairs oocyte maturation and has an impact on embryo development, thus evidencing the importance of this protease during IVM.
Collapse
Affiliation(s)
- Gabriela Rizo
- Instituto Superior de Investigaciones Biológicas (INSIBIO), Área Biología Experimental, CONICET-Universidad Nacional de Tucuman, Tucumán, Argentina.,Instituto de Biología 'Dr. Francisco D. Barbieri', Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
| | - Antonio Daniel Barrera
- Instituto Superior de Investigaciones Biológicas (INSIBIO), Área Biología Experimental, CONICET-Universidad Nacional de Tucuman, Tucumán, Argentina.,Instituto de Biología 'Dr. Francisco D. Barbieri', Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
| | - Luis Emanuel Jimenez
- Instituto de Química del Noroeste Argentino (INQUINOA), CONICET-Universidad Nacional de Tucuman, Tucumán, Argentina
| | - Elina Vanesa García
- Instituto Superior de Investigaciones Biológicas (INSIBIO), Área Biología Experimental, CONICET-Universidad Nacional de Tucuman, Tucumán, Argentina.,Instituto de Biología 'Dr. Francisco D. Barbieri', Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
| | - Daniela C García
- Instituto Superior de Investigaciones Biológicas (INSIBIO), Área Biología Experimental, CONICET-Universidad Nacional de Tucuman, Tucumán, Argentina.,Instituto de Biología 'Dr. Francisco D. Barbieri', Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina.,Facultad de Agronomía y Agroindustrias, Instituto de Ciencias Químicas, UNSE, Santiago del Estero, Argentina
| | - Mariela Roldán-Olarte
- Instituto Superior de Investigaciones Biológicas (INSIBIO), Área Biología Experimental, CONICET-Universidad Nacional de Tucuman, Tucumán, Argentina.,Instituto de Biología 'Dr. Francisco D. Barbieri', Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
| |
Collapse
|
|
32
|
Satala D, Satala G, Karkowska-Kuleta J, Bukowski M, Kluza A, Rapala-Kozik M, Kozik A. Structural Insights into the Interactions of Candidal Enolase with Human Vitronectin, Fibronectin and Plasminogen. Int J Mol Sci 2020; 21:ijms21217843. [PMID: 33105833 PMCID: PMC7660097 DOI: 10.3390/ijms21217843] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/17/2020] [Accepted: 10/19/2020] [Indexed: 12/16/2022] Open
Abstract
Significant amounts of enolase—a cytosolic enzyme involved in the glycolysis pathway—are exposed on the cell surface of Candida yeast. It has been hypothesized that this exposed enolase form contributes to infection-related phenomena such as fungal adhesion to human tissues, and the activation of fibrinolysis and extracellular matrix degradation. The aim of the present study was to characterize, in structural terms, the protein-protein interactions underlying these moonlighting functions of enolase. The tight binding of human vitronectin, fibronectin and plasminogen by purified C. albicans and C. tropicalis enolases was quantitatively analyzed by surface plasmon resonance measurements, and the dissociation constants of the formed complexes were determined to be in the 10−7–10−8 M range. In contrast, the binding of human proteins by the S.cerevisiae enzyme was much weaker. The chemical cross-linking method was used to map the sites on enolase molecules that come into direct contact with human proteins. An internal motif 235DKAGYKGKVGIAMDVASSEFYKDGK259 in C. albicans enolase was suggested to contribute to the binding of all three human proteins tested. Models for these interactions were developed and revealed the sites on the enolase molecule that bind human proteins, extensively overlap for these ligands, and are well-separated from the catalytic activity center.
Collapse
Affiliation(s)
- Dorota Satala
- Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Kraków, Poland; (D.S.); (M.B.)
| | - Grzegorz Satala
- Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland;
| | - Justyna Karkowska-Kuleta
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Kraków, Poland; (J.K.-K.); (A.K.); (M.R.-K.)
| | - Michal Bukowski
- Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Kraków, Poland; (D.S.); (M.B.)
| | - Anna Kluza
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Kraków, Poland; (J.K.-K.); (A.K.); (M.R.-K.)
| | - Maria Rapala-Kozik
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Kraków, Poland; (J.K.-K.); (A.K.); (M.R.-K.)
| | - Andrzej Kozik
- Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Kraków, Poland; (D.S.); (M.B.)
- Correspondence:
| |
Collapse
|
|
33
|
Ikezoe T. Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies. Int J Hematol 2020; 113:34-44. [PMID: 32902759 DOI: 10.1007/s12185-020-02992-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/22/2020] [Accepted: 08/28/2020] [Indexed: 11/26/2022]
Abstract
Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.
Collapse
Affiliation(s)
- Takayuki Ikezoe
- Department of Haematology, Fukushima Medical University, Fukushima, 960-1295, Japan.
| |
Collapse
|
|
34
|
Roth K, Strickland J, Copple BL. Regulation of macrophage activation in the liver after acute injury: Role of the fibrinolytic system. World J Gastroenterol 2020; 26:1879-1887. [PMID: 32390699 PMCID: PMC7201151 DOI: 10.3748/wjg.v26.i16.1879] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/31/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
The liver functions, in part, to prevent exposure of the body to potentially harmful substances ingested in the diet. While it is highly efficient at accomplishing this, it is frequently prone to liver injury due to the biotransformation of xenobiotics into toxic metabolites. To counter this injury, the liver has evolved a unique capacity to rapidly and efficiently repair itself. Successful resolution of acute liver injury relies on hepatic macrophage populations that orchestrate the reparative response. After injury, Kupffer cells, the resident macrophages of the liver, become activated and secrete proinflammatory cytokines. These cytokines recruit other immune cells, including monocyte-derived macrophages, to the liver where they contribute to the repair process. Monocyte-derived macrophages traffic into the necrotic foci where they rapidly phagocytose dead cell debris. Simultaneous with this process, these cells change phenotype from a proinflammatory macrophage to a pro-restorative macrophage that produce pro-mitogenic growth factors and anti-inflammatory cytokines. Ultimately this process triggers resolution of inflammation, and along with proliferation of other hepatic cells, restores the liver architecture and function. While the mechanisms regulating specific macrophage functions during repair remain to be elucidated, recent studies indicate a key role for the fibrinolytic system in coordinating macrophage function during repair. In this review, we will highlight the function and role of hepatic macrophages in repair after acute liver injury, and will discuss the role of the fibrinolytic enzyme, plasmin, in regulation of these various processes.
Collapse
Affiliation(s)
- Katherine Roth
- Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States
| | - Jenna Strickland
- Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States
| | - Bryan L Copple
- Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States
| |
Collapse
|
|
35
|
Fallah M, Viklund E, Bäckman A, Brodén J, Lundskog B, Johansson M, Blomquist M, Wilczynska M, Ny T. Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds. Cell Death Dis 2020; 11:201. [PMID: 32205839 PMCID: PMC7089956 DOI: 10.1038/s41419-020-2397-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 03/04/2020] [Accepted: 03/04/2020] [Indexed: 12/18/2022]
Abstract
Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-β signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.
Collapse
Affiliation(s)
- Mahsa Fallah
- Department of Medical Biochemistry and Biophysics, Umeå University, 901-87, Umeå, Sweden
| | - Emil Viklund
- Department of Medical Biochemistry and Biophysics, Umeå University, 901-87, Umeå, Sweden
| | | | | | - Bertil Lundskog
- Department of Medical Biosciences, Pathology, Umeå University, 901-87, Umeå, Sweden
| | - Michael Johansson
- Department of Radiation Sciences, Umeå University, 901-87, Umeå, Sweden
| | - Michael Blomquist
- Department of Radiation Sciences, Umeå University, 901-87, Umeå, Sweden
| | - Malgorzata Wilczynska
- Department of Medical Biochemistry and Biophysics, Umeå University, 901-87, Umeå, Sweden
- Omnio AB, Tvistevägen 48, 907-36, Umeå, Sweden
| | - Tor Ny
- Department of Medical Biochemistry and Biophysics, Umeå University, 901-87, Umeå, Sweden.
| |
Collapse
|
|
36
|
Carmona P, Mendez N, Ili CG, Brebi P. The Role of Clock Genes in Fibrinolysis Regulation: Circadian Disturbance and Its Effect on Fibrinolytic Activity. Front Physiol 2020; 11:129. [PMID: 32231582 PMCID: PMC7083126 DOI: 10.3389/fphys.2020.00129] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 02/06/2020] [Indexed: 12/30/2022] Open
Abstract
The fibrinolytic system is critical during the onset of fibrinolysis, a fundamental mechanism for fibrin degradation. Both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) trigger fibrinolysis, leading to proteolytic activation of plasminogen to plasmin and subsequently fibrin proteolysis. This system is regulated by several inhibitors; plasminogen activator inhibitor-1 (PAI-1), the most studied, binds to and inactivates both tPA and uPA. Through the action of plasmin, this system regulates several physiological processes: embryogenesis, activation of inflammatory cells, cell proliferation and death, synaptic plasticity, wound healing, and others. The deregulated intervention of fibrinolysis in the pathophysiology of various diseases has been widely studied; findings of altered functioning have been reported in different chronic non-communicable diseases (NCD), reinforcing its pleiotropic character and the importance of its physiology and regulation. The evidence indicates that fundamental elements of the fibrinolytic system, such as tPA and PAI-1, show a circadian rhythm in their plasmatic levels and their gene expression are regulated by circadian system elements, known as clock genes – Bmal, Clock, Cry-, and accessory clock genes such as Rev-Erb and Ror. The disturbance in the molecular machinery of the clock by exposure to light during the night alters the natural light/dark cycle and causes disruption of the circadian rhythm. Such exposure affects the synchronization and functioning of peripheral clocks responsible for the expression of the components of the fibrinolytic system. So, this circadian disturbance could be critical in the pathophysiology of chronic diseases where this system has been found to be deregulated.
Collapse
Affiliation(s)
- Pamela Carmona
- Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.,Programa de Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco, Chile.,Laboratory of Integrative Biology, Center for Excellence in Translational Medicine, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Natalia Mendez
- Laboratorio de Cronobiología del Desarrollo, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Carmen G Ili
- Programa de Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco, Chile.,Laboratory of Integrative Biology, Center for Excellence in Translational Medicine, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Priscilla Brebi
- Programa de Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco, Chile.,Laboratory of Integrative Biology, Center for Excellence in Translational Medicine, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| |
Collapse
|
|
37
|
Shih JH, Kao LT, Chung CH, Liao GS, Fann LY, Chien WC, Li IH. Protective Association Between Calcium Channel Blocker Use and Breast Cancer Recurrence in Postsurgical Women: A Population-Based Case-Control Study in Taiwan. J Clin Pharmacol 2020; 60:785-792. [PMID: 32020656 DOI: 10.1002/jcph.1579] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/18/2019] [Indexed: 12/14/2022]
Abstract
Neoadjuvant chemotherapy induces metastasis of residual breast cancers through activation of tumor-associated macrophages. Previous studies have indicated that calcium channel blockers (CCBs) exert anti-inflammatory and antimigratory effects on macrophages via attenuating Ca2+ entry into macrophages. However, no existing empirical research has addressed the relationship between previous CCB use and breast cancer recurrence. In this study, 4840 Taiwanese women aged ≥20 years with breast cancer who underwent breast surgery from January 1, 2007, to December 31, 2015, were enrolled. The date of cancer recurrence was defined as the index date. Logistic regression was performed to evaluate the relationship between previous CCB exposure and cancer recurrence among female patients who underwent surgery for breast cancer. After adjusting for demographic characteristics, comorbidities, and tumor-node-metastasis stage, the adjusted odds ratio (OR) for CCB exposure within 5 years before the index date in women with recurrence compared with nonrecurrent controls was 0.73 (95% confidence interval [CI], 0.53-0.97). Further analysis revealed that the adjusted OR for CCB exposure between the surgery and index dates in women with recurrence relative to nonrecurrent controls was 0.72 (95%CI, 0.66-0.95). In particular, prior CCB use was significantly associated with a lower risk (34%) of breast cancer recurrence among women 20 to 54 years old (OR, 0.66; 95%CI, 0.47-0.83). This study uncovered a protective association between previous CCB use and breast cancer recurrence.
Collapse
Affiliation(s)
- Jui-Hu Shih
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Li-Ting Kao
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.,School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan.,Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
| | - Guo-Shiou Liao
- General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Li-Yun Fann
- Operating Room, Taipei City Hospital, Taipei, Taiwan
| | - Wu-Chien Chien
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.,School of Public Health, National Defense Medical Center, Taipei, Taiwan.,Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - I-Hsun Li
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.,Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| |
Collapse
|
|
38
|
Li C, Ma Y, Fei F, Zheng M, Li Z, Zhao Q, Du J, Liu K, Lu R, Zhang S. Critical role and its underlying molecular events of the plasminogen receptor, S100A10 in malignant tumor and non-tumor diseases. J Cancer 2020; 11:826-836. [PMID: 31949486 PMCID: PMC6959022 DOI: 10.7150/jca.36203] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 11/13/2019] [Indexed: 12/28/2022] Open
Abstract
S100A10 is a small molecular weight protein expressed in the cytoplasm of many cells and one of the members of the S100 protein family that binds calcium and forms the largest subgroup of EF-hand proteins. The regulatory processes of S100A10 are complicated. S100A10 participates in the regulation of a variety of tumor and non-tumor diseases through cascade reactions with multitudinous signaling molecules. In malignant tumors, such as acute promyelocytic leukemia (APL) and lung cancer, S100A10 is likely involved in their progression, including invasion and metastasis through the regulation of plasmin production and subsequent plasmin-dependent stimulation of other proteases, such as matrix metalloproteinase (MMP)-2 and -9. Both the plasmin and MMPs are capable of inducing degradation of the extracellular matrix (ECM) and basement membrane, which is a critical step for tumor progression. In non-tumor diseases, the distribution of S100A10 in the brain and its interaction with 5-hydroxytryptamine 1B (5-HT1B) receptor, an important mediator in the central nervous system that maintains a dynamic balance of the neurotransmitters, correlates with depression-like behavior. S100A10 also participates in inflammatory responses through the regulation of peripheral macrophage migration to the inflammatory sites, which depends on the generation of plasmin and other proteinases at the surface of macrophages. Considerable attention should be paid to understand the significant role of S100A10 in the modulation of malignant tumor and non-tumor diseases.
Collapse
Affiliation(s)
- Chunyuan Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Yi Ma
- Department of ophthalmology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Fei Fei
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Zugui Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Qi Zhao
- Tianjin Medical University, Tianjin, P.R. China
| | - Jiaxing Du
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Kai Liu
- Tianjin Medical University, Tianjin, P.R. China
| | - Rui Lu
- Tianjin Medical University, Tianjin, P.R. China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| |
Collapse
|
|
39
|
Martins L, Amorim BR, Salmon CR, Leme AFP, Kantovitz KR, Nociti FH. Novel LRAP-binding partner revealing the plasminogen activation system as a regulator of cementoblast differentiation and mineral nodule formation in vitro. J Cell Physiol 2019; 235:4545-4558. [PMID: 31621902 DOI: 10.1002/jcp.29331] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/30/2019] [Indexed: 01/30/2023]
Abstract
Amelogenin isoforms, including full-length amelogenin (AMEL) and leucine-rich amelogenin peptide (LRAP), are major components of the enamel matrix, and are considered as signaling molecules in epithelial-mesenchymal interactions regulating tooth development and periodontal regeneration. Nevertheless, the molecular mechanisms involved are still poorly understood. The aim of the present study was to identify novel binding partners for amelogenin isoforms in the cementoblast (OCCM-30), using an affinity purification assay (GST pull-down) followed by mass spectrometry and immunoblotting. Protein-protein interaction analysis for AMEL and LRAP evidenced the plasminogen activation system (PAS) as a potential player regulating OCCM-30 response to amelogenin isoforms. For functional assays, PAS was either activated (plasmin) or inhibited (ε-aminocaproic acid [aminocaproic]) in OCCM-30 cells and the cell morphology, mineral nodule formation, and gene expression were assessed. PAS inhibition (EACA 100 mM) dramatically decreased mineral nodule formation and expression of OCCM-30 differentiation markers, including osteocalcin (Bglap), bone sialoprotein (Ibsp), osteopontin (Spp1), tissue-nonspecific alkaline phosphatase (Alpl) and collagen type I (Col1a1), and had no effect on runt-related transcription factor 2 (Runx2) and Osterix (Osx) mRNA levels. PAS activation (plasmin 5 µg/µl) significantly increased Col1a1 and decreased Bglap mRNA levels (p < .05). Together, our findings shed new light on the potential role of plasminogen signaling pathway in the control of the amelogenin isoform-mediated response in cementoblasts and provide new insights into the development of targeted therapies.
Collapse
Affiliation(s)
- Luciane Martins
- Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, State University of Campinas, Piracicaba, SP, Brazil
| | - Bruna Rabelo Amorim
- Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, DF, Brazil
| | - Cristiane Ribeiro Salmon
- Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, State University of Campinas, Piracicaba, SP, Brazil.,UNIP, Dental Research Division, School of Dentistry, Paulista University, Sao Paulo, SP, Brazil
| | - Adriana Franco Paes Leme
- LNBio, Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory, Campinas, SP, Brazil
| | - Kamila Rosamilia Kantovitz
- Department of Pediatric Dentistry, Piracicaba Dental School, State University of Campinas, Piracicaba, SP, Brazil.,Department of Dental Materials, São Leopoldo Mandic School of Dentistry and Research Center, São Leopoldo Mandic College, Campinas, SP, Brazil
| | - Francisco Humberto Nociti
- Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, State University of Campinas, Piracicaba, SP, Brazil
| |
Collapse
|
|
40
|
Hagiwara K, Harimoto N, Yokobori T, Muranushi R, Hoshino K, Gantumur D, Yamanaka T, Ishii N, Tsukagoshi M, Igarashi T, Tanaka H, Watanabe A, Kubo N, Araki K, Hosouchi Y, Shirabe K. High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer. Ann Surg Oncol 2019; 27:924-930. [PMID: 31463696 DOI: 10.1245/s10434-019-07708-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. METHODS Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. RESULTS TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. CONCLUSIONS Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.
Collapse
Affiliation(s)
- Kei Hagiwara
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan.
| | - Takehiko Yokobori
- Department of Innovative Cancer Immunotherapy, Gunma University, Maebashi, Japan.,Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan
| | - Ryo Muranushi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Kouki Hoshino
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Dorgormaa Gantumur
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Takahiro Yamanaka
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norihiro Ishii
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Mariko Tsukagoshi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University, Maebashi, Japan
| | - Takamichi Igarashi
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Hiroshi Tanaka
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Akira Watanabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Norio Kubo
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Kenichiro Araki
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Yasuo Hosouchi
- Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Maebashi, Japan
| |
Collapse
|
|
41
|
Liu X, Li H, Deng H, Zheng C, Yan H, Chen Z, Bian A, Chen J, Zheng K. Glyceraldehyde-3-Phosphate Dehydrogenase of Babesia microti Is a Plasminogen- and Actin-Binding Protein. Front Vet Sci 2019; 6:228. [PMID: 31355216 PMCID: PMC6637311 DOI: 10.3389/fvets.2019.00228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 06/25/2019] [Indexed: 01/17/2023] Open
Abstract
Babesia microti, an intraerythrocytic protozoa, can cause an emerging tick-borne disease-Human babesiosis. The parasite can successfully invade host red blood cells owing to the assistance of molecules expressed by babesia. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the housekeeping intracellular glycolytic enzyme, can also be expressed in the external of cells, where contributes to binding to several molecules such as plasminogen and actin. In the present study, we identified B. microti GAPDH (BmGAPDH) and generated the recombinant BmGAPDH (rBmGAPDH) via an E. coli expression system. Furthermore, we confirmed its catalytic dehydration activity in vitro. Moreover, we also demonstrated that rBmGAPDH could bind to human plasminogen and mouse α-actin. In addition, we demonstrated that rBmGAPDH could recognize anti-B. microti mouse serum. In conclusion, BmGAPDH is a multifunctional glycolytic enzyme, which can bind to host plasminogen and α-actin.
Collapse
Affiliation(s)
- Xiangye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Huiqin Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Hongkuan Deng
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Chen Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Hongru Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Zetian Chen
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Anning Bian
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Jiaxu Chen
- Key Laboratory of Parasite and Vector Biology, Chinese Center for Disease Control and Prevention, WHO Collaborating Centre for Malaria, Schistosomiasis and Filariasis, Ministry of Health of China, National Institute of Parasitic Diseases, Shanghai, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
|
42
|
Salvia R, Grimaldi A, Girardello R, Scieuzo C, Scala A, Bufo SA, Vogel H, Falabella P. Aphidius ervi Teratocytes Release Enolase and Fatty Acid Binding Protein Through Exosomal Vesicles. Front Physiol 2019; 10:715. [PMID: 31275155 PMCID: PMC6593151 DOI: 10.3389/fphys.2019.00715] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 05/23/2019] [Indexed: 12/16/2022] Open
Abstract
The molecular bases of the host-parasitoid interactions in the biological system Acyrthosiphon pisum (Harris) (Homoptera, Aphididae) and Aphidius ervi (Haliday) (Hymenoptera, Braconidae) have been elucidated allowing the identification of a gamma-glutamyl transpeptidase, the active component of maternal venom secretion, and teratocytes, the embryonic parasitic factors responsible for host physiology regulation after parasitization. Teratocytes, cells deriving from the dissociation of the serosa, the parasitoid embryonic membrane, are responsible for extra-oral digestion of host tissues in order to provide a suitable nutritional environment for the development of parasitoid larvae. Teratocytes rapidly grow in size without undergoing any cell division, synthesize, and release in the host hemolymph two proteins: a fatty acid binding protein (Ae-FABP) and an enolase (Ae-ENO). Ae-FABP is involved in transport of fatty acids deriving from host tissues to the parasitoid larva. Ae-ENO is an extracellular glycolytic enzyme that functions as a plasminogen like receptor inducing its activation to plasmin. Both Ae-FABP and Ae-ENO lack their signal peptides, and they are released in the extracellular environment through an unknown secretion pathway. Here, we investigated the unconventional mechanism by which teratocytes release Ae-FABP and Ae-ENO in the extracellular space. Our results, obtained using immunogold staining coupled with TEM and western blot analyses, show that these two proteins are localized in vesicles released by teratocytes. The specific dimension of these vesicles and the immunodetection of ALIX and HSP70, two exosome markers, strongly support the hypothesis that these vesicles are exosomes.
Collapse
Affiliation(s)
- Rosanna Salvia
- Department of Sciences, University of Basilicata, Potenza, Italy
| | - Annalisa Grimaldi
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Rossana Girardello
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Carmen Scieuzo
- Department of Sciences, University of Basilicata, Potenza, Italy
| | - Andrea Scala
- Department of Sciences, University of Basilicata, Potenza, Italy
| | - Sabino A. Bufo
- Department of Sciences, University of Basilicata, Potenza, Italy
- Department of Geography, Environmental Management & Energy Studies, University of Johannesburg, Johannesburg, South Africa
| | - Heiko Vogel
- Department of Entomology, Max Planck Institute for Chemical Ecology, Jena, Germany
| | | |
Collapse
|
|
43
|
Chen R, Yu Y, Feng Z, Gan R, Xie X, Zhang Z, Xie Q, Wang W, Ran T, Zhang W, Xiong Q, Shao G. Featured Species-Specific Loops Are Found in the Crystal Structure of Mhp Eno, a Cell Surface Adhesin From Mycoplasma hyopneumoniae. Front Cell Infect Microbiol 2019; 9:209. [PMID: 31263685 PMCID: PMC6585157 DOI: 10.3389/fcimb.2019.00209] [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: 02/21/2019] [Accepted: 05/29/2019] [Indexed: 12/18/2022] Open
Abstract
Enolase is an evolutionarily conserved enzyme involved in the processes of glycolysis and gluconeogenesis. Mycoplasma hyopneumoniae belongs to Mycoplasma, whose species are wall-less and among the smallest self-replicating bacteria, and is an important colonizing respiratory pathogen in the pig industry worldwide. Mycoplasma hyopneumoniae enolase (Mhp Eno) expression is significantly increased after infection and was previously found to be a virulence factor candidate. Our studies show that Mhp Eno is a cell surface-localized protein that can adhere to swine tracheal epithelial cells (STECs). Adhesion to STECs can be specifically inhibited by an Mhp Eno antibody. Mhp Eno can recognize and interact with plasminogen with high affinity. Here, the first crystal structure of the mycoplasmal enolase from Mycoplasma hyopneumoniae was determined. The structure showed unique features of Mhp Eno in the S3/H1, H6/S6, H7/H8, and H13 regions. All of these regions were longer than those of other enolases and were exposed on the Mhp Eno surface, making them accessible to host molecules. These results show that Mhp Eno has specific structural characteristics and acts as a multifunctional adhesin on the Mycoplasma hyopneumoniae cell surface.
Collapse
Affiliation(s)
- Rong Chen
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Yanfei Yu
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Zhixin Feng
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Rong Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Xing Xie
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Zhenzhen Zhang
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Qingyun Xie
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Weiwu Wang
- Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, China
| | - Tingting Ran
- Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, China
| | - Wei Zhang
- Key Lab of Animal Bacteriology of Ministry of Agriculture, OIE Reference Lab for Swine Streptococcosis, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Qiyan Xiong
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China.,Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Guoqing Shao
- Key Laboratory of Veterinary Biological Engineering and Technology of Ministry of Agriculture, National Center for Engineering Research of Veterinary Bioproducts, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China.,Institute of Life Sciences, Jiangsu University, Zhenjiang, China
| |
Collapse
|
|
44
|
Margheri F, Laurenzana A, Giani T, Maggi L, Cosmi L, Annunziato F, Cimaz R, Del Rosso M. The protease systems and their pathogenic role in juvenile idiopathic arthritis. Autoimmun Rev 2019; 18:761-766. [PMID: 31181328 DOI: 10.1016/j.autrev.2019.06.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 02/11/2019] [Indexed: 12/20/2022]
Abstract
Numerous proteases produced by synovial cells of arthritic joints, chondrocytes, macrophages and polymorphonuclear cells have been identified as responsible for the joint damage in rheumatoid arthritis. There are few scientific contributions aimed to identify similar mechanisms in the joints of patients with juvenile idiopathic arthritis. Recently, some mechanisms emerged, triggered by the TH17 and TH1/TH17 lymphocytes, which could shed new light on unexpected pathogenic pathways of joint damage in the JIA, mainly regarding the RANK-RANKL pathway. Other novelties are linked to the mechanisms of acidification of the synovial fluid, which create a microenvironment suitable for the extracellular activity of lysosomal enzymes. Some biological drugs currently used in the therapy of JIA can interfere with these mechanisms.
Collapse
Affiliation(s)
- Francesca Margheri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Anna Laurenzana
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Teresa Giani
- Department of Pediatrics, Rheumatology Unit, Anna Meyer Children's Hospital, Italy
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Lorenzo Cosmi
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | | | - Rolando Cimaz
- Department of Clinical Sciences and Community Health, University of Milano, Italy.
| | - Mario Del Rosso
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| |
Collapse
|
|
45
|
He X, Drelich A, Yu S, Chang Q, Gong D, Zhou Y, Qu Y, Yuan Y, Su Z, Qiu Y, Tang SJ, Gaitas A, Ksiazek T, Xu Z, Zhou J, Feng Z, Wakamiya M, Lu F, Gong B. Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis. Life Sci 2019; 221:1-12. [PMID: 30738042 DOI: 10.1016/j.lfs.2019.02.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 02/04/2019] [Accepted: 02/04/2019] [Indexed: 01/09/2023]
Abstract
Plasmin-mediated fibrinolysis at the surface of vascular endothelial cells (SVEC) plays a key role in maintaining vascular hemostasis, in which the cAMP pathway participates. After externalization to the SVEC, annexin A2 (ANXA2) serves as a platform for conversion of plasminogen to plasmin. Here we describe a regulatory role of the exchange protein directly activated by cAMP (EPAC) in ANXA2 externalization and vascular fibrinolysis. Knockout of EPAC1 in mice results in a decreased ANXA2 expression on the SVEC associated with increased fibrin deposition and fibrinolytic dysfunction. Reduced levels of EPAC1 are also found in endocardial tissues beneath atrial mural thrombi in patients. Notably, administration of recombinant ANXA2 ameliorates fibrinolytic dysfunction in the EPAC1-null mice. Mechanistically, EPAC1 regulates the SVEC plasminogen conversion depended on ANXA2. EPAC1 promotes tyrosine-23 phosphorylation of ANXA2, a prerequisite for its recruitment to the SVEC. Our data thus reveal a novel regulatory role for EPAC1 in vascular fibrinolysis.
Collapse
Affiliation(s)
- Xi He
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China
| | - Aleksandra Drelich
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Shangyi Yu
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China
| | - Qing Chang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Dejun Gong
- Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China
| | - Yixuan Zhou
- Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China
| | - Yue Qu
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yang Yuan
- Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China
| | - Zhengchen Su
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yuan Qiu
- Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79409, USA
| | - Shao-Jun Tang
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Angelo Gaitas
- Department of Neurology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Thomas Ksiazek
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Zhiyun Xu
- Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Zongdi Feng
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Maki Wakamiya
- Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Fanglin Lu
- Department of Cardiovascular Surgery, Changhai Hospital, Shanghai 200433, China.
| | - Bin Gong
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
| |
Collapse
|
|
46
|
Kanno Y. The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis. Int J Mol Sci 2019; 20:ijms20030619. [PMID: 30709025 PMCID: PMC6387418 DOI: 10.3390/ijms20030619] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 02/08/2023] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc.
Collapse
Affiliation(s)
- Yosuke Kanno
- Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto 610-0395, Japan.
| |
Collapse
|
|
47
|
Swedberg JE, Wu G, Mahatmanto T, Durek T, Caradoc-Davies TT, Whisstock JC, Law RHP, Craik DJ. Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma. J Med Chem 2018; 62:552-560. [DOI: 10.1021/acs.jmedchem.8b01139] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Joakim E. Swedberg
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Guojie Wu
- ARC Centre of Excellence in Advanced Molecular Imaging, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Tunjung Mahatmanto
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Thomas Durek
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | | | - James C. Whisstock
- ARC Centre of Excellence in Advanced Molecular Imaging, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Ruby H. P. Law
- ARC Centre of Excellence in Advanced Molecular Imaging, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - David J. Craik
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| |
Collapse
|
|
48
|
Tantyo NA, Karyadi AS, Rasman SZ, Salim MRG, Devina A, Sumarpo A. The prognostic value of S100A10 expression in cancer. Oncol Lett 2018; 17:1417-1424. [PMID: 30675195 PMCID: PMC6341771 DOI: 10.3892/ol.2018.9751] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 11/15/2018] [Indexed: 12/30/2022] Open
Abstract
S100A10, a member of the S100 protein family, commonly forms a heterotetrameric complex with Annexin A2. This is essential for the generation of cellular plasmin from plasminogen, which leads to a cascade of molecular events crucial for tumor progression. S100A10 upregulation has been reported in a number of cancers, suggesting that it may have potential as a prognostic biomarker, as well as predicting sensitivity to anticancer drugs. This review evaluates the direct and indirect relationships between S100A10 and cancer progression by investigating its role in cancer. Research papers published on PubMed and Google Scholar between 2007–2017 were collated and reviewed. We concluded that S100A10 affects the development of the hallmarks of cancer as explained by Hanahan and Weinberg in 2011, most notably by activating the invasion and metastasis of cancer cells. However, further studies are required to explore the underlying biological mechanisms of S100A10.
Collapse
Affiliation(s)
- Normastuti Adhini Tantyo
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta Timur 13210, Indonesia
| | - Azrina Saraswati Karyadi
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta Timur 13210, Indonesia
| | - Siti Zulimas Rasman
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta Timur 13210, Indonesia
| | | | - Astrella Devina
- Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta Timur 13210, Indonesia
| | - Anton Sumarpo
- Department of Biochemistry, Faculty of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta Utara 14440, Indonesia
| |
Collapse
|
|
49
|
Plasminogen modulates formation of reactive oxygen species in human platelets. UKRAINIAN BIOCHEMICAL JOURNAL 2018. [DOI: 10.15407/ubj90.06.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
50
|
Plasminogen-binding proteins as an evasion mechanism of the host's innate immunity in infectious diseases. Biosci Rep 2018; 38:BSR20180705. [PMID: 30166455 PMCID: PMC6167496 DOI: 10.1042/bsr20180705] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/27/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023] Open
Abstract
Pathogens have developed particular strategies to infect and invade their hosts. Amongst these strategies’ figures the modulation of several components of the innate immune system participating in early host defenses, such as the coagulation and complement cascades, as well as the fibrinolytic system. The components of the coagulation cascade and the fibrinolytic system have been proposed to be interfered during host invasion and tissue migration of bacteria, fungi, protozoa, and more recently, helminths. One of the components that has been proposed to facilitate pathogen migration is plasminogen (Plg), a protein found in the host’s plasma, which is activated into plasmin (Plm), a serine protease that degrades fibrin networks and promotes degradation of extracellular matrix (ECM), aiding maintenance of homeostasis. However, pathogens possess Plg-binding proteins that can activate it, therefore taking advantage of the fibrin degradation to facilitate establishment in their hosts. Emergence of Plg-binding proteins appears to have occurred in diverse infectious agents along evolutionary history of host–pathogen relationships. The goal of the present review is to list, summarize, and analyze different examples of Plg-binding proteins used by infectious agents to invade and establish in their hosts. Emphasis was placed on mechanisms used by helminth parasites, particularly taeniid cestodes, where enolase has been identified as a major Plg-binding and activating protein. A new picture is starting to arise about how this glycolytic enzyme could acquire an entirely new role as modulator of the innate immune system in the context of the host–parasite relationship.
Collapse
|